Amboss Infectious Disease

Beta-lactam antibiotics

A large group of antibiotics that includes penicillins, carbapenems, aztreonam, and cephalosporins Mechanism of actionInhibit cell wall synthesis by blocking peptidoglycan crosslinkingThe beta-lactam structure mimics the D-ala-D-ala residue of bacterial peptidoglycanIrreversibly binds to penicillin-binding proteins (transpeptidases responsible for peptidoglycan crosslinking), stalling the catalytic reaction because the beta-lactam cannot be cleavedBacterial death as a result of an inability to synthesize new cell wall during replicationActivate autolytic enzymesBeta-lactam antibiotics are bactericidal CNS penetration: only when meninges are inflamedExceptions: ceftriaxone and aztreonam always have good CNS penetration Route of eliminationPrimarily renalExceptions Primarily biliary: nafcillinBoth renal and biliary: other anti-staphylococcal penicillins (e.g., oxacillin, dicloxacillin), ceftriaxone General adverse effectsPenicillin allergy (hypersensitivity reactions)Jarisch-Herxheimer reaction (e.g., when treating syphilis) Beta-lactamase inhibitors Beta-lactamases, which are usually produced by gram-negative and anaerobic organisms, can split the beta-lactam ring and render certain beta-lactamantibiotics ineffective. Beta-lactamase inhibitors increase the spectrum of antibiotic activity. DrugsClavulanic acid (combined with amoxicillin = co-amoxiclav) Sulbactam (combined with ampicillin)Tazobactam (combined with piperacillin)

HIV-associated conditions AIDS (acquired immunodeficiency syndrome) is the final stage of HIV infection and is defined by the development of certain diseases (AIDS-defining conditions) or a CD4 cell count of < 200 cells/μL in HIV-infected patients. AIDS-defining conditions include malignancies (e.g., primary lymphoma of the brain) and certain opportunistic infections (e.g., Pneumocystis pneumonia, cerebral toxoplasmosis). There are also opportunistic infections that commonly occur in HIV patients that are not considered AIDS-defining conditions. This learning card provides an overview of AIDS-defining and other HIV-associated conditionsThe advanced disease stage of an HIV infection characterized by a CD4+ T cell count <200/μL or the presence of AIDS-defining illnesses (e.g., esophageal or bronchial candidiasis, pneumocystis pneumonia, wasting syndrome, Kaposi's sarcoma).

AIDS-defining conditions The CDC defines AIDS as the development of an AIDS-defining condition or a CD4 cell count of < 200 cells/μL in HIV-infected patients. The management of AIDS-defining conditions and prevention of opportunistic infections includes Optimization of antiretroviral therapy (most effective measure)Antimicrobial prophylaxis: depends on CD4+ T-cell count (see table below) Prophylaxis is not recommended to prevent infections with Bartonella spp., Candida spp., Cryptosporidium, or cytomegalovirus. )Immunization (see Vaccinations in HIV-infected individuals) Supportive measures: avoid exposure HIV wasting syndrome Variable Unintentional weight loss of ≥ 10%, fatigue, fever, diarrhea Caused by various factors (e.g., diarrhea due to secondary infection, reduced appetite, changes in metabolism) Optimization of nutrition Prevention of nausea/vomiting Treatment of gastrointestinal infections (e.g., CMV colitis) Kaposi sarcomaVariable (typically < 500/mm3)Vascular proliferation on skin and mucosae (initially particularly face/oral cavity and chest)Caused by HHV-8Skin biopsy: spindle-shaped cells, leukocyteinfiltration, and angiogenesisLocal: surgical excision, laser therapy or cryotherapySystemic: α-interferon Cervical cancer (invasive) Variable See human papillomavirus infection Lymphoma Variable (Hodgkin lymphoma)< 100 (Primary CNS lymphoma)Focal neurological deficits, neuropsychiatric symptoms, signs of ↑ ICP, and/or seizuresCT/MRI: ring-enhancing lesion (typically solitary )In primary CNS lymphoma, PCR results are positive for EBV DNA. See also Hodgkin lymphoma and non-Hodgkin lymphoma. Reactivation tuberculosis< 400Cough, hemoptysis, weight loss, night sweats, feverSee tuberculosis.Tuberculosis therapyRegardless of CD4+T-cell count, all patients should be screened for latent tuberculosis → if positive, suppression therapy should be initiated (see "Tuberculosis therapy" for details). Coccidioidomycosis < 250Fever, cough, chest painAmphotericin B + itraconazolePatients with CD4+T-cell count < 250 cells/μL: coccidioidomycosis screening in endemicregions + preemptive treatment with fluconazole therapy in positive cases Cryptosporidiosis < 100Chronic, watery diarrhea with nausea and abdominal painsAcid-fast cysts in stoolAntiparasitic therapy (e.g., nitazoxanide) HIV-related encephalopathy (AIDS dementia) < 200 (typically untreated patients with advanced HIVinfection) Subcortical dementiaSee "HIV-associated CNS lesions" below for details.Optimize antiretroviral treatment, but avoid efavirenz Progressive multifocal leukoencephalopathy(PML)< 200Focal-neurologic deficits, altered mental status, impaired vigilanceMRI: disseminated, non-enhancing white matter lesions without mass effectSupportive Pneumocystis pneumonia< 200Most common cause of death in patients with AIDS!Gradual onset with low-grade fever, dyspneaand non-productive coughLaboratory: ↑ beta-D-glucanCXR: diffuse bilateral infiltrates ("ground-glass" appearance)Treatment: trimethoprim/sulfamethoxazole (TMP/SMX) (+ sometimes glucocorticoids )Prophylaxis: TMP/SMX in patients with CD4+ T-cell count < 200 cells/μL; alternative: aerosolized pentamidine (e.g., during first trimester of pregnancy) or in patients with sulfa drug allergy: atovaquone or dapsone Isosporiasis < 200Watery diarrhea, abdominal pains, fever, weight lossTrimethoprim/sulfamethoxazole Histoplasmosis < 150Fatigue, fever, weight lossCough and dyspneaDiarrhea, abdominal painHepatosplenomegaly, hepatic and renal failure, coagulopathy, pancytopenia, shockSeizures, altered consciousness Microscopy: oval yeast cells inside macrophagesAmphotericin B (for 2 weeks), then itraconazole (for 1 year)Prophylaxis in patients with CD4+ T-cell count < 150 cells/μL in hyperendemic regions (e.g., American Midwest): itraconazole Cerebral toxoplasmosis < 100Impaired vigilance, focal neurologic deficits, seizures, feverContrast CT/MRI: multiple contrast-enhanced lesions Most common cause of cerebral abscess in HIV patients Toxoplasma chorioretinitis is also possible. Treatment: Pyrimethamine + sulfadiazine + folinic acid (leucovorin) Prophylaxis in patients with CD4+ T-cell count < 100 cells/μL: trimethoprim/sulfamethoxazole Cryptococcosis(extrapulmonary, especially cryptococcal meningitis)< 100See cryptococcal meningitis Amphotericin B 10-14 days, followed by flucytosine/fluconazole 8-10 weeks → lifelong maintenance therapy with fluconazole Candidiasis < 100 Clinical features of esophageal candidiasis: dysphagia, white plaque (scrapeable) , associated with oral thrush Microscopy: pseudohyphae Oral/esophageal: nystatin, fluconazole, or caspofungin Disseminated: amphotericin B, caspofungin, or fluconazole Herpes simplex infections< 100Unusual manifestations of infection, including: Chronic ulcers (> 1 month)Esophagitis (onset at age > 1 month)Bronchitis or pneumonitisSee herpes virus infections. Acyclovir, valacyclovir, or famciclovirAlternatives: foscarnet or cidofovir Cytomegalovirus infection < 50CMV colitis endoscopy shows linear ulcersCMV retinitis: fundoscopy shows cotton-wool spotsBiopsy: intracellular inclusions ("owl's eye")Ganciclovir, foscarnet, or cidofovir Tuberculosis-like disease< 50Caused by Mycobacterium avium complex (MAC) infection Cough, sputum, weight loss, night sweats, feverTreatment Clarithromycin or azithromycinPLUS ethambutolRifabutin may be added in some cases MAC prophylaxis in patients with CD4+ T-cell count < 50 cells/μL: azithromycin, rifabutin, or clarithromycin Other HIV-associated conditions Bartonella henselae (bacillary angiomatosis) Shingles and varicella-zoster virus retinitis Molluscum contagiosum EBV infection (oral hairy leukoplakia: white, non-scrapable plaques on the sides of the tongue) Invasive aspergillosis Aphthous ulcers HIV-associated nephropathy Proctitis Cerebrovascular events Metabolic encephalopathies See "HIV-associated ocular manifestations" below. Some AIDS-defining conditions are opportunistic infections, but the terms are not interchangeable!

Hepatitis C Hepatitis C is an infection caused by the hepatitis C virus (HCV), which attacks liver cells and causes liver inflammation. The virus is mainly transmitted parenterally, especially through IV drug use or needlestick injuries in healthcare settings. Most patients are asymptomatic in the acute phase, but may develop fever, malaise, fatigue, or jaundice. Transition to chronic infections occurs in up to 85% of cases since asymptomatic patients are rarely diagnosed and treated. Chronic infection is associated with increased mortality due to cirrhosis and hepatocellular carcinoma. Suspicion of HCV infection due to exposure, clinical presentation, or elevated aminotransferase levels should be followed up with HCV antibody and HCV RNA testing to confirm the diagnosis. Acute HCV infectionis treated with interferon-α, while a combination of two direct-acting antivirals (e.g., ledipasvir, sofosbuvir) is recommended in cases of chronic infection. More than 90% of patients are cured with adequate treatment.

Acute HCV infection HCV infection acquired in the past 6 months Acute hepatitis C: acute HCV infection + impaired liver function Chronic HCV infection HCV infection persisting for more than 6 months Frequency: affects 50-85% of HCV-positive individuals Chronic hepatitis C: chronic HCV infection + impaired liver function + potential extrahepatic manifestations Prevalence: 1-2% of the US population has chronic HCV infection∼ 3% of the world's population is HCV-positive.The prevalence varies greatly among geographic locations (e.g., high prevalence in Africa, the Middle East, Central and East Asia). Incidence: ∼ 17,000 new infections per year in the US Pathogen Hepatitis C virus (HCV: RNA virus, flavivirus) Chronic infectious risk is multifactorial and ultimately derives from the host's inability to achieve true immunity despite the production of neutralizing antibodies against the viral envelopeFlawed proofreading capability of RNA dependent RNA polymerase introduces mutations into genes encoding viral glycoprotein envelope, allowing for continuous novel antigen productionRapid replication rate produces many antigenically unique viral envelopesConsequently, the production of host antibodies is delayed relative to the production of new mutant virions so infection continues There are six genotypes: In the US, the main ones are genotype 1 (65-80%) and genotype 2 (10-15%). Reinfection with another HCV genotype is possible even after previous infection. Transmission ParenteralNeedle sharing among IV drug usersNeedlestick injury (e.g., health care workers) Organ transplantation, dialysis, blood transfusion Sexual: rare (in contrast to HBV and HIV) Perinatal (vertical) High-risk groups for HCV infection IV drug users (especially long-time users) Hepatitis B virus (HBV) or HIV-positive individuals Prisoners Recipients of blood transfusions or organ transplants before 1992 Clinical features Incubation period: 2 weeks to 6 months Acute course Asymptomatic in 80% of cases Symptomatic (see also acute viral hepatitis) Malaise, fever, myalgias, arthralgiasRUQ pain, tender hepatomegalyNausea, vomiting, diarrheaJaundice, possibly pruritus Chronic course Findings often mild, nonspecific (e.g., fatigue) Liver cirrhosis (30% of cases) within 20 years of infection Extrahepatic features (common) Hematological: mixed cryoglobulinemia, monoclonal gammopathies, lymphomaRheumatological: membranoproliferative glomerulonephritis, polyarteritis nodosa, Sjögren syndromeDermatological: porphyria cutanea tarda, lichen planusOthers: diabetes mellitus, thyroiditis, sialadenitis ApproachEIA/ELISA for anti-HCV antibodies: positive in cases of acute, chronic, and previous HCV infection PCR for HCV RNA if antibodies are positive If positive PCR: active HCV infection (may be acute or chronic) If negative PCR: no active infection, but prior infection Determines HCV genotype and virus titer → assists in treatment planning and monitoring Liver function tests↑ Transaminases with AST/ALT ratioRatio < 1: acute hepatitis Ratio ≥ 1: chronic hepatitis ↓ total protein/albumin, coagulation (particularly ↑ prothrombin time), ↓ cholinesteraseCholestasis parameters: ↑ γ-GT, ↑ alkaline phosphatase, ↑ bilirubin Inflammation markers: leukocytosis, ↑ ferritin Liver biopsy indications (see "Pathology" below for findings) If diagnosis is unclearFor evaluating fibrosis in patients with chronic hepatitis C Evaluation of response to therapy Ultrasound: detection of cirrhosis and neoplasia, e.g., HCC Rule out coinfections: HIV, hepatitis A virus (HAV), hepatitis B virus (HBV) serology necessary Treatment Acute hepatitis C Goal: prevent transition to chronic infection! Treatment: interferon-α or peginterferon-α (PEG-INF) for 6 month There is no post-exposure prophylaxis available! Chronic hepatitis C Treatment goalsComplete cure Eradication of HCV RNA in serum as defined by SVR (sustained virologic response) Treatment regimensChosen based on viral genotype, history of antiviral treatment, and degree of liver fibrosisCombination of two direct-acting antivirals (DAAs)Ledipasvir + sofosbuvir for 12 weeks (genotypes 1, 4, 5, 6)Sofosbuvir + velpatasvir for 12 weeks (all 6 genotypes)Interferon + ribavirinMay be used to in the treatment of genotypes 2 and 3Interferon-based treatment is still used for cases of treatment failure.Ribavirin on its own may be combined with DAAs to increase antiviral activity.In addition to any treatment regimen, give vaccinations for hepatitis A and B Interferon and ribavirin are associated with severe side effects and teratogenicity! Complications Rarely fulminant hepatitis (liver failure) Liver cirrhosis Hepatocellular carcinoma Secondary hemochromatosis Considerations in pregnancy Vertical transmission approx. 3-5%C-section does not lower risk of transmissionAvoid amniocentesis or the use of fetal scalp electrode (↑ risk)HCV-infected patients may breastfeed as normal Postpartum treatmentCurrently available medication regimens are contraindicatedGive the infant vaccinations for hepatitis A and B

Laryngitis Laryngitis is an inflammation of the larynx that may manifest in acute or chronic forms. Acute laryngitis is commonly caused by viral infection of the nasopharynx that descends into the larynx or by severe damage to the vocal cords due to smoking or vocal strain. The primary symptoms are hoarseness (loss of voice) and a dry cough. Acute laryngitis may progress to chronic laryngitis if symptoms persists for more than three weeks. Direct or indirect visualization of the vocal cords and glottis (inflamed, hyperemic mucosa with edema and possibly exudates) is usually sufficient to diagnose the condition. Laboratory tests including complete blood count (CBC) and culture swabs should be carried out, particularly in chronic cases. Voice rest and cessation of smoking are the most important measures for treating the condition.

Acute laryngitis: inflammation of the vocal fold mucosa and larynx for < 3 weeks Chronic laryngitis: inflammation of the vocal fold mucosa and larynx for > 3 weeks uteInfection Viral infections rhinovirus, adenovirus, influenza from the nasopharynx ; most common causeBacterial infections; usually secondary to preexisting viral laryngitis H. influenzae, S. pneumoniae, S. aureus Environmental Vocal strain Inhalation of airborne irritantsRarely, systemic diseases like Wegener's granulomatosis, rheumatoid arthritis, and sarcoidosis ChronicGastroesophageal reflux disease (GERD): most common causeSmokingRecurring upper respiratory infection (URTI) Clinical features Hoarseness/loss of voice Dry cough (barking cough may occur in severe cases) Fever, dysphagia, and lymph node enlargement in cases of severe infection Accessory respiratory muscle use in case of narrowed airway Inspiratory stridor is common in children Symptoms of the underlying disease (e.g., retrosternal pain in GERD, frontal headaches in sinusitis, etc.) Subtypes and variants Acute types specific to childrenAcute laryngitis of the subglottic structuresLaryngotracheitis (croup)Laryngeal diphtheriaAcute laryngitis of the supraglottic structures: epiglottitisSee also "Differential diagnoses of pediatric inspiratory stridor" in croup Acute membranous laryngitis Caused by nonspecific, pyogenic organisms; distinct from pseudomembranous laryngitis (laryngeal diphtheria), which is caused by C. diphtheriae Diagnosis Diagnosis of both forms of laryngitis is primarily based on clinical history, examination findings, and laryngoscopy. Laryngoscopy Laryngoscopy helps visualize the vocal cords and the supraglottic structures (glottis, arytenoids, aryepiglottic folds). Either of the following types of laryngoscopy can be implemented to establish a diagnosis. TypesIndirect: can be performed during a routine physical examination Does not allow for as much visualization as direct laryngoscopyCaution is needed in suspected cases of acute epiglottitis, as it can trigger a laryngeal spasm, especially in children. Direct: allows for detailed examination of the larynx, including vocal fold movement Flexible endoscope (in patients who are awake)Rigid laryngoscope (in patients under general anesthesia)Can be used to obtain tissue for biopsy, cultures, and smears (to identify the presence of organisms) FindingsAcute laryngitisErythema and small dilated vasculature on the inflamed vocal foldsVocal fold movement is maintained, but aperiodic and closure is incomplete. Chronic laryngitisMucus (especially in the posterior wall of the larynx), erythema, and edema are the most common findings → lead to minimal movement Pus associated with bacterial infectionVocal cord atrophy Cobblestoning of mucosa in laryngopharyngeal reflux/GERD associated laryngitis Treatment The following modalities are used to treat both acute and chronic laryngitis: Vocal rest (voice rest) Cessation of smoking Speech therapy Steam inhalation Antibiotics are given only in cases of bacterial superinfection.

Antivirals against herpes viruses

Acyclovir Valacyclovir(prodrug of acyclovir with greater oral bioavailability) Penciclovir Famciclovir(prodrug of penciclovir) Guanosine analog (nucleoside analog): initially HSV/VZV-codedthymidine kinase monophosphorylates the guanosine analog to an active intermediate, which is then phosphorylated by cellular kinases The phosphorylated drug is incorporated into the replicating viral DNA strand and inhibits the viral DNA polymerase → termination of viral DNA synthesis Selective action in infected cells only → minimal effect on host cells' DNA replication Mutated viral thymidine kinase Acyclovir: crystal-induced acute kidney injury Prevention: dosage adjustment, adequate hydration ↑ Transaminases Gastrointestinal symptoms Thrombotic thrombocytopenic purpura Active infections with Herpes simplex Varicella zoster EBV (weak activity) Famciclovir: herpes zoster Ganciclovir Valganciclovir(prodrug of ganciclovir with greater oral availability) Guanosine analog (nucleoside analog): initially phosphorylated to 5' monophosphate by the CMV-coded UL97 kinase → further phosphorylated to triphosphate by cellular kinases The phosphorylated drug is incorporated into the replicating viral DNA strand and inhibits the viral DNA polymerase → termination of viral DNA synthesis Lower selectivity than acyclovir and penciclovir → can affect host cell's DNA replication Mutated viral UL97 kinase Hematological abnormalities Pancytopenia(additive effect when administered with NRTIs) Nephrotoxicity Gastrointestinal symptoms CNSHeadacheConfusionParesthesias Systemic treatment of choice for cytomegalovirus(CMV) retinitis in immunocompromisedpatients (e.g., with AIDS) CMV prophylaxis in transplant recipients at risk for CMV infection Foscarnet(pyrophosphateanalog)Viral DNA/RNA polymerase inhibitor and HIV reverse transcriptase inhibitor: direct inhibition of viral DNA polymerasesby binding to the pyrophosphate binding site of enzymeDoes not require activation by viral kinaseMutated viral DNA polymeraseNephrotoxicityGastrointestinal symptomsCNSHeadacheConfusionParesthesiasSeizures due to electrolyte abnormalities(e.g., hypocalcemia)Hematological abnormalities LeukopeniaNeutropeniaGanciclovir-resistant CMV retinitisAcyclovir-resistant HSV CidofovirViral DNA polymerase inhibitor: direct inhibition of viral DNA polymerasesDoes not require activation by viral kinase Nephrotoxicity(reduced with administration of probenecid and IV fluids) CMV retinitis Acyclovir-resistant HSV

Nosocomial infections Risk factors

Age > 70 years Lengthy hospital stays → high risk of infection Via medical staff (e.g., insufficient disinfection of hands, clothing) and contact surfaces (e.g., equipment, furniture) Via indoor air (may be contaminated by droplets from infected patients, staff, or procedures like bronchoscopy) Metabolic diseases (especially diabetes mellitus) and immunosuppression Prior antibiotic use Iatrogenic (caused by treatment or a diagnostic procedure) Invasive instruments and foreign bodies: catheters, intravenous catheters, endotracheal tubes Conditions which require a high amount of interventional procedures (e.g., shock, major trauma, acute renal failure, coma)Mechanical ventilation

Disinfectants and antiseptics

Alcohols (e.g., isopropyl alcohol and ethyl alcohol)Causes membrane damage and denaturation of proteins Bacteria,Enveloped viruses,Fungi Bisbiguanides (e.g., chlorhexidine)At low concentrations: leakage of intracellular components due to cell membrane disruptionAt high concentrations: cause precipitation of intracellular proteins and nucleic acids Phenol (e.g., orthophenylphenol and ortho-benzyl-para-chlorophenol)At low concentrations: inactivates essential enzymes and induces leakage of metabolitesAt high concentrations: disrupts cell wall and precipitates cell proteins Halogen-releasing agentsIodine and iodophors (e.g., povidone-iodine and poloxamer-iodine) Sporicidal Halogenation of RNA, DNA, and proteinsBacteriaViruses Fungi Sporicidal (with prolonged contact time) Chlorine-releasing agents (e.g., sodium hypochlorite and chlorine dioxide)Highly active oxidizing agents that denature proteins and nucleic acids and disrupt oxidative phosphorylation (e.g., effective against highly resistant spores of Clostridiumspecies) Hydrogen peroxideAn oxidant that produces hydroxyl free radicals (•OH), which damage essential cell components, including lipids, proteins, and DNA Sporicidal Aldehydes (e.g., glutaraldehyde)Microbicidal effect is mediated by alkylation of sulfhydryl, hydroxyl, carboxyl, and amino groups of RNA, DNA, and proteins. Sporicidal Quaternary ammonium compounds (e.g., benzalkonium chloride) Induces inactivation of energy-producing enzymes, denaturation of essential cell proteins, and disruption of the cell membraneBacteria (not mycobacteria)Enveloped viruses)FungiNo

Antivirals against influenza viruses

Amantadine Rimantadine, M2 ion channel blocker, Weak NMDA receptor antagonist, Neurological AtaxiaLivedo reticularisPeripheral edemaAnxiety Gastrointestinal symptoms, Amantadine: orthostatic dysregulation, QT interval prolongation, Influenza A Parkinson disease Oseltamivir,Zanamivir,Peramivir, Neuraminidase inhibitor Gastrointestinal symptoms Headache Upper respiratory tract infections Influenza A and B Prophylaxis of influenza in adults and pediatric patients 5 years and older In influenza A and B, rapid administration of neuraminidase inhibitors within 1-2 days of symptom onset is vital to reduce the duration of illness and alleviate symptoms.

Polyenes

Amphotericin BIntravenousIntrathecalBladderirrigation Bind to ergosterol in the fungal cell membrane, which forms pores that disrupt electrolyte balance Severe systemic mycosesInvasive candidiasisCryptococcal diseaseSporotrichosisAspergillosisBlastomycosisCoccidioidesHistoplasmosisMucormycosis Bladder wash for fungal cystitis Intrathecally for fungal meningitis Very broad spectrum of efficacy Available as Amphotericin BdeoxycholateLipid-based formulations Important contraindications Renal dysfunctionHepatic dysfunction Pregnancy and breastfeeding: not generally recommended in breastfeeding mothers Toxicity can cause arrhythmias → cardiac arrest Nephrotoxicity Fever, chills Hypotension IV phlebitis("amphoterrible") Hypokalemia Hypomagnesemia Anemia Hearing loss Neuropathy Nystatin(topical, oral ) Vaginal candidiasis Diaper rash Oropharyngeal candidiasis("Swish and swallow") Broad spectrum of efficacy Prophylactic administration in immunosuppression Gastrointestinal symptoms Contact dermatitis, Stevens-Johnsonsyndrome

Antibiotic prophylaxis

Antibiotics are commonly used for prophylaxis against infections in the following situations: Immunocompromised patients (e.g., HIV, following organ transplantation, neutropenia) Infective endocarditis (see prophylaxis for endocarditis) Before and/or after surgical procedures Post-exposure prophylaxis (e.g., doxycycline against malaria)

Antibiotics

Antibiotics are employed against bacterial as well as some parasitic infections. They have either a bacteriostatic or a bactericidal effect and can be effective against a small group of bacteria (narrow-spectrum) or a wide range of pathogens (broad-spectrum). Most antibiotics work by inhibiting cell wall synthesis, protein synthesis, or nucleic acid synthesis in bacteria. Common side effects include allergies and cross-reacting hypersensitivities, as well as nephrotoxic and hepatotoxic effects. Many antibiotics are contraindicated in certain patient groups (e.g., children, pregnant or lactating women). In the case of severe infections, early initiation of one or more antibiotics without waiting for a microbiological confirmation is indicated (empirical antibiotic therapy), with the aim of targeting the most likely pathogen(s). Because of widespread use of antibiotics (often misuse!), antibiotic-resistant pathogens have emerged (e.g., MRSA, Pseudomonas).

Antifungals

Antifungals are used in the treatment of mycotic infections such as candidiasis, cryptococcal disease, aspergillosis, and dermatophytosis. They are primarily divided into three major groups (polyenes, azoles, and allylamines) and are differentiated based on their chemical structure and specific spectrum of efficacy. Whereas intravenous broad-spectrum antifungals (such as fluconazole or lipid formulations of amphotericin B) cover almost all known fungi, topical agents (such as clotrimazole) often have a limited scope of activity. Hepatotoxicity, skin reactions, headaches, and gastrointestinal symptoms are common side effects.

T cell activation

Antigens are processed by antigen-presenting cells (i.e., macrophages, monocytes, B cells, and dendritic cells). These cells present antigens (peptidefragments) via MHC molecules. T cell activation ("priming") mainly occurs in secondary lymphoid organs, such as lymph nodes. Antigen-presentation by a dendritic cellExogenous antigens are presented via MHC II to TCR/CD4.Endogenous antigens, cross-presentation of antigens are presented via MHC I to TCR/CD8. Co-stimulatory signal: Interaction of a second set of molecules mediates survival and proliferation of T cell.On the dendritic cell: B7 protein (CD80 or CD86)On the T cell: CD28Antigen presentation without this co-stimulatory signal will lead to T-cell anergy.Effect: T-helper cell: via activation of NFAT produces cytokines that activate other cells, e.g., B cells, macrophages, and cytotoxic T cellsCytotoxic T cell: destroys cells that possess antigens (signals malignancy or viral infection)

Autoantibodies

Antinuclear antibodies (ANA)Nuclear antigensVarious connective tissue diseases (particularly SLE)Rheumatoid arthritisVasculitisBorreliosis Antineutrophil cytoplasmic antibodies (ANCA)Cytoplasmic antigensGranulomatosis with polyangiitis (cANCA)Microscopic polyangiitis (pANCA)Gastrointestinal Crohn diseaseUlcerative colitis Thyroid peroxidase antibodies (TPO Ab)Thyroid peroxidaseHashimoto thyroiditisGraves disease TSH receptor antibodiesTSH receptorGraves diseaseHashimoto thyroiditis Transglutaminase antibodiesTissue transglutaminase in the bowelGluten‑sensitive enteropathy ACh receptor antibodiesAcetylcholine receptorMyasthenia gravis Anti-glomerular basement membrane antibodiesType IV collagen on glomerular basement membraneGoodpasture syndrome Anti-β2 glycoprotein antibodiesGlycoproteinAntiphospholipid syndrome Anticardiolipin antibodiesCardiolipinAntiphospholipid syndromeSystemic lupus erythematosus Rheumatoid factorIgM against Fc region of IgGRheumatoid arthritis Anti-CCP antibodyCitrullinated peptidesRheumatoid arthritis Lupus anticoagulantCell membrane phospholipidsAntiphospholipid syndromeSystemic lupus erythematosus Anticentromere antibodiesCentromeresCREST syndrome Anti-desmoglein antibodiesDesmosomesPemphigus vulgaris Anti-glutamic acid decarboxylase antibodiesIslet cell cytoplasmType I diabetes Anti-hemidesmosome antibodiesHemidesmosomesBullous pemphigoid Anti-synthetase antibodies (anti-Jo-1 antibodies)tRNA synthetasePolymyositisDermatomyositis Anti-SRP antibodiesSignal recognition particlePolymyositisDermatomyositis Anti-Mi-2 antibodies (anti-helicase antibodies)HelicasePolymyositisDermatomyositis Anti-mitochondrial antibodiesLiver cells mitochondriaPrimary biliary cirrhosis Anti-intrinsic factor antibodiesParietal cellsPernicious anemia Anti-phospholipase A2 receptor antibodiesPhospholipase A2 receptorMembranous nephropathy Anti-Scl-70DNA topoisomerase IScleroderma Anti-smooth muscle antibodiesSmooth muscleAutoimmune hepatitis Anti-SSA; Anti-SSB (anti-Ro, anti-La)Intracellular autoantigensSjogren syndrome Anti-presynaptic calcium channel antibodiesVoltage-gated calcium channelLambert-Eaton syndrome p-ANCANeutrophil myeloperoxidaseMicroscopic polyangiitisChurg-Strauss syndromeUlcerative colitis c-ANCANeutrophil proteinaseGranulomatosis with polyangiitis Anti-histone antibodiesHistonesDrug-induced lupus erythematosus Anti-dsDNADouble-stranded DNASystemic lupus erythematosus Anti-Smith antibodiesNonhistone nuclear proteinsSystemic lupus erythematosus Anti-U1 RNP antibodiesRibonucleoproteinMixed connective tissue disease

Antiviral agents

Antivirals are a class of medications that are used to treat viral infections. Most viral infections resolve spontaneously in immunocompetent individuals. The aim of antiviral therapy is to minimize symptoms and infectivity as well as to shorten the duration of illness. These drugs act by arresting the viral replication cycle at various stages. Currently, antiviral therapy is available only for a limited number of infections. Most of the antiviral drugs currently available are used to treat infections caused by HIV, herpes viruses, hepatitis B and C viruses, and influenza A and B viruses. Because viruses are obligate, intracellular parasites, it is difficult to find drug targets that interfere with viral replication without also harming the host cells. Unlike other antimicrobials, antiviral drugs do not deactivate or destroy the microbe (in this case, the virus) but act by inhibiting replication. In this way, they prevent the viral load from increasing to a point where it could cause pathogenesis, allowing the body's innate immune mechanisms to neutralize the virus. This learning card provides an overview of the most commonly used antiviral agents. For more information on antiretroviral agents used in the treatment of HIV, which is known as highly active antiretroviral therapy (HAART), see HIV therapy.

Helminth infections Helminths, i.e., parasitic worms, are a group of macroparasites encompassing a variety of species that can infect their hosts in three different ways: ingestion of eggs or larvae (e.g., via contaminated food and water or fecal-oral route), direct penetration of the skin, and via the bite of vectors (e.g., certain species of flies and mosquitoes). Helminths are classified based on their macroscopic appearance as nematodes (i.e, roundworms; genera include Toxocara, Enterobius, Trichuris, Ascaris, Trichinella, Strongyloides, Ancylostoma, Necator), cestodes (i.e.,tapeworms; genera include Taenia, Diphyllobothrium, Echinococcus), or trematodes (i.e., flukes; genera include Schistosoma, Metorchis, Fasciola). Most helminth species colonize the gastrointestinal tract of their hosts, provoking symptoms such as abdominal pain, nausea, and diarrhea. The larvae of certain helminth species, such as those of the Ascaris and Ancylostoma genus, migrate from the intestines via the portal vein to the lungs, potentially causing asthma-like symptoms (e.g., dry cough, wheezing). Other species, such as Taenia solium, are capable of colonizing other human tissue, such as the brain or the liver, which can lead to life-threatening complications (e.g., neurocysticercosis). Diagnosis of helminth infection is made primarily via evidence of eosinophilia in the blood and direct detection of worms, eggs, or larvae in stool samples. Serum IgE levels are often elevated. Treatment consists of anthelmintic agents such as albendazole or praziquantel. For helminth infection prevention, see "Food and water safety" in the learning card on food poisoning. Echinococcosis and schistosomiasis are discussed in separate learning cards.

Ascariasis PathogenAscaris lumbricoidesAscaris are nematodes (roundworms), and are also known by the synonym "giant roundworm." Epidemiology: most common helminth infection worldwide (mainly affecting children in tropical and developing countries) Mode of transmission: fecal-oral Life cycle: oral ingestion of eggs → eggs hatch to release larvae → larvae invade intestinal walls → migration to lungs via portal vein → migration into alveoli, trachea ("tracheal migration"), larynx → larvae are expectorated and swallowed back into the intestine → larvae returning to the intestine mature into adult worms, which then lay new eggs. Clinical features Early symptoms : dry cough, blood-tinged sputum, wheezing (see also "Löffler syndrome")Late symptoms : anorexia, abdominal discomfort, nausea, vomiting, and diarrheaAdditional symptoms due to blockage by adult worms depend on the location of the obstruction: Bowel obstruction, especially at ileocecal valveObstruction of the appendix → features of appendicitisObstruction of biliary and pancreatic ducts → features of cholestasis, pancreatitis DiagnosisInitial test: complete blood cell (CBC) count showing eosinophiliaConfirmatory test: stool sample showing the presence of worms; visible eggs with a knobby appearance under microscope Treatment: bendazoles and pyrantel pamoate You could get sick if you EATTT Enterobius, Ascaris, Toxocara, Trichinella, Taenia! Enterobiasis PathogenEnterobius vermicularis (pinworm)Pinworms are nematodes (roundworms). EpidemiologyMost common helminthic infection in the U.S.Prevalence in the US: ∼ 40 millionPrimarily children 5-10 years of age Mode of transmissionInitial infection: fecal-oralReinfection: digital-oral after scratching anal region Clinical featuresAnal pruritus (especially at night)♀: vulvovaginitis, particularly in childrenOccasionally symptoms of intestinal infection (nausea, vomiting, and abdominal pain, sometimes severe enough to mimic appendicitis) Diagnosis: tape test Treatment: bendazoles or pyrantel pamoateDuring pregnancy: pyrantel pamoate is the drug of choiceShould only be administered if pregnancy is compromised (e.g., weight loss, sleeplessness)If indicated, preferably not start until the 3rd trimester, when risk to the fetus is likely reduced Trichiuriasis PathogenTrichuris trichiura (whipworm)Whipworms are nematodes. Mode of transmission: fecal-oral Life cycle: host ingests eggs → eggs hatch and release larvae in the small intestine → larvae mature into adult worms in colon → adult worms lay eggs, which are shed in feces Clinical featuresMostly asymptomaticIn children: severe infection causes diarrhea, iron deficiency anemia, growth retardation, rectal prolapse DiagnosisMicroscopic examination of stool for eggs Concentration technique can be used for light infections. Treatment: mebendazole or albendazole Toxocariasis PathogenToxocara canis (dog roundworm), Toxocara mystax (synonym: Toxocara cati, cat roundworm)Toxocara are nematodes. Nematodes are a group of worms also referred to as roundworms. Mode of transmission: fecal-oral Incubation period: 2-4 weeks Clinical features Visceral toxocariasis (also called visceral larva migrans): caused by larvae migrating through the organsFever and flu-like symptomsAdditional symptoms depend on the affected organs: Hepatomegaly and abdominal painRespiratory symptoms: dyspnea, wheezing, cough, pneumonia (see also "Löffler syndrome")RashOcular toxocariasis (also called ocular larva migrans): caused by larvae migrating into the eyeUnilateral vision loss and resulting strabismusLeukocoriaInflammation, scarring, and possible detachment of the retina DiagnosisInitial tests Complete blood cell (CBC) count: eosinophilia↑ Serum total IgEConfirmatory test : ELISA detects IgG antibodies to Toxocara excretory/secretory antigens Treatment: bendazoles Trichinellosis PathogenTrichinella spiralis and other Trichinella spp.Trichinella are nematodes. Mode of transmissionConsumption of undercooked meat (especially pork) containing encysted larvaeFecal-oral (rarely) Life cycle: host ingests meat that contains cysts → larvae invade the small bowel mucosa → larvae develop into adult worms → adult worms release larvae, which then migrate to muscles, where they encyst Clinical featuresIntestinal phase : abdominal pain, diarrhea, nausea, and vomitingMuscle phase Myositis: myalgia, muscle swelling, weaknessPeriorbital edemaOther symptoms include: fever, rash, splinter hemorrhages, retinal and conjunctival hemorrhages, chemosis DiagnosisCBC shows eosinophilia (and sometimes leukocytosis).Confirmatory test: serological detection of antibodies↑ Creatinine kinase Treatment: bendazoles Complications Cardiac: ECG changes (e.g., arrhythmias)CNS: meningitis, encephalitisPulmonary: myositis involving respiratory muscles, pneumonia Hookworm infections (ancylostomiasis; necatoriasis) PathogenHuman hookworms (Ancylostoma duodenale and Necator americanus): nematodes (roundworms)Zoonotic hookworms, i.e., cat and dog hookworms that can also infect humans (Ancylostoma braziliense and Ancylostoma caninum) Mode of transmission: percutaneous penetration of larvae (primarily via the feet) Human hookworm life cycle: soil contaminated with human feces containing hookworm eggs → eggs hatch into larvae → penetration of larvae into skin (usually the feet) → larvae migrate to lungs via blood and lymphatic vessels → migration via the bronchi and trachea to the larynx → larvae are expectorated and swallowed back into the intestine → larvae mature into adult worms that colonize the intestinal tract → female hookworms lay eggs in the intestines that are eliminated with the feces Zoonotic hookworms are usually unable to break through the basement membrane after entering the human epidermis (humans are accidental intermediate hosts) → migration through the epidermis for several weeks Clinical featuresCutaneous entry: pruritus, erythema, maculopapular rash, occasionally with serpiginous marks representing larval tracks In zoonotic hookworm infections, only cutaneous symptoms are present, which is termed cutaneous larva migrans (CLM) Respiratory tract: dry cough, wheezing → see Löffler syndromeIntestine : abdominal pain, weight loss, nausea, vomiting, diarrheaAnemia DiagnosisInitial test: complete blood cell (CBC) count may show eosinophilia and microcytic anemiaConfirmatory test: consecutive stool examination for eggs or worms Treatment: For human hookworms: bendazoles or pyrantel pamoateFor CLM: bendazoles, ivermectin Strongyloides, Ancylostoma, and Necator get into your feet from the SANd! Strongyloidiasis PathogenStrongyloides stercoralisStrongyloides are nematodes (roundworms). Mode of transmission: Larvae excreted in feces penetrate the skin, e.g., while a potential host is walking barefoot. Life cycle: penetration and migration into the skin → migration of larvae via the bloodstream to the lungs → migration via the alveoli and bronchial system to the pharynx → swallowing and autoinfection → larvae mature into adult, egg-producing worms in the intestine → eggs develop into "free-living" infectious larvae and are excreted in feces Incubation period: 1-4 weeks Clinical features Cutaneous phase: swelling, erythema, maculopapular rash, and serpiginous lesions or urticarial tracts (larva currens is pathognomonic); pruritusPulmonary phase: dry cough and wheezing, rarely pneumonia (see also "Löffler syndrome")Intestinal phase: abdominal pain, diarrhea, anorexia, nausea, and vomiting Complications: hyperinfection syndrome, possibly leading to organ dysfunction and septic shock, and occurring especially in immunosuppressed individuals (e.g., AIDS, steroid therapy) DiagnosisInitial test: complete blood cell (CBC) count may show eosinophiliaConfirmatory test: consecutive stool examination for mobile larvae Treatment: ivermectin or bendazoles Onchocerciasis Pathogen: Onchocerca volvulus Mode of transmission: bite of the female blackfly Life cycle: host is bitten by blackfly → larvae are introduced into bite wound → larvae mature into adult worms that reside in subcutaneous or intramuscular tissue → adult worms produce microfilariae → microfilariae migrate through subcutaneous tissue, causing clinical symptoms → female fly consumes microfilariae during a blood meal → Microfilariae mature into larvae, thus, completing the cycle. Clinical featuresOcular onchocerciasisKeratitis UveitisOptic atrophyOnchochorioretinitisOcular lesions can progress to blindness (hence the common name "river blindness")Onchocercal skin diseaseOnchocercomata (subcutaneous nodules): deep, nonpalpable nodules found over various bony prominencesGeneralized pruritic lesionsHyperpigmented papules (sowda)Skin atrophy (due to loss of skin elasticity) Hanging groin Depigmentation (leopard-skin appearance)Systemic manifestations Weight lossGeneralized musculoskeletal complaints (e.g., back and joint pain)Inguinal and femoral herniaAllergic reactions to microfilariae may occur DiagnosisSkin snips (gold standard): superficial skin biopsies are taken from an inflamed area and are incubated in saline, causing microfilariae to leave the skin sample. Microfilarial load can be determined microscopically. At least two specimens are sampled and examined for motile microfilariae.Specimens of subcutaneous nodules can also be sampled and examined for adult worms.Slit-lamp examination: investigation of choice for ocular onchocerciasisMazzotti test: a provocative test that involves administering diethylcarbamazine (DEC) to induce microfilarial death and exacerbate symptoms. A positive test is highly suggestive of onchocerciasis.Serology: an unreliable means of diagnosis as it cannot distinguish between active and past infection Treatment: ivermectin Everything turns black in onchocerciasis: black flies, black skin nodules, black vision (blindness). Lymphatic filariasis PathogensWuchereria bancrofti: a nematode; responsible for most cases of lymphatic filariasis worldwideBrugia malayi and Brugia timori: found in Asia Mode of transmission: female mosquito bite (Aedes, Mansonia, Anopheles, and Culex) Incubation period: 9-12 months Life cycle: Mosquito introduces filarial larvae into host via bite wound → Larvae mature into adult worms that reside in the lymphatic system → Adult worms produce microfilariae → Microfilariae move throughout vascular and lymphatic system → Microfilariae are consumed by a female fly during a blood meal →Microfilariae mature into larvae, thus completing the cycle. Clinical featuresFeverPainful lymphadenopathy (due to worms invading lymph nodes, causing inflammation) and retrograde lymphangitis → lymphedema with disfiguration of the lower extremities (elephantiasis)Hydrocele DiagnosisBlood smear obtained at night (and staining with Giemsa or hematoxylin and eosin): detection of microfilariae Serology: elevated levels of antifilarial IgG4 TreatmentDiethylcarbamazine (DEC): drug of choiceIvermectin: used in areas where onchocerciasis is prevalent, as DEC can worsen onchocercal eye diseaseElevation of the affected extremity, exercise, and wearing therapeutic shoes: recommended for those with lymphedemaSurgery for hydrocele Intestinal taeniasis Taenia saginata (beef tapeworm) Taenia solium (pork tapeworm) Ingestion of larvae (cysticerci) in raw or undercooked beef/pork Often asymptomatic Symptoms caused by adult worms in the intestinal tract: abdominal pain, anorexia, weight loss, nausea, and vomiting Initial test: complete blood cell (CBC) count may show eosinophilia (in only ∼ 45% of patients) Confirmatory test: stool examination → detection of eggs and/or worms Praziquantel Cysticercosis Taenia solium (pork tapeworm) Fecal-oral ingestion of eggs from feces of humans with intestinal taeniasis ymptoms caused by cysticerci accumulation in subcutaneous tissue, muscles, brain, spinal cord, and eyes Palpable subcutaneous cysts Myalgia Neurocysticercosis : increased intracranial pressure, neurological deficits, seizures Ocular cysticercosis: eye pain, loss of visual acuity or vision in one eye Initial tests: as with intestinal taeniasis Additional testing Imaging: MRI/CT showing multiple, small (< 1 cm) cystic ring-enhancing lesions in the brain with a membranous wall + often an invaginated scolex during earlier stages+ calcified cyst remnants in later stagesLumbar puncture: ↑ protein, ↓ glucose, mononuclear pleocytosis Confirmatory test: serum enzyme-linked immunotransfer blot (EITB) assay Albendazole + corticosteroids Alternatively: praziquantel Avoid raw pork meat and inspect for cysticerci Adequately freeze and cook meat to destroy viable cysticerci Proper disposal of human feces Hand washing before meal preparation You could get sick if you EATTT Enterobius, Ascaris, Toxocara, Trichinella, Taenia! Diphyllobothriasis (Diphyllobothrium latum or fish tapeworm infection) Pathogen: Diphyllobothrium latum (fish tapeworm - a cestode) Mode of transmission: consumption of raw or undercooked freshwater fish Clinical featuresUsually asymptomaticChronic infection leads to vitamin B12 deficiency → anemia and/or neurological symptoms DiagnosisInitial test: complete blood cell (CBC) count may show eosinophilia, megaloblastic anemiaConfirmatory test: stool examination for eggs or proglottids (i.e., segments of adult tapeworms) Treatment: praziquantel Fascioliasis Pathogen: Fasciola hepatica, Fasciola gigantica Mode of transmissionConsumption of contaminated freshwater plants (e.g., watercress)Drinking contaminated freshwater Life cycleMetacercariae on freshwater plants are ingested by herbivorous mammals e.g., sheep, cattle (both definitive hosts), or humans (incidental hosts) → migration of the organism through the intestinal wall, then liver parenchyma, and into the biliary ducts → adult fluke release eggs into the biliary ducts, which are then passed in the stool of the host.Snails serve as the intermediate hosts. Clinical featuresAcute phase: fever, right upper quadrant pain, and hepatomegalyChronic biliary phase: abdominal pain, nausea, vomiting, and diarrheaFeatures of biliary obstruction: biliary colic, cholangitis, cholelithiasis, and obstructive jaundice DiagnosisMicroscopic examination: detection of eggs in the stool or bile sampleCBC count: eosinophilia (marked in the acute phase)Enzyme-linked immunosorbent assay (ELISA)Endoscopy: adult flukes in the biliary tract TreatmentTriclabendazoleERCP in case of biliary obstruction

Opportunistic fungal infections

AspergillosisPathogen: Aspergillus fumigatus, Aspergillus flavusRisk factors: immunocompromiseand chronic granulomatous infectionABPA: associated with asthma and cystic fibrosis; causes bronchiectasis and eosinophiliaPulmonary aspergilloma: chronic cough, hemoptysisInvasive aspergillosis: fever, cough, respiratory distressEndocarditisABPA: eosinophilia, elevated IgE levels, pulmonary infiltrates chest x-ray or CTPulmonary aspergilloma: x-ray or CT shows mobile fungus ball; serology is positive AspergillusIgGInvasive aspergillosis: tissue biopsy showing 45° angle branching septate hyphae with fruiting bodiesABPA: oral prednisone for severe cases; itraconazole for recurrent episodesPulmonary aspergilloma: lobectomy for massive hemoptysisInvasive aspergillosis: IV voriconazole, caspofungin, or amphotericin B CandidiasisPathogen: Candida albicansRisk factors: immunosuppression(e.g., HIV, diabetes mellitus), medications (antibiotics, steroids, cytostatic agents, immunosuppressive therapy), ↑ estrogenlevels during pregnancy, hematologic malignancies (e.g., acute myeloid leukemia, multiple myeloma), compromised skin(excessive moisture, local lesions from dentures or burns)Oral thrushCandida esophagitisVaginal yeast infectionCandidiasis of the skin: erythematouspatches with small satellite lesions in intertriginous areas and digital web spacesDiaper dermatitisDisseminated: sepsis, meningitis, multiple abscesses, endocarditisBest initial: KOH testshowing budding yeasts and pseudohyphae at 20°CConfirmatory: fungal culture (blood or tissue)AIDS-defining illness: IF esophagus, trachea, bronchi, or lungparenchyma are involvedVulvovaginitis(uncomplicated): topical azoleOral: nystatin; if refractory oral fluconazoleEsophagitis: oral or IV fluconazoleSuperficial skin candidiasis: topical antifungalsSystemic: IV echinocandins(e.g., caspofungin) CryptococcosisPathogen: Cryptococcus neoformansRisk factors: AIDS, exposure to pigeon droppingsAIDS-defining illness: IF extrapulmonaryCryptococcal meningoencephalitisor brain abscess: headache, fever, signs of increased intracranial pressure, confusion, absent meningeal signsIsolated pneumoniais possibleLP: India ink stain(clear halo ), positive cryptococcalantigen (also in blood), and fungal culture (Sabouraud agar) showing ∼ 10-μm yeastwith thick polysaccharidecapsule and narrow, unequal buddingMucicarmine: A narrow-spectrum stain used in the diagnosis of C. neoformans.Stains the thick polysaccharidecapsule bright redLatex agglutination test: detects capsular antigen (very specific)IV amphotericin Band flucytosinefollowed by oral fluconazoleMaintenance therapy: oral fluconazole (until symptoms resolve and CD4> 100/mm3for at least 1 year)Serial therapeutic LPs for ↑ intracranialpressure Pneumocystis pneumoniaPathogen: P. jirovecii(previously P. carinii)Risk factors: immunosuppression(especially if CD4count < 200/μL)AIDS-defining illnessPneumocystis pneumonia: fever, exertional dyspnea, nonproductive cough, weight loss, impaired oxygenationChest x-ray or CT: diffuse, bilateral ground-glass opacities Bronchoalveolar lavage or lung biopsy(if sputum is negative): silver stain and immunofluorescence show disc-shapedyeasts High-doseTMP-SMX(treatment and prophylaxis) or dapsone+/- pyrimethaminePrednisone(moderate to severe hypoxemia)Prophylaxis: CD4< 200 cells/mm3 Mucormycosis Pathogen: zygomycetes Mucorand Rhizopus Risk factors: diabetic and immunocompromisedpatients Patients with chronic sinus infection lasting for more than 3 months are predisposed to mucormycosis. Invasive chronic sinusitis and orbital cellulitis: headache, facial pain, black necroticeschar on face; possible cranial nerve involvement Head CT: sinusitis with orbital and intracranial involvement Tissue biopsy(confirmatory): wide-angled branching of broad nonseptate hyphae Surgical debridement IV amphotericin Bor isavuconazole

Molds PathogenicityUsually an opportunistic pathogenMold antigens are one of the most frequent causes of allergies.Molds produce various toxins. Infection is caused by either aerogenic uptake or is foodborne (e.g., aflatoxins). MorphologyFormation of monomorphic septate hyphae that branch at 45° and mycelium Mold can infest food products and acquire a fuzzy appearance that is macroscopically visible.

Aspergillus fumigatus Ubiquitous occurrence Some species produce aflatoxins Allergic bronchopulmonary aspergillosis (ABPA) Aspergilloma Invasive pulmonary aspergillosis Endocarditis ABPA: oral prednisone if severe; itraconazole if recurrent Pulmonary aspergilloma: lobectomy Invasive aspergillosis: IV voriconazole, caspofungin, amphotericin B

B Cell Overview

B cells (B lymphocytes)Major component of the adaptive immune system (especially humoral immune response)Originate in the bone marrow, where they develop to mature, naive B cellsMature B cells circulate in between the blood and secondary lymphatic organs (e.g., lymph nodes, spleen, MALT) Activation of mature B cells: occurs in response to an antigen Each B cell responds to a specific antigen depending on its unique B-cell receptor. Nonprotein antigens: B cell activation occurs independentlyProtein or peptide antigens: B cell activation involves Ig class switching, which requires the involvement of T-helper cells After activation: B cells differentiate into plasma cells that produce and secrete antibodies (see immunoglobulins), e.g., to opsonize bacteria which facilitates phagocytosis.

Deep neck infections Deep neck infections include peritonsillar abscess (PTA), parapharyngeal abscess (PPA), and retropharyngeal abscess (RPA). PTA commonly occurs in adolescents or young adults as a complication of acute tonstillitis. Clinical features include fever, sore throat, dysphagia, a "hot-potato" voice, and trismus (lockjaw). Diagnosis is primarily based on examination of the pharynx, which demonstrates a characteristic fluctuant, enlarged tonsil and contralateral deviation of the uvula. Antibiotics and incision and drainage of the abscess are the mainstay of treatment. PPA and RPA are more common in children < 5 years of age, and typically occur secondary to dental infections or upper respiratory infections, respectively. PPA and RPA both present with nonspecific features of tonsillitis. In addition, PPA may lead to medialdisplacement of the lateral pharyngeal wall and tonsil, while RPA may lead to unilateral swelling of the posterior pharyngeal wall. The diagnosis of PPA is made with CT, while RPA is usually confirmed with either lateral x-ray, which shows widening of the prevertebral space, or CT if x-ray is non-diagnostic. In both PPA and RPA, IV empiric antibiotic therapy is routinely administered and surgery may be necessary in certain cases. Deep neck infections are clinically significant because of their potentially life-threatening complications, including the spread of infection to vital nearby structures and airway compromise

Basic anatomy of the neck Two major fascial layers: superficial cervical and deep cervical fascia The deep cervical fascia is divided into 3 layers: investing, pretracheal and prevertebral layers. The carotid sheath consists of fascia from all three deep layers and surrounds the common carotid artery, internal jugular vein, and vagus nerve. Deep neck spaces are spaces between these deep layers. The retropharyngeal space communicates laterally with the parapharyngeal space and may drain into the prevertebral space.The danger space extends from the skull base to the posterior mediastinum and is posterior to the retropharyngeal space. Peritonsillar Abscess Most common in adolescents and young adults Most common deep neck infection Acute tonsillitis Features of tonsillitis "Hot potato" voice Trismus Uvula shifted to the contralateralside Inflamed ipsilateral tonsil: fluctuant, swollen, erythematous with exudates (ipsilateral bulging of the palatine arch) Clinical diagnosis IV antibiotics Surgical drainage Parapharyngeal Abscess Most common in children < 5 years of age Dental infections (most common) Acute tonsillitis Peritonsillar abscess Pharyngeal or salivary gland infections Features of tonsillitis Sometimes trismus Medial displacement of the lateral pharyngeal wall and tonsil (posterior space abscess) or indurated swelling below the angle of the mandible down to the hyoid bone (anterior space abscess) CT Retropharyngeal Abscess Most common in children < 5 yearsof age Contiguous or lymphatic spread from upper respiratory tract infections(most common) or other nearby infections Local penetrating pharyngeal trauma Features of tonsillitis Sometimes trismus Unilateral swelling of the posteriorpharyngeal wall (possible fluctuance) Neck asymmetry, with neck swelling and anterior cervical lymphadenopathy(→ inability to extend neck) Lateral x-ray: widened prevertebral (soft tissue) space CT TreatmentIV antibioticsSurgical drainage Peritonsillar abscess EpidemiologyMost common deep neck infection Most common in adolescents and young adults EtiologyPathogens: Streptococcus pyogenes (most common), Streptococcus anginosus, viridans streptococci, Staphylococcus aureus, and Haemophilus species, often in a polymicrobial environment Acute bacterial tonsillitis (see acute tonsillitis) Clinical featuresFeatures of tonsillitis: fever, malaise, severe sore throat, dysphagia, and odynophagia"Hot potato" voice (muffled speech), drooling, or halitosisTrismus Uvula shifted to the contralateral side, with inferior and medial displacement of tonsilUnilateral fluctuant, swollen, erythematous tonsil with exudates (ipsilateral bulging of the palatine arch) Ipsilateral cervical lymphadenopathy (and neck swelling) DiagnosisUsually a clinical diagnosisGram stain and culture of aspirated abscess fluid, and throat culture to identify causative pathogenContrast-enhanced CT if there is a clinical suspicion of other diagnoses or complications TreatmentAirway management is always the first step!IV antibiotics with good gram-positive and anaerobic coverage: empiric clindamycin or ampicillin-sulbactam . Incision and drainage or needle aspiration (surgical drainage): risk of airway obstruction, complications, or immunodeficiency. Tonsillectomy indicated if: Unresponsive to drainage and antibioticsRecurrent tonsillitis or peritonsillar abscess, or other complications occurAirway obstruction is present Complications Can become life-threatening due to airway compromiseFurther spread of infection into the parapharyngeal space (PPA), retropharyngeal space (RPA), mediastinum (mediastinitis), or fascia(necrotizing fasciitis) Aspiration pneumonia Internal jugular vein thrombosis or thrombophlebitis Bacteremia and sepsis Parapharyngeal abscess EpidemiologyMost common in children < 5 years of age♂ > ♀ EtiologyPathogens: Streptococci (viridans streptococci, S. pneumoniae), staphylococci (including MRSA), Haemophilus influenzae, oral anaerobes (Peptostreptococci, Bacteroides species), often in a polymicrobial environment Oropharyngeal infectionsDental infections (most commonly)Acute tonsillitisPeritonsillar abscess into the parapharyngeal space Pharyngeal or salivary gland infections Clinical featuresFeatures of peritonsillar abscess, especially trismusPosterior space abscess: medial displacement of the lateral pharyngeal wall and tonsilAnterior space abscess: indurated swelling below the angle of the mandible down to the hyoid boneRespiratory distress: dyspnea, stridor Limited cervical neck extension DiagnosisGram stain and culture of aspirated abscess fluid, and throat culture to identify causative pathogenCT Confirms diagnosisDetermines extent of infectionEnables CT-guided abscess aspiration, or drainage TreatmentAirway management is always the first step!IV broad-spectrum antibiotics: ampicillin-sulbactam, penicillin G or ceftriaxone plus metronidazole, or clindamycin. Surgical drainage ComplicationsAirway obstructionSpread of infection to retropharyngeal space, carotid sheath (presents with torticollis) and then mediastinum (internal carotid arteryerosion jugular vein thrombophlebitis, and mediastinitis), or cranial nerves (Horner syndrome, hoarseness, unilateral paresis of the tongue, and other neurologic deficits) Aspiration pneumonia with spontaneous pus drainage Bacteremia and sepsis Parapharyngeal infections can become life-threatening because of their proximity to the retropharyngeal space, carotid sheath, and airway! Retropharyngeal abscess EpidemiologyGenerally the most dangerous deep neck infectionMost common in children < 5 years of age ♂ > ♀Overall incidence in the U.S. has increased. EtiologyPathogen: Streptococci (viridans Streptococci, S. pneumoniae), Staphylococci (including MRSA), Haemophilus influenzae, oral anaerobes(Peptostreptococci, Bacteroides species), often in a polymicrobial environment Direct or indirect causes: Contiguous or lymphatic spread from oral (most common) or upper respiratory tract infectionsLocal penetrating pharyngeal trauma (e.g., from small bones such as of fish or chicken, or medical instruments)Spread from other deep neck infections (nasopharynx, sinuses, adenoids) Clinical featuresFeatures of tonsillitis and trismus (minimal)Neck asymmetry with unilateral swelling of the posterior pharyngeal wall (possible fluctuance) → inability to extend neckTorticollisAnterior cervical lymphadenopathyRespiratory distress Infants may also present with lethargy, cough, poor intake, rhinorrhea, and agitation. DiagnosisContrast-enhanced CT: shows hypodense lesion in retropharyngeal space, soft-tissue swelling, peripheral ring enhancement, mass effectInitial step if in no signs of respiratory compromise Confirms diagnosis in patients with a suspicion of RPA and with a negative x-rayDetermine extent of infection to other spaces and presence of foreign bodiesDifferentiate between cellulitis and abscessGram stain and culture of aspirated abscess fluid and blood to identify causative pathogenLateral neck x-ray: shows a widened prevertebral (soft tissue) space (gas in the retropharyngeal space and lordosis) [16] Differential diagnosisOther deep neck infectionsTrauma Other causes of neck swelling or respiratory distress: anaphylaxis or angioedema, retropharyngeal tumorsOther causes of neck stiffness: meningitis, cervical spine osteomyelitis, dystonia TreatmentAirway management is always the first step if the patient has signs of respiratory distressHospitalization for all children and any patient with respiratory compromiseIV broad-spectrum antibiotics: empiric options include ampicillin-sulbactam or clindamycin. Needle aspiration or incision and drainage of abscess (surgical drainage) should be performed immediately in patients with a compromised airway or other life-threatening complications Complications Airway obstructionSpread of infection to carotid sheath (internal carotid artery erosion, jugular vein thrombophlebitis) and then mediastinum (acute necrotizing mediastinitis with widened mediastinum on chest x-ray ) Infection can spread and enter the skull base (epidural abscess) or the posterior mediastinum (pericarditis). Aspiration pneumoniaAtlantoaxial dislocationBacteremia and sepsis In patients with airway compromise, airway management should be performed before any other diagnostic or treatment measures!

Immunization schedule

Birth: Hep B 2 mos: Hep B, Rotavirus, DTaP, Hib, Pneumococcal, Poliovirus 4 mos: Rotavirus, DTaP, Hib, Pneum, Poliovirus 6 mos: Hep B, DTaP, Hib, Pneum, Poliovirus 12 mos: MMR, VAR, Hep A, Influenza, Hib 11-12 YEARS: Tdap, Meningococcal Diphtheria and tetanus toxoids, acellular pertussis (DTaP) 2,4,6,15m,Child,Teen,10 yrs, 27-36wks Preg Tdap at 27-36 weeks Rotavirus vaccine (RV) 2,4,6m Hepatitis B vaccine (HepB) B,2,6 Hemophilus influenza type b vaccine(Hib) 2,4,6, asplenia Pneumococcal conjugate (PCV13): 2,4,6,12 For all adults age ≥ 65with an immunocompromising condition, PCV13 vaccinefollowed by PPSV23vaccine at least 8 weekslater is recommende equential PCV13 and PPSV23 are also recommended for people age < 65 with certain high-risk conditions. Pneumococcal polysaccharide (PPSV23): HR over 2y Not lifelong Recommended for all adults ≥ 65 years Sequential PCV13 and PPSV23 are recommended for individuals age < 65 with certain high-riskconditions. For adults age < 65 who are current smokers or have a chronic medical condition, PPSV23vaccine alone is recommended. Inactivated poliovirus vaccine (IPV):2,4,6, child Influenza vaccine (IIV, LAIV) For 1 season; a yearly vaccineis recommended for all patients every flu season(Oct-April in northern hemisphere; May-Oct in southern hemisphere Hepatitis A vaccine (HepA) 2-dose series at 12-24 months (time between doses: 6-18 months) Human papillomavirus vaccine(HPV) 11yr Recommended for high-riskgroups, minimum age 9 years 3-doseseries Meningococcal conjugate 11yr Recommended for high-risk groups, minimum age 6 weeks for Hib-MenCY, 2 months for MenACWY-CRM and 9 months for MenACWY-D Booster dose at age 16 if first dose Repeat every 5 years in high-risk groups Meningococcal B vaccine MenB vaccine series (2 or 3 doses depending on the brand) may be administered to adolescents and young adults aged 16-23 years to provide short-termprotection against most strains of serogroup B meningococcal disease (clinical discretion); minimum age 10 years Repeat every 2-3 years in high-risk groups as long as the increased risk is present Measles, mumps, rubella vaccine(MMR) 12m,child Recommended for high-risk groups (before traveling outside the US, 1st dose 6 to11 months before departure; reimmunization with 1st dose at 12 to 15 months and 2nd dose 4 weekslater) Varicella vaccine (VAR) 12m, child

Yeasts PathogenicityUsually an opportunistic pathogenCan infect the skin, mucous membranes, or internal organs MorphologyDemonstrate budding cells and pseudomyceliumSingle yeast cells are 5-8 μm in size.Gram-positive staining

Candidaspecies Candida albicans is the most common Candida species worldwide and is almost exclusively found in humans. Vaginal yeast infection, balanitis Oral thrush Candida esophagitis Invasive candidiasis Local: ciclopirox, nystatin, clotrimazole, miconazole, ketoconazole Systemic: IV caspofungin or micafungin (echinocandins); alternatives include fluconazole or amphotericin B Cryptococcus neoformans Humans are infected via contaminated dust particles. Possesses a capsule, which can be visualized using India Ink Cryptococcal meningitis Cryptococcosis Amphotericin B plus flucytosine, followed by fluconazole → maintenance therapy with fluconazole for at least 12 mont Malassezia furfur Yellow-orange fluorescence under Wood lamp Particularly present in the infundibulum of the hair follicle Tinea versicolor Involved in the pathogenesis of seborrheic eczema Local: selenium sulfide lotion or shampoo; miconazole, ketoconazole, or terbinafine Systemic: fluconazole or itraconazole

Treatment of common fungal infections

Candidiasis Oropharyngeal: oral clotrimazole (troches) Esophageal: fluconazole Vaginal: topical miconazole Cutaneous: topical nystatin (powder) Systemic: IV amphotericin B (sometimes in combination with flucytosine) Aspergillosis Invasive aspergillosis: voriconazole (first-line), caspofungin , IV amphotericin B Cryptococcosis First 2 weeks: IV amphotericin B + flucytosine Afterwards (maintenance therapy): oral fluconazole Blastomycosis Histoplasmosis Coccidioidomycosis Sporotrichosis Oral itraconazole Severe cases: IV amphotericin B Tinea versicolor Topical ciclopirox Topical miconazole Selenium sulfide Dermatophytosis Topical azoles Oral itraconazole Oral griseofulvin Terbinafine: onychomycosis

Echinocandins

Caspofungin(IV) Anidulafungin(IV) Micafungin (IV) Inhibit synthesis of β-glucan (a component of the fungal cell wall) Invasive aspergillosis Invasive candidiasis (particularly biofilm-embedded candida ) Broad spectrum efficacy Only minimal distribution to the CSF Flushing Hypotension Hepatotoxicity Gastrointestinal upset Phlebitis/pain at injection site Fever, shivering

Vulvovaginitis Vulvovaginitis refers to a large variety of conditions that result in inflammation of the vulva and vagina. The causes may be infectious (e.g., bacterial vaginosis in most cases) or noninfectious. Physiologically, the normal vaginal flora (mainly lactobacilli) keeps pH levels of the vaginal fluids low, thus preventing the overgrowth of pathogenic and opportunistic organisms. Disruption of that flora (e.g., due to sexual intercourse) predisposes to infection and inflammation. Diagnosis of infectious vulvovaginitis is based on histology examination of vaginal discharge. Treatment consists of administration of antibiotics or antifungals (depending on the pathogen). Atrophic vaginitis is the most common non-infectious cause of vulvovaginitis and frequently affects elderly women after menopause as a result of decreased estrogen levels. The diagnosis is clinical and treatment includes application of topical estrogen creme.

Causes Common causes of infectious vulvovaginitis Bacterial vaginosisVaginal yeast infectionTrichomoniasis Other causes of infectious vulvovaginitis (see respective learning cards for more information) GonorrheaChlamydial genitourinary infectionEnterobius vermicularis (especially in prepubescent girls)Scabies ("seven-year itch")Pediculosis pubis ("crabs", pubic lice) Bacterial vaginosis Gardnerella vaginalis Grey/milky Fishy odor Metronidazole Clue cells Positive whiff test pH > 4.5 Trichomoniasis Trichomonas vaginalis Flagellated and motile Frothy, yellow-green Foul-smelling Metronidazole Treat sexual partner(s) Flagella on protozoa in smear test pH > 4.5 Vaginal yeast infection Candida albicans White, crumbly Odorless Topical azoles or nystatin Oral fluconazole Recent history of antibiotictreatment Pseudohyphae on KOH pH 4-4.5 Gonorrhea Neisseria gonorrhoeae Purulent, creamy Odorless Ceftriaxone IV/IM Treat sexual partner(s) Chlamydia infections Chlamydia trachomatisserotype D-K Purulent, bloody Odorless Azithromycin or doxycycline Treat sexual partner(s) Bacterial vulvovaginitis Bacterial vaginosis Epidemiology: most common vaginal infection in women (40-45% of all cases) Pathogen: Gardnerella vaginalis (a gram-variable rod) (Gram-variable) PathogenesisLower concentrations of Lactobacillus and overgrowth of Gardnerella vaginalis and other anaerobes, without vaginal epithelialinflammation due to absent immune responseSexual intercourse is the primary risk factor, but it is not considered an STDOther risk factors include intrauterine devices (IUDs), douching, and pregnancy Clinical featuresCommonly asymptomaticIncreased vaginal discharge, usually gray or milky with fishy odor Pruritus and pain are uncommon Diagnostics: vaginal discharge sample Amsel's criteria: 3 of 4 must apply to confirm diagnosis Whiff test : add 1-2 drops of 10% KOH to vaginal fluid → intensification of the fishy odorVaginal pH > 4.5No leukocytes visible on microscopyClue cells: vaginal epithelial cells covered with bacteria identified on wet mount preparationA sample of vaginal fluid/discharge is transferred to a slide and mixed with normal saline.The slide is then examined under a microscope. TreatmentFirst-line: oral metronidazoleAlternative: topical metronidazole or clindamycinOral probiotics Complications: infection of mother results in higher risk of preterm delivery Vaginal yeast infection (Vulvovaginal candidiasis) Epidemiology: second most common cause of vulvovaginitis (20-25% of all cases) Pathogen: primarily Candida albicans Pathogenesis: overgrowth of C. albicans precipitated by the following risk factors Pregnancy Immunodeficiency, both systemic (e.g., diabetes mellitus, HIV, immunosuppression) and local (e.g., topical corticosteroids)Antimicrobial treatment (e.g., after systemic antibiotic treatment) Clinical featuresWhite, crumbly, and sticky vaginal discharge that may appear like cottage cheese and is typically odorlessErythematous vulva and vaginaVaginal burning sensation, strong pruritus, dysuria, dyspareunia DiagnosticsPseudohyphae on wet mount with potassium hydroxide (KOH) Vaginal pH within normal range (4-4.5) TreatmentTopical azole (e.g., miconazole, clotrimazole)Alternatively: nystatin pessary (where available) or single-dose oral fluconazole Trichomoniasis Pathogen: Trichomonas vaginalis Anaerobic, motile protozoan with flagella Transmission: sexual Clinical featuresFoul-smelling, frothy, yellow-green, purulent dischargeVulvovaginal pruritus, burning sensation, dyspareunia, dysuria, strawberry cervix DiagnosisSaline wet mount of vaginal smear: protozoa with multiple flagella If wet mount is inconclusive → culture pH of vaginal discharge > 4.5 Treatment: oral metronidazole or tinidazole for patient and sexual partner(s) Noninfectious vulvovaginitis Atrophic vaginitis EtiologyLow estrogen levels (e.g., after menopause, bilateral oophorectomy, radio-/chemotherapy, immunological disorders)Atrophy of epithelium in vagina and vulva Clinical featuresDecreasing labial fat padVaginal soreness, drynessDyspareunia, burning sensation after sexDischarge, occasional spotting Commonly associated with receding pubic hair Diagnostics: primarily a clinical diagnosis, additional tests (e.g., pH test, wet mount) are often nonspecific Treatment: estrogen cream (topical) or tablets (systemic) Others May affect all age groups, but especially common in prepubescent girls Chemical irritants (e.g., soaps, shampoos) Allergic (e.g., to detergents; see extra information) Mechanical (e.g., clothing; see extra information) Vulvovaginitis in pediatric patients Vulvovaginitis is the most frequent gynecological disorder encountered in prepubertal children. Etiology: The most common cause is poor hygiene.Use of perfumed soaps and bubble bathsLocalized skin disordersForeign body in the genitourinary tract In some cases, sexual abuse Pathophysiology: Estrogen levels are lower in prepubescent girls, making the vulvar skin and vaginal mucosa very thin. This makes them more susceptible to vulvovaginitis of any cause. Clinical features: Vaginal discharge: often bloody, purulent, or foul-smellingPain in the lower abdomen and suprapubic regionIncreased urinary frequency, burning on urination, and dysuriaIn some cases, visible segment of a foreign body at the genital opening Diagnosis: If an infectious etiology is suspected, then appropriate Gram stain, culture, prep, DNA PCR, etc. should be conducted.Direct visualization of the foreign body, either on physical examination or by means of pelvic ultrasonography, plain pelvic radiography, vaginography, or MRI Treatment: In case of foreign body: removal of foreign body First line of treatment: warm saline irrigation of the vagina in an outpatient setting If irrigation fails, removal under general anesthesiaAntibiotics/antifungals are usually not needed if successful removal is achieved, as the vulvovaginitis would then spontaneously resolve.Topical or oral antibiotics/antifungalsConservative measures: improving hygiene, avoidance of tight clothing

HIV-associated CNS lesions Differential diagnosis of CNS lesions in HIV-positive patients with CD4+ T-cell count < 200/mm3:

Cerebral toxoplasmosisReactivation of a prior infection with T. gondiiMost common neurologic AIDS-defining conditionHeadacheFeverAltered mental statusSeizuresContrast CT: multiple ring-enhancing lesions predominantly in the basal gangliaCSF: pleocytosis, elevated proteinPyrimethamine, sulfadiazine, and leucovorin Primary CNS lymphoma (PCNSL)An extranodal non-hodgkin lymphomaAssociated with EBV infectionHeadacheFocal neurologic deficitsNeuropsychiatric symptoms (e.g., personality changes)Seizures (< 15%)Contrast CT: solitary ring-enhancing lesionCSF: EBV positiveBiopsy (confirmatory test)High dose methotrexatewith/without whole brain radiotherapy Oral/IV corticosteroids: after histological diagnosis; to control symptoms of raised ICP Cerebral abscessAbscess formation most commonly due to Staphylococcus, Streptococcus, Salmonella, Aspergillus, NocardiaLess common than cerebral toxoplasmosisand PCNSLDisseminated infectionFeverHeadacheSymptoms of elevated intracranial pressureNeurologic deficitsSeizuresContrast CT: focal intraparenchymal lesion with a central hypodense (necrotic) area and peripheral ring enhancementBiopsy (with CT-guided stereotactic aspiration): best confirmatory testEmpirical antibiotic therapy If size < 2.5 cm, history of symptoms < 1 week, and no signs of ICP → antibiotic therapywithout surgical drainage may be attemptedSurgical drainage + empirical antibiotics: if the above criteria are not met Progressive multifocal leukoencephalopathy(PML)Demyelinating disease of the CNS caused by reactivation of the JC virusRapidly progressive focal-neurologicdeficits (e.g., visual field defects, hemiparesis)Cognitive impairmentImpaired vigilance Contrast CT: disseminated, non-enhancing white matterlesions without mass effectCSF analysis: JC virusDNA on PCRSupportive therapy HIV-associated encephalopathy(AIDS dementia)Dissemination of HIV into the CNS (particularly in advanced HIV infection and/or untreated patients) Subcortical dementia (memory loss, depression, movement disorders) Progression to severe neurologic deficits (impaired vigilance, aphasia, gait disturbances)MRI: multiple subcortical hyperintense non-enhancinglesionsHistopathology: giant cells with multiple nuclei(formed through fusion of HIV-infected monocytes) Antiretroviral therapy (cART)Supportive therapy

Chloroquine and hydroxychloroquine

Chloroquine and hydroxychloroquine are drugs derived from the quinoline molecule. Both are used as antimalarial blood schizonticides, and hydroxychloroquine is also frequently used as an antirheumatic. Their mechanism of action is not entirely understood. However, despite their varying therapeutic dosage and toxicity, both drugs have similar clinical indications and side effects. One of their most serious side effects is retinal toxicity, referred to as 4AQ retinopathy or chloroquine retinopathy, which must be screened for in all cases of long-term use. Effects Widely-accepted mechanisms of action Anti-malarial action: the drugs accumulate in the parasite's food vacuole → inhibit polymerization of heme into hemozoin and form the heme-chloroquine complex, which is highly toxic to the schizont → lyse membranes and kill the parasiteAnti-rheumatoid action: these drugs interfere with "antigen processing" in macrophages and other antigen-presenting cells → decrease the formation of peptide-MHC protein complexes → down-regulate the immune response against autoantigenic peptides Side effects Visual disturbances: in cases of long-term use, regular ophthalmological exams are recommended Irreversible retinopathy: key fundoscopic feature is Bull's eye maculopathy Reversible corneal opacityBlurred visionPhotophobia Gastrointestinal: e.g., nausea with cramps (most common), anorexia, vomiting Neurologic: e.g., sensorineural deafness, tinnitus, cranial nerve palsies, and myasthenia-like muscle weakness Dermatologic: e.g., photosensitivity, pruritus, alopecia, bleaching of hair Indications Treatment and prophylaxis of malaria due to Plasmodium malariae, P. ovale, or susceptible strains of P. falciparum (not P. vivax) (see also antimalarial medication) Used in mild courses of the following rheumatic diseases: Rheumatoid arthritis (basic therapy)Systemic and discoid lupus erythematosus (without organ involvement) Porphyria cutanea tarda (in low doses)

Chorioamnionitis, neonatal infection, and omphalitis Chorioamnionitis is defined as an intrauterine infection of the fetal membranes and amniotic fluid caused by bacteria ascending from the vagina. The most common pathogens are Ureaplasma and Mycoplasma species. Infected women typically present with fever, purulentvaginal discharge, and malodorous amniotic fluid. The combination of maternal (> 120/min) and fetal tachycardia (> 160/min) is highly indicative of intrauterine infection, and the condition should be managed promptly with antibiotics, supportive care, and possibly early delivery. Chorioamnionitis, as well as colonization of the maternal genital tract with group B Streptococcus, may also be the cause of dangerous infections in the newborn. These include pneumonia, meningitis, and sepsis, and may be difficult to differentiate because symptoms in neonates are often nonspecific. Common findings include irritability, lethargy, temperature changes, dyspnea, and signs of cardiocirculatory distress (e.g., hypotension). If neonatal infection is suspected, diagnostic procedures should be initiated immediately to identify the pathogen and source of infection (e.g., blood and urine cultures). Management consists mainly of swift initiation of broad-spectrum empiric antibiotic therapy. Without proper treatment, systemic neonatal infections are associated with a high risk of complications and increased mortality rates. Newborns are also commonly affected by localized infections such as omphalitis, an infection of the umbilical stump. The condition is most often caused by Staphylococcus aureus and group A Streptococcus and occurs 3-9 days after delivery. Clinical features include localized inflammation, swelling, and purulent discharge, which may progress to complications like sepsis and necrotizing fasciitis if not treated adequately with antibiotics (e.g., ampicillin, gentamicin).

Chorioamnionitis Etiology Infection of the amniotic fluid, fetal membranes, and placenta Most commonly due to ascending cervicovaginal bacteria Common bacteria: Ureaplasma urealyticum (up to 50% of cases), Mycoplasma hominis (up to 30% of cases), Gardnerella vaginalis, bacteroides, group B Streptococcus, E. coli Risk factorsProlonged labor or premature rupture of membranes (PROM)Pathological bacterial colonization of vaginal tract (e.g., STDs, frequent UTIs)Iatrogenic: multiple digital vaginal exams, invasive procedures (e.g., amniocentesis) Symptoms MaternalFever (> 38 °C or > 100°F)Tachycardia > 120/minUterine tenderness, pelvic painMalodorous and purulent amniotic fluid, vaginal dischargePremature contractions, PROM Fetal tachycardia > 160/min in cardiotocography Diagnosis Chorioamnionitis is a clinical diagnosis (fever plus ≥ 1 additional symptom). Tests support or confirm diagnosis if the clinical presentation is ambiguous (e.g., in subclinical chorioamnionitis). Maternal blood tests: Leukocytosis > 15.000 cells/μL (∼ 70-90% of cases)↑ CRP Bacterial culturesUrogenital secretionsAmniotic fluid (most reliable, but rarely conducted) Group B Streptococcus screening: cervicovaginal and rectal swabs Management Maternal antibiotic therapyVaginal birth: IV ampicillin plus gentamicin (broad coverage)Cesarean birth: IV ampicillin and gentamicin, plus clindamycin (anaerobe coverage to minimize post-cesarean complications, e.g., endometritis) DeliverySwift delivery is generally indicated to minimize both maternal and fetal complications. Cesarean section is not generally indicated, but is often necessary because of obstetrical complications (e.g., insufficient contractions). For treatment of newborns, see "Neonatal infection" below. Complications MaternalUterine atony, postpartum hemorrhage, endometritisSeptic shock, DIC, venous thrombosis, pulmonary embolism, death Fetal/neonatalFetal death, premature birthAsphyxia, intraventricular hemorrhage, cerebral palsyNeonatal infection (see below) Neonatal infection and sepsis Etiology Early-onset infection/sepsis≤ 72 hours after delivery Common causes: chorioamnionitis, bacterial colonization of the maternal genital tract (pathogen transfer to the infant)Common pathogens: group B Streptococcus (GBS, Streptococcus agalactiae) and E. coli; less common are Listeria monocytogenes (see congenital listeriosis), Staphylococcus aureus, Enterococcus, and Haemophilus influenzae. Late-onset infection/sepsis> 72 hours after deliveryCommon causes: nosocomial infectionCommon pathogens: group B Streptococcus (GBS, Streptococcus agalactiae) and E. coli; less common are coagulase-negativeStaphylococcus, Staphylococcus aureus, Klebsiella, Pseudomonas Risk factorsMaternalFeverPROM, premature laborInfections (e.g., UTI)FetalPremature birth, low birth weight, low Apgar scoreDifficult deliveryAsphyxiaIntravascular catheter or nasal cannula (in late-onset sepsis) Streptococcus agalactiae and Escherichia coli are the most common causes of both early- and late-onset neonatal sepsis! Symptoms General presentation Nonspecific Irritability, lethargy, poor feeding Temperature changes (fever and hypothermia both possible) Cardiocirculatory: tachycardia, hypotension, poor perfusion, and delayed capillary refill > 3 sec Respiratory: tachypnea, dyspnea (e.g., expiratory grunting), apnea (more common in preterm infants) Skin tone: jaundiced and/or bluish-gray (indicates poor perfusion) Specific symptoms Neonatal meningitisOften no signs of meningism Early phase: general symptoms (see above), vomitingLate phase: bulging fontanelles, shrill crying, seizures, stupor Neonatal pneumoniaTachypnea with intercostal/sternal retractions and nasal flaringReduced oxygen saturation with cyanosis Diagnosis Blood cultures or urine culture for suspected UTIIn GBS sepsis: blood agar plate reveals β-hemolytic, gram positive cocci that enlarge the area of hemolysis formed by S aureus Blood testsLeukocytopenia or leukocytosis, thrombocytopenia↑ CRP Lumbar puncture: test cerebrospinal fluid for possible meningitis Chest x-ray: may reveal clear signs of pneumonia (e.g., segmental infiltrates) but more often nonspecific with diffuse opacities Management Supportive care (cardiopulmonary monitoring and support) Broad-spectrum antibiotics: IV ampicillin and gentamicinIndications: clinical suspicion, confirmed or suspected maternal infection (e.g., chorioamnionitis) Adapt therapy according to antibiogram results Prophylaxis for neonatal GBS infection IndicationMaternal GBS colonizationDetermined via culture of vaginal and rectal swabs, which are indicated between 35-37 weeks' gestationAnytime GBS bacteriuria occurs during pregnancy or if a previous newborn had a GBS infection The presence of risk factors (e.g., chorioamnionitis, fever, ↑ CRP, premature contractions, PROM) MedicationIntrapartum IV penicillin G or ampicillin (readminister every 4 hours until delivery)If previous mild penicillin reaction: IV cefazolinIf severe penicillin allergy: clindamycin Prognosis May cause septic shock within hours if treatment is inadequate (mortality rate up to 50%) The longer symptoms are present, the higher the risk of developing meningitis. Omphalitis Etiology Bacterial infection of the umbilical stump occurring 3-9 days after delivery Pathogens: Staphylococcus aureus, group A Streptococcus, E. coli, Klebsiella pneumoniaeClostridium tetani: common cause of omphalitis and neonatal tetanus in developing countries Risk factors: low birth weight, prolonged labor, maternal infection Symptoms Periumbilical redness, tenderness, swelling, and hardening Purulent discharge Signs of systemic infection (see "Neonatal infection" above) Diagnosis Generally a clinical diagnosis, although cultures should be conducted Bacterial cultures: pathogen identification and antibiogram (sample of discharge) In systemic infection: blood and cerebrospinal fluid cultures (detection of sepsis and meningitis) Management Broad-spectrum IV antibioticsAntistaphylococcal penicillin (e.g., ampicillin) plusAminoglycosides (e.g., gentamicin) Surgery: complete debridement if complications arise Complications Sepsis Necrotizing fasciitis and myonecrosis (infectious muscle involvement): rare; associated with high mortality rates Prevention Keep the navel dry (frequent diaper change) Observe general hygiene measures

Pyridone derivatives

Ciclopirox(topical) Not fully understood; disrupt DNA, RNA, and protein synthesis Tinea versicolor Dermatophytosis (e.g., onychomycosis) Seborrheic dermatitis of the scalp Broad spectrum efficacy Important contraindications: do not apply to eye or mucous membranes Facial edema Ventricular tachycardia Skin irritations Pruritus

Rhinitis Rhinitis usually refers to inflammation of the nasal mucosa as a result of a type 1 hypersensitivity reaction (allergic rhinitis) and/or upper respiratory tract infection (infectious rhinitis). Clinical manifestations of rhinitis include nasal congestion, sneezing, rhinorrhea, and post-nasal drip. Furthermore, patients with allergic rhinitis complain about itching eyes and exacerbation of symptoms in certain seasons or with exposure to various allergens (e.g., dust). Management of allergic rhinitis involves identifying and avoiding the causative allergen. Nasal decongestants such as oral antihistamines (e.g., cetirizine) and intranasal sympathomimetics (e.g., xylometazoline) are used for symptomatic relief. Intranasal glucocorticoids are also very effective in the management of allergic rhinitis but should be used judiciously. Certain rarer forms of rhinitis - such as vasomotor rhinitis - are not associated with an inflammatory process. Vasomotor rhinitis is caused by a number of autonomic and/or hormonal stimuli that increase blood flow to the nasal mucosa, resulting in nasal congestion and rhinorrhea. Treatment of vasomotor rhinitis primarily involves avoiding the causative stimulus. Because infectious rhinitis almost always simultaneously involves the sinuses (rhinosinusitis), it is discussed in the sinusitis learning card.

Classification Allergic rhinitis: an IgE-mediated process Non-allergic rhinitis: not the result of an IgE-mediated process Infectious rhinitisVasomotor rhinitis Allergic rhinitis Definition: acute or chronic rhinitis caused by exposure to an inhaled allergen EtiologyType I hypersensitivity reactionGenetic predisposition to atopy Clinical featuresRecurrent episodes of sneezing, nasal congestion, rhinorrhea, and post-nasal drip Itchy nose and throatPale, boggy nasal mucosa with hypertrophic turbinates, and/or nasal polyps may be seen in long-standing cases of allergic rhinitis. Cobblestone appearance of the posterior pharyngeal wallAssociated allergic conditions Allergic conjunctivitisAtopic dermatitis and/or bronchial asthmaLong-standing allergic rhinitis can predispose the patient to recurrent sinusitis and/or otitis media. Diagnostics RAST (radioallergosorbent test): measures serum concentrations of IgE antibodies against a specific allergenPrick and intradermal tests to identify the allergen TreatmentAvoid exposure to the putative allergen (e.g., allergen, dust).1st line: use one or more of the following drugs Intranasal spraysAntihistamines (e.g., azelastine) Decongestants (α1-sympathicomimetics such as phenylephrine, oxymetazoline, xylometazoline) Corticosteroids (e.g., budesonide, fluticasone) Sodium cromoglycate Ipratropium bromide Oral drugsAntihistamines (e.g., cetirizine, levocetirizine, loratadine) Decongestants (α1-sympathicomimetics such as phenylephrine and pseudoephedrine)Intranasal sympathomimetics should not be used for more than three days because of the risk of rebound nasal congestion (rhinitis medicamentosa)! Leukotriene receptor antagonists (e.g., monteleukast) 2nd line: controlled exposure to gradually increasing doses of the allergen in order to hyposensitize the IgE response (imunotherapy) 3rd line: resection of hypertrophic nasal turbinates to relieve nasal obstruction Vasomotor rhinitis Definition: Vasomotor rhinitis is a general term for rhinitis that is caused by an increase in blood flow to the nasal mucosa as a result of: Autonomic stimuli: ↓ sympathetic and/or ↑ parasympathetic activity Hormonal stimuli EtiologyMost often idiopathicDrug-induced rhinitis is caused by one of the following drugs: Antihypertensives (e.g., ACE inhibitors, propanolol)NSAIDsRhinitis medicamentosa: rebound nasal congestion that is seen upon discontinuing intranasal sympathomimetics (e.g., xylometazoline)Gustatory rhinitis: rhinitis that is associated with spicy food and/or alcohol Emotional stimuli (e.g., anxiety, excitement)Irritant odors (e.g., cigarette smoke, perfumes, car exhaust) Weather patterns (e.g. cold and dry air, changes in temperature and humidity) Honeymoon rhinitis: rhinitis associated with sexual activity Hormonal rhinitisRhinitis associated with pregnancy and the use of oral contraceptive pillsRhinitis associated with hypothyroidism Clinical featuresSneezing, nasal congestion, rhinorrhea, and post-nasal dripHypertrophic turbinates may be seen in long-standing cases of vasomotor rhinitis. Treatment: Address the underlying cause of rhinitis (e.g., discontinue the offending drug)Medical therapy Primary therapy: intranasal antihistamines (e.g., azelastine) and/or intranasal glucocorticoids (e.g., fluticasone)Adjunctive therapy: nasal decongestants (psedoephedrine) and intranasal instillation of hypertonic NaCl solution Surgical therapy Resection of hypertrophic nasal turbinates in order to relieve nasal obstruction Differential diagnoses Other conditions that may present with nasal congestion include: Nasal polyps Deviated nasal septum Adenoid hypertrophy (in case of children) Foreign nasal bodyEpidemiology: mostly young children (2-5 years)Etiology: organic (e.g., food items) or inorganic objects (e.g., pearls, stones, small toys) are inserted into the nose Clinical featuresUnilateral, foul smelling, purulent rhinorrhea Nasal obstructionEpistaxisDiagnosticsHeadlight or otoscopeFlexible fiberoptic endoscopy Treatment: removal through positive pressure techniques ; if this fails, extraction via endoscopy and anesthesia

Bacterial gastroenteritis Bacterial gastroenteritis is caused by a variety of organisms, including Campylobacter, Salmonella, Shigella, Yersinia, Vibrio cholerae, Staphylococcus aureus, diarrheagenic Escherichia coli, Clostridium difficile, Clostridium perfringens, and noncholera Vibrio species. Infection may be foodborne, fecal-oral, or involve direct or indirect animal transmission. Clinical features can be mild, manifesting as abdominal painand diarrhea, or severe, including vomiting and watery or inflammatory diarrhea, fever, and hypotension. Stool analysis may reveal leukocytes or blood in certain cases. Stool cultures may be considered in severe gastroenteritis. Bacterial gastroenteritis is usually self-limiting and only requires supportive therapy. However, antibiotics are indicated when supportive therapy does not suffice or in immunosuppressed patients. Adequate food and water hygiene is crucial for preventing disease.

Clinical featuresMild-moderate: abdominal pain, diarrheaSevere: tachycardia, hypotension, fever, bloody or profuse watery diarrhea, and metabolic acidosis Secretory diarrhea Enterotoxin or bacterial invasion shifts water and electrolyte excretion/absorption in proximal small intestine → watery diarrhea, vomiting WBC negative,No blood Bacillus cereus Rice ETEC Recent travel (e.g., Asia, Africa, the Middle East, Mexico, Central, and South America) Clostridium perfringens Undercooked meat and raw legumes Staphylococcus aureus Inadequately refrigerated food Vibrio cholerae Profuse secretory diarrhea Invasive diarrhea Pathogens penetrate the mucosa and invade the reticuloendothelial system of the distal small intestine→ enteric fever WBC positive (fecal mononuclear leukocytes) Blood may be present Yersinia Milk/pork;May manifest as pseudoappendicitis Salmonella typhi or paratyphi Recent travel (e.g., Asia, Africa, Central, and South America) Typically manifests in three stages: fever with relative bradycardia; rose-colored exanthem on the lower chest and abdomen; and hepatosplenomegaly Inflammatory diarrhea Bacteria or cytotoxins damage the colonic mucosa → blood in stool and fever WBC positive (fecal polymorphonuclear leukocytes) Blood present Campylobacter Most common bacterial organism pathogen responsible for foodborne gastroenteritis in the US EHEC Undercooked meat; most common association with hemolytic-uremic syndrome (HUS) Clostridium difficile Recent antibiotic use Shigella Second most common association with hemolytic-uremicsyndrome (HUS) NoncholeraVibrio species Shellfish Salmonella(non-typhoidal) Poultry/eggs Diagnosis: stool analysisLeukocytes, occult blood, and/or lactoferrin (best initial tests) Stool culture (confirmatory test): indicated in suspected invasive bacterial enteritis, severe illness, or fever (> 38.5 degrees), required hospitalization, or stool tests positive for leukocytes/occult blood/lactoferrinClostridium difficile toxin: if patient has a recent history of antibiotic useStool microscopy in certain cases (e.g., ova and parasites) Differential diagnosis: See "Differential diagnosis"in food-related diseases. TreatmentUsually self-limiting: supportive therapy (see diarrhea)Antibiotic therapy is not routinely indicated in bacterial gastroenteritis.Indications for antibiotic therapy Complicated diarrhea with high-grade fever and severe symptomsHigh-risk population group (e.g., infants, patients with comorbidities such as sickle cell disease)Confirmed C. difficile infection Contraindicated for EHEC! ComplicationsDehydration (most common; especially severe in shigellosis, cholera)MalnutritionPermanent carrier status PreventionFood and water hygieneReport diseases according to the CDC guidelines: salmonellosis, shigellosis, yersiniosis, cholera, shiga toxin-producing Escherichia coli (EHEC) colitis, non-cholera Vibrio species infections, vancomycin-resistant Staphylococcus aureus food poisoningCholera vaccination See also the overview of diarrhea and food poisoning. Campylobacter enteritis (campylobacteriosis) Pathogen Campylobacter jejuni, Campylobacter coliCurved, gram-negative, oxidase-positive rods with polar flagellaMost common pathogen responsible for foodborne gastroenteritis in the USHighly contagious TransmissionFecal-oralFoodborne (undercooked meat, and unpasteurized milk) and contaminated waterDirect contact with infected animals (cats and dogs)/animal products Incubation period: 2-4 days Clinical featuresDuration: up to a weekHigh fever, aches, dizzinessInflammatory (bloody) diarrhea (50% of cases)Severe abdominal pain may present as pseudoappendicitis or colitis Treatment: (in severe cases) macrolides (e.g., erythromycin or azithromycin) Complications (more common and severe in HIV-positive patients) Guillain-Barré syndromeReactive arthritisAcute abdomen: cholecystitis, pancreatitisBacteremia Salmonellosis (Salmonella gastroenteritis) Pathogen: Salmonella enterica serotype Enteritidis, Salmonella enterica serotype TyphimuriumGram-negative bacteria, obligate pathogenProduces hydrogen sulfideDoes not ferment lactose2nd most common pathogen responsible for bacterial foodborne gastroenteritis Transmission: foodborne (poultry, raw eggs, and milk) Incubation period: 0-3 days Clinical featuresDuration: 3-7 daysFever (usually resolves within 2 days), chills, headaches, myalgiaSevere vomiting and inflammatory (watery-bloody) diarrhea Treatment (antibiotic therapy in severe cases) Fluoroquinolones (e.g., ciprofloxacin)Alternative: TMP-SMX or cephalosporins (e.g., ceftriaxone), depending on the antimicrobial susceptibility test Antibiotic treatment prolongs fecal excretion of the pathogen; only indicated for systemic manifestations or diarrhea > 9/day Complications: (especially in immunocompromised patients, e.g., HIV) BacteremiaReactive arthritisSystemic disease: osteomyelitis, meningitis, myocarditis Special variant of salmonella infections: enteric fever (see typhoid fever) Shigellosis (bacillary dysentry) Pathogen: Shigella dysenteriae, Shigella flexneri, Shigella sonneiGram-negative rods, toxigenic bacteria→ Shiga toxinEnter colonic M cells via pinocytosis and travel from cell to cell via actin filaments → both facilitate evasion of the immune system TransmissionFecal-oral (especially a concern in areas with poor sanitation)Foodborne (unpasteurized milk products and raw, unwashed vegetables)Contaminated water Incubation period: 0-2 days Infectivity: highly contagious; very low infective dose possible (from 10 bacteria upwards) Clinical featuresDuration: 2-7 daysHigh-fever, tenesmusProfuse inflammatory, mucoid-bloody diarrhea Treatment: in severe cases, antibiotic therapy with fluoroquinolones or 3rd generation cephalosporins ComplicationsHUS Intestinal complications (e.g., toxic megacolon, colonic perforation, intestinal obstruction, proctitis, rectal prolapse) Febrile seizures Reactive arthritis Cholera Pathogen: Vibrio choleraeRare in developed countriesGram-negative, oxidase positive, curved bacterium with a single polar flagellum → produces cholera toxinCholera toxin stimulates adenylate cyclase via activation of Gs → increased cyclic AMP → increased ion secretion (mainly chloride) TransmissionFecal-oralUndercooked seafood or contaminated water (e.g., non-segregated drinking water and sewage systems) Incubation period: 0-2 days InfectivityAcid-labile (grows well in an alkaline medium) → High infective dose required (over 108 pathogens) Clinical featuresLow-grade fever, vomitingProfuse 'rice-water' stools Diagnosis: dipstick (rapid test; initial test) and stool culture (confirmatory) TreatmentUrgent fluid replacement Antibiotic therapy in severe cases: doxycycline; alternatively, erythromycin in children ComplicationsSevere dehydrationPneumonia may occur in children. Yersiniosis Pathogen: Yersinia enterocolitica, Yersinia pseudotuberculosisGram-negative, rod-shaped, pleomorphic bacterium; obligate pathogen TransmissionFoodborne (e.g., raw/undercooked pork, unpasteurized milk products)Contaminated waterDirect/indirect contact with infected animal (e.g., dogs, pigs, rodents, and their feces) Incubation period: 4-6 days Clinical featuresDuration: 1-46 daysLow-grade fever, vomitingInflammatory diarrhea (may be bloody in severe cases)Pseudoappendicitis → mesenteric lymphadenitis, particularly in the ileum, with typical signs of appendicitis Diagnosis: direct pathogen detection in culture or cold enrichment Treatment: in severe cases, antibiotic therapy with fluoroquinolones or 3rd generation cephalosporins (depends on susceptibility to the drug) Complications: particularly in patients with HLA-B27Reactive arthritisErythema nodosumAcute abdomen: appendicitis, bowel perforation, toxic megacolon, cholangitisBacteremia Clostridium perfringens enterocolitis Pathogen: Clostridium perfringensGram-positive, anaerobic, spore-forming rod-shaped bacterium → produce exotoxinsAlso causes gas gangrene Transmission: foodborne (undercooked or poorly refrigerated meat, legumes) Incubation period: 6-24 hours Clinical featuresDuration: < 24 hoursSevere abdominal crampingWatery diarrhea Diagnosis: toxin detection in stool cultures Treatment: supportive therapy only Complications: clostridial necrotizing enteritis Requires antibiotic therapy: penicillin, metronidazoleSurgery may be required for complicated and/or refractory disease (e.g., perforation) Noncholera Vibrio infection PathogenVibrio parahaemolyticus : non-lactose fermenter, gram-negative bacilliVibrio vulnificus: lactose fermenter, gram-negative bacilli TransmissionFoodborne (raw or undercooked shellfish)Wounds infected by contaminated sea water Incubation period: 12-52 hours Clinical featuresInflammatory diarrheaLow-grade fever, vomiting, abdominal painCellulitis, bullous skin lesions Treatment: in severe infection or wound infection, doxycycline or fluoroquinolone (e.g., ciprofloxacin) ComplicationsComplications of noncholera Vibrio infection are common in patients with high levels of free iron (e.g., liver disease, hemochromatosis) or immunocompromise.Septic shock and necrotizing fasciitis associated with Vibrio vulnificus infection (rare)

Additional non-gastrointestinal symptoms Food Poisoning

Clostridium botulinum Descending paralysisAdult botulism: inadequately canned foodsWound botulism: contaminated woundsInfant botulism: contaminated soil, honeyAdult botulism: 12-36 hoursWound botulism: 10 days(range 4-14 days)Infant botulism: 2-4 weeksAdults: respiratory support, antitoxinInfants: respiratory support, hyperimmune human serumDo not use antibiotics! Histamine fish poisoningFlushing, urticariaInadequately refrigerated fish 5 min to 1 hSupportiveAntihistamines Brucellosis (Brucellaspp.)Cyclical fever, arthralgiasUnpasteurized dairy productsContact with animals (e.g., hunter) 2-4 weeks (range: 5 days to 5 months) Doxycycline, rifampin, TMP-SMX Hepatitis A (Hepatitis A virus)Jaundice, commonly following initial GI symptoms Fecal-oral28 days (range 14-50 days) Supportive (generally self-limiting)Immune serum globulin VaccineVibrio vulnificusSepsis (especially in immunocompromised individuals)Cellulitis (from wound infections)Self-limiting gastroenteritisOysters, undercooked seafood1-7 daysDoxycycline + 3rd generation cephalosporins Salmonella typhi and paratyphiTyphoid fever (endemic in developing countries)Fecal-oralHours Fluoroquinolones , 3rd generation cephalosporins, azithromycinVaccine available but not effective

Adverse effects of immunization

Common adverse effectsAffects ∼ 1/3Usually begin within the first 48-72 hours after administration and last 1-2 daysSymptoms Local swelling, redness, and pain at the injection siteLow-grade feverHeadachesTirednessFlu-like symptomsLive attenuated vaccine: can cause mild form of the disease, usually appearing within 1-3 weeks of administration : usually caused by replication of the attenuated vaccine strain Rare adverse effectsSerious allergic reaction (generally < 1 per million doses) Live attenuated vaccine: attenuated course of the disease following immunization (e.g., vaccine-related measles) Vaccine injury (∼ 1/1,000,000): permanent injury from a vaccination or a vaccine-related complication (e.g., encephalopathy, seizures, brachial neuritis)

Skin and/or mucous membrane disinfection

Commonly used agents: alcohols (e.g., ethanol) , biguanides, phenols Mechanism of action: protein denaturation Advantage: rapid onset of action and well tolerated Disadvantages: Ineffective against bacterial spores and nonenveloped viruses)Decrease in antiseptic/disinfecting efficacy after contact with proteins (e.g., blood) Alternative: iodine preparations Surface disinfection Commonly used agents: aldehyde, halogens, ammonium compounds, oxidants (e.g., hydrogen peroxide) Mechanism of action: denaturation of various structures (proteins, nucleic acids, cell nuclei) Advantage: high efficacy also against spores and non-enveloped viruses, minimal decrease in antiseptic/disinfecting efficacy after contact with proteins (e.g., blood) Disadvantage: poorly tolerated Alternative: quarternary ammonium compounds Disadvantage: ineffective against gram-negative bacteria, mycobacteria, and mycoplasma; decreased efficacy after contact with proteins

Congenital TORCH infections

Congenital infections are caused by pathogens transmitted from mother to child during pregnancy (transplacentally) or delivery (peripartum). They can have a substantial negative impact on fetal and neonatal health. The acronym TORCH stands for the causative pathogens of congenital infections: Toxoplasma gondii, others (including Treponema pallidum, Listeria, Varicella, and parvovirus B19), rubella virus, cytomegalovirus (CMV), and herpes simplex virus (HSV). TORCH infections can cause spontaneous abortion, premature birth, and intrauterine growth restriction (IUGR). These infections can also cause abnormalities in the CNS, the skeletal and endocrine systems, and the complex organs (e.g., cardiac defects, vision and hearing loss). Prophylaxis is of great importance during pregnancy. Primary prevention includes vaccination for varicella and rubella (prior to pregnancy), hygiene measures (washing hands and avoiding certain foods), and screening for syphilis during pregnancy. Affected infants require regular follow-ups to monitor for hearing loss, ophthalmological abnormalities, and developmental delays. Several other pathogens can also be vertically transmitted during pregnancy and have detrimental effects on the fetus and/or newborn. These include HIV in pregnancy, perinatal hepatitis B, group B Streptococci, E. coli, gonococcal infections and chlamydial infections, West Nile virus, Zika virus, measles virus, enterovirus, and adenovirus. The pathogens are discussed in more detail in their respective learning cards

Fever Differential diagnoses by fever characteristics

Continuous fever Temperature permanently over 38°C (100.4°F); daily fluctuations < 1°C (1.8°F)Viral and bacterial infections (e.g., typhoid fever, lobar pneumonia) Remittent feverTemperature permanently over 38°C (100.4°F); daily fluctuations ≥ 1°C (1.8°F)Viral infections, acute bacterial endocarditis Intermittent feverHigh spike and rapid defervescence Pyogenic/focal infection, TB, juvenile idiopathic arthritis, infective endocarditis, malaria, leptospira, borrelia, schistosomiasis, lymphoma Relapsing feverDays of fever followed by an afebrileperiod of several days and then a relapse into additional days of fever, usually after 14-21 daysTick-borne relapsing fever and louse-borne relapsing fever Pel-EbsteinfeverFever lasting 1-2 weeks followed by an afebrile period of 1-2 weeksHodgkin lymphoma Periodical feverFever that recurs over months or years in the absence of associated viral or bacterial infection or malignancyPeriodic fever syndromes (e.g., familial Mediterranean fever, hyper-IgD syndrome) Still disease, Crohn disease, Behcet disease, relapsing malaria (tertian malaria, quartan malaria), drug fever, factitious fever Biphasic feverA fever that breaks and returns once moreDengue fever , leptospirosis Undulant fever Temperature rises gradually and falls like a wave over days to weeksBrucellosis Postoperative feverHas a highly variable course and many different causes; Wind, Water, Walk, Wound, Wonder drugs, Womb

Diarrhea Diarrheal diseases are very common and, in most cases, self-limiting. Diarrhea is defined either as the presence of more than three bowel movements per day, water content exceeding 75%, or a stool quantity of at least 200-250 g per day. Acute diarrhea lasts for no longer than 14 days and is typically caused by viral or bacterial infection or food poisoning. Chronic diarrhea is often caused by underlying gastrointestinal or endocrinological conditions, such as inflammatory bowel disease or hyperthyroidism. Further symptoms may include fever, bloody stools, abdominal pain, and nausea and vomiting in cases of gastroenteritis. Diagnostic tests for acute diarrhea are usually unnecessary, but they may include CBC, stool samples, or colonoscopy for severe or chronic cases. Most cases of diarrhea only require symptomatic treatment, such as oral rehydration, while severe cases may necessitate administration of antibiotics and hospitalization for IV fluid replacement.

Definition Diarrhea is present if one of the following criteria is fulfilled: Frequent defecation: ≥ three times per dayAltered stool consistency: water content > 75%Increase in stool quantity: more than 200-250 g per day Acute diarrhea: lasting ≤ 14 days Persistent diarrhea: lasting > 14 days Chronic diarrhea: lasting > 30 days ViralNorovirus infectionRotavirus infectionCytomegalovirus infection BacterialCampylobacter enteritisShigellosisSalmonellosisCholeraDiarrheagenic E. coli infectionYersiniosisAntibiotic-associated diarrhea (Clostridium difficile infection)Typhoid fever Mycobacterium avium-intracellulare ParasiticProtozoan GiardiasisAmebiasisCryptosporidiosis Helminth infections ToxocariasisEnterobiasisAscariasisTrichinosisTaenia infections (taeniasis)Hookworm infectionDiphyllobothriasis Foodborne toxinsS. aureus intoxicationBotulismBacillus cereus infection Food poisoningAflatoxinHistamine toxicityChemical contaminants (e.g., lead, cadmium, insecticides) GastrointestinalMalabsorptionCeliac diseaseLactose intolerancePancreatic insufficiencyDiabetic autonomic neuropathyInflammatory bowel disease: Crohn's disease, ulcerative colitisMicroscopic colitisIrritable bowel syndromeTumor/stenotic processes → paradoxical diarrhea EndocrinologicalCarcinoidHyperthyroidismAddison's diseaseGastrinoma MedicationQuinidine, cytotoxic agents Risk factors and disease transmission Transmission by direct contact and droplets Day care attendance, nursing home residency, hospitalization Contaminated food and water (see traveler's diarrhea) Animal exposure Exudative-inflammatory diarrheaDamage to the intestinal mucosa may cause cytokine-induced water hypersecretion, impair absorption of osmotically active substances or fat, or disrupt water and electrolyte absorption.Mucus, blood, and leukocytes present in stoolShigellosis, salmonellosis, enteroinvasive E. coli, enterohemorrhagic E. coli, campylobacteriosis, amebiasisUlcerative colitis, Crohn disease Secretory diarrheaActive secretion of water into the intestinal lumen via inhibition/activation of enzymes (e.g., ↑ cAMP activity)(Foodborne) infections (cholera, enterotoxigenic E. coli)Endocrine tumors (e.g., carcinoid tumors, gastrinoma)Impaired absorption of bile acids/saltsMalabsorption disorders or history of ileal resection Drugs (e.g., colchicine) Osmotic diarrheaWater is drawn into the intestinal lumen by poorly absorbed substances (e.g., salt, sugar, laxatives).Laxatives, citrate of magnesia Malabsorption, lactose intolerance Motor diarrheaRapid intestinal passage due to increased bowel movements HyperthyroidismCarcinoid syndromeDrugs (e.g., erythromycin) The loss of bicarbonate-rich fluid in severe diarrhea may cause non-anion gap metabolic acidosis! Clinical features Acute or chronic diarrhea (see "Definition" above) Further possible symptoms FeverAbdominal pain and crampingBlood in stoolNausea and vomiting in cases of gastroenteritisSigns of dehydration in severe cases Chronic cases: malnutrition and, in children, failure to thrive Disease courses can range from mild to severe with need of hospitalization. Traveler's diarrhea Infections which typically occur in patients with a history of recent travel Very common while traveling in Asian ("Delhi belly"), African, and Latin American countries ("Montezuma's Revenge") A major cause of diarrhea among children in developing countries May be exudative-inflammatory diarrhea or secretory diarrhea Most commonly caused by enterotoxigenic Escherichia coli (ETEC) Other pathogens: Campylobacter jejuni, Shigella spp., Salmonella spp., other E. coli strains (e.g., EAEC), protozoa (e.g., Giardia), viral diarrhea (norovirus, rotavirus, astrovirus) Factitious diarrhea Definition: self-induced diarrhea, usually by laxative abuse; often occurs in individuals with factitious disorders EpidemiologyMost prevalent in womenPatients are usually employed in the health field. History of multiple hospital admissions Clinical findings: chronic watery diarrhea without identifiable cause DiagnosisLaboratory tests: metabolic alkalosis, hypokalemia, hypermagnesemia Colonoscopy: may show melanosis coli in cases of anthraquinone abuse TreatmentCorrection of electrolyte disturbances and dehydrationReferral to psychotherapy Laxative abuse SubstancesBulking agent: flaxseedOsmotic laxatives: lactulose, macrogols (polyethylene glycol), magnesium sulfate, sodium sulfateDiphenolic laxatives: bisacodyl, sodium picosulfateAnthraquinones: senna, aloe vera, rhubarb Clinical featuresOsmotic diarrhea, meteorismDehydrationHypokalemia Melanosis coli: benign hyperpigmentation of the colonic mucosa caused by anthraquinone abuse Colonoscopy: dark brown pigmentation of the colon, interspersed with pale patches reflecting lymph folliclesBiopsy: lipofuscin-laden macrophages on PAS staining Diagnostics The workup for diarrhea includes a detailed patient history (e.g., recent travel), physical examination, and laboratory tests to assess severe cases. Laboratory tests Laboratory tests are usually not required in acute cases and are instead reserved for diagnosis of severe or chronic disease. IndicationsDiarrhea lasting > 4 daysHigh feverBlood in stoolsSuspicion of IBDImmunosuppression TestsCBC: may show anemia or leukocytosisStool samples: leukocytes; ova and parasitesStool culture Indications: suspected invasive bacterial enteritis, severe illness, or fever (> 38.5 degrees), required hospitalization, or stool tests positive for leukocytes/occult blood/lactoferrinC. difficile toxin assay Imaging Colonoscopy: in patients with chronic diarrhea without identifiable cause CT: if diverticulitis or IBD is suspected Treatment Since most cases of acute diarrhea are self-limited, treatment is mostly symptomatic, focusing on oral rehydration, and rarely requires medication. Rehydration (especially in children)Mild to moderate dehydration: oral rehydration therapy with electrolyte-containing fluids, e.g., apple juice or oral rehydration solution Severe cases: consider hospitalization; hydration with IV sodium chloride at 0.9% Antidiarrheal agents (e.g., loperamide): may be given in mild to moderate cases; should be avoided if there is fever or blood in stools (indicative of systemic disease) Antibiotics: are generally not indicated Treatment of the underlying condition in cases of chronic diarrhea

Affinity maturation

Definition: A process in which B cells interact with Th cells within the germinal center of secondary lymphoid tissue in order to secrete immunoglobulins with higher affinity for specific antigens. Mechanisms that lead to increased affinity Somatic hypermutation: Point mutations that create random alterations in the variable region of the antibody gene.Clonal selection: B cells that possess antibodies with higher affinity for the antigen have a survival advantage through positive selection → proliferate and predominate within the follicle.

Autoimmunity

Definition: Autoimmunity refers to an immune reaction against the body's own cells that occurs as a result of a loss of immunological tolerance. Presumed pathogenesis: Autoreactive B lymphocytes are physiologically eliminated in the bone marrow, spleen, or lymph nodes. T lymphocytes that attack the body's own cells are either sorted out in the thymus or undergo apoptosis in peripheral lymphoid tissues (e.g, lymph nodes, adenoids, Peyer's patches) due to a lack of stimulation. If the selection mechanisms fail, this results in the immune cells attacking the body's own cells, which leads to autoimmune inflammation. Epidemiology: Women have a disproportionately higher incidence of autoimmune diseases. CausesMostly idiopathicSometimes elicited by a previous infection (e.g., Guillain-Barré syndrome, rheumatic fever). The underlying pathomechanism is molecular mimicry Examples of a genetic predisposition HLA-B8, e.g., myasthenia gravis, Graves disease, Addison diseaseHLA‑B27, e.g., ankylosing spondylitis, reactive arthritis, psoriatic arthritis, ulcerative colitisHLA-DR4, e.g., rheumatoid arthritis, type 1 diabetes, pemphigus vulgaris, Addison diseaseHLA-DR3, e.g., type 1 diabetes, SLE, Hashimoto thyroiditis, Graves diseaseHLA-D2, e.g., SLE, Goodpasture syndrome, multiple sclerosisHLA‑DQ2/HLA-DQ8, e.g., gluten‑sensitive enteropathyHLA-DR5, e.g., Hashimoto thyroiditisHLA-A3, e.g., hemochromatosis ConsequencesThe presence of autoreactive B lymphocytes causes the production of irregular antibodies, which can trigger various diseases.It can also be used as a diagnostic tool (see the table below).In T-cell‑mediated autoimmune reactions, there are usually no detectable specific antibodies (e.g., in multiple sclerosis).

Live attenuated vaccines

Definition: Modified functioning virus or bacterium. The vaccine has the ability to replicate in the patient's body but does not cause disease. Mechanism of actionThe immune response is similar to infection with a "wild" pathogen.Specific B-cells against an antigen are formed. AdministrationOral vaccine or subcutaneous/intramuscular injection in children > 12 monthsNot indicated in children < 9 months (the rotavirus vaccine is an exception, which is first given at 6 weeks of age)Usually lifelong immunizationSecond dose usually recommended to "catch" non-responders (not as a boost)Multiple live vaccines can be given simultaneously, but if given at different times they should be at least 4 weeks apart to avoid possible interference.May be administered simultaneously with inactivated vaccines Available vaccinesMeaslesMumpsRubellaVaricella Zoster Yellow feverRotavirusInfluenza (intranasal)Oral polio, Sabin (no longer available in the US) BCG Typhus (oral) Special considerations: Live attenuated vaccines can theoretically revert back to their disease-causing form. However, this has only been observed in the case of the oral polio vaccine.

Immunologic memory

Definition: The ability of the immune system to recognize antigens from previous encounters and quickly and efficiently initiate an immune response to subsequent exposure to the antigen. ProcessInitial exposure to a potentially dangerous agent (antigen)Primary immune response: activation of B cells and T cells (see the sections on B cells and T cells above)Formation of memory B cells and memory T cellsMemory B cells: Specialized plasma cells that have the ability to persist for decades following the elimination of an antigen and produce high-affinityantibodies throughout their lifespan. [9][10]Undergo proliferation, somatic hypermutation, clonal selection, and antigen switching (see T cell‑dependent B cell activation) Arrested in their differentiation and persist in the marginal zone of follicles Memory T cells: Specialized T cells that persist following a primary immune response to an antigen and have the ability to elicit an immediate immune response to subsequent exposure to the same antigen. [10][11]Following a primary immune response, ∼ 90% of effector T cells die via apoptosis; a small fraction of the effector T cells survive to become memory T cells.Effector memory T cells (TEM cells, CCR7 negative cells): CD4+ T cells or CD8+ T cells that persist in the circulation and peripheral tissue. CD4+ TEM cells produce proinflammatory cytokines (e.g., IFN-γ, IL-4, IL-5).CD8+ TEM cells contain preformed perforin granules for immediate cytotoxicity.Central memory T cells (CCR7 positive cells): Persist in secondary lymphoid tissue and are able to differentiate into effector memory T cells upon activation. Subsequent immune response: Re-exposure to the antigen activates the memory cells. Memory B cells secrete high-affinity antibodies and accelerate the secondary immune response to the antigen.Memory T cells mature to TEM cells and trigger an immediate release of cytokines or cytotoxicity.Repeated exposure to the antigen leads to more efficient immune responses.

Bacillary angiomatosis

Definition: a skin condition occurring in immunocompromised patients (especially patients with AIDS and CD4 count < 100 cells/μL) that is characterized by vascular proliferation, resulting in lesions on the skin and possibly in other organs (GI tract, respiratory tract) Etiology: Bartonella bacteria (primarily Bartonella henselae or Bartonella quintana ) Clinical featuresCutaneous lesions: solitary or multiple, red, flesh-colored or colorless papules and nodules that bleed easilyConstitutional symptoms: fever, chills, malaise, anorexia DiagnosticsBiopsy of affected tissue (definitive diagnosis)Vascular proliferationThe Warthin-Starry stain is used to visualize bacilli.Neutrophilic infiltrate Differential diagnosisKaposi's sarcomaCherry angiomaHemangiomaDermatofibromaPyogenic granuloma Treatment: erythromycin or doxycycline Prevention: avoid cat scratches

Kaposi sarcoma

Definition: malignant, multifocal, highly vascularized tumor caused by the human herpesvirus 8 (HHV8 ) Classification: HIV-associated Kaposi sarcoma Clinical featuresMultiple cutaneous or visceral, elevated tumors with rapid growthInitial manifestation on skin and mucosae (especially face/oral cavity and chest) Over time, organ involvement is possible. If the gastrointestinal tract is involved: abdominal pain and diarrhea, possibly hemorrhage and bowel obstruction if severe DiagnosticsSkin biopsy: spindle-shaped cells, leukocyte infiltration, and angiogenesis.Chest x-ray, sonography of the abdomen and lymph nodes TreatmentTreatment of the underlying disease → antiretroviral treatment in HIV patientsSymptomatic therapy: Local: intralesional administration of vinblastine or radiation therapySystemic: pegylated liposomal doxorubicin or liposomal daunorubicin Prognosis: very variable

Fever of unknown origin (FUO)

Definition: temperature elevation > 38.3°C (101°F) lasting ≥ 3 weeks without a definitive diagnosis despite thorough clinical investigation Infections and cancer account for the majority of cases of FUO! ClassificationClassical FUO Criteria: according to the definition + present at ≥ 3 outpatient visits or ≥ 3 days in hospitalCauses: infection, autoimmune disease, and malignant neoplasmNosocomial FUOCriteria: new temperature elevation > 38.3°C (101°F) in patients who have been admitted to the hospital at least 24 hours ago present at ≥ 3 days of evaluation Causes: surgery, medications, intravascular devices, TVT, pulmonary embolism, Clostridium difficile enterocolitis, sinusitisHIV-associated FUOCriteria: according to the definition but lasting > 4 weeks for outpatients and > 3 days for inpatients with confirmed HIV infectionCauses: CMV, Pneumocystis pneumonia, Mycobacterium avium-intracellulare, Kaposi sarcoma, and lymphoma Diagnostic approachThe patient history should be taken and physical examination should be performed several times as the inflammatory process develops.The pattern of fever should be documented and analyzed.History should include: Contact with animalsTravel historyDiet historyImmunosuppressionFamily historySocial and sexual historyOccupational historyDrugs and medicationsSpecific investigations should be guided by physical findings and clinical suspicion.If there are no diagnostic clues, the following tests should be performed: CBC with differential ESR and C-reactive protein Electrolytes Liver function tests At least three sequential blood cultures Urine culture Urinalysis PPD test Chest X-ray If there are no findings from the tests above, abdominal and chest CT should be performed. Patients with a negative workup generally have a favorable prognosis, with resolution of fever over time.

T cell subtypes Rule of 8: MHC I x CD 8 = 8. MHC II x CD 4 = 8.

Differentiated T cells express specific T-cell receptors that allow them to recognize antigens presented by MHC molecules on the surface of antigen-presenting cells (e.g., macrophages). General T cell markers: CD3, CD28, TCR Surface proteins determine T cell function. CD4+ -Th1 cells Fight intracellular pathogens Macrophages Cytotoxic T cellsNK cellsB cells → production of IgGInfections with intracellular pathogens (e.g., Mycobacteria, Salmonella)IL-12 receptor deficiencyType I diabetes, rheumatoid arthritis, multiple sclerosis CXCR3CCR5 -Th2 cells Fight extracellular parasites Eosinophils Mast cells Basophils B cells → production of IgE Helminth infections Type 1 hypersensitivity (asthma, allergic rhinitis) CRTH2CCR4CCR3 -Th17 cells Fight extracellular parasites Neutrophils Hyper IgE syndrome -Follicular helper T (TFH) cells Support B cells in lymphoid follicles B cell isotype switching and antibodyproduction in the follicles Autoimmune diseases CCR6+CCR4 Treg cells Regulate T cells Promote immune self-tolerance Prevent formation of autoantibodies Effector T cells IPEX syndrome CD3 CD4 CD25 FOXP3 CD8+Mature cytotoxic T cellsRecognize and kill virus-infectedor neoplastic cells MacrophagesHIV, hepatitis B Adult T cell lymphoma All T cells carry specific membrane-bound marker proteins that distinguish them from other lymphocytes. These general T-cell markers are CD3, CD28(which binds to B7 during T-cell activation) and the T-cell receptor.. The two major T cell types are the cytotoxic T cells (CD8+) and T-helper cells (CD4+, CD40L+, CXCR4/CCR5+).. Subpopulations within the CD4+ subset have been identified by the cytokines they secrete or their surface markers (the following list is not exhaustive).

T cell effects

Direct cell lysis or induction of apoptosis via perforin and proteases from cytotoxic T cells (CD8+)Activated via antigen presentation by MHC class I receptors Induce apoptosis of virus-infected or malignant cellsRelease granules that contain perforin, granzyme B, granulysinRelease cytokines (including IFN‑γ, TNF-β, and TNF‑α) → macrophage activationClinical relevance: involved in organ rejection, induce apoptosis of donor graft cells Cellular‑mediated response via Th1 cell (CD4+)Activated via antigen presentation by MHC class II receptorsImmune response to intracellular pathogens (viruses, intracellular bacteria)Release cytokines (including IFN‑γ, IL‑2, and TNF‑α) → cytokines stimulate macrophages (positive feedback) and CD8+ cytotoxic T cells IFN‑γ, IL-2, and TNF‑α induce granuloma formation against foreign bodies that cannot be eliminated by the immune cells.Clinical relevance: Tuberculosis in HIV infection Cellular‑mediated response via Th2 cell (CD4+)Activated via antigen presentation by MHC class II receptorsImmune response to extracellular pathogens (bacteria, parasites)Release cytokines (including IL-4, IL-5, IL-13) which stimulate eosinophils, basophils and mast cells

Measles Measles (Rubeola) is a highly infectious disease that is caused by a paramyxovirus. There are two phases of disease: a catarrhal (prodromal) stage and an exanthem stage. The catarrhal stage is characterized by a fever with conjunctivitis, coryza, cough, and pathognomonic Koplik spots on the buccal mucosa. The sudden development of a high fever, malaise, and exanthem represents the next phase. The exanthem stage is typically characterized by an erythematousmaculopapular rash that originates behind the ears and spreads to the rest of the body towards the feet. Infection is usually self-limiting and followed by lifelong immunity. Disease management includes vitamin A supplementation, symptomatic treatment, and possible post-exposure prophylaxis (PEP). Measles causes transient immunosuppression and may lead to serious complications such as encephalitis, otitis, or pneumonia. A rare but lethal late complication of measles is subacute sclerosing panencephalitis (SSPE), which may also affect immunocompetent individuals. Vaccination against measles (active immunization) is administered in association with the mumps and rubella (MMR) vaccine; the first dose is recommended between the ages of 12-15 months and the second dose between 4-6 years of age or at least 28 daysafter the first dose. The prognosis is good in uncomplicated cases; newborns and immunocompromised patients are more likely to suffer from severe complications.

Distribution: Measles typically occurs in regions with low vaccination rates and in developing countries. Peak incidence: < 12 months of age Infectivity: ∼ 90%; highly contagious 5 days before and up to 4 days after the onset of exanthem Pathogen: Morbillivirus = RNA virus of the Paramyxoviridae family Route of transmission: direct contact with or inhalation of virus-containing droplets Incubation period Duration: ∼ 2 weeks after infection Prodromal stage (catarrhal stage) Duration: lasts ∼ 4-7 days PresentationCoryza, Cough, and Conjunctivitis (the "3 Cs") Fever Koplik spots Pathognomonic enanthem of the buccal mucosa Tiny white or bluish-gray spots, resembling "grains of sand", on an irregular erythematous background Exanthem stage Duration: appears 1-2 days after enanthem and lasts ∼ 7 days PresentationHigh fever, malaise Generalized lymphadenopathyErythematous maculopapular, blanching, partially confluent exanthem Usually begin in the face, frequently behind the ears along the hairlineDisseminates to the rest of the body towards the feet (palm and sole involvement is rare)The rash begins to fade after ∼ 5 days of onset; leaving a brown discoloration and desquamation in severely affected areas Recovery stage The cough may persist for another week and it may be the last remaining symptom. Diagnostics Measles should be suspected in a patient with typical clinical findings. Laboratory tests are always necessary to confirm the diagnosis. CBC: ↓ leukocytes, ↓ platelets SerologyGold standard: detection of Measles-specific immunoglobulin M (IgM) antibodies IgG antibodies Identification of pathogenDirect virus detection via reverse-transcriptase polymerase chain reaction (RT-PCR) possible Differential diagnoses of pediatric rashes Scarlet fever Fine erythematous, maculopapular, blanching exanthem Usually begins in the neck region; disseminates to the head, trunk, and extremitiesDistinct appearance in the groin and bends of the joints Pastia's linesBrown discoloration and desquamation of the skin during the second to fourth week of infection Early symptoms: sudden onset with high fever Exanthem stage (within 48 hours following disease onset) Typical red flushed appearance of the cheeks with perioral pallorRed tongue with papillaryhyperplasia → "strawberry tongue"Tonsillopharyngitis Rubella Pink maculopapular, non-confluentexanthem Begins at the head, primarily behind the ears → extends to the trunk and extremitiesTransient; symptoms usually disappear within 3 days General health primarily unaffected; mild disease Suboccipital and post-auricularlymphadenopathy Forchheimer sign: pin-pointenanthem of the soft palate Fifth disease(erythema infectiosum) Maculopapular, initially confluentexanthem → adopts a lace-likeand reticular appearance over time Initially typical red flushed appearance of the cheeks with perioral pallor; "slapped cheek" appearance; spreads to extremities and trunk Mild pruritus in 50% of cases Becomes more pronounced after exposure to sunlight or heatExanthemfades after ∼5-8 days; may be recurrent for several months following the initial infectionGeneral health primarily unaffected (mild disease) Arthritis Roseola infantum(exanthem subitum) Rose-pinkmaculopapular, patchy, blanching exanthemOriginates on the trunk; may spread to face and extremitiesDevelops as the feversubsidesFrequently observed from only several hours to a maximum of 3 days Initial sudden high fever for 3-5 days(three-day fever); otherwise good general condition Nagayama spots: A papularenanthem may be occasionally observed on the uvula and soft palate Followed by a sudden decrease in temperaturewith the development of a rapidly spreading exanthem(exanthem subitum) Chickenpox(Varicella) Vesicular rash on an erythematousbackground; simultaneous occurrence of various stages of rash ("starry sky"appearance): papules, vesicles, crusted papules and hypopigmented healed lesions Rash begins on the trunk, scalp, face and proximallimbsInvolve hands, feet and mucous membranesSevere pruritusExanthemfades after ∼1 week Prodromepossible but not typical (1-2 days prior to the onset of exanthem) FeverHeadacheand muscle or joint pain Associated oropharyngeal and urogenital ulcers Hand, foot, and mouth disease Tender macules and vesicular rash, especially affecting the feet and hands, and sometimes the buttocks and groin areas Rarely generalizedExanthemfades after ∼4 days Poor general condition Highly contagious In most cases,begins with stomatitis and enanthem: involve the tongue, buccal mucosa and hard palate; the vesicleserode leaving behind an erythematousbase Fever Almost always self‑limiting Measles Treatment Symptomatic treatment Vitamin A supplementation PEP in patients without prior vaccination (→ see "Prevention" below) In immunosuppressed patients and severe cases of measles: administration of immunoglobulin Complications Complications are likely to occur when the fever does not subside after a few days from the onset of the exanthem! Bacterial superinfection: otitis media, pneumonia, laryngotracheitis Gastroenteritis (Viral) giant-cell pneumonia Acute encephalitis, often with permanent neurological deficits Frequency: ∼ 1:1000Develops within days of infectionAcute disseminated encephalomyelitis may develop within weeks Subacute sclerosing panencephalitis (SSPE): a lethal, generalized, demyelinating inflammation of the brain caused by persistent measles virus infectionEpidemiology: very rare Primarily affects males between 8 and 11 years old Usually develops at least 7 years after measlesThree clinical stagesDementia Epilepsy and myoclonus Decerebration (increased tone, vegetative state, coma) Diagnosis Electroencephalography: paroxysmal delta waves (very slow, 1-3/s), periodic sharp and slow wave complexesCerebrospinal fluid: elevated anti-measles antibody titer (IgG) Prognosis The prognosis of measles infection is good in uncomplicated cases. Fatal courses are more likely in newborns and immunocompromised patients. The fatality rate in developing countries is high due to secondary bacterial infections mmunization Vaccine: live, attenuated virus in combination with the mumps and rubella (MMR) vaccine and possibly varicella(MMRV) vaccine Primary immunizationTwo vaccinations during childhood → see immunization scheduleIn adults born after 1957 with unknown immunization or incomplete status PEP Indication: In negative or indeterminate serology Active immunization : Immunocompetent patients after direct exposurePassive immunization Vulnerable, chronically ill, and immunocompromised patients Further measures for individuals with contactPersons with close contact to infected individuals should avoid communal facilities. Not required for: immunization, postexposure prophylaxis, or following prior infection Reporting regulations Measles is a notifiable disease. Cases should be reported within 24 hours to the CDC or National Center for Immunization and Respiratory Diseases (NCIRD).

Malaria Malaria is a potentially life‑threatening tropical disease caused by Plasmodium parasites, which are transmitted through the bite of an infected female Anophelesmosquito. The clinical presentation and prognosis of the disease depend on the Plasmodium species. Malaria has an incubation period of 7-42 days and may present with relatively unspecific symptoms like fever, nausea, and vomiting. Therefore, it is often misdiagnosed. Clinically suspected cases are confirmed by direct parasite detection in a blood smear. Patients are treated with antimalarial drugs (e.g., chloroquine, quinine), some of which may also be used as a prophylaxis during trips to endemic regions. However, the most important preventive measure is adequate protection against the Anopheles mosquito (e.g., mosquito nets, repellents, protective clothing, etc.). Malaria is a notifiable disease and should be suspected in all patients with fever and a history of travel to an endemic region.

DistributionMost cases of malaria occur in tropical Africa (West and Central Africa).Transmission also occurs in other tropical and subtropical regions such as Asia (e.g., India, Thailand, Indonesia), and Latin America (e.g., Brazil, Colombia) Pathogen: PlasmodiaEukaryotic parasites (belonging to the Sporozoa group)For different species, see the table below. Vector: the female Anopheles mosquito Host: humans Partial resistance against malariaCarriers of sickle‑cell mutation Other hemoglobinopathies (e.g., thalassemia, Hb C) Infection with malaria subsequently leads to the development of specific Plasmodium antibodies that result in partial immunity for a limited amount of time (less than a year) Plasmodium vivax Plasmodium ovale Tertian malaria (usually less severe) Every 48 hoursPlasmodium malariaeQuartan malaria (usually less severe)Every 72 hoursPlasmodium falciparumFalciparum malaria (most severe form; also known as malignant tertian malaria)Irregular Plasmodium knowlesi Quotidian malariaIrregular Life cycle of Plasmodium (simplified) Asexual development in humans Transmission of Plasmodium sporozoites via Anopheles mosquito bite → sporozoites travel through the bloodstream to the liver of the host Liver: sporozoites enter hepatocytes → sporozoites multiply asexually → schizonts are formed containing thousands of merozoites → release of merozoites into the bloodstream Circulatory system → two possible outcomes: Merozoites enter erythrocytes → maturation to trophozoites → red cell schizonts are formed containing thousands of merozoites → release of merozoitesinto the bloodstream (which causes fever and other manifestations of malaria) → penetration of erythrocytes recurs Merozoites enter erythrocytes → differentiation into gametocytes (male or female) Sexual development in female Anopheles mosquito A mosquito bites an infected human and ingests gametocytes → gametocytes mature within the mosquito intestines → sporozoites are formed and these migrate to the salivary glands → transmission of sporozoites to humans via mosquito bite Developmental stages of Plasmodium in RBCs Immature trophozoite: thick, dark purple ring‑shaped inclusions (similar to signet ring cell carcinoma) With Plasmodium falciparum: fine rings Mature trophozoite: ameboid rings With Plasmodium falciparum: finer rings in comparison to immature trophozoites Immature schizont: irregular round, ameboid, almost filling the entire erythrocyteWith Plasmodium falciparum: hardly detectable in the blood Mature schizont: conglomerate of 6-24 merozoites (round with central darkening), which develops from an immature schizont With Plasmodium falciparum: hardly detectable in the blood Gametocytes Macrogamete: mature female (sexual) form, visible as a round structure filling almost the entire erythrocyte Microgamete: mature male (sexual) form, visible as a round structure within the erythrocyte. In comparison to macrogametes, it is smaller and has a brighter nucleus. Clinical features Incubation: 7-42 daysRelapse in P. ovale or P. vivax infectionFollowing the successful treatment of tertian malaria, some Plasmodium forms (hypnozoites) may persist within the liver and cause reinfection after lying dormant for months or even years. Course: tertian and quartan malaria are associated with less severe symptoms, the involvement of fewer organs (rarely CNS or gastrointestinal symptoms), and a markedly lower risk of severe malaria. Flu‑like symptoms High feverTertian malaria: periodic fever spikes every 48 hrsQuartan malaria: periodic fever spikes every 72 hrsFalciparum malaria (malignant tertian malaria): irregular fever spikes without a noticeable rhythmDiaphoresis (sweating) Weakness, paleness, dizziness Increased bleeding risk → in severe cases, disseminated intravascular coagulation may occur. Gastrointestinal: diarrhea, abdominal pain, nausea, and vomiting Liver: hepatosplenomegaly, discrete jaundice Severe malaria: can lead to severe organ dysfunction Most commonly a result of falciparum malariaKidneys: flank pain, oliguria, hemoglobinuriaCerebral: hallucinations, confusion, impaired consciousness, or even comaCardiopulmonary: heart failure, pulmonary edema, shock History: recent or distant travel to regions where malaria is endemic CBCHemolytic anemia: ↓ Hb, ↓ haptoglobin, ↑ LDH, ↑ indirect bilirubin, ↑ reticulocytes Thrombocytopenia Possibly leukocytopenia Blood smear: confirms suspected cases by visualizing parasites within RBCs Best initial test: thick blood smear (high sensitivity); detects the presence of parasites. Confirmatory testing: thin blood smearLower sensitivity than thick blood smear, but higher specificityParasites are visible within red blood cells since the morphology of erythrocytes is preserved.Allows determination of Plasmodium speciesEvaluation of parasite and erythrocyte morphology Schüffner granules with P. vivax and P. ovale Rapid diagnostic tests (RDTs) Determination of specific malaria antigens, e.g., HRP2, pLDH, and aldolaseBenefits: quick determination of malaria infection in areas lacking high‑quality malaria microscopyAll RDT results should always be confirmed via microscopy (if available). Serological testsNot appropriate for acute diagnosis of malaria because antibodies are undetectable for 1-2 weeksPositive serological results indicate past contact with Plasmodium P. vivax, P. ovale (chloroquine‑sensitive) Chloroquine OR hydroxychloroquine + Primaquine: to eradicate hypnozoites of P. vivax and P. ovale and prevent relapse P. vivax (chloroquine‑resistant) quinine sulfate plus doxycycline or tetracycline, or, atovaquone-proguanil, or artemether-lumefantrine, or mefloquine. Quartan malaria Treatment of choice: chloroquine or hydroxychloroquine Falciparum malaria Uncomplicated falciparum malariaChloroquine‑sensitive Chloroquine OR hydroxychloroquineChloroquine‑resistantArtemether-lumefantrineOR Atovaquone‑proguanilOR Quinine PLUS doxycyclineOR Quinine PLUS tetracyclineOR Quinine PLUS clindamycinOR Mefloquine Severe falciparum malariaAll regionsArtesunate followed by artemether/lumefantrine OR Quinidine PLUS doxycyclineOR Quinidine PLUS tetracyclineOR Quinidine PLUS clindamycinIntensive care and supportive therapy (lowering fever, avoiding hypoglycemia) are essential. Plasmodium falciparum and, more recently, Plasmodium vivax are increasingly resistant to chloroquine. Chloroquine or hydroxychloroquine Irreversible retinopathy! CNS: agitation, anxiety, confusion Gastrointestinal discomfort PrimaquineHemolytic crisis in G6PD deficiency MefloquineCNS: dizziness, confusion, nightmares, hallucinations, seizuresRashGastrointestinal discomfort Atovaquone-proguanilGastrointestinal discomfortQuinineCNS: headache, mental status alteredGastrointestinal discomfortFever, flushingDoxycycline or tetracyclinePhotosensitivityNephro- and hepatotoxicityDamage to mucous membranes (these antibiotics should be taken with a lot of water) Artemether-lumefantrineGastrointestinal discomfortProlonged QT intervalQuinidinePalpitations, angina pectorisCNS: dizziness, fatigue, headacheRashGastrointestinal discomfortArtesunateHemolytic crisis in G6PD deficiency Mosquito bite prevention Avoid exposureExercise particular caution during peak biting periods Mosquito nets Protective clothing (covering most of the skin, light colors)Mosquito repellent, such as DEET (N,N-diethyl-meta-toluamide) Mosquito controlReduce breeding sites (e.g., eliminate pools of water, optimize plant watering)Insecticide spraying Malaria prophylaxis Should be initiated before traveling to regions with a high risk of malaria: e.g., tropical Africa, Asia, and Latin America Drug of choice is based on the area Areas with P. falciparumIf chloroquine-resistant P. falciparum (most malaria endemic regions): atovaquone-proguanil, doxycycline, mefloquineIf chloroquine-sensitive P. falciparum: chloroquineAreas without P. falciparum (some areas of Central/South America, Mexico, China, South Korea): primaquine Agents that are safe during pregnancy: chloroquine, mefloquine Prophylactic medication cannot prevent infection but suppresses the clinical course and symptoms by killing the parasite before it can cause a severe infection. There is no prophylactic medication that provides protection against all potential parasites. Standby emergency treatment IndicationTraveling to endemic regions with a medium to high risk of malariaDepending on the risk, either prophylactic or standby emergency treatment may be recommended (when in doubt: prophylactic medication). DrugsAtovaquone-proguanilArtemether-lumefantrine(Chloroquine) Obligation to report Report all laboratory‑confirmed cases of malaria to the local or state health department.

Monobactams

Drug: IV aztreonam Clinical use: intrinsic beta-lactamase resistanceVery effective against gram-negative bacilli only (the opposite of vancomycin), including nosocomial PseudomonasAlternative for penicillin-allergic patients Alternative to aminoglycosides for patients with renal insufficiencyBroad-spectrum coverage in combination with vancomycin or clindamycinSynergistic with aminoglycosides Adverse effects: gastrointestinal upset

Tetracyclines

Drugs Oral or IV tetracyclineOral doxycyclineOral demeclocycline Oral or IV minocycline Mechanism of actionInhibits bacterial protein synthesis by blocking incoming aminoacyl-tRNA from binding to the ribosome acceptor site.Bacteriostatic CNS penetration: poor Route of eliminationRenal elimination Doxycycline: only GI elimination Clinical useAtypical bacteria such as Borrelia, Mycoplasma, Rickettsia, Anaplasma, Ehrlichia, Chlamydia, Ureaplasma, Vibrio cholerae Acne Adverse effectsHepatotoxicityDeposition in bones and teeth → discoloration of teeth and inhibition of bone growth in childrenDamage to mucous membranes (e.g., esophagitis) Photosensitivity: UV light is absorbed by the drug, which releases energy to the surrounding area and damages exposed areasDegraded tetracyclines associated with Fanconi syndrome ContraindicationsChildren < 8 yearsPregnancyBreastfeeding womenRenal failure (except doxycycline)Hepatic failure (relative contraindication)

Glycopeptides

Drugs: Oral or IV vancomycin Mechanism of actionInhibits cell wall synthesis by binding the terminal D-ala-D-ala moiety of cell-wall precursor peptides, therefore only effective against gram-positivebacteria.Vancomycin is bactericidal. CNS penetration: only when meninges are inflamed Route of elimination: renal Clinical use: especially effective against multidrug-resistant organismsBroad-spectrum coverage against gram-positive bacteria only Methicillin-resistant Staphylococcus aureus (MRSA)S. epidermidisEnterococciClostridium difficile Adverse effectsNephrotoxicity Ototoxicity/vestibular toxicity Rapid infusions are associated with anaphylactoid reactions ("red man syndrome" or "red neck syndrome") ThrombophlebitisNeutropenia ContraindicationsPregnancy (relative contraindication)

Amphenicols

Drugs: chloramphenicol Mechanism of actionInhibits bacterial protein synthesis by blocking peptidyl transferase at the 50S subunitBacteriostatic CNS penetration: good Route of elimination: renal elimination Clinical use Meningitis caused by H. influenzae, N. meningitidis, and/or S. pneumoniaRickettsia (Rocky Mountain spotted fever) Adverse effectsDose-dependent bone-marrow suppression: anemia, leukopenia, thrombocytopeniaAplastic anemiaGray baby syndrome (in infants ): cyanosis, vomiting, flaccidity, hypothermia, shock ContraindicationsInfancyLast trimester of pregnancyHepatic failure (relative contraindication)

Lincosamides

Drugs: clindamycin Clindamycin is indicated for anaerobes above the diaphragm and metronidazole treats anaerobes below it! Mechanism of actionInhibits bacterial protein synthesis by binding the 50S subunit of the bacterial ribosome and inhibiting peptide translocationBacteriostatic CNS penetration: poor Route of elimination: both renal and biliary Clinical use Anaerobes (e.g., Clostridium, Bacteroides) Aspiration pneumoniaLung abscessesPartially effective against gram-positive aerobes (MRSA) Babesiosis Adverse effectsGI upsetPseudomembranous colitisFeverCross-resistance with macrolides ContraindicationsPregnancy (relative contraindication)

Lipopeptides

Drugs: daptomycin Mechanism of actionIncorporation of potassium ion-channels into the cell membrane of pathogens, leading to rapid membrane depolarization→ Inhibition of intracellular synthesis of DNA, RNA, and proteins. Bactericidal CNS penetration: poor Route of elimination: renal Clinical useGram-positive aerobesHowever, daptomycin only has limited efficacy against Enterococci. MRSA (except for pneumonia as it is bound and inactivated by surfactant)Vancomycin-resistant Enterococci (VRE) Adverse effectsReversible myopathyRhabdomyolysisAllergic pneumonitis

Epoxides

Drugs: fosfomycin Mechanism of actionInhibits cell wall synthesis by inhibiting the formation of N-acetylmuramic acid (a component of bacterial cell wall)Bactericidal CNS penetration: only when meninges are inflamed Route of elimination: renal elimination Clinical use: women with uncomplicated urinary tract infections (e.g., cystitis) Adverse effects: mild electrolyte imbalances (e.g., hypernatremia, hypokalemia), diarrhea

Oxazolidinones

Drugs: linezolid Mechanism of actionInhibition of bacterial protein synthesis by binding at the 50S subunit of the bacterial ribosome BacteriostaticAdditionally bactericidal only against streptococci CNS penetration: good Route of elimination: both biliary and renal elimination Clinical use: gram-positive resistant bacteria (VRE, MRSA) Adverse effectsBone marrow suppression (especially thrombocytopenia)Peripheral neuropathyGI upsetSerotonin syndrome ContraindicationsConcurrent use with monoamine oxidase inhibitors (MAOI) and selective serotonin reuptake inhibitors (SSRIs)

Nitrofurans

Drugs: nitrofurantoin Mechanism of actionNonspecific binding to bacterial ribosomal proteins → impaired metabolism, impaired protein, DNA, and RNA synthesisBactericidal Route of elimination: mostly renal Clinical use: treatment of and/or prophylaxis against lower urinary tract infections (e.g., urethritis, cystitis) Adverse effectsGastrointestinal side effectsReversible peripheral neuropathyPulmonary fibrosisTriggers hemolytic anemia in G6PD-deficient patients ContraindicationsRenal injury Breastfeeding women

Glycylcyclines

Drugs: tigecycline Mechanism of actionA glycylcycline that inhibits bacterial protein synthesis by blocking peptidyl transferase at the 30S subunitBacteriostatic CNS penetration: poor Route of elimination: mostly biliary Clinical useGram-positive aerobes MRSAAnaerobesPartially effective against gram-negative aerobes Atypical bacteria: Borrelia, Mycoplasma, Rickettsia, Chlamydia Adverse effectsGI upsetHepatotoxicityDeposition in bones and teeth Damage to mucous membranes (these antibiotics should be taken with a lot of water)Photosensitivity ContraindicationsPregnancyHepatic failure (relative contraindication)Should be used with caution for children < 8 years and lactating women

Aminoglycosides

DrugsIM or IV gentamicinIV or IM amikacinIV or IM tobramycinIV or IM streptomycinOral neomycin Mechanism of actionInhibits bacterial protein synthesis by binding to the 30S subunit of the bacterial ribosome Damage to the cell wallBactericidalSynergistic effect when combined with beta-lactam antibiotics: Beta-lactams inhibit cell wall synthesis → facilitate entry of aminoglycoside drugs into the cytoplasm CNS penetration: poor Route of elimination: renal Clinical useSevere gram-negative bacilli infectionsNot effective against anaerobes Neomycin, which is not absorbed systemically, is administered orally to prepare the gut for bowel surgery.Streptomycin: Mycobacterium tuberculosis, M. avium-intracellulare Adverse effectsNephrotoxicity Ototoxicity and vestibulotoxicity (impaired hearing and balance) Neuromuscular blockade ContraindicationsMyasthenia gravis, botulismRenal failure (relative contraindication)Pregnancy (relative contraindication) Streptomycin is absolutely contraindicated during pregnancy Mechanism of antibiotics resistance: Secreted bacterial enzymes inact

Carbapenems

DrugsIV imipenem (+ cilastatin) IV meropenemIV ertapenemIV doripenem Clinical use: broad-spectrum antib iotics with intrinsic beta-lactamase resistanceGram-positive cocci Gram-negative bacilliAnaerobes Adverse effects: considered a "last resort" drug because of its significant adverse effects Secondary fungal infectionsCan lower seizure threshold (especially imipenem)Gastrointestinal upsetRashThrombophlebitis

Polymyxins

DrugsIV or IM polymyxin BIV or IM polymyxin E (colistin) Mechanism of action A cationic detergent molecule the disrupts cell wall membranesBinds to and inactivates endotoxinsBactericidal CNS penetration: poor Route of elimination: mostly renal Clinical useTopical antibioticsSystemically against severe gram-negative infections including Pseudomonas, Acinetobacter, and species of EnterobacteriaceaPolymyxins are not effective against gram-positive organisms Adverse effects (severe) NephrotoxicityNeurotoxicityUrticaria, eosinophilia, and/or anaphylactoid reactions ContraindicationsRenal failure (relative contraindication) NOTES

Sulfonamides and trimethoprim

DrugsOral or IV cotrimoxazole (TMP/SMX) = trimethoprim (TMP) + sulfamethoxazole (SMX)Oral sulfisoxazole Oral sulfadiazine + pyrimethamine Trimethoprim (TMP) Treats Marrow Poorly. Mechanism of actionInhibition of bacterial folic acid synthesis TMP inhibits dihydrofolate reductase (DHFR), a key enzyme in purine synthesis DHFR reduces dihydrofolic acid to tetrahydrofolic acid (THF), using NADPHTHF can subsequently be converted to methylene-THFMethylene-THF is an important cofactor for thymidylate synthetase, which catalyzes the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP)Both SMX and TMP are bacteriostatic, but become bactericidal when combined CNS penetration: good Route of elimination: primarily renal Clinical useSMX Gram-positive bacteriaGram-negative bacteriaSimple urinary tract infections (UTIs)NocardiaChlamydiaTMP/SMXShigellaSalmonellaRecurring UTIsProphylaxis and treatment of P. jiroveciiProphylaxis of toxoplasmosis Adverse effectsSMX Aplastic anemia and pancytopeniaHyperkalemiaRash Gastrointestinal distressPhotosensitivityNephrotoxicity (especially tubulointerstitial nephritis) Kernicterus in infancyTriggers hemolytic anemia in G6PD-deficient patientsDisplaces albumin-binding drugs (e.g., warfarin)TMP: may be alleviated by leucovorin rescue Megaloblastic anemiaLeukopenia/granulocytopeniaHyperkalemia, particularly in HIV-positive patients Artificially increased creatinine (despite unchanged GFR) ContraindicationsLast trimester of pregnancyBreastfeeding women

Macrolides

DrugsOral or IV erythromycinOral or IV azithromycin Oral clarithromycin Mechanism of actionInhibits bacterial protein synthesis by blocking translocation; binds to the 23S ribosomal RNA molecule of the 50S subunit Bacteriostatic CNS penetration: poor Route of elimination: biliary Clinical useAtypical pneumoniaMycoplasma pneumoniaLegionella pneumophilaChlamydophila pneumoniaeUpper respiratory infectionsSTIs caused by Chlamydia (including chancroid)Gram-positive cocci Bordetella pertussisNeisseriaErythromycin: gastroparesis (e.g., resulting from diabetes mellitus) Mycobacterium Azithromycin: treatment and prophylaxis of avium complex infection Adverse effectsIncreased intestinal motility → GI discomfort QT-interval prolongation Acute cholestatic hepatitisEosinophiliaRashCYP3A4 inhibition ContraindicationsPregnancy Erythromycin is relatively contraindicated in hepatic failure.

Nitroimidazoles GET GAP on the Metro! (Giardia, Entamoeba, Trichomonas, Gardnerella, Anaerobes (Clostridium, Bacteroides), H. Pylori → Metronidazole)

DrugsOral or IV metronidazole Mechanism of actionCreates free radicals within the cell, which leads to DNA-strand breaks Bactericidal CNS penetration: good Route of elimination: renal Clinical useCertain protozoa (Entamoeba, Giardia histolytica, Trichomonas)Anaerobes (e.g., Clostridium, Bacteroides) Facultative anaerobesGardnerella vaginalisHelicobacter pylori as part of a triple therapy regimenAdverse effectsNeurotoxicity (e.g., headache) Disulfiram-like reaction when consumed with alcohol (flushing, tachycardia, hypotension) Nitroimidazoles inhibit acetaldehyde dehydrogenase → accumulation of acetaldehyde → immediate hangover-like symptoms Metallic taste Contraindications Breastfeeding women Hepatic failure (relative contraindication)

Fluoroquinolones

DrugsOral: norfloxacin, moxifloxacin, gemifloxacinOral or IV ciprofloxacin, ofloxacin, levofloxacin Mechanism of actionInhibition of prokaryotic topoisomerase II (DNA gyrase) and topoisomerase IVBactericidal CNS penetration: good Route of eliminationPrimarily renalMoxifloxacin undergoes biliary excretionAbsorption is reduced when coadministered with polyvalent cations (e.g. magnesium, calcium, or iron) Clinical useGram-negative bacilli causing urinary and GI infectionsGenital pathogens Neisseria gonorrhoeae, Chlamydia trachomatis, Ureaplasma urealyticumCiprofloxacin is effective against PseudomonasPneumonia Certain forms of atypical pneumonia (e.g., Legionella, Mycoplasma, and Chlamydophila pneumoniae)Also effective against anaerobesGemifloxacin is highly potent against penicillin-resistant pneumococci. Adverse effectsIn children: potential damage to growing cartilage; reversible arthropathyMuscle ache, tendinitis, tendon rupture (especially the Achilles tendon) Hyperglycemia/hypoglycemia Peripheral neuropathyCan lower the seizure thresholdQT prolongation PhotosensitivityGI upset Contraindications< 18 yearsPregnancyBreastfeeding womenEpilepsy, stroke, CNS lesions/inflammationQT prolongationRenal failure (relative contraindication)Hepatic failure (relative contraindication) Mechanisms of resistanceBacterial mutations can occur in genes that mediate: DNA gyrase and topoisomerase IV enzymesCell wall permeabilityEfflux pumps

Rotavirus infection Rotaviruses are a common cause of viral gastroenteritis in infants and young children and are transmitted via the fecal-oral route. After a short incubation periodof one to three days, patients present with vomiting, watery diarrhea, high-grade fever, and malaise. Diagnosis is established through antigen detection in stool. Treatment is supportive and mainly involves replacing fluids, although infection may be prevented altogether by vaccination.

Epidemiology A major cause of severe diarrhea in infants and children in the US (especially during the winter) Leading cause of severe diarrhea among infants and children worldwide, although all age groups are susceptible to infection. Most commonly occurs in daycare centers and kindergarten Etiology Pathogen: Rotavirus is a nonenveloped, segmented, double-stranded RNA reovirus. Transmission: fecal-oral route (e.g., by contact with hands, objects, food, water contaminated with the virus) Pathophysiology Mucosal damage and villous atrophy in the gastrointestinal tract impair absorption of sodium and loss potassium → nonbloody, watery diarrhea Clinical features Incubation period: 1-3 days Fever, malaise Abdominal pain Vomiting and watery diarrheaCan be severe: > 10 loose, watery stools within 24 hoursUsually lasts 3-7 days Mild to severe dehydration: See clinical signs of significant dehydration. Diagnostics Antigen detection in stool via enzyme immunoassay (EIA): a highly sensitive test that can be performed quickly and easily Differential diagnoses Norovirus infection Bacterial gastroenteritis Food poisoning Treatment SupportiveOral rehydrationIV fluids in patients with severe dehydration revention VaccinationRotavirus vaccination (a live attenuated vaccine) is recommended for all infants unless there is a contraindication. Contraindications include:Infants with severe combined immunodeficiency (SCID)Infants with a history of intussusception: rotavirus vaccine is associated with intussusceptionIndividuals with a history of severe allergic reaction after exposure to a previous rotavirus vaccine or to any of its componentsImmunization schedule Dose 1: 2 months of age Dose 2: 4 months of ageDose 3: 6 months of age (if required)

Rubella Rubella, or German measles, is an infectious disease that is caused by the rubella virus. Since the introduction of the measles, mumps, and rubella (MMR) vaccine, it is a relatively rare condition. Rubella is transmitted via airborne droplets and has a mild clinical course. The clinical presentation begins with nonspecific flu-like symptoms and post-auricularand/or suboccipital lymphadenopathy. An exanthem phase may overlap or follow; this phase is characterized by a rash that typically starts behind the ears and progresses distally, developing into a generalized maculopapular rash. Rubella is usually self-limiting and involves symptomatic treatment. Immunization with a live, attenuated vaccine, in association with the measles and mumps vaccine, is highly recommended. The first dose is administered between 12-15 months of age and the second dose between 4-6 years of age. Complications of infection during pregnancy may cause congenital rubella syndrome with severe malformations (e.g., hearing loss, cataracts, heart defects, intellectual disabilities).

Epidemiology A rare disease in the US following the implementation of the MMR vaccine Etiology PathogenRubella virus, an RNA virus of the family TogaviridaeHumans are the only hosts. Route of transmissionAirborne droplets or transplacentalInfectivity: 7 days prior to and 7 days following the appearance of an exanthem Low infectivity and virulence Clinical features Patients with rubella infection are asymptomatic in ∼ 50% of cases. Young children have a far milder course than older children and adults; the latter group often presents with prodromal symptoms, other systemic complaints (e.g., arthritis), and a longer duration of infection. Prodromal phase Incubation period: 2-3 weeks after infection Duration: 1-5 days FindingsPost-auricular and suboccipital lymphadenopathy and occasionally splenomegalyMild and nonspecific symptoms such as low-grade fever, mild sore throat, conjunctivitis, headache, and aching jointsForchheimer sign: enanthem of the soft palate Exanthem phase Duration: lasts 2-3 days FindingsFine, nonconfluent, pink maculopapular rash Begins at the head, primarily behind the ears, extends to the trunk and extremities, sparing palms and solesRash may be itchy in adultsPolyarthritis Diagnostics Although rubella infection may be considered a clinical diagnosis, laboratory confirmation is necessary for certain patient groups to assess the risk of complications such as e.g., congenital rubella in pregnant women or encephalitis. Laboratory testsCBC: leukocytopenia with relative lymphocytosis and increased plasma cellsConfirmatory test: serologyDetection of IgM antibodies ≥ 4-fold increase in IgG titer For prenatal and congenital diagnosis → see congenital rubella syndrome. Symptomatic treatmentSevere pruritis: antihistaminesSevere polyarthritis: rest and nonsteroidal anti-inflammatory drugs For treatment of congenital rubella syndrome and seronegative women following exposure to rubella virus, see congenital rubella syndrome Complications Thrombocytopenic purpura Rubella during pregnancy (TORCH infection): congenital rubella syndrome Rare: rubella encephalitis, bronchitis, otitis, myocarditis, pericarditis Prognosis The disease usually has a benign course and the exanthem disappears rapidly. Joint pain may persist for several weeks; arthralgia may persist up to a month in adults. Immunization Live attenuated virus that is administered in combination with the measles and mumps vaccine (see immunization schedule) Two vaccinations are recommended because of potential non-responders (5%): First dose: 12-15 months of ageSecond dose: 4-6 years of age or at least 28 days following the first dose. Check vaccination status ELISA (preferred method), latex agglutination, hemagglutination inhibition, or immunofluorescent antibody assay.A titer of ≥ 1:32 indicates immunity to rubella. Women of child-bearing age, without vaccination or unclear vaccine status, should be vaccinated prior to pregnancy! Precautions during infection Patients with rubella infection should be isolated for 7 days after the onset of the rash. Precautions regarding droplet transmission should be taken. Reporting requirements Rubella cases should be reported to the CDC or to the National Center for Immunization and Respiratory Diseases (NCIRD) within 24 hours of confirmation.

Unilateral cervical lymphadenopathy Unilateral cervical lymphadenopathy (UCL) refers to the localized swollen lymph node(s) on one side of the neck and is usually associated with bacterial infections. Acute UCL is most commonly caused by S. aureus and Streptococcus species, while chronic UCL is the result of tuberculous or nontuberculous mycobacterial infections. UCL is most often seen in children under 5 years of age and typically affects the submandibular or deep cervical lymph nodes. In acute UCL, these are often tender, warm, and mobile, and may be accompanied by feverand malaise. Chronically inflamed lymph nodes are typically nontender and become indurated and matted over time. Laboratory tests for inflammatory markers, serology, and bacterial cultures from pus samples are used to monitor the course of the disease and detect pathogens. Biopsies may be needed to rule out malignant etiologies. Most cases of UCL are treated empirically with antibiotics such as clindamycin to cover the most common pathogens. Surgical incision and drainage may be indicated in cases with suppurative lymphadenitis.

Epidemiology Age: most common in children < 5 years Etiology Most commonly in response to bacterial infections (up to > 80% of cases)AcuteS. aureusGroup A Streptococcus (e.g., Streptococcus pyogenes)Oral anaerobes Group B Streptococcus (GBS) Francisella tularensis Subacute or chronicNontuberculous mycobacteria (e.g., M. avium-intracellulare and M. scrofulaceum) Mycobacterium tuberculosis Bartonella henselae Toxoplasma gondii Kawasaki disease, PFAPA syndrome Malignancy: leukemia, lymphoma, metastasis of oral mucosa cancers Connective tissue disorders (e.g., juvenile rheumatoid arthritis, systemic lupus erythematosus) Clinical features Usually child appears healthy; possibly history of preceding upper respiratory tract infection or dental conditions May have symptoms of an underlying infection (e.g., fever, malaise, tachycardia) Lymph node involvement Most common: submandibular or deep cervical nodes (> 80% of cases)3-6 cm large, tender, warm, possibly erythematous skin over the nodeLymph nodes may become fluctuant and form an abscess over time or become indurated. Chronic cases: insidious enlargement; nontender, immobile, matted nodes; may form to sinus tracts Diagnostics Laboratory testsCBC, ESR, CRP Serology: if tularemia or cat-scratch disease is suspectedTuberculin test in chronic cases Bacterial cultureBlood culture Throat swab and oral swab Gram stain and culture of material obtained from fine needle aspiration Histopathological evaluation of sample obtained by excisional biopsy Imaging: ultrasound exam or CT scanning Differential diagnoses UnilateralCongenital neck masses Submandibular abscessThyroid tumorsMetastatic cancer BilateralViral infections: cytomegalovirus, Epstein-Barr virusStreptococcal pharyngitisToxoplasmosis Treatment AntibioticsConservative management by active observation for disease regression may be recommendable for children with no fever and non-tender lymphadenopathy.All other cases are treated empirically with oral antibiotics for 10-14 days (e.g., clindamycin)In cases of MRSA or clindamycin-resistance: TMP-SMX, doxycycline Supportive therapy: antipyretics, analgesics, warm compresses Surgical measures: incision and drainage of large abscesses

Infectious mononucleosis Infectious mononucleosis (IM), also called "mono" or the "kissing disease", is an acute condition caused by the Epstein-Barr virus (EBV). The disease is highly contagious and spreads via bodily secretions, especially saliva. Infection frequently goes unnoticed in children; mainly adolescents and young adults exhibit symptoms. Symptomatic individuals typically first experience fever, malaise, and fatigue, which is later accompanied by acute pharyngitis, tonsillitis, lymphadenopathy, and/or splenomegaly lasting up to a month. IM is also sometimes associated with a measles-like exanthem, especially in individuals who are falsely diagnosed with bacterial tonsillitis and given ampicillin or amoxicillin. To avoid misdiagnosis, suspected cases are confirmed with a heterophile antibody test (monospot test), or in some cases, positive serology. Patients exhibit lymphocytosis, often with atypical T lymphocytes on a peripheral smear. IM is treated symptomatically, as it is usually self-limiting. Although complications are rare, IM is associated with atraumatic splenic rupture due to splenomegaly and multiple malignancies (e.g., Hodgkin's lymphoma, Burkitt lymphoma).

Epidemiology Approx. 90-95% of adults are EBV-seropositive worldwide. Peak incidence of symptomatic disease: 15-24 years Incidence: 500/100,000 per year in the US Etiology Pathogen: Epstein-Barr virus (EBV), also called human herpes virus 4 (HHV-4) Transmission: Infectious mononucleosis is highly contagious and spreads via bodily secretions, especially saliva → "kissing disease" Pathophysiology EBV infects B lymphocytes in mucosal epithelium (e.g., oropharynx, cervix) via the CD21 receptor → infected B lymphocytes induce a humoral (B-cell) as well as a cellular (T-cell) immune response → an increased concentration of atypical lymphocytes in the bloodstream, which are CD8+ cytotoxic T cells that fight infected B lymphocytes Clinical features Incubation period: 4-8 weeks Clinical courseSymptoms typically occur in adolescents and young adults and last for 2-4 weeks.Young children are often asymptomatic. Splenomegaly (50% of cases), fever, fatigue, malaise Pharyngitis and/or tonsillitis (reddened, enlarged tonsils covered in pus); palatal petechiae Bilateral cervical lymphadenopathy (especially posterior) that may become generalized and can, in severe cases, lead to airway obstruction Abdominal pain Possibly hepatomegaly and jaundice Maculopapular rash (similar to measles): caused by the infection itself in about 5% of cases, but is generally 50% associated with the administration of aminopenicillin (e.g., ampicillin or amoxicillin) Diagnostics Clinical suspicion of IM is confirmed via antibody testing. Monospot test: detects heterophile antibodies produced in response to EBV infection using RBCs from horses; specificity of ∼ 100%, sensitivity of 85% Laboratory analysis: elevated LDH and liver transaminases Peripheral smear: lymphocytosis with > 10% atypical lymphocytes (in some cases, up to 90%) Serology: indicated if IM is suspected but a monospot test is negative Anti-viral capsid antigen antibodies (anti-VCA) Anti-VCA IgM: appears early and vanishes ∼ 3 months after infectionAnti-VCA IgG: appears after 2-4 weeks and persists for life Pathology Histopathology of lymph nodes Reactive follicular hyperplasia due to increased activation of B lymphocytes Paracortical expansion through numerous, large immunoblasts (B and T cells), later expanding throughout the entire node Atypical Reed-Sternberg-like cells may be observed, which is why the disease is sometimes mistaken for Hodgkin's disease. Differential diagnoses Mononucleosis-like syndromesStreptococcal pharyngitisAcute HIV infectionCMV infection (CMV mononucleosis)Viral hepatitisToxoplasmosis Diphtheria Acute leukemia Treatment Symptomatic therapy Avoid physical activity that may trigger splenic rupture (e.g., contact sports) for at least 3 weeks after the onset of symptoms. Fluids (IV administration if necessary) Analgesics/antipyretics (e.g., acetaminophen) Complications Immunocompromised patients are more prone to complications. Nervous systemGuillain-Barré syndrome (GBS)MeningoencephalitisCranial nerve (esp. CN VII)Primary CNS lymphomaHematological systemHemophagocytic lymphohistiocytosisAutoimmune hemolytic anemia, thrombocytopenia Other organs Upper airway obstruction due to oropharyngeal inflammation and lymphadenopathySplenic ruptureOral hairy leukoplakia (typically in HIV patients) Associated malignanciesBurkitt lymphoma (BL), a non-Hodgkin lymphomaAssociated with EBV infectionEndemic BL: occurs mainly in Africa; typically affects the jaw and facial bonesSporadic BL: presents with abdominal masses or bone marrow involvementImmunodeficiency-related BL: similar to sporadic BL (typically in HIV patients)Hodgkin lymphomaNasopharyngeal carcinomaPost-transplant lymphoproliferative disorder; EBV reactivation in patients with severe immunosuppression (e.g., post-transplantation) Commonly progresses to B-cell lymphoma: poor prognosisTreatment: reduce immunosuppressive therapy

Herpes simplex encephalitis Herpes simplex encephalitis (HSE) is an inflammation of the brain parenchyma, typically in the medial temporal lobe, that is caused by either herpes simplex virus type-1 (HSV-1) or type-2 (HSV-2). It is the most common cause of fatal sporadic encephalitis in the US. HSE has a bimodal distribution, commonly affecting patients younger than 20 years of age and older than 50 years of age. Patients with HSE typically present with a prodrome of headaches and fever, followed by sudden focal neurological deficits and altered mental status. Characteristic clinical findings and brain imaging showing temporal lesions should raise suspicion of HSE. Lumbar puncture often reveals lymphocytic pleocytosis. The diagnosis is best confirmed with polymerase chain reaction (PCR) testing of cerebrospinal fluid. Because HSE has a rapidly progressive and potentially fatal course, treatment with acyclovir should begin as soon as the disease is suspected. Relapse of HSE is possible. The mortality rate is as high as 70% in the absence of appropriate treatment.

Epidemiology Bimodal distribution: < 20 years and > 50 years of age Most common cause of fatal sporadic encephalitis in the US Etiology Pathogen: herpes simplex virus Neonates: both HSV-1 and HSV-2Adult: usually HSV-1 Transmission: see herpes simplex virus infections Infectivity: highly contagious Pathophysiology HSV infection may lead to encephalitis in both immunocompetent and immunocompromised patients. Mechanism of brain infection Primary infection Reactivation Clinical features Prodromal phase Duration: few hours to days Nonspecific symptomsFeverHeadacheNausea and vomitingMalaise Acute or subacute encephalopathy Focal neurological deficits (primarily affects the medial temporal lobe) [5]Altered sense of smell and loss of visionAphasiaMemory lossHemiparesisAtaxiaHyperreflexia Seizures (focal or generalized) Altered mental status (e.g., confusion, disorientation, lowered level of consciousness) Behavioral changes (e.g., hypersexuality, hypomania, agitation) Meningeal signs (e.g., nuchal rigidity, photophobia) may occur. Coma HSE may resemble bacterial meningitis, but the combination of altered mental status, seizures, and focal neurological deficits is more common for HSE! Diagnostics Imaging Magnetic resonance imagingMost sensitive and specific imaging modality, especially in the early stagesHyperintense temporal lobe lesions and signal abnormalities (usually in the hippocampus) Computed tomographyOften normal during the early stagesA unilateral hypodense zone can be observed in the insular cortex, which may become bitemporal with disease progression. Lumbar puncture PCR (gold standard): direct, early detection of the pathogen [3] CellsLymphocytic pleocytosis [3]Erythrocytes may be detected in hemorrhagic encephalitis Other parametersOpening pressure: normal or elevatedProtein levels: slightly elevated, ↑ cerebrospinal fluid (CSF)/serum albumin ratioGlucose levels: normalLactate: varies, mainly normal to slightly elevated Electroencephalography (EEG) Unilateral or bilateral lobe discharge Pathology Macroscopic: typical temporal lobe distribution with visible necrosis Microscopic:Hemorrhagic-necrotizing inflammationEosinophilic nuclear inclusions (Cowdry bodies Differential diagnoses Other causes of encephalitis (e.g., CMV in immunocompromised) Meningitis Stroke Epilepsy Migraine headache Treatment should be initiated while awaiting definitive diagnosis of the condition, as the progression of HSE is very rapid! [8] First-line: immediate IV acyclovir Second-line : foscarnet [9] To prevent relapses following the relief of symptoms: valacyclovir Treatment of cerebral edema with proper positioning (head up) and/or hyperosmolar substances (mannitol, glycerol) in the event of raised intracranial pressure If necessary, anticonvulsant treatment (e.g., phenytoin) [10] Be cautious of acyclovir nephrotoxicity! Manage with adequate hydration and dose tapering; do not switch to foscarnet, which is even more nephrotoxic! Prognosis Fatal in up to 70% of cases if left untreated [2] In patients receiving treatment, the mortality rate is still as a high as 20-30%. [3] Relapse may occur Residual deficits may remain in some cases (e.g., paresis, cognitive deficits, psychopathological symptoms)

Creutzfeldt-Jakob disease Creutzfeldt-Jakob disease (CJD) is a neurodegenerative condition that is caused by misfolded protein particles (prions). Prion diseases are very rare overall. CJD is the most common prion disease in humans. In most cases, no direct cause of CJD can be established. However, there are also familial forms due to gene mutation or acquired forms as prion particles can be transmitted between individuals, making CJD an infectious disease. Accumulation of prion particles in the brain eventually leads to neuronal degeneration and clinical onset of the disease. The cardinal symptoms of CJD are rapidly progressive dementia and myoclonus. Most patients die within 12 months following disease manifestation. Imaging, EEG, and cerebrospinal fluid (CSF) tests provide diagnostic evidence, although a definite diagnosis can only be made via biopsy or autopsy. To date, no curative treatment is available.

Epidemiology CJD is the most common prion disease in humans. Etiology CJD is divided into three different types: Sporadic (∼ 85%): no identifiable cause Familial (∼ 10-15%): various mutations in the PRNP gene Acquired (< 1%)Iatrogenic CJD: transmission during medical procedures (e.g., via organ transplantation, blood transfusion)Variant CJD (vCJD): by ingestion of beef infected with bovine spongiform encephalopathy (BSE) (BSE is a transmissible prion disease occurring in cattle. Infection leads to vCJD in humans.) Pathophysiology CJD is caused by "infectious" prions (PrPSc) that are usually produced endogenously but may also be acquired (see "Etiology"). PrPSc → conformational change of physiological PrPc → formation of condensation centers + PrPSc accumulation → plaque formation → neuronal cell death → progression to spongiform encephalopathy (seen as intracytoplasmic vacuoles within the neurons of cerebral and cerebellar cortex on H&E) Clinical features Latency period varies greatly, but ∼ 10 years is common and ≥ 30 years has been recorded Prodromal symptoms (nonspecific): e.g., sleep disorders, headaches, fatigue Rapidly progressing dementia Other neuropsychiatric symptoms: e.g., visual hallucinations, depression Myoclonus: can often be triggered by startling (e.g., loud noises) Seizures Cerebellar disturbances (e.g., gait instability) and extrapyramidal deficits Akinetic mutism Autonomic problems (e.g., sweating) Instrumental diagnostics CSF analysis: neuron‑specific enolase, S100 protein, tau protein, 14-3-3 protein Imaging: MRI EEG: triphasic periodic sharp wave complexes with a frequency of 1-2 Hz Brain biopsy: Diagnosis can only be confirmed by biopsy/autopsy and subsequent neuropathological examination. Differential diagnoses Other diseases commonly associated with the development of dementia: See differential diagnosis of subtypes of dementia in major neurocognitive disorder Other prion diseases (Gerstmann-Sträussler-Scheinker syndrome, Kuru) Huntington disease Mitochondrial encephalopathy Encephalitis Morbus Wilson Treatment No curative therapy available Symptomatic treatment and eventually palliative care Following disease manifestation, most patients die within 12 months, usually from complications such as pneumonia!

Influenza Influenza is a highly contagious disease that typically occurs during the winter months. It is caused by the influenza viruses A, B, and C. There are various subtypes of the type A viruses, which are classified based on their surface antigens H (hemagglutinin) and N (neuraminidase). Since the viruses constantly undergo genetic changes, new subtypes and strains develop fairly often. Most infected individuals do not show symptoms. However, if they are symptomatic, they typically present with sudden onset of high fever, headache, muscle/joint aches, nonproductive cough, and severe malaise. Inflammatory markers are usually normal or slightly elevated. Diagnosis can be established with the help of rapid antigen testing if acute infection is suspected (e.g., for hospitalized patients or nursing home residents). In some cases, bacterial superinfection (most commonly with Staphylococcus aureus and Streptococcus pneumoniae) may develop, which is associated with productive cough and high levels of inflammatory markers. Usually, supportive treatment (i.e., rehydration and antipyretics) is sufficient. However, antiviral therapy may be considered for patients with early or severe disease, especially those at high risk for complications. The most commonly used agents are the neuraminidase inhibitors oseltamivir and zanamivir. If therapy is initiated within 48 hours after the onset of symptoms, a decrease in symptoms, a shortened duration of disease, and a reduction of complications may be achieved. Hygiene precautions and vaccination (recommended for all persons aged 6 months and older) help prevent the spread of influenza viruses.

Epidemiology Distribution: Influenza viruses have a worldwide distribution. Seasonal pattern: Most infections occur during the fall and winter. Etiology Virus: Influenza virus A and B (and rarely influenza C) RNA viruses of the family orthomyxovirusesEnveloped virus with a helical capsidSingle-stranded, negative-stranded, segmented (8 segments)Replication in cell nucleus Person-to-person transmission: directly via respiratory droplets (sneezing or coughing) or indirectly through contact with contaminated surfaces Classification Influenza A: The term "influenza" typically refers to influenza A infections. Viruses are classified into various subtypes based on glycoproteins of the viral envelope. Hemagglutinin (H): H1, H2, H3, and H5 most relevantNeuraminidase (N): N1, N2, and N7 most relevant Influenza B/C (less common): significantly milder course No evidence of genetic shift in influenza B → risk of epidemics is much lower Replication cycle Influenza viruses bind to the respiratory tract epithelium. Viral hemagglutinin (H) binds sialic acid residues (neuraminic acid derivatives) on the host cell membrane → virus fusion with the membrane → entry into the cell The virus replicates in the nucleus of the cell. The new virus particles travel to the cell membrane → formation of a membrane bud around the virus particles (budding) Viral neuraminidase (N) cleaves the neuraminic acid → virions exit the cell Host cell dies → cellular breakdown triggers a strong immune response Genetic mutations Antigenic shiftTwo subtypes of viruses (e.g., human and swine influenza) infect the same cell and exchange genetic segments (reassortment) to create new subtypes (e.g., H3N1 → H2N1). Occurs in particular when human pathogenic and animal pathogenic influenza viruses exchange genetic informationCauses pandemics (limited to a specific time period) Antigenic driftMinor changes in antigenic structure (hemagglutinin and/or neuraminidase) via random point mutationDoes not alter the subtype (e.g., H5N1 or "avian flu"). Causes epidemics (limited to a specific population or region) Clinical features The clinical presentation of influenza infection is asymptomatic or mild in 75% of cases. Influenza presents with very characteristic features, hence the term "flu-like symptoms". Incubation period: a few hours to several days Sudden onset of high fever, chills, headache, arthralgia, myalgia, fatigue, and malaise Patients often develop acute bronchitis with a cough that is usually dry but may produce small amounts of clear or blood-tinged sputum. Hypotension and bradycardia are common (especially among women and older patients) Blood testsNormal or slightly elevated inflammatory markersRelative lymphocytosis Rapid antigen testUsed for early diagnosisDetection of various influenza A/B antigens via nasal or pharyngeal swabsHigh specificity, limited sensitivity Serological testing (e.g., via complement fixation) Used to diagnose an infection after it has resolved (not relevant in acute illness)Infection is likely if serum antibody titers increase 4-fold within 1-2 weeks after acute illness Bacterial superinfection in influenza may lead to a strong elevation in inflammation markers! Supportive therapy Rehydration Antipyretics and analgesia (e.g., acetaminophen) to decrease fever Antitussives (e.g., dextromethorphan) to relieve dry cough. Antiviral therapy IndicationsPatients with severe disease or patients at risk of developing complications (see "Complications" below)Sometimes considered if there is a high suspicion of early disease (e.g., prodromal symptoms and recent exposure) Should be initiated as soon as possible (within the first 48 hours) Neuraminidase inhibitors: inhibit the release of viruses from the host cell. Inhalative zanamivirOral oseltamivirIV Peramivir High-risk groups for complications Elderly individuals ≥ 65 years of age Children < 5 years of age, especially < 2 years of age Pregnant women (and women up to two weeks after giving birth) Individuals with chronic medical conditions (e.g., asthma, heart disease, diabetes mellitus, immunocompromise) Nursing home residents Native American Most severe and dangerous complication Primary influenza pneumoniaHemorrhagic pneumonia with poor prognosis (less common than secondary bacterial bronchitis/pneumonia)May progress to acute respiratory distress syndrome (ARDS) with respiratory/multiorgan failure Secondary bacterial bronchitis/pneumoniaClinical presentation: After flu symptoms have improved, patients suddenly become febrile again and develop a productive cough with large amounts of purulent (sometimes bloody) sputum.Bacteria: most frequently Streptococcus pneumoniae, but also other typical pneumonia pathogens such as S. aureus and Haemophilus influenzaeSigns suggestive of secondary infection with S. aureusHyperacute onset of symptomsHypoxemiaHemoptysisMultiple cavitary lesions on chest x-ray: pneumatoceles Antibiotics: Penicillinase-resistant agents should be used. Aminopenicillins in combination with beta-lactamase inhibitors (e.g., amoxicillin + clavulanic acid) or a combination with a penicillinase-resistantpenicillin (e.g., oxacillin) Other complications Upper respiratory tract (caused by bacterial superinfection, especially in children) Acute otitis mediaSinusitisCroup Myositis and rhabdomyolysis Myocarditis Encephalitis Prognosis MortalityIncreased in patients at high risk for influenza-related complications (see "Complications" above) Average number of annual influenza-related deaths in the US: 23,000 to 48,000 Influenza vaccine Recommendation Annual flu shot for all persons aged 6 months and older every flu season as soon as the vaccine becomes availableParticularly important in health care professionals and individuals with an increased risk of influenza-related complications (see "Complications" above)Egg allergy is no longer considered a contraindication VaccinesConsist of viral strains that most likely appear during the flu seasonGoal of vaccination is to stimulate the formation of host antibodies against viral hemagglutininCan be either Inactivated vaccine (more common)Live attenuated: intranasally administeredThe influenza mutant is temperature-sensitive and therefore replicates in the nose but not in the lung.See contraindications for the live attenuated vaccine.Trivalent or quadrivalent The trivalent vaccine protects against two influenza A viruses (currently a H1N1 and a H3N2 subtype) and one influenza B virus.In addition to these types, the quadrivalent vaccine protects against a second influenza B vi Chemoprophylaxis Antiviral medications may be considered in patients with exposure to an infected person under certain circumstances (e.g., high risk of complications, contraindications for the vaccine, and influenza outbreaks in nursing homes).

African trypanosomiasis African trypanosomiasis (sleeping sickness) is an infectious disease caused by the protozoan parasite Trypanosoma brucei, which is transmitted by the bite of the tsetse fly. The disease is endemic to sub-Saharan Africa; all cases that occur in the US are the result of travel to endemic regions. There are two forms of the disease with distinct geographical distributions and rates of clinical progression. West African sleeping sickness is caused by T. b. gambiense and progresses slowly, while East African sleeping sickness is caused by T. b. rhodesiense and progresses rapidly. Patients with either subtype of the disease initially present with a painful nodule or chancreat the site of the bite, followed by a hemolymphatic phase with fever and lymphadenopathy (stage I). Eventually, patients develop CNS symptoms (stage II), which are characterized by behavioral changes and a reversal of the sleep-wake cycle. If the disease is left untreated, patients will succumb to coma and die. The disease is diagnosed if the trypomastigote is found in chancre fluid, lymph node aspirates, or blood smears. The drug of choice for stage I T. b. gambiense infection is pentamidine, while suramin is the drug of choice for stage I T. b. rhodesiense. An eflornithine-nifurtimox combination is the drug of choice for stage II T. b. gambiense infection, while melarsoprol is the drug of choice for stage II T. b. rhodesiense. No vaccine or chemoprophylaxis for African trypanosomiasis is available.

Epidemiology Distribution: Sub-Saharan Africa Incidence: < 15,000 estimated cases in 2014 Etiology Pathogen: Trypanosoma bruceiT. brucei is a hemoflagellate protozoan. Two subspecies: Trypanosoma brucei rhodesiense, Trypanosoma brucei gambiense Route of infection: vector transmission by the bite of the tsetse fly Life cycle in the tsetse fly Ingestion of the trypomastigote form of T. brucei by the tsetse fly during a blood mealTransformation of the trypanosomal form of T. brucei into procyclic trypomastigotes within the gut of the tsetse flyProcyclic trypomastigotes leave the gut and transform into epimastigotes.Migration of epimastigotes to the salivary glands, where they transform into metacyclic trypomastigotesInjection of metacyclic trypomastigotes from the salivary gland to the bite site during the next blood meal Life cycle in the human body Multiplication of the metacyclic trypomastigotes at the inoculation site causes a primary indurated lesionEntry into the bloodstream and transformation of metacyclic trypomastigotes into trypomastigotesStage I (hemolymphatic phase): multiplication of trypomastigotes in blood (parasitemia) and lymphoid tissueStage II (neurologic phase): Trypomastigotes cross the blood-brain barrier and enter the CNS → Immune-mediated damage causes progressive meningoencephalitis and diffuse demyelination. Stage I (hemolymphatic phase) Trypanosomal chancre (local primary lesion) A red, painful, indurated, nodular swelling 2-5 cm in size that develops at the bite site within 2 weeks of the biteResolves spontaneously within 1-2 weeks Intermittent fever: caused by antigenic variation , malaise, headache, weight loss, arthralgia Painless lymph node enlargement Winterbottom sign: painless cervical lymphadenopathy in the posterior triangle of the neck Erythematous, annular (targetoid), or maculopapular rash that may or may not be pruritic Symptoms of anemia Stage II (neurologic phase) Headache Behavioral changes: confusion, apathy, psychosis Daytime somnolence, which may be associated with night-time insomnia Ataxia Kerandel sign: delayed hyperesthesia Cachexia Coma Death Diagnostics General findingsCBC: anemia, granulocytopenia↑ ESR↑ IgM levels Confirmatory testsLocal primary lesion: direct visualization of trypomastigotes in chancre fluidStage I: direct visualization of trypomastigotes in thin and thick peripheral blood smears or lymph node aspirates Stage II: lumbar puncture and CSF examination Trypomastigotes may be directly visualized. Lymphocytic pleocytosis ↑ Protein and IgM levels A history of travel to an endemic region is an important diagnostic clue! CSF examination must be performed for all patients with suspected or confirmed African trypanosomiasis to rule out stage II disease because the drug of choice depends on the stage of the disease. Treatment General Early in-patient treatment is very important. The drug of choice for trypanosomiasis is dependent on the stage of the disease and the subspecies of T. brucei (see the table below). Follow-up: CSF examination should be repeated every six months for two years. Stage IFirst-line: pentamidine Second-line: suramin Suramin Stage II First-line: eflornithine AND nifurtimox Second-line: melarsoprol Instructions for people traveling to or working in endemic regionsUse preventive measures in the daytime Wear long-sleeved protective clothing with neutral colors Use insect repellants Public health measures in endemic regionsVector control methods such as insecticide spraying and fly trapsPopulation screening programs and early treatment of infections to decrease the number of human hosts No chemoprophylaxis and no vaccine for T. brucei is available.

Leishmaniasis Leishmaniasis is a parasitic disease caused by protozoans of the Leishmania genus, which are transmitted by infected phlebotomine sand flies. Depending on the parasite subtype and the strength of the host's immune system, the disease manifests in a cutaneous or visceral form. Cutaneous leishmaniasis is characterized by skin ulcers. The most important clinical manifestation of visceral leishmaniasis is kala-azar (Hindi for "black fever"), which presents with fever, weight loss, hepatosplenomegaly, and immunosuppression. Leishmaniasis is diagnosed by microscopic visualization of macrophages containing amastigotes in blood smears or tissue. Local treatment (cryotherapy, topical paromomycin) suffices for most cases of cutaneous leishmaniasis. Visceral leishmaniasis requires systemic treatment with amphotericin B.

Epidemiology Distribution: endemic in the Mediterranean region, Africa, India, southwest and central Asia, South and Central America Incidence (worldwide): Visceral: 50,000- 90,000 infections/year Cutaneous: 600,000-1,000,000 infections/year Etiology Pathogen: Leishmania donovani (protozoan) TransmissionVector: phlebotomine sandflies Reservoir: mammals (especially dogs, humans, and rodents) Cutaneous leishmaniasis Clinical features Localized cutaneous leishmaniasisIncubation period: weeks to monthsManifestation: solitary or multiple reddish macules/papules around the sandfly bite that quickly increase in size and develop central ulceration Mucosal leishmaniasisSome Leishmania subtypes cause mucosal leishmaniasis, which can develop months to years after cutaneous leishmaniasis infection that was not treated properly Manifestation: commonly affects the nasopharynx (mucosal bleeding, nasal blockage) Diagnostics Detection of pathogen in skin biopsyMicroscopy with visualization of macrophages with amastigotes PCR Treatment The objective of treatment is to manage clinical symptoms Uncomplicated disease (no immunosuppression, small lesions, no mucosal involvement) No systemic treatmentLocal treatment (cryotherapy, thermotherapy, or topical paromomycin) for skin lesions that do not heal spontaneously. Complicated disease (mucosal involvement, numerous lesions, immunosuppression) See treatment of visceral leishmaniasis Prognosis Treatment reduces the recurrence rate of cutaneous leishmaniasis, accelerates healing of lesions, and reduces the risk of dissemination and incidence of mucosal leishmaniasis. Visceral leishmaniasis Clinical features Incubation period: 2-6 months Many patients are asymptomatic. Kala-azar (hindi for "black fever," in reference to the darkening of the skin it can cause) Usually insidious progression Flu-like symptoms, spiking feversWeight lossLymphadenopathyHepatosplenomegalyAscites and edemaPancytopeniaPossible darkened or gray skin color (especially on the palms and soles)Immunosuppression may lead to secondary bacterial infections in advanced disease Diagnostics Laboratory tests Hemolytic anemiaNeutropenia, eosinopenia, thrombocytopenia Detection of pathogen Microscopy of tissue biopsy (e.g., bone marrow) with visualization of macrophages with amastigotes PCR Treatment Amphotericin B is the preferred monotherapy in Europe, North America, and South America. Other drugs that may be used include: Sodium stibogluconateMiltefosineParomomycin Kala-azar is highly fatal without treatment!

Japanese encephalitis Japanese encephalitis is a mosquito-borne viral disease endemic in Asia and the Western Pacific. Disease transmission occurs through the bite of infected Culex tritaeniorhynchus mosquitoes. Clinically, Japanese encephalitis virus (JEV) infection can range from asymptomatic disease to acute encephalitis, which occurs in < 1% of patients. Despite its rarity, acute encephalitis with altered mental status and neurological deficits remains the most important clinical manifestation; it typically develops following a short period of non-specific febrile illness. Seizures are common, especially in children. Other known clinical manifestations include acute psychosis and flaccid paralysis. Elevations in white blood cell count and CSF pleocytosis are often present, along with characteristic thalamic lesions on brain MRI. Definitive diagnosis is made through serology. Vaccinations are available for travelers and as part of childhood immunization programs in some endemic areas.

Epidemiology Distribution: endemic throughout most of Asia and parts of the Western Pacific region IncidenceA significant cause of viral encephalitis in Asia∼ 68,000 cases occur every yearTypically affects individuals < 15 years old The incidence in travelers from non-endemic regions is estimated to be < 1 case per million. Etiology Pathogen: Japanese encephalitis virus (JEV), a mosquito-borne flavivirus TransmissionTwo main patterns of transmission During the warmer months in temperate areas of Asia (e.g., China, Japan, South Korea)Year-round transmission in tropical areas (e.g., Cambodia, Thailand) with peaks during the rainy seasonThe primary mosquito vector is Culex tritaeniorhynchus .Pigs and wading birds (e.g., herons and egrets) are major hosts in the JEV cycle. Pigs are particularly important, as they develop high levels of viremia and are often kept in close proximity to human dwellings.Humans are dead-end hosts. Clinical features Incubation period: 5-15 days > 99% of cases are subclinical. Acute encephalitis (most common clinical presentation) Non-specific prodromal symptoms such as fever, vomiting, headaches, and generalized weaknessHigh fever and altered level of consciousnessSymptoms progress over a few days into focal neurological deficits, movement disorders, psychosis, or seizures.In severe cases: coma, flaccid paralysis, death Laboratory findings ↑ White blood cell count Hyponatremia secondary to SIADH CSF analysisElevated opening pressureMild to moderate pleocytosis with a predominant lymphocytosisElevated proteinNormal glucose Imaging Brain MRI: hyperintense lesions in the thalamus, basal ganglia, midbrain, pons, and medulla. Diagnostic testing Serum or CSF immunoglobulin M (IgM) antibodies are diagnostic.Usually detectable 3-8 days after illnessFalse-positive elevations in serum IgM antibodies can be positive post-vaccination.Convalescent samples of immunoglobulin G (IgG) antibodies can be tested if acute (IgM) samples are negative. Differential diagnoses Viral encephalitides (e.g., HSV encephalitis) Other arbovirusesSt. Louis encephalitis virusWest Nile virusMurray Valley encephalitis virus Aseptic meningitis Bacterial meningitis Treatment No specific treatment available Supportive care is the mainstay of treatment, with a particular focus on: Control of intracranial pressureMaintaining adequate cerebral perfusionSeizure control Corticosteroids and ribavirin have shown no clear benefit. Prognosis ∼ 30% of patients who develop acute encephalitis die. In survivors, neurologic, cognitive, and psychiatric sequelae are common Prevention Vaccination IndicationsTravelers spending > 1 month in endemic areasTravelers spending < 1 month in endemic areas during periods of JEV transmission Children < 15 years who live in areas with high JEV transmission Administration2 doses, 28 days apartGiven at least one week before exposureBooster if last dose ≥ 1 year ago Contraindications: See general contraindications for vaccination. Mosquito-bite prevention Wear light-colored clothing Use insect repellants Avoid activities between dusk and dawn (when Culex tritaeniorhynchus is most active) Place screens at doors and windows Remove open water containers to minimize mosquito breeding

Dengue Dengue is a viral disease transmitted by mosquitoes (especially Aedes aegypti) and is widely distributed throughout the tropics and subtropics. Dengue classically presents with high fever, headache, body aches, exanthem, and generalized lymphadenopathy. Symptoms usually subside within one week. Some cases progress to the more severe dengue hemorrhagic fever (DHF) with thrombocytopenia, spontaneous bleeding, and potentially shock (dengue shock syndrome). Treatment is supportive. A vaccination is available for use in children, living in endemic areas, with confirmed prior dengue virus infection.

Epidemiology Distribution: tropical regions worldwide, particularly Asia (e.g., Thailand) IncidenceMost common viral disease affecting tourists in tropical regions∼ 400 million infections per year worldwide Etiology PathogenDengue virus (Serotype: DENV 1-4) RNA virus of the genus Flavivirus Transmission route [3]Vector-borne: mosquitoes most commonly from the species Aedes aegypti These mosquitoes can also transmit chikungunya, Zika virus, and yellow fever. Classic dengue fever Incubation period: 2-14 days Children are usually asymptomatic Starts with fever and malaise that lasts ∼ 1 week Severe arthralgia and myalgia (often referred to as "break-bone fever") Severe headache and retro-orbital pain Maculopapular, measles-like exanthem (typically appears 2-5 days following fever) Generalized lymphadenopathy If symptoms appear more than 2 weeks after returning from a dengue-endemic region, it is very unlikely that dengue is the cause! Dengue hemorrhagic fever (DHF) Occurs in 1-2% of cases Generally develops as the initial fever subsides (∼ 1 week after onset) Clinical manifestationsTemperature change: ranges from hypothermia to a second spike in feverAbdominal pain, vomitingChanges in mental status (e.g., confusion)Hemorrhagic manifestations (e.g., petechiae, epistaxis, gingival bleeding) Positive capillary fragility test [7]Increased vascular permeability → signs of pleural effusion and/or ascites Dengue shock syndrome (DSS): DHF + shock Laboratory testsLeukopeniaThrombocytopenia↑ ASTHct elevated ≥ 20% of normal values if vascular permeability (in DHF) Best test for confirming infection: serology (IgM, IgG) AlternativesPCRMolecular methods (ELISA): detection of viral antigen Differential diagnoses Malaria Other viral hemorrhagic feversEspecially Chikungunya (exhibits similar symptoms with an emphasis on bilateral polyarthralgia) Zika virus infection Treatment Symptomatic treatmentFluid administration to avoid dehydrationAcetaminophen Dengue hemorrhagic feverBlood transfusions in case of significant internal bleeding (e.g., epistaxis, gastrointestinal bleeding, or menorrhagia)IV fluids Prevention Avoid exposure, use of mosquito repellent (see also → mosquito bite prevention) A tetravalent attenuated live vaccine (CYD-TDV) has been approved for use in children between 9-16 years of age who live in endemic areas and have a laboratory confirmed prior dengue virus infection

Poliomyelitis Poliomyelitis, or polio, is a disease caused by poliovirus, a type of human Enterovirus. Poliovirus spreads via fecal-oral transmission. Although the majority of poliovirus infections are asymptomatic, some may invade the central nervous system, leading to motor neuron death and irreversible paralysis that can cause respiratory insufficiency and death. The main clinical manifestations of poliomyelitis are weakness, decreased muscle tone, and hyporeflexia. The diagnosis is established based on polymerase chain reaction (PCR) findings of poliovirus RNA in cerebrospinal fluid. Poliomyelitis has been eradicated in most parts of the world thanks to the success of global vaccination initiatives. The treatment of poliomyelitis is mainly supportive. Patients with brainstem or respiratory muscle involvement may require intubation and mechanical ventilation. The majority of patients do not regain their full strength after recovery. Some patients go on to develop post-polio syndrome, a poorly understood syndrome characterized by progressive disability and muscle weakness decades after the initial polio infection

Epidemiology Due to widespread vaccination measures, poliomyelitis has been eradicated from the United States and most other countries. Poliovirus is still endemic in Afghanistan, Nigeria, and Pakistan. Etiology Causative agentPoliovirus is an RNA virus in the family Picornaviridae, genus enterovirus, and has three serotypes.Poliovirus type 1 causes most paralytic manifestations of poliomyelitis.Humans are the only hosts. Transmission routeFecal-oral route: absorption of poliovirus in the intestinal tract Rarely, droplet transmission may occur during epidemics. Incubation time7-14 days Pathophysiology The virus replicates in the gastrointestinal tract following oral ingestion → enters the bloodstream → potential invasion of the grey matter of the spinal cord(particularly the anterior horn cells) → myelitis Clinical features Over 90% of infections with poliovirus are asymptomatic. Clinical infection is observed in less than 10% of cases and less than 1% of infected individuals develop paralysis. The clinical forms of poliomyelitis are: Poliomyelitis without CNS involvement (abortive poliomyelitis) (4-8% of cases) Nonspecific symptoms: gastroenteritis, fever, nausea, sore throat, myalgia, and headaches for 1-3 days Complete recovery without complications or transition to poliomyelitis with CNS involvement Poliomyelitis with CNS involvement Nonparalytic poliomyelitis: aseptic meningitic form (1-2% of cases) Clinical findingsBegins several days following abortive poliomyelitis (often temporary, symptom-free interval)Fever, neck stiffness, headache, vomiting, muscle painNeck muscle weakness (head drop sign: head falls back when placed in a supine position)No paresis! Cerebrospinal fluid (CSF) diagnostics: lymphocytic pleocytosis, normal glucose levels, and normal or slightly elevated protein levels Paralytic poliomyelitis (less than 1% of cases) Clinical findingsOccurs 2-3 days following the meningitic form after a brief symptom-free intervalFeverSevere back, neck, and muscle painAsymmetric flaccid paralysis worsens over hours to daysMost commonly affects the leg muscles, although the arms, abdomen, trunk, thorax, and eyes may be affectedParalysis is usually more severe in proximal muscles than in distal muscles.Diminished deep tendon reflexes ComplicationsAscending paralysis with diaphragmatic involvement → respiratory failureBulbar form with brain stem involvement (rare): damage to the cerebral or autonomic nerve centers (cranial nerves and respiratory center) → centralrespiratory paralysis Post-polio syndrome (post-poliomyelitis syndrome, PPS) Most frequent complication observed following poliovirus infection (up to 40% of survivors) Occurs decades after infection Manifests with progressive muscle weakness and pain, even in areas that were not affected by the initial infection Diagnostics The best diagnostic test is PCR amplification of poliovirus RNA from CSF. CSF fluid will also show high protein levels and pleocytosis with either neutrophils (early infection) or lymphocytes (late infection). Differential diagnoses Other viral infections Guillain-Barré syndrome Acute intermittent porphyria Treatment Pain relief Mechanical ventilation if needed Close monitoring of blood pressure and respiratory function Prognosis The prognosis is dependent on the form of poliomyelitis. In the abortive and nonparalytic forms, complete recovery without complications occurs within 2 weeks. In the paralytic form, the most serious short-term risk is death due to diaphragmatic involvement. After recovery, most patients have residual deficits, including muscle weakness or contractures and muscle pain. Post-polio syndrome may lead to muscle weakness and pain decades after polio infection. Prevention Immunization The inactivated poliovirus vaccine (IPV) is recommended for childhood immunization in the United States and most high-income countries. In the US, children receive 4 doses of IPV, at 2, 4 and 6-18 months, followed by a booster dose at 4-6 years. See immunization schedule. The live attenuated oral poliovirus vaccine (OPV) is used for childhood immunization in low-income countries because it is less costly. It has a slightly increased risk of vaccine-associated paralytic polio and is being gradually replaced in favor of the IPV worldwide.

Rabies Rabies is a neurotropic virus contracted from the bite of an infected animal. The virus enters the patient's skin from the saliva of the animal and migrates along the peripheral nerves to the central nervous system (CNS). An incubation period of 1-12 weeks typically precedes the clinical appearance of the disease, which manifests with a prodrome of nonspecific flu-like symptoms, followed by acute rabies encephalitis. Clinical findings include fever, hydrophobia, hypersalivation, and stupor alternating with mania. Coma and eventually death due to respiratory and circulatory collapse ensue. A minority of rabies cases are paralytic rather than encephalitic, presenting with ascending paralysis similar to that of Guillain-Barré syndrome and culminating in cardiac and respiratory arrest. With adequate post-exposure prophylaxis (PEP) (i.e., with rabies immunoglobulin plus rabies vaccine) and wound care following a rabid animal bite, rabies infection is preventable. No curative treatment is available once the signs and symptoms of rabies have appeared, and the disease is almost always fatal. Preexposure prophylaxis with the rabies vaccine is recommended for individuals traveling to areas where the virus is widespread, as well as for those with jobs that predispose them to infection (e.g., veterinarians).

Epidemiology Found in animal reservoirs in most countries throughout the world Considerable divide between developed and developing countries in terms of human death due to rabies Incidence worldwide: Up to 70,000 people die of rabies each year. Incidence in the US: Three people on average die of rabies each year. Etiology PathogenRabies is caused by several different members of the Rhabdoviridae family.Rhabdoviruses are rod or bullet shapedGenus: LyssavirusssRNA TransmissionMost common animal reservoir worldwide: dogs Most common animal reservoirs in the US: bats, raccoons, skunks, and foxesSpread through saliva of rabid animal after bite injuryVia aerosols (e.g., bat caves); rare Pathophysiology Rabies virus binds the ACh receptor of peripheral nerves in the bite wound → migrates retrogradely along the axonal microtubules(using motor protein dynein) → enters the CNS → infects the brainDiencephalon, hippocampus, and brainstem are involved first Causes acute, progressive, and fatal encephalitis → encephalitic rabiesIn < 20% of cases, causes ascending flaccid paralysis → paralytic rabies (see "Clinical features" below) Rabies is almost always fatal once the symptoms have appeared! Incubation period: 1-12 weeks average Prodromal symptoms Flu-like symptoms (e.g., fever, malaise)Locally: pain, paresthesia, and pruritus near the bite site Encephalitic rabies (most common type) Hydrophobia: Rabies patients experience involuntary, painful pharyngeal muscle spasm when trying to drink; later on in the disease, the sight of water alone may provoke nausea or vomiting. CNS symptomsAnxiety, agitation, and combativeness alternating with calm periodsConfusion and hallucinationsPhotophobiaFasciculationsSeizures↑ Muscle tone and reflexes with nuchal rigidity Autonomic symptoms: e.g., hypersalivation, hyperhidrosis Coma and death within days to weeks of the development of neurological symptoms Paralytic rabies (< 20% of cases) Flaccid paralysis, gradually ascending and spreading from bite wound Paraplegia and loss of sphincter tone Respiratory failure and death Diagnostics Bite injury from a suspicious animal: For PEP algorithm see "Treatment" section below Clinical rabies History: exposure to a potentially rabid animal Laboratory diagnosis Serum Non-immunized patient: rabies antibodiesImmunized patient: rising serum antibodies over a few days CSF: findings characteristic of encephalitis Skin: biopsy from the back of the neck for RT-PCR and immunofluorescence stainingSaliva: RT-PCR for viral RNA, viral culture Postmortem brain tissue autopsy: Negri bodies (eosinophilic cytoplasmic inclusion bodies typically found in the cerebellum and hippocampus) Risk evaluation of animal bites Administer PEPBite by a known wild reservoir for rabies (e.g., bats, raccoons, skunks, foxes), if the animal is not available for testing or if the test comes back positive Bite by a domestic carnivore (e.g., dog) not available for observation or displaying symptoms of rabies Observe/test animal and possibly administer PEPAttack by an unvaccinated domestic carnivore without symptoms of rabies (e.g., dog) → observe animal for a 10-day periodAnimal remains normal: PEP is not necessaryAnimal starts to display symptoms of rabiesEuthanize and study brain samples of the animalAdminister PEP to patientPEP is stopped if test results of the animal are negative PEP is not requiredBite by a vaccinated domestic carnivoreBite by an indoor domestic herbivore Post-exposure prophylaxis Cleaning and debridement, as with all bite wounds Tetanus shot and antibiotic prophylaxis may be indicated Nonimmunized patient: postexposure prophylaxis (passive-active immunization)Rabies immunoglobulin is given into the site of the wound by injection (passive immunization) PLUS inactivated rabies vaccine is given IM on days 0, 3, 7, and 14 (active immunization) Prior immunizationEven patients who have been vaccinated against rabies should be treated after exposure!Rabies vaccine IM on days 0 and 3.No immunoglobulin Check antibody titers on day 14. Symptomatic encephalitic or paralytic rabies Palliative treatment (pain management and sedation) Prognosis Mortality: Symptomatic rabies is almost always fatal. Rabies is preventable following exposure to a rabid animal with adequate PEP (see "Treatment" section above) Prevention Vaccination (preexposure prophylaxis) Inactivated (killed) vaccine IndicationsPeople with frequent occupational contact with potentially rabid animals Travelers to regions in which rabies is widespread (especially if PEP may not be readily available) Obligation to report Rabies is a nationally notifiable disease according to the CDC.

Giardiasis Giardiasis is a common parasitic infection caused by the protozoan Giardia lamblia. Transmission usually occurs via the fecal-oral route (e.g., from contaminated drinking water) when traveling or living in an endemic region. Giardia live in two states: as active trophozoites in the human body and as infectious cysts surviving in various environments. Following ingestion of the cyst, individuals may experience abdominal cramps and frothy, greasy diarrhea. Diagnosis of giardiasis involves analyzing stool for microscopic confirmation of cysts or trophozoites, and possibly immunoassays to detect antigens. Treatment consists of antibiotic administration with metronidazole.

Epidemiology Giardia lamblia is widespread throughout the world and affects ∼ 200 million people per year worldwide. Incidence: estimated 5-8/100,000 per year in the US In the US, Giardiasis is the most common intestinal disease caused by parasites. Etiology Pathogen: Giardia lamblia (also known as Giardia intestinalis or duodenalis), a protozoan TransmissionWaterborne: from drinking of recreational water (e.g., lakes, rivers, ponds, swimming pools)Fecal-oral (e.g., through food handlers, people in daycare and nurseries): Giardia cysts are passed into the environment from the feces of infected people and animals.Swallowing of cysts in contaminated water → entry of Giardia into the gastrointestinal tractInfection is more likely to occur after traveling to endemic regions such as the tropics, subtropics, and North-Americanmountain regions. Pathophysiology Life cycle: 2 stages Trophozoite: active form of the pathogen that multiplies, lives within the host's body Morphology: long oval shape with two nuclei and four pairs of flagella that resemble a kiteCysts: excreted, infectious form of the pathogen, able to survive in moist environments Morphology: oval, four nucleiIngestion of cysts → excystation and conversion to trophozoite form → rapid multiplication, adhesion to intestinal walls → encystation in large bowel → excretion of cysts → possible reinfection Mechanism of injury: Although several theories exist, it is commonly suspected that infection with Giardia leads to impaired function and structure of intestinal tissue , resulting in malabsorption and diarrhea. Clinical features Infection with Giardia lamblia must be considered as a differential diagnosis for persistent diarrhea. 3-25 days after ingestion of cysts → diarrhea consisting of soft, voluminous, frothy, and greasy stools (stools tend to float; no blood!) May lead to dehydration Excessive gas, abdominal pain, and cramps Fatigue, nausea/vomiting, anorexia May be asymptomatic Diagnostics Stool analysis: microscopic confirmation of cysts or trophozoites Immunoassay: detection of Giardia lamblia antigens in stool Gastroduodenoscopy: confirms trophozoites in duodenal fluids, but generally not indicated Treatment Metronidazole (commonly used in the US) Tinidazole (single oral dose) Alternatives: nitazoxanide, albendazole, or mebendazole

Hepatitis A Hepatitis A infection is caused by the hepatotropic hepatitis A virus (HAV) and is usually transmitted via the fecal-oral route. About half of all cases of HAV infection that occur in the US are acquired during visits to countries that are endemic for HAV (e.g., tropical or subtropical regions). HAV infection results in acute hepatitis with a clinical course characterized by prodromal symptoms of fever and malaise, followed by jaundice. As in any other case of acute viral hepatitis, high levels of serum transaminase and mixed hyperbilirubinemia are observed. Serological detection of anti-HAV IgM, which is elevated during an acute infection, confirms the diagnosis. While prodromal symptoms resolve within a few weeks, jaundice usually resolves within 1-3 months. No chronic sequelae occur and acute hepatic failure occurs only in very rare cases. Therefore, supportive care is usually the only treatment required. As of 2006, routine immunization against hepatitis A is recommended for all children older than 12 months. Certain high-risk groups, such as tourists to areas where HAV is endemic, should also be immunized against HAV if they have not been vaccinated in the past. An important differential diagnosis is another feco-orally transmitted viral infection: hepatitis E (HEV). The clinical presentation of HEV is almost identical to that of HAV, with the exception that pregnant women are at a high risk of developing acute liver failure. Serological tests help to distinguish HEV from HAV.

Epidemiology Hepatitis A infection is the second most common cause of acute hepatitis in the US. Hepatitis A is very common in tropical and subtropical regions. Incidence (in the US): 2,000 cases per year (50% acquired during travels abroad) Etiology Pathogen: hepatitis A virus Belongs to the family of Picornaviridae and the genus Hepatoviridae. It is a small (27 nm in diameter), non-enveloped virus with single-stranded, positive-sense RNA Route of transmission: fecal-oralContaminated food, e.g., raw shellfish Risk groups: children, employees of day care centers, convicts, men who have sex with men Infectious period: 2 weeks before to 1 week after the onset of the illness Pathophysiology HAV is not cytopathic in itself; research suggests that liver damage is caused by cellular immunity (especially CD8+ T cells). Clinical features Incubation period: 2-6 weeks HAV infection in children is typically asymptomatic. The risk of symptomatic infection increases with age and coinfection (e.g., with hepatitis B). Acute viral hepatitis: three phases Prodromal phase: ∼ 1-2 weeksFever, malaiseAnorexia, nausea, vomitingRight upper quadrant pain and tender hepatomegalyIcteric phase: ∼ 2 weeks JaundiceDark urine and pale stools PruritusResolution of symptoms The mortality rate is 0.1-0.3% because few patients progress to acute liver failure. Patients do not become carriers nor develop chronic hepatitis (unlike in hepatitis B and C). Laboratory findings ↑↑ Serum transaminase (AST, ALT) Mixed hyperbilirubinemiaPossibly ↑ ALP, ↑ γ-GT Urine analysis: ↑ urine bilirubin, ↑ urobilinogen Confirmatory test↑ Anti-HAV IgM: active infection (Anti-HAV IgM antibody levels begin to rise 1 week after the onset of the illness and peak at around 3 weeks, after which point they decline. Anti-HAV IgM can be found in serum 3-6 months after the infection.)↑ Anti-HAV IgG: past infection or vaccinationHAV RNA can be detected by PCR in stool and serum samples. Liver biopsy (not normally necessary): Periportal inflammation, ballooning degeneration, bridging necrosis, and Councilman bodies (apoptotic hepatocytes) Differential diagnoses For an overview comparing the different types of viral hepatitis: see differential diagnosis of viral hepatitis. Hepatitis E Pathogen: hepatitis E virus (HEV)The hepatitis E virus, which belongs to the family of Hepeviridae and the genus Orthohepeviridae, is a small (34 nm in diameter), non-enveloped virus with single-stranded, positive-sense RNA. Epidemiology: HEV is not common in the US. Route of transmission: fecal-oral Pathophysiology: the degree of hepatic injury is usually mild and the patient may present with clinical features of acute hepatitis Clinical features: Incubation period: 2-8 weeksClinical features are similar to those of hepatitis A (see "Symptoms/clinical findings" above).In the majority of cases, the disease is self-limiting with complete recovery. Fulminant hepatitis among pregnant womenPatients do not become carriers nor develop chronic hepatitis (unlike in hepatitis B and C). DiagnosticsLaboratory findings are the same as in hepatitis A.Confirmatory test Anti-HEV IgM: active infectionAnti-HEV IgG: past infectionHEV RNA can be detected by PCR in stool and serum samples. Treatment: supportive care Prevention: no vaccine available Fulminant hepatitis due to HEV is relatively common among pregnant women (occurring in up to 20% of cases) and is life-threatening for both the mother and fetus! Treatment Disease is self-limiting → supportive care Prevention Hepatitis A pre-exposure prophylaxis Travelers should be advised to follow primary preventive measures such as hand-washing and following proper food and water safety Routine active immunization is now recommended for all children over 12 months consisting of a first IM dose of hepatitis A vaccine followed by a booster dose after 6 months (see also "Immunization schedule") Active immunization is also recommended for certain high-risk groups who have not been immunized in the past: Travelers to foreign countries where HAV is endemic.Men who have sex with menPatients with chronic liver disease Hepatitis A post-exposure prophylaxis Post-exposure prophylaxis is indicated for all previously unvaccinated individuals who have been exposed to a serologically confirmed case of HAV infection. In order to be effective, post-exposure prophylaxis should be administered within two weeks of exposure. Healthy individuals aged 1-40 years: active immunization with hepatitis A vaccine Infants, individuals older than 40 years, patients with chronic liver disease and/or immunosuppression: passive immunization with anti-HAV immunoglobulins Hepatitis A is a notifiable disease.

Acute otitis media Acute otitis media (AOM) is a viral or bacterial infection of the middle ear that is most commonly caused by Streptococcus pneumoniae. AOM is a common infection in children under the age of five years and it usually follows an upper respiratory tract (URT) infection. It is characterized by an acute onset of symptoms (e.g., otalgia, fever, anorexia) with signs of middle ear inflammation (e.g., bulging tympanic membrane, effusion). Mild unilateral infections can be managed without antibiotics, as they are often self-limiting. Bilateral AOM or severe symptoms are usually treated with oral amoxicillin. Tympanostomy and insertions of tympanostomy tubes is recommended in children with recurrent AOM. Complications are rare and occur mostly in immunosuppressed patients or in AOM due to highly virulent, drug-resistantbacteria. The most common complication is acute mastoiditis, but facial palsy, labyrinthitis, and in rare cases, even intracranial abscessesmay also occur.

Epidemiology Highest incidence between 6-24 months of age∼ 70% of children < 2 years old experience AOM at least onceSlightly higher incidence in boys Immunization of infants against pneumococci has decreased the incidence of AOM tiology Etiology Bacterial superinfection following a viral URT infection (95% of cases) S. pneumoniae (most common: 35% of cases)Haemophilus influenzae (25% of cases)Moraxella catarrhalis (15% of cases)Group A ß-hemolytic streptococci (in older children) Risk Factors for AOM Bottle feeding/formula feeding, inadequate breastfeeding Pacifier use Passive cigarette smoke Children who attend day care centers Poor socioeconomic status Pathophysiology The eustachian tube (ET) connects the middle ear with the nasopharynx and is lined with cilia, which drain the middle ear secretions into the nasopharynx. Obstruction/blockage of the ET → lack of ventilation and drainage of the middle ear → Resorption of the air in the middle ear → negative middle ear pressure → retraction of the tympanic membrane → otalgia and conductive hearing lossAccumulation of middle ear secretions → bacterial superinfection → pus in the middle ear → bulging tympanic membrane → severe otalgia, fever Predisposing factors for ET obstructionInflammation of the ET mucosa Viral URT infection (most common cause)Allergic rhinitisMechanical obstruction of the ET Enlarged adenoidsNasal polypsCleft palateInfants: the ET of infants is shorter, narrower, and more horizontal → nasopharyngeal secretions easily reflux into the ET → more prone to developing AOM Clinical features In infantsIrritabilityIncessant cryingRefusal to feed (anorexia)Repeatedly touching the affected earFever and febrile seizuresTender mastoid in late stages In older childrenOtalgia/earache, commonly with throbbingHearing loss in the affected earFeverTender mastoid in late stages Diagnostics Otoscopy: tympanic membrane (TM) evaluationEarly findings Retracted and hypomobileLoss of light reflexLate findings Cartwheel TM Red bulging TM with loss of landmarksYellow spot on TM (antero-inferior quadrant of pars tensa) which indicates site of imminent ruptureIf TM rupture → purulent/serosanguinous discharge in the external auditory canal Tuning fork test: conductive hearing loss Treatment Symptomatic pain management (paracetamol, ibuprofen) Antibiotics: not always indicated Indications Bilateral otitis mediaSymptoms do not improve after 48 hoursSevere illness in children (very high fever, vomiting, malaise, and immunosuppression)First line: oral amoxicillinAdd clavulanic acid if no improvement after 48 hoursAlternative for patients with penicillin allergyIf past immediate reaction → macrolides (e.g., azithromycin, clarithromycin, erythromycin)If past delayed reaction → cephalosporins (e.g., cefuroxime/ceftriaxone) Surgical proceduresTympanocentesis: Aspiration of contents of middle ear using a sterile needle, indicated in patients who do not respond to initial therapy (allows for culture of bacteria contained in middle ear fluid)Myringotomy: Incision in the TM to drain pus, indicated in patients with severe otalgia and bulging TMMyringotomy with tympanostomy: Incision in the TM and insertion of small tubes into the TM to allow air to enter the middle earand fluid to drain, indicated in children with recurrent AOM Complications Complications are rare and are usually only seen in the following cases: Highly virulent bacteria (Group A ß-hemolytic streptococci). Immunocompromised host Inadequate dose/duration of antibiotics Bacterial drug resistance Intratemporal complications Mastoiditis Definition: inflammation of the mastoid air cells Epidemiology: often occurs in children < 5 years Pathophysiology: infection spreads from the middle ear cavity into the mastoid, which is a closed bony compartment → collection of pus under tension and hyperemic resorption of the bony walls → destruction of the air cells (coalescent mastoiditis) → mastoid becomes a pus-filled cavity (empyema mastoid) Clinical featuresPersistence/recurrence of otalgia and fever after initial improvementEar discharge becomes profuse (discharge persisting > 3 weeks suggests mastoiditis).Tender and edematous mastoidEar displaced laterally and forwardIn advanced stages, the retroauricular sulcus is obliterated and the ear can be pushed forward. DiagnosticsOtoscopy: The TM may be perforated.First test: CT scan of the temporal boneOpacification of the mastoid air cellsErosion of the air cell wallsPus in the mastoid cavity (areas of enhancement on CT)X-ray of the mastoid Early stage: The air cells appear cloudy and indistinct.Advanced stage: A cavity can be seen in the mastoid. TreatmentAntibiotic treatment is always indicatedVancomycin alone: in patients who have not recently received antibiotics and who do not have a history of recurrent AOMVancomycin + ceftazidime or cefepime or piperacillin-tazobactam: patients who recently recieved antibiotics and/or had an episode of AOM within the past 6 months Tympanostomy (myringotomy) + tympanostomy tube insertion: for early stages of mastoiditis Mastoidectomy: is indicated in severe cases that do not improve with antibiotics + tympanostomy. Labyrinthitis Etiology: Inflammation spreads to the inner ear (labyrinth) through the round window. Clinical featuresSevere vertigo, nausea, and vomitingHearing lossNystagmus towards healthy ear for weeks to months DiagnosticsChange of lateralization in Weber's test Audiometry: sensorineural hearing loss TreatmentIV antibiotics + tympanostomy with insertion of tympanostomy tube + glucocorticoidsMastoidectomy (to treat the source of infection in AOM) Peripheral facial palsy Intracranial complications Otogenic abscess Route of spread: direct spread of infection from the middle ear through the destroyed bone overlying the dura or through an emissary vein TypesEpidural abscessSubdural abscessCerebral abscess: The ipsilateral temporal lobe is the most common site (ipsilateral cerebellar abscess is second most common). Clinical featuresPersistent headache and otorrheaSigns of raised ICPSigns of meningeal irritationFocal neurological deficits Diagnostics: MRI/contrast-enhanced CT Treatment: IV antibiotics + drainage + mastoidectomy

Human immunodeficiency virus Infection with the human immunodeficiency virus (HIV) leads to a complex disease pattern which ultimately results in chronic immunodeficiency. HIV can be transmitted sexually, parenterally, or vertically (e.g., peripartum from mother to child). Infection is most common in the young adult population between 20 and 30 years of age. The virus infects macrophages and other CD4+ cells, leading to the destruction of CD4 T cells and thereby impairing one of the key mechanisms of cellular immune defense. There are three major stages: acute infection, clinical latency, and acquired immunodeficiency syndrome (AIDS). For clinical staging, detailed classifications have been established by the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO). During the stage of acute infection, the virus reproduces rapidly in the body, which can lead to acute, nonspecific (e.g., flu-like) symptoms (also known as acute retroviral syndrome, ARS) within 2-4 weeks. However, approximately half of all infected individuals remain asymptomatic. Once the stage of acute infection subsides, the clinical latency stage begins. Again, many individuals remain asymptomatic during this period, while others develop non-AIDS-defining conditions (e.g., oral hairy leukoplakia). The last stage, AIDS, is characterized by AIDS-defining conditions (e.g., Kaposi's sarcoma) and/or a CD4 count< 200 cells/μL. HIV infection can reliably be detected via antigen/antibody-based tests. In patients with confirmed infection, the most important parameters for monitoring the disease are CD4 count and viral load. HIV treatmentinvolves a combination of antiretroviral drugs (combination antiretroviral therapy, cART). In addition, HIV-relatedcomplications (e.g., HIV wasting syndrome, opportunistic infections) will require management. There have been significant advances in treatment so that the average life expectancy of HIV patients receiving current antiretroviral drugsis approaching that of the general population.

Epidemiology Incidence (in the US) HIV infection: peak incidence between ages 20 and 30 (∼ 35/100,000)AIDS: peak incidence approx. age 45 (∼ 14/100,000)Ethnicity: Incidence is significantly higher in the Black population than in other population groups. Prevalence US: ∼ 1.2 million Global: ∼ 37 million Pathogen (human immunodeficiency virus) Lymphotropic lentivirus (from the family of retroviridae) Consists of the two species HIV-1 and HIV-2 HIV-1: most common species worldwide HIV-2: restricted almost completely to West Africa Routes of transmission Sexual: responsible for ∼ 80% of infections worldwide Risk per sexual act Risk for men who have sex with men (MSM): 0.5% for receptive partner Risk for male-to-female sex 0.1% for female partner0.05% for male partnerModifying factors Viral load: studies have shown that transmission is unlikely if viral load is < 400 copies/ml Circumcision: reduced risk of infection for circumcised men Coinfection: genital inflammation (e.g., as a result of coinfection with other pathogens such as HPV or genital herpes) increases local virus concentration and therefore risk of transmission Genital mucosal damage: increases risk of transmission Parenteral transmissionNeedle sharing: 0.67% per exposure through needle-sharing contact Needlestick injuries: 0.36% per injury Infectious blood on mucous membranes: 0.1% per exposureBlood transfusions: 0.00005% risk per transfusion (1 in 2 million) Vertical transmission: from mother to child During childbirth (∼ 5-15%) Through breastfeeding after birth (∼ 5-20%) Structure of HIV Physical structure: icosahedral with a conical capsid and a spiked envelope Genome : 9 genes encoding a total of 15 proteins (e.g., reverse transcriptase , integrase , and envelope proteins) pol gene codes for a polyprotein that consists of protease, reverse transcriptase, and integrasegag gene codes for gag protein, which consists of matrix protein, nucleocapsids, and capsid proteinsenv gene codes for surface glycoproteins, gp41 and gp120 Natural history of HIV infection Initial infection and HIV replication cycleHIV enters the body (e.g., via mucosal lesions or via infection of mucosal/cutaneous immune cells.), then attaches to the CD4 receptor on target cells with its gp120 glycoprotein (binding)Cells that have CD4 receptors: T lymphocytes (e.g., T helper cells), macrophages, monocytes, dendritic cells(CNS).Viral envelope fuses with host cell, capsid enters the cell. For fusion, CD4 receptor and a coreceptor (CCR5 in macrophages, and CCR5 or CXCR4 in T-cells) must be present.Patients without CCR5 receptors appear to be resistant to HIV, those patients either have a homozygousCCR5 mutation (substantial resistance) or a heterozygous CCR5 mutation (slower course).Virion's RNA is transcribed into DNA and then integrated into the host's DNA Viral DNA is replicated and virions are assembledVirion repurposes a portion of the cell's membrane as envelope and leaves the cell (budding) → cell death Progression to chronic immunodeficency HIV infects CD4+ lymphocytes, then reproduces and spreads to other CD4+ lymphocytes near the original site of infection → infection of CD4+ lymphocytes concentrated in specialized lymphoid tissue (e.g., lymph nodes or gut-associated lymphatic tissue (GALT) ) → explosive growth and dissemination → acute HIV syndrome with high viral load Window period: The time between infection and detectability of HIV antibodies. After the acute stage, viral load decreases and remains at roughly that level for approximately 8-10 years (clinical latency stage )→ loss of CD4+ lymphocytes (especially T cells) impairs immune function and thereby facilitates opportunistic infections and development of malignancies (AIDS) → these secondary diseases are usually the cause of death in patients with HIV Viral load predicts the rate of disease progression! CD4 count correlates with immune function! The role of immune response Because HIV infects cells of the immune system itself, activation of cellular immunity is a factor that paradoxically helps the virus spread and ensures chronic persistence of the infection. HIV evades immune control via: Genetic mutation and recombination Downregulation of MHC class I surface molecules in infected cells General considerations In early HIV infection, patients are often asymptomatic. Incubation period: usually 2-4 weeks Infectiousness: two peaks (1st peak: within the first months after infection; 2nd peak: during AIDS-stage) Acute HIV infection Also referred to as acute retroviral syndrome (ARS) or described as a mononucleosis-like syndrome. Fever Fatigue Myalgia and arthralgia Headache Generalized nontender lymphadenopathy Generalized rash Gastrointestinal symptoms (nausea, diarrhea, weight loss) Oropharyngeal symptoms (sore throat, ulcerations, painful swallowing) Clinical latency and AIDS Clinical latencyPatients may still be asymptomaticNon-AIDS-defining conditionsChronic subfebrile temperaturesPersistent generalized lymphadenopathyLocalized opportunistic infections (e.g., oral candidiasis , vaginal infections )Oral hairy leukoplakia (lesions located mainly on the lateral borders of the tongue) Chronic diarrhea (> 1 month)Skin manifestations (e.g. molluscum contagiosum, warts, exacerbations of psoriasis, shingles) AIDS: see learning card on HIV-associated conditions Test patients with a history of injecting drugs who present with otherwise unexplained weight loss, depression, and/or dementia for HIV! Candidiasis in the esophagus, unlike oral candidiasis, is an AIDS-defining condition! Primary HIV infection: acute retroviral syndrome or asymptomatic Clinical stage 1: persistent generalized lymphadenopathy (PGL) or asymptomatic Clinical stage 2: e.g., unexplained moderate weight loss (< 10%), recurrent fungal/viral/bacterial infections Clinical stage 3: e.g., unexplained severe weight loss (> 10%), unexplained chronic diarrhea (> 1 month), unexplained persistent fever (≥ 36.7°C intermittent or constant > 1 month), persistent/severe fungal/viral/bacterial infections , unexplained anemia (< 8 g/dL) and/or neutropenia (< 500 cells/μL) and/or chronic thrombocytopenia (< 50,000/μL) for more than 1 month Clinical stage 4: AIDS-defining conditions (e.g., Kaposi sarcoma) Indications Test all patients with clinical features of acute or chronic HIV infection All individuals with possible past exposure, especially high-risk individuals : regular testing (e.g., annually) One-time testing is recommended early in every pregnancy HIV-testing requires patient consent (opt-out) Initial diagnostic approach Both screening tests and confirmatory tests detect anti-HIV antibodies in the blood Screening testsCombination antigen/antibody tests : detect both HIV antigen (p24) and anti-HIV antibodies → a negative result essentially rules out HIV infection (almost 100% sensitivity)Antibody-only tests (HIV serology) ELISA (enzyme-linked immunosorbent assay): standard method for detecting antibodies within approx. 1-3 hours; requires laboratoryRapid tests: can deliver results in ∼ 20 minutes and do not require a laboratory, which makes them suitable as an alternative to the more complex tests in some outpatient settings. Confirmatory testsHIV-1/HIV-2 antibody differentiation immunoassay : can detect both HIV-1 and HIV-2 in ∼ 20 minutes and distinguish between the two typesWestern blot: tests may be negative up to 2 months after infection; results are usually available after several days and HIV subtype O is not reliably detected. Detection of viral RNACan detect HIV infection earlier than antibody/antigen-based tests but FDA-approved tests are limited to HIV-1Indications:Neonatal HIV infectionPatients with indeterminate results Patients presenting before seroconversionScreening of blood donors Post-treatment monitoringViral RNA load: indicator of ART responseDecrease in viral loads indicates effective treatmentPrognostic marker in long-term treatment CD4+ count: correlates with overall immune function CD4+ counts increase in response to successful ART therapyCritical measurement for initiating opportunistic infection prophylaxisCD4+:CD8+ ratio: Used in the immunological evaluation of long-term follow-up casesExpected increase in ratio with successful ART therapyCorrelates with immune dysfunction and viral reservoir size CBC: possibly lymphocytopenia Antiretroviral HIV therapy General approachAll persons infected with HIV (regardless of CD4 count) should begin combined antiretroviral therapy (cART) as soon as possible. Therapy should be determined based on the HIV genotype Antiretroviral drugs Nucleoside reverse transcriptase inhibitors (NRTI): e.g., zidovudine, lamivudine, emtricitabine, abacavir, stavudine, didanosineMechanism of action: NRTIs act as nucleoside analogs → prevent the formation of 3' to 5' phosphodiester linkages → inhibit reverse transcription of RNA to DNANRTIs require intracellular phosphorylation for activation, and their efficacy is thus reliant on kinase availability and activity, which is variable depending on cell functionality and activation state.Side effectsBone marrow suppression → neutropenia, anemiaMitochondrial toxicity → myopathy, neuropathy, hepatic steatosis, and lactic acidosisAbacavir-related hypersensitivity syndrome Didanosine/stavudine: pancreatitisHIV-associated lipodystrophy: abnormal distribution of fat (clinical presentation varies greatly) Loss of subcutaneous fatty tissue (lipoatrophy) of face and extremitiesMetabolic changes: impaired glucose tolerance, hyperlipoproteinemia (elevated triglycerides, elevated total cholesterol, lowered HDL)Probable accumulation of fat in liver, muscles, abdomen, breasts and neck (buffalo hump)Resistance: caused by mutations in the gene that codes for reverse transcriptase (pol gene) Non-nucleoside reverse-transcriptase inhibitors (NNRTI): e.g., nevirapine, efavirenzMechanism of action: non-competitive inhibitors of viral reverse transcriptaseNNRTIs do not require intracellular phosphorylation for activation but are direct inhibitors.Side effects:Hepatotoxicity (nevirapine)CNS toxicity (efavirenz)Hypersensitivity reactions (including Stevens-Johnson syndrome) Nucleotide analogs (also called nucleotide reverse-transcriptase inhibitors; NtRTI): e.g., tenofovir Protease inhibitors (PI): e.g., indinavir, ritonavir, nelfinavir, lopinavirMechanism of action: inhibition of viral protease → inability to cleave viral polypeptides → generation of viral proteins impaired → only immature (non-infectious) virions are producedSide effects:GI intolerance (nausea, diarrhea), lipodystrophy and fat accumulation , nephrolithiasis and crystal-inducednephropathyHyperglycemia: inhibition of insulin-dependent glucose transporters (GLUT 4) → peripheral insulin resistance→ impaired glucose tolerance Integrase inhibitors (INI): e.g., raltegravir, dolutegravirMechanism of action: inhibition of the viral integrase . Fusion inhibitor: enfuvirtideMechanism of action: competitively binds to the viral protein gp41 and thereby prevents fusion with the cell CCR5-antagonist: maravirocMechanism of action: blocks the CCR5 coreceptor that is essential to cell infection for some HIV genotypes(R5 viruses) Not generally recommended because of comparatively high costs and limited clinical data Recommended regimens3 NRTI (e.g., zidovudine, lamivudine, abacavir) OR2 NRTI (e.g., lamivudine + abacavir) AND1 NNRTI (e.g., efavirenz) OR1 PI (e.g., lopinavir) OR1 INI (e.g., raltegravir) Hepatotoxic drugs (e.g. nevirapine) are contraindicated if there is coinfection with HBV or HCV! Most NRTIs end in "-ine", protease inhibitors in "-navir", and integrase inhibitors end in "-gravir!" Complications See the learning card on HIV-associated conditions Prognosis Morbidity and mortality among patient subsets Untreated HIV infection has a mortality rate of > 90% (average time from infection to death approx. 8-10 years) Progression varies among individuals: some patients may die within a few years while others remain asymptomatic for decades Untreated individuals with advanced HIV infection usually die within a few years (median survival is 12-18 months) Some untreated individuals show only slow progression and can remain asymptomatic for more than 20 years. In rare cases, untreated individuals have no detectable viremia and continue to have high CD4 counts for long periods The average life expectancy of HIV-infected patients who receive adequate antiretroviral treatment is ∼ 8 yearslower than noninfected individuals of the same age. Individual prognosis depends on various factors, including: Adequate antiretroviral treatment Viral set point and CD4 count Exposure to opportunistic pathogens ,Individual genetic propertiesHIV species and subtypePreexisting conditions Prevention HIV post-exposure prophylaxis Indications Injury with HIV-contaminated instruments or needlesContamination of open wounds or mucous membranes with HIV-contaminated fluidsUnprotected sexual activity with a known or potentially HIV-infected person Timing: Initiate as soon as possible (ideally within one to two hours after exposure) Drugs: A three-drug regimen is recommended (similar to cART treatment). Typically, this includes a nucleoside/nucleotide combination NRTI plus an integrase inhibitor: Tenofovir-emtricitabine + dolutegravirTenofovir-emtricitabine + raltegravir Measures after needle stick injury or other contaminationLet the wound bleed. Rinse/flush with water and soap and/or antiseptic agent.Immediately seek medical attention.If occupational exposure: report incident immediately. Vaccinations in HIV-infected individuals Efficacy of immunization is reduced in HIV-infected individuals (due to impaired immune function) The immunization schedule should be observed with the exception that: live-attenuated influenza, varicella zoster, and MMR vaccines should not be given if CD4 count < 200 cells/μl (CD4 percentage < 15% in patients ≤ 5 years) or if AIDS-defining conditions are present. The inactivated polio vaccine should be used instead of the live-attenuatedpolio vaccine. Immunizations that are not part of the standard immunization schedule: Inactivated vaccines are generally safeLive vaccines should generally not be given to severely immunocompromised patients HIV in pregnancy TransmissionHighest risk during birth (perinatal vertical transmission)Prenatal transmission is possibleRisk depends on maternal viral load Reducing risk of transmissionCombined antiretroviral therapy (cART) is recommended throughout pregnancy However, most antiretroviral drugs are not approved for use during pregnancy. Delivery method Viral load > 1,000 copies/mL (or unknown) near time of delivery: increased risk of HIV transmissionCesarean delivery should be scheduled at 38 weeks (even if the mother received cART during pregnancy)HIV post-exposure prophylaxis with zidovudine, lamivudine and nevirapine OR zidovudine and nevirapineViral load ≤ 1,000 copies/mL and mother has received cART during pregnancy: low risk of HIV transmissionVaginal delivery may be considered as an alternative to cesarean sectionHIV post-exposure prophylaxis with zidovudine for the newbornBreastfeeding should generally be avoided , because risk of transmission is 5-20% . Diagnosis in infants: if < 18 months, diagnosis is confirmed via PCR, not ELISA Suspect HIV in infants with failure to thrive, diffuse lymphadenopathy, diarrhea, and thrush, especially if the mother is a high-risk parent!

Pyogenic liver abscess A pyogenic liver abscess is a rare disease characterized by solitary/multiple collections of pus within the liver. The infection is caused by bacteria and is usually polymicrobial, with E. coli and K. pneumoniae being the common causative organisms. The majority of cases are caused by ascending infection from a biliary tract pathology (e.g., cholangitis due to choledocholithiasis, i.e. biliary strictures). Due to the liver's dual blood supply from the portal vein and the hepatic artery, an infectious focus in the gastrointestinal tract or bacteremia exposes the liver to high bacterial loads. Patients, typically middle-aged/elderly males, present with non-specific symptoms, such as fever, malaise, and weight loss. Right upper quadrant pain and tender hepatomegaly are specific features of a liver abscess but are often absent. Diagnosis is confirmed on abdominal imaging (ultrasound or CT), which demonstrates intrahepatic fluid-filled lesions with surrounding edema. Broad-spectrum IV antibiotics (ampicillin + sulbactam) and percutaneous/surgical drainage of the abscess cavity is the mainstay of treatment. Complications include sepsis, pneumonia, and abscess rupture into the peritoneum/thorax. Advancements in diagnostics and treatment have reduced the complications and mortality rates of pyogenic liver abscesses.

Epidemiology Incidence: 2-3 cases per 100,000 people in the United States Peak incidence: 50-60 years Sex: slight male predominance Risk factors Diabetes mellitus Hepatobiliary disease (e.g., cholelithiasis, transplant recipients, hepatic tumors) Pancreatitis Gastrointestinal malignancy (esp. colorectal carcinoma) Crohn's disease Etiology by source Biliary tract (∼ 60%): Most common cause Choledocholithiasis Biliary strictures Cholangitis Portal vein (∼ 20%) Acute appendicitis Diverticulitis Crohn's disease Gastrointestinal malignancies Peritonitis (bowel perforation) Hepatic artery (∼ 15%) Sepsis Bacteremia (infectious endocarditis, IV drug use) Contiguous area (< 5%) Subphrenic abscess Perinephric abscess Pancreatic abscess Trauma (Rare) Penetrating trauma (e.g. gunshot or surgery) Blunt trauma Others Cryptogenic (∼ 20%) Secondary infection of hepatic tumors Secondary bacterial infection of amebic liver abscess (Entameoba Histolytica) Secondary infection of hydatid cyst of the liver (Echinoccos) Hepatic chemoembolization Microbiology Pyogenic liver abscess (80% of liver abscesses)Polymicrobial infection (most common)E. coli is the most common causative organism.K. pneumoniae is the second most common. Other causative bacteria: Enterococci, Streptococci, Staphylococcus aureus, Proteus vulgaris, anaerobes Non-pyogenic liver abscessFungal infection (< 10% of cases): Candida species (most common) Amebic liver abscess (< 10% of cases): Entamoeba histolytica Clinical features Classic triad of pyogenic liver abscess Fever (with/without chills and rigors) MalaiseRight upper quadrant pain Other symptomsAnorexia and weight lossNausea and vomitingSymptoms of diaphragmatic irritation Physical examinationJaundiceTender hepatomegalyIntercostal tenderness Epigastric tenderness Decreased breath sounds in right lower lobe of the lung Features of sepsis Diagnostics Laboratory tests Complete blood count: neutrophilic leukocytosis, normocytic normochromic anemia Liver function tests: ↑ alkaline phosphatase (90%), ↑ AST and ALT, hypoalbuminemia, hyperbilirubinemia Inflammatory markers: ↑ ESR and CRP Blood culture: positive in ∼ 50% of cases Imaging Abdominal imaging is a confirmatory test for pyogenic liver abscess Abdominal ultrasound (US): seen as solitary/multiple, poorly demarcated, fluid-filled, round hypoechoic lesion(s) within the hepatic parenchyma with surrounding edema and hyperemia . Abdominal CT scan: Findings are similar to those on abdominal ultrasound; a peripheral rim enhancement is seen on IV contrastadministration. Percutaneous aspiration and culture of the aspirate Both diagnostic and therapeutic (see "Treatment" section below) Performed under US or CT guidance Aspirated material is cultured to determine the organism and its antibiotic-susceptibility profile. Differential diagnoses Pyogenic liver abscesses need to be differentiated from other space-occupying lesions of the liver. Amebic liver abscess Hepatic echinococcosis (hydatid cyst of the liver) Hepatic cysts Benign liver tumors Hepatocellular carcinoma Liver metastases Treatment Pyogenic liver abscesses are generally treated with both IV antibiotics and percutaneous drainage of the abscess. Some patients may require surgical drainage. Antibiotics Indicated in all cases Broad-spectrum IV antibiotics: ampicillin + sulbactam; piperacillin + tazobactam; 3rd generation cephalosporin + metronidazole (until antibiotic susceptibility is available) Drainage of the abscess cavity Indicated in nearly all cases of pyogenic liver abscess Indication for percutaneous drainage/needle aspiration: solitary abscess Small (< 5 cm) abscess: percutaneous needle aspirationLarge (> 5 cm) abscess: percutaneous drainage and intracavitary catheter placement If percutaneous drainage/aspiration fails, a second attempt at percutaneous drainage/aspiration can be made before abscess will require surgical drainage. Indications for surgical drainage (open/laparoscopic)Multiple or loculated abscessesDeep-seated abscess not amenable to percutaneous drainageRuptured abscessThick viscous pus which cannot be drained percutaneouslyUnderlying disease which requires surgical intervention (e.g., choledocholithiasis, appendicitis, etc.) Contraindications: coagulopathy (e.g., international normalized ratio (INR) > 1.5; thrombocytopenia due to sepsis) Complications Rupture Into the abdomen → peritonitisInto the chest → empyemaInto the retroperitoneum → retroperitoneal abscess Sepsis Pneumonia Pleural effusion Prognosis Mortality ratesUntreated pyogenic liver abscess: 100%With treatment: ∼12 % Poor prognostic factorsPyogenic abscess with sepsisAdvanced age (> 70 years)Multiple abscessesPolymicrobial infection; anaerobic infectionImmunosuppression (e.g., malignancy, diabetes)Need for surgical drainage

Shingles Shingles (herpes zoster) is a dermatomal rash with painful blistering that is caused by the reactivation of the varicella-zoster virus (VZV). The initial infection with VZV usually occurs early in life, presenting as chickenpox (varicella), after which the virus remains dormant in the dorsal root ganglia. Immunocompromised individuals (e.g., from stress or as a result of naturally declining immune function with age) are at increased risk of VZV reactivation. Shingles is generally a clinical diagnosis, although further testing (e.g., PCR) may be indicated in unclear cases. Treatment with antiviral drugs, such as acyclovir, is usually effective. Potential complications include encephalitis and, particularly in the elderly population, painful postherpetic neuralgia. VZV may also affect the cranial nerves. Involvement of the trigeminal nerve may cause visual impairment up to blindness (herpes zoster opthalmicus), while involvement of the facial and vestibulocochlear nerves can cause facial paralysis and hearing loss (herpes zoster oticus). These presentations, in particular, require urgent medical attention to prevent serious complications.

Epidemiology Incidence: 215/100,000 per year Sex: ♀ = ♂ Peak incidence: Approx. ⅔ of patients are older than 50 years; incidence increases with age Immunocompromised individuals are at particular risk of VZV reactivation and may be caused by: Decline in immune function with advancing age Chronic stress Malignancy HIV infection, acquired immune deficiency syndrome (AIDS) or immune reconstitution inflammatory syndrome (IRIS) Immunosuppressive therapy Malnutrition Primary infection (chickenpox): respiratory transmission → VZV inoculates the lymphoid tissue of the nasopharynx and, subsequently, regional lymphoid tissue → viremia + chickenpox → recovery from chickenpox, but virus remains dormant in dorsal root ganglia (unless reactivated → recurrent infection) Recurrent infection (shingles): VZV reactivated (e.g., due to immunocompromise) → virus replicates in the dorsal root ganglia → travels through peripheral sensory nerves to the skin → shingles (less contagious than primary infection) Clinical features Fever, headaches, fatigue Dermatomal distribution typically of 1-3 dermatomes on one side of the body, most commonly between T3 and L3 → torso, hips, waist, groin, and ventral region of the upper legs) Severe pain Usually described as "burning", "throbbing", or "stabbing"Allodynia may occurRashErythematous maculopapular rash that quickly evolves into vesicular lesionsVesicles are initially clear → pustulation and rupture typically occur after 3 or 4 days Crusting and involution typically occurs between day 7 and 10 Lesions may become necrotic (herpes zoster gangrenosum), generalized (herpes zoster generalisatus ) or may not present at all (zoster sine herpete) .ParesthesiaItching Motor deficits (rare) Disseminated disease (rash involves more than the primary 1-3 dermatomes) may occur in immunocompromised individuals Herpes zoster ophthalmicus Definition: reactivation of VZV in the ophthalmic division of the trigeminal nerve Clinical featuresFever and skin symptoms as in shingles (see "Symptoms/clinical findings" above) Herpes zoster keratitisInvolvement of the ophthalmic nerve: reduced corneal sensitivity with severe pain in the innervated regions (forehead, bridge and tip of the nose) Involvement of the nasociliary nerve: Severe intraocular infection is possible (uveitis, iritis, conjunctivitis, keratitis, and optic neuritis) Zoster lesion on the tip of the nose = positive Hutchinson's sign Herpes zoster oticus Definition: reactivation of VZV in the geniculate ganglion, affecting the seventh (facial) and eighth (vestibulocochlear) cranial nerves(also known as Ramsay Hunt syndrome) Clinical featuresFever and skin symptoms as in shingles in the auditory canal and pinna (see "Symptoms/clinical findings" above)Eighth nerve → vertigo and sensorineural hearing loss (SNHL) Seventh nerve → facial paralysis Diagnosis: tone audiometry Herpes zoster ophthalmicus can lead to blindness! Herpes zoster oticus can result in hearing loss and permanent facial paralysis on the affected side! Clinical presentation is usually sufficient for diagnosis. If the clinical picture is not conclusive, diagnosis is confirmed by laboratory tests (e.g., PCR, DFA test), especially if encephalitis is suspected ) Tzanck test of lesions shows multinucleated giant cells with eosinophilic, intranuclear Cowdry A inclusions Potential malignancies should be ruled out in a recurrent herpes zoster infection of unknown cause! Treatment of skin lesions (e.g., wet dressings with 5% aluminum acetate) Anti-inflammatory and analgesic therapy Antiviral therapy :acyclovir, valacyclovir or famciclovir Immunocompromised patients and/or those with disseminated disease should receive IV acyclovir. Consider hospitalization if: The patient is immunocompromisedSymptoms are atypical and/or severe (e.g., pain that requires strong medication, involvement of more than two dermatomes or dissemination )Signs of myelitis, meningoencephalopathy, ophthalmic involvement or severe bacterial superinfection Complications Post-herpetic neuralgiaEpidemiologyOccurs in ∼ 10-15% of overall herpes zoster casesStrong association with age Clinical features: attacks of acute, intense pain, persisting for at least 3 months in the area previously affected by the rashTreatmentFirst choice: tricyclic antidepressants (e.g., amitriptyline) Relative contraindications: patients with heart disease, epilepsy, or glaucomaShould be used in caution with elderlyAlternatives: gabapentin, pregabalin Second-line: topical capsaicin, opioids, intrathecal glucocorticoid injectionsPrognosis: Chronic pain develops in approximately 25-50% of affected individuals if remission does not occur within 12 months Herpes zoster encephalitisRisk factors: impaired immunity, more than one prior episode of herpes zoster infection, cranial/cervical affliction or disseminated zosterUsually manifests as delirium within days after vesicular eruption Often results in stroke Prevention Chickenpox: live vaccine that is recommended for: Children: 1st dose at 12-15 months, 2nd dose at 4-6 years (see "Immunization schedule")Persons aged ≥ 13 years with insufficient immunity (with or without previous vaccination) Shingles: live vaccine≥ 50 years: zoster immunization is generally recommended

Leptospirosis Leptospirosis is a zoonotic disease caused by gram-negative Leptospira bacteria. Direct transmission to humans occurs when broken skin and mucous membranes come into contact with the urine of infected animals such as rodents. The early phase of the disease is mild and characterized by non-specific symptoms (e.g., fever, headache, and myalgia). In most cases, symptoms resolve spontaneously after a week. However, in 10% of cases, the disease progresses rapidly to a severe form (icterohemorrhagic leptospirosis, or Weil disease), which typically presents with a triad of jaundice, bleeding manifestations, and acute kidney injury. Diagnosis is based on patient history, clinical findings, and laboratory tests. Treatment consists of antibiotics and supportive care.

Epidemiology Leptospirosis is the most common zoonotic disease worldwide and is most common in the tropics Low incidence in the US (100-200 cases per year): Half of these are cases reported in Hawaii. Etiology Pathogen: Leptospira (especially L. interrogans) is a genus of gram-negative spirochete bacteria. Route of infection Contact with soil, food, and/or water contaminated with the urine of infected animals → entry of Leptospira through skin/mucous membrane lesionsOccupational groups at risk: farmers, sewer workers; water sports enthusiasts may also be affected. Clinical features The incubation time is 2-30 days. The disease has a mild form, which is characterized by non-specific symptoms that generally resolve spontaneously after a week. In 10% of cases, the disease progresses rapidly to a severe form (icterohemorrhagic leptospirosis, or Weil disease). Mild (anicteric) leptospirosis Clinical manifestations during the early phase are due to bacteremiaHigh fever, headacheDiarrhea, vomitingConjunctival suffusion: bilateral diffuse reddening of the conjunctivae Rash Myalgias (especially in the calves and lower back) Severe leptospirosis (Weil disease, icterohemorrhagic leptospirosis) Clinical features are due to systemic spread and multiorgan involvement Hepatitis → hepatomegaly, jaundice, acute liver failureHemorrhagic diathesisPurpuraPulmonary hemorrhage → hemoptysisAcute kidney injury (interstitial nephritis, acute tubular necrosis) → oliguria, hematuriaCardiac abnormalities (e.g. myocarditis, pericarditis, arrhythmia, conductivity impairment) Diagnostics Dark-field microscopy of urine or blood samples Serological tests PCR: detect leptospiral DNA in bodily fluids Culture Treatment For mild leptospirosis: aminopenicillins (ampicillin, amoxicillin), doxycycline For severe leptospirosisIV penicillin G (drug of choice), 3rd generation cephalosporins (e.g., ceftriaxone)Supportive therapy for multiorgan failure Prevention Leptospirosis is a notifiable disease. [2] Disease control: implement appropriate pest control, vaccination of livestock and pets

Pelvic inflammatory disease Pelvic inflammatory disease (PID) is caused by a bacterial infection that spreads beyond the cervix to infect the upper female reproductive tract, including the uterus, fallopian tubes, ovaries, and surrounding tissue. The most common pathogens that cause PID are Chlamydia andGonococci. Symptoms may vary considerably; while some women are asymptomatic, others may complain of mild pressure pain and discharge or present with signs of systemic inflammation such as fever and severe abdominal pain. Diagnosis is based on clinical findings and may be supported by ultrasound, PCR, and/or cultures of cervical and urethral discharge. Calculated parenteral antibiotic therapy is indicated in women with suspected PID. Complications include sterility due to impairment of the fallopian tubes.

Epidemiology Lifetime prevalence in the US (women aged 15-44): ∼ 6% > 1 million women experience an episode of PID/year. PID is one of the most common causes of infertility. Etiology PathogenMost common: Chlamydia trachomatis and Neisseria gonorrhoeaeLess common (consider coinfections): E. coli, Ureaplasma, and other anaerobes Risk factorsMultiple sexual partners, unprotected sexA history of prior STIs and/or adnexitisInfrequently: IUD [4] Risk is lower during pregnancy but if occurs PID increases the risk of maternal morbidity and preterm births. [5] Possible sites of infectionCervix (cervicitis), or endometrium (endometritis)Fallopian tubes (salpingitis), ovaries (oophoritis), or a combination of both (adnexitis)Surrounding pelvic structures or even the peritoneum (peritonitis) Clinical features Lower abdominal pain (generally bilateral), which may progress to acute abdomen Nausea, vomiting Fever Dysuria, urinary urgency Menorrhagia and metrorrhagia Dyspareunia Abnormal vaginal discharge Diagnostics Diagnosis is primarily based on clinical findings. Further diagnostic tests help confirm the diagnosis, especially in ambiguous cases. Important diagnostic criteriaPatient history: most often a sexually active young womanLower abdominal painVaginal examination Cervical motion tenderness (CMT) Uterine and/or adnexal tenderness Purulent, bloody cervical and/or vaginal discharge Blood tests: elevated ESR, leukocytosis Pregnancy test: to rule out an (ectopic) pregnancy. Cervical and urethral swab: gonococcal and chlamydial DNA (PCR) and cultures (see gonorrhea and chlamydia infections) Giemsa stain of discharge can show cytoplasmic inclusions in C. trachomatis infections, but not N. gonorrhoeae ImagingUltrasound: free fluid, abscesses, pyosalpinx/hydrosalpinx Exploratory laparoscopyIndication: in ambiguous cases and if patient does not respond to treatment PID may present with symptoms of appendicitis due to periappendicitis or perihepatitis. Symptoms may also resemble those of an ectopic pregnancy! Ectopic pregnancyLower unilateral abdominal pain and guardingVaginal bleedingAmenorrheaPositive pregnancy testUltrasound shows echogenic massMethotrexate or surgical removalPIDLower bilateral abdominal painFeverMenorrhagia and metrorrhagiaDyspareuniaCervical dischargeCervical motion tenderness (CMT)AntibioticsAppendicitisInitially diffuse epigastric painLater localized right lower quadrant painNausea and vomitingFeverMcBurney's point tendernessUltrasound shows appendiceal diameter of > 6 mm.AppendectomyKidney stonesUnilateral colicky flank painPain may radiate to the lower abdomen and genital areaHematuriaUltrasound shows urinary tract obstruction and radiolucent stones.Destruction or removal of stoneOvarian cyst ruptureUnilateral abdominal painSudden onset during physical activity (exercise, sexual intercourse)Ultrasound: adnexal mass and fluid in the pelvisNegative pregnancy testContinued surveillance or surgery Cervicitis Definition: inflammation of the uterine cervix EtiologyInfectious (most common): C. trachomatis, N. gonorrhea, herpes simplex virus, T. vaginalisNoninfectious : localized trauma (e.g., cervical caps, diaphragms, tampons), chemical irritation (e.g., contraceptive creams, latex exposure), malignancyRisk factors: multiple partners, young age, new sexual partner within the last 6 months, unprotected intercourse Clinical featuresOften asymptomaticUsually no fever Vaginal discharge: may be purulent, blood-tinged, and/or malodorousDyspareuniaPostcoital or intermenstrual bleedingLower abdominal or pelvic pain Symptoms of the underlying condition (e.g., genital lesions in HSV infections)Physical examination Abdominal palpation: tenderness/discomfortBimanual examination: motion tenderness of the cervixPelvic examination: erythematous, edematous, friable cervix ; possibly visible discharge DiagnosticsDiagnosis mainly clinical Further tests for identification of a pathogen Assess vaginal secretions for appearance, pH <4.5 , leukocyte count, and visible pathogens (e.g., protozoa in T. vaginalis infections)Swab samples for bacterial cultureNAAT for N. gonorrhea and C. trachomatis TreatmentAntibiotics are tailored to the organism causing infection (see gonorrhea, chlamydia infections, trichomoniasis, herpes simplex virus infections).Evaluate sex partner(s) of patients with infectious cervicitis.Follow-up to evaluate treatment success. Complications: PID Treatment Empirical antibiotic therapy (also consider coinfections!) Outpatient regimen One single dose of IM ceftriaxone and oral therapy with doxycyclineIf signs of vaginitis or recent gynecological instrumentation → add oral metronidazole.Inpatient regimen (parenteral antibiotics) Indications: no response to or unable to take outpatient oral regimen, non-compliance concerns (e.g., teenagers), high fever Cefoxitin or cefotetan plus doxycycline or Clindamycin plus gentamicinSwitch to oral therapy with doxycycline after clinical improvement. Complications Short-term complicationsPelvic peritonitisFitz-Hugh-Curtis syndrome (perihepatitis) Long-term complicationsTubo-ovarian abscess: may spread to adjacent organs (e.g., bladder, bowel)Infertility: caused by adnexitis, adhesion of the fallopian tubes and ovaries, and tubal scarring (resulting in loss of ciliary action and tubal occlusion)Ectopic pregnancyChronic salpingitis and hydrosalpinx

Hepatitis B Hepatitis B virus (HBV) is a common viral infection worldwide and can be transmitted sexually, parenterally, or perinatally. After an incubation period of 1-6 months, most patients present with an asymptomatic or mild inflammation of the liver, which usually resolves spontaneously within a few weeks or months. However, 5% of all adult patients and 90% of infants born to a hepatitis B-positive mother develop chronic hepatitis. Chronically infected individuals may be either asymptomatic carriers or exhibit ongoing hepatic inflammation with an increased risk of liver cirrhosis and hepatocellular carcinoma. Serologic testing, which is decisive for diagnosing HBV, initially involves measurement of HBs antigen. An increase in serum anti‑HBs (also known as seroconversion) is a sign of recovery or successful immunization. Chronic hepatitis is indicated by persistently elevated HBs antigen levels, as well as high HBV DNA and transaminase levels in cases of persistent liver inflammation. Treatment of acute hepatitis B consists of supportive measures. In the case of fulminant hepatitis, liver transplantationmay be necessary. For chronic hepatitis B, pegylated interferon alpha and nucleoside/nucleotide analogs (e.g., tenofovir) are used to reduce viral replication and infectivity. Prophylactic immunization with a recombinant vaccine is recommended for all age groups. Other preventative measures include post-exposureprophylaxis for newborns of hepatitis B-positive mothers and unvaccinated individuals with recent exposure to those who are hepatitis B-positive.

Epidemiology More than 248 million people worldwide are chronically infected. ∼ 600,000 deaths annually from HBV-related liver disease High prevalence in Asia, Africa, and the Amazon basin United States In 2014, there were 20,000 new hepatitis B infections and ∼ 2 million people with chronic hepatitis B.Acute hepatitis B has declined by ∼ 82% after the introduction of the hepatitis B vaccine in 1991. Virus Hepatitis B virus (HBV: DNA virus, hepadnavirus) Transmission The frequency and patterns of transmission vary worldwide. Sexual ParenteralNeedlestick injury Contaminated instruments and shared needles Contaminated blood products Perinatal High-risk groups for HBV infection IV drug users Individuals whose close contacts have chronic HBV infection Infants of HBV-positive mothers Professions with exposure to human blood and/or seminal/vaginal fluids Individuals with multiple sex partners or sex partners of HBV-positive people Patients undergoing hemodialysis; organ or blood transfusion recipients Hepatitis C virus (HCV) or HIV-positive individuals Acute infection Hepatocytes infected by the hepatitis B virus express viral peptides on their surfaces → lymphocytes recognize HBV-derived peptides and become activated (CD8+ cytotoxic T cells) → lymphocytes attack liver cells (cellular immune response) → hepatic inflammation with destruction of hepatocytes Replication cycleAfter entering the host cell's nucleus, the viral polymerase completes the positive strand of the virus' partially double-stranded relaxed circular DNA(rcDNA).The rcDNA is converted to covalently closed circular DNA (cccDNA) primarily by host enzymes in a process that is not entirely understood. The cccDNA is then transcribed into viral mRNA by host RNA polymerase.The viral mRNA leaves the nucleus and is translated into HBV core proteins and reverse transcriptase in the cytoplasm.Viral mRNA and reverse transcriptase are packaged into a capsid, where viral mRNA is then reverse-transcribed into viral rcDNA.New viral DNA genomes are enveloped and leave the cell as progeny virions. Chronic infection If clearance of the virus fails Persistent hepatic inflammation with necrosis, mitosis, and regeneration processes → cirrhosis, cellular dysplasia → HCC Integration of HBV DNA into the host genome → altered expression of endogenous genes, chromosomal instability → HCC Incubation period 1-6 months Acute infection Acute HBV infections are defined as infections that were acquired in the past 6 months. Serum sickness-like syndrome can develop during the prodromal (preicteric) period: rash, polyarthritis, fever Subclinical hepatitis (70% of cases) Symptomatic hepatitis (30% of cases; see also acute viral hepatitis)Fever, skin rash, arthralgias, myalgias, fatigueNauseaJaundiceRight upper quadrant painSymptoms usually resolve after 1-3 months Fulminant hepatitis (∼ 0.5% of cases) Most adults will clear infection Recovery rates in adults are very good, with less than 5% of cases progressing to chronic infections. In contrast, the risk of developing chronic hepatitis is considerably higher in infants infected perinatally (90%) and young children (20-50%)! Chronic infection Chronic HBV infections are defined as infections persisting for more than 6 months with detection of HBsAg and possibly symptoms of liver damage. Most patients are inactive, non-contagious carriers. Potential reactivation of chronic inactive hepatitis: may be asymptomatic , imitate acute hepatitis, or result in hepatic failure Cirrhosis, stigmata of chronic liver disease (25% of cases) Extrahepatic manifestations (10-20% of cases) Polyarteritis nodosaMembranous glomerulonephritis HBsAg Hepatitis B surface antigen Protein on the surface of HBV; first evidence of infection Anti-HBsIndicates immunity to HBV due to vaccination or resolved infectionUsually appears 1-3 months after infection. HBcAg Hepatitis B core antigen Protein of the nucleocapsid Anti‑HBcAnti-HBC IgM indicates recent infection with HBV (≤ 6 months)Anti-HBc IgG indicates resolved or chronic infections HBeAg Hepatitis B envelope antigen Protein secreted by the virus that indicates viral replication and infectivity Anti‑HBeIndicates long-term clearance of HBV HBV DNA DNA of HBV Inactive chronic infection HBV DNA≤ 2000 IU/mL Testing algorithm Screening: HBsAg (detectable 1-5 months after infection) and anti‑HBc IgMIf HBsAg is positive → measure HBeAg and HBV DNA Seroconversion of HBsAg to anti‑HBs indicates acute hepatitis resolution. Additional tests Laboratory studies Transaminases (AST, ALT)Acute hepatitis: ↑ with AST/ALT ratio of < 1 (> 1 in fulminant infection)Chronic hepatitis: variable values (usually < 100 U/L; in active infection > 100 U/L) with AST/ALT ratio of ≥ 1↑ γ‑GT, bilirubin, GLDH, and/or APIn cirrhosis: ↓ albumin, CHE Abdominal ultrasoundAcute hepatitis↑ Brightness of portal vein radicle walls↓ Echogenicity of the liverChronic hepatitis↓ Brightness and number of portal vein radicle walls↑ Liver echogenicity Liver biopsy (see "Pathology" below) Test of common coinfections (e.g., hepatitis C/D, syphilis, HIV) Pathology Acute viral hepatitis Eosinophilic single-cell necrosis (Councilman body) Kupffer cell proliferation Bridging necrosis Chronic viral hepatitis Formation of lymphoid follicles and mononuclear infiltrates Piecemeal necrosis: periportal liver cell necrosis with lymphocytic infiltration ; indicates chronic active hepatitis and poor prognosis Fibrous septa Ground glass hepatocytesDefinition: Hepatocytes with swollen transparent cytoplasm due to hyperplasia of the endoplasmic reticulum.Only in hepatitis BResult from an increased production of viral membrane particles (HBsAg) Hepatitis Avirus (HAV)PicornavirusNon-envelopedvirusPositive sense, single-stranded, linear RNAFecal-oral15-50Acute hepatitis: fever, malaise, loss of appetite, nausea, abdominal pain, jaundice, ↑ AST/ALTChildren < 6 yearsoften have no symptomsAnti-HAVIgMSupportiveFood and water hygieneImmunizationFull recoverywithin ∼ 3 monthsDoes not become chronicHepatitis Bvirus (HBV)HepadnavirusEnveloped virusPartially double-stranded, circular DNAParenteral, sexual, perinatal30-180Often asymptomaticSerum sickness-like reaction in prodrome phaseAcute hepatitis(see above)Stigmata of cirrhosis in chronic casesHBsAgAnti-HBcHBeAg Acute: supportiveChronic: interferon-α or tenofovirSafe sex; screening of blood products; use of sterile instruments and needlesHBVvaccination, post-exposureprophylaxisFulminant hepatitisChronic disease (possibly cirrhosis, HCC)Hepatitis Cvirus (HCV)FlavivirusEnveloped virusPositive sense, single-stranded, linear RNAParenteral(rarely sexual or perinatal)14-180Often asymptomaticAcute hepatitis(see above)Stigmata of cirrhosis in chronic casesAnti-HCVIgMHCV RNAAcute: interferon-α or peginterferon-αChronic: interferon-αplus ribavirin or DAAs (cure possible)Liver transplantationUse of sterile instruments and needles; safe sexNo vaccinationfor HCVavailableChronic disease (possibly cirrhosis, HCC)Hepatitis Dvirus (HDV)DeltavirusEnveloped virusNegative sense, single-stranded, circular RNAAlways coinfection with HBVHDV is a defective virus that requires the HBsAg for entry into hepatocytesParenteral(rarely sexual, perinatal)Coinfection: 45-160Superinfection: 14-56Acute hepatitis(see above) Superinfection: worse prognosis (fulminant hepatic failure)HDV-RNAAnti-HDVIgMPeginterferon-αPrevention of HBV infection(see "Prevention" below)Fulminant hepatitisHigh risk of severe chronic liverdiseaseHepatitis Evirus (HEV)HepevirusNon-envelopedvirusPositive sense, single-stranded, linear RNAFecal-oral15-64Similar to hepatitis A, often milder courseAnti-HEVIgMAcute: supportiveFood and water hygieneFulminant hepatitisHigh mortality rate in pregnant women Treatment Acute hepatitis B Supportive care For treatment of acute liver failure, see "Complications" below Chronic hepatitis B Antiviral treatmentIndication: chronic active hepatitis B (see "Diagnostics" above) with evidence of liver inflammation (ALT ≥ 2 times upper limit) or cirrhosisGoals Reduce HBV DNA below detectable levelsSeroconversion of HBeAg to anti‑HBeReverse liver diseaseNucleoside/nucleotide analogs : indicated for patients with both decompensated and compensated liver disease and nonresponders to interferontreatment Tenofovir is commonly the drug of choice EntecavirPegylated interferon alfa (PEG-IFN-a) : especially in younger patients with compensated liver disease Regimen is shorter than nucleoside/nucleotide analogs Contraindications Decompensated cirrhosisPsychiatric conditionsPregnancyAutoimmune conditionsLeukopenia or thrombocytopeniaCoinfection with HDV is best treated with PEG-IFN-a. Surgical treatmentLiver transplantationIn cases of end-stage liver disease due to HBVIn cases of fulminant hepatic failure (emergent transplantation) Complications Hepatitis D virus infection Epidemiology: 5% of all chronically infected HBV patients are carriers of the hepatitis D virus. Pathogen: Hepatitis D virus (HDV)Incomplete viral particle resembling a viroidDefective single-stranded RNA virusUtilizes the HBsAg coat of HBV for propagation Transmission: sexual, parenteral, perinatal (only possible in combination with HBV ) Course Coinfection: more severe acute hepatitis, but 90% rate of convalescenceSuperinfection of a chronic HBsAg carrier: ↑ risk of liver cirrhosis In rare cases, fulminant hepatitis Acute liver failure Definition: rapidly worsening liver function resulting in coagulopathy and hepatic encephalopathy Fulminant liver failure: onset of hepatic encephalopathy within 8 weeks of initial symptoms (e.g., jaundice)Subacute liver failure: onset within ≤ 26 weeks EtiologyDrugs/toxins Acetaminophen toxicity (most common)Phenytoin, halothane, isoniazidAmanita phalloides Aflatoxin Further risk factors: alcohol, cocaine Viral hepatitis: hepatitis A, B, E, or B + D, CMVVascular disorders: Budd-Chiari syndrome, ischemic hepatitisPregnancy-related: HELLP syndrome, acute fatty liver of pregnancyOthers: autoimmune hepatitis, Wilson's disease Clinical featuresJaundiceSigns of hepatic encephalopathy: altered mental state, asterixisSymptoms of cerebral edema: nausea, vomiting, confusion DiagnosticsLaboratory findings: ↑ PT with INR ≥ 1.5, often ↑↑ ALT and AST, ↑ bilirubin level, and platelet count ≤ 150,000/mm3Further diagnostics: depending on the suspected underlying cause Viral serologiesToxicology screening (e.g., acetaminophen level)Autoimmune hepatitis serologyRUQ abdominal ultrasound TreatmentEarly transfer to a liver transplant center Intravenous N-acetylcysteine Address/prevent complications: e.g., cerebral edema, encephalopathy, coagulopathy, renal failure, and infection Address underlying cause: e.g., antiviral treatment for hepatitis B, steroids for autoimmune hepatitis, or delivery for HELLP syndromeLiver transplantation is the only therapeutic option for patients without sufficient regeneration of hepatocytes. Prognosis: The mortality rate without liver transplantation ranges from 30% (acetaminophen toxicity) to 80% (non-acetaminophen-related liver failure). Long-term complications of hepatitis B Liver cirrhosis Hepatocellular carcinoma (HCC) Reactivation of previous HBV infection due to immunosuppression Prevention Pre-exposure vaccination: recommended for all unvaccinated individuals (see immunization schedule) Post-exposure prophylaxis (PEP) for hepatitis BGoal: prevention of HBV infectionIndication: exposure to HBV (e.g., percutaneous, ocular, mucosal)Administration Documented vaccine responder with HBsIgG ≥ 10 mIU/mL: no intervention neededDocumented non-responder : Administer two doses of hepatitis B immune globulin (HBIG) separated by 1 monthUnvaccinated individuals or incompletely vaccinated: simultaneous administration of hepatitis B immune globulin (HBIG) and hepatitis B vaccine (see also perinatal hepatitis B) and completion of original vaccination seriesVaccinated with 3 doses of hepatitis B vaccine but postvaccination anti-HBs status is unknown or anti-HBs <10 mIU/mL:1 dose of HBIG andAdministration of 3 consecutive doses of the hepatitis B vaccine and retest of anti-HBs level or alternativelyAdministration of 1 dose of the vaccine and retest for anti-HBs in 1-2 months and if needed 2 additional doses and then retest anti-HBs level. Perinatal hepatitis B Whereas maternal hepatitis B infections rarely cause fetal complications during pregnancy, the risk of perinatal transmission is high, especially if the maternal viral load is increased. If an infant becomes infected, the risk of developing chronic hepatitis is 90%. Maternal screening for HBsAg should be performed on all women at the first prenatal visit. Management for HBsAg-positive mothers In mild disease and/or low HBV DNA levels, therapy may be delayed until after birthIn severe disease (e.g., cirrhosis) and/or high HBV DNA, therapy with nucleoside/nucleotide analogs (especially tenofovir) is commonly recommendedDelivery: spontaneous vaginal delivery possible Newborn immunization: within 12 hours of birth (first dose of hepatitis B vaccine series plus 1 dose of HBIG) Breastfeeding: allowed as long as passive‑active postexposure prophylaxis was given Infected newborns: Usually asymptomatic, but up to 90% risk developing chronic infection and significant risk of cirrhosis and progression to hepatocellular carcinoma if left untreatedSerum studies: Normal or only slightly elevated transaminases High viral replication rate Interferon therapy is contraindicated during pregnancy!

Congenital rubella infection

Epidemiology Most mothers have been vaccinated, so congenital infection is rare. Pathogen Rubella virus Transmission MotherMainly via airborne dropletsSee rubella. FetusTransplacental from infected motherRisk of congenital rubella syndromeIn the first trimester (period of organogenesis): 90% (especially 1-11 weeks gestation)16-20 weeks gestation: very low (< 1%)> 20 weeks gestation: no documented cases Clinical features Miscarriage, preterm birth, fetal growth restriction (especially likely if infection occurs during the first trimester) Congenital rubella syndrome Triad of congenital rubella syndromeCataracts: Other eye manifestations may also occur later in life (e.g., salt and pepper retinopathy, glaucoma).Cochlear defect: bilateral sensorineural hearing lossCardiac defect: most common defect (e.g., patent ductus arteriosus, pulmonary artery stenosis)Additional nonspecific clinical features EarlyHepatosplenomegaly, jaundiceHemolytic anemia, thrombocytopeniaPetechiae and purpura (blueberry muffin rash) Petechiae and purpura, i.e., blueberry muffin rash (caused by extramedullary hematopoiesis in the skin) Petechiae and purpura, i.e., blueberry muffin rash (in the case of congenital rubella infection the rash is caused by extramedullary hematopoiesis in the skin)Transient meningitis and/or encephalitisPneumoniaLateCNS defects: microcephaly, intellectual disability, panencephalitisSkeletal abnormalitiesEndocrine disorders (e.g., diabetes, thyroid dysfunction)Vascular diseaseImmune defects Diagnosis Newborn and motherPCR for rubella RNA (throat swab, CSF)Serology (abnormally high or persistent concentrations of IgM and/or IgG antibodies)Viral culture (nasopharynx, blood) FetusIgM antibody serology (chorionic villi, amniotic fluid)PCR for rubella RNA (chorionic villi, amniotic fluid) Treatment Intrauterine rubella infection< 16 weeks: Counsel to terminate pregnancy.> 16 weeks: reassurance Congenital rubella syndrome: supportive care (based on individual disease manifestations) and surveillance (including monitoring for late-term complications) Prevention Immunization of seronegative women before pregnancy Nationally notifiable condition: Suspected congenital rubella syndrome must be reported to the local or state health department. Triad of congenital rubella syndrome: CCC = Cataracts, Cochlear defects, Cardiac abnormality

Tinea versicolor Tinea versicolor (pityriasis versicolor) is a benign superficial skin infection that occurs most often in young adults during hot and humid weather and is most commonly caused by the fungi Malassezia globosa and Malassezia furfur. The infection is characterized by finely scaling, hypopigmented or hyperpigmented macules on the trunk. Patients often become aware of the disease after sun exposure because the lesions do not tan and become more visible against the recently tanned surrounding skin. Diagnosis is commonly made clinically, but can be confirmed with the "spaghetti and meatballs" pattern on KOH preparation of skin scrapings. Antifungal topical medications such as selenium sulfide and miconazole are considered first-line treatment. Oral fluconazole and itraconazole may be considered for those with severe, widespread, or refractory disease. Lesions will resolve completely over time, but recurrences are common.

Epidemiology Occurs worldwide, with a higher incidence in tropical climates More prevalent in healthy individuals of 15-24 years of age Etiology PathogensMalassezia globosa and Malassezia furfur are the predominant species. Dimorphic, lipophilic yeasts that are part of normal skin flora Not contagious Risk factorsWarm and humid climates Excessive sweating, seborrhea, and oily skinImmunosuppressionCushing syndromeGenetic predisposition Widely accepted mechanism: pathogens infect the stratum corneum → degrade lipids → produce acids that damage melanocytes and cause inflammation → hypopigmentation or hyperpigmentation of skin, respectively Round, well-demarcated macules that reveal a fine, subtle scale with gentle scraping → can coalesce into patches (which may have irregular shapes) Colors vary from hypopigmentation, pityriasis versicolor alba, to hyperpigmentation, pityriasis versicolor rubra, and from white to brown or reddish brown. Lesions do not tan in the sunlight. Mild pruritus Common sites are the trunk and chest, but the neck, abdomen, upper arms, and thighs may also be affected. Diagnostics Usually a clinical diagnosis Confirmatory test: potassium hydroxide (KOH) preparation of skin scrapings demonstrates the "spaghetti and meatballs" pattern Ultraviolet light (Wood's lamp) may reveal a coppery-orange or yellow fluorescence (∼ 30% of cases) Differential diagnoses Vitiligo Seborrheic dermatitis Pityriasis rosea Treatment Topical antifungals (first-line therapy) Selenium sulfide lotion or shampoo Azoles (miconazole or ketoconazole) or allylamines (terbinafine) Oral antifungalsReserved for disease that is severe, widespread, or unresponsive to topical therapy to reduce the possible risks of systemic medication (not typically used in children) Oral fluconazole or itraconazole are the preferred oral agents. The lesions will resolve without any permanent changes within 1-2 months of therapy. Recurrences are common and treatment may need to be repeated intermittently.

Fifth disease Erythema infectiosum (fifth disease) is one of the clinical syndromes caused by human parvovirus B19 infection. The virus is transmitted by respiratory droplets and primarily affects children between the ages of five and fifteen. Erythema infectiosum begins with a mild febrile illness followed two to five days later by a maculopapular rash that is especially noticeable on the cheeks (i.e., "slapped‑cheek" rash) and may be pruritic. Once the rash has appeared, the infected individual is no longer contagious and usually feels well again. Erythema infectiosum is self‑limiting, and the rash usually resolves within seven to ten days, but may be recurrent over several weeks. Whereas adult infection is characterized much more by arthritic symptoms and less by a rash, parvovirus B19 infection also manifests with joint symptoms in a minority of children. There is no specific vaccine or treatment for parvovirus B19 infection, though symptomatic treatment for arthralgias or pruritus can be used. Previous parvovirus B19 infection results in lifelong immunity against the virus. Because of its ability to infect erythrocyteprogenitor cells, parvovirus B19 can cause transient anemia in infected patients, as well as complications such as a transient aplastic crisis in patients with chronic hemolytic diseases (e.g., sickle cell disease), and chronic pure red cell aplasia in the immunocompromised. Infection with parvovirus B19 (one of the TORCHcongenital infections) during pregnancy may also have serious consequences for the fetus.

Epidemiology Peak incidence: 5-15 years Prevalence of seropositivity∼ 10% in preschool children ∼ 70% in adults Pathogen Human parvovirus B19 Family: ParvoviridaeSingle‑stranded DNA virus (linear)Nonenveloped Humans are the only reservoir for parvovirus B19. Route of transmission Main route: aerosol Other routes: Hematogenous transmissionTransplacental transmission: In seronegative pregnant women, transmission to the unborn fetus may occur (in up to 30% of cases). Pathophysiology Parvovirus B19 binds to the P antigen (globoside) on erythroid progenitor cells → cellular invasion → viral DNA enters the nucleus of erythroid cells → viral DNA replication → cytotoxicity → clinical manifestations + transient cessation of erythropoiesis Disease course Incubation period: 4-14 days Infectivity: Only contagious before onset of rash Asymptomatic in ∼ 25% of cases Clinical symptoms Mild cold‑like symptoms Exanthem: 2-5 days following the onset of cold‑like symptoms Initial diffuse redness of the face with perioral sparing (slapped‑cheek rash)Spread of exanthem to the extremities and trunkInitially confluent and maculopapular; adopts a lace‑like, reticular appearance over time as it clears.Associated with mild pruritus (in ∼ 50% of cases)Fades after ∼ 7-10 days; may be recurrent over several weeks (becoming more pronounced after exposure to sunlight or heat) Third phase with rash that varies with exposure to sun or heat and resolves spontaneously after several weeks Parvovirus B19-associated arthritis Epidemiology: affects < 10% of children and up to 60% of adults (♀ > ♂) infected with parvovirus B19 Clinical findingsArthralgia with symmetrical, nondestructive polyarthritis, particularly in the joints of the fingers, hand, knee, and ankle Usually resolves after 3-4 weeks Complications: In some cases, persistent arthritis may develop (see "Complications" below). iagnostics The diagnostic approach for parvovirus B19 infection varies by patient group. However, all groups may be affected by transient normocytic anemia with a low reticulocyte count because of the ability of the virus to infect erythrocyte progenitor cells. Immunocompetent children Erythema infectiosum is typically a clinical diagnosis (i.e., slapped‑cheek or lace‑like appearance of rash) in this patient population. Immunocompetent adults Lab tests only if diagnosis is unclear Antibody testingIgM antibodyAppears within ∼ 10 days of initial exposure, indicating acute illnessRemains positive for 2-3 monthsIgG antibodyAppears approx. 2 weeks following infectionRemains positive for life Differentiating between parvovirus B19‑associated arthritis and acute rheumatoid arthritis may require additional tests (see diagnostics section of rheumatoid arthritis) Patients with transient aplastic crisis and immunocompromised patients CBC with reticulocytes↓ Reticulocytes (0-1%) ↓ Hemoglobin below patient's baseline by ≥ 2 g/dL (aplastic crisis) or (< 8 g/dL) (severe anemia as in pure red cell aplasia) Initial diagnostic test: viral DNA testing (nucleic acid amplification testing (NAAT) such as PCR of blood or bone marrow) Adjunctive diagnostic test: serologic antibody testing (in immunocompetent adults) Pregnant women See parvovirus B19 infection during pregnancy Differential diagnoses One of the classic pediatric exanthem diseases Drug hypersensitivity reaction Rheumatoid arthritis Treatment Treatment is not necessary in most cases, as the disease is often self-limiting Analgesics and nonsteroidal anti‑inflammatory drugs (NSAIDs) Short course of low‑dose prednisone for parvovirus B19‑associated arthritis For treatment of parvovirus infection in pregnancy, see parvovirus B19 infection during pregnancy. Complications Transient aplastic crisis in patients with chronic hemolytic diseases Fifth disease Pathophysiology: parvovirus B19 infection of stem cells Treatment: blood transfusions if anemia is symptomatic Chronic pure red cell aplasia in immunocompromised patients Pathophysiology: parvovirus B19 infection of proerythroblasts Treatment: blood transfusions for severe anemia; intravenous immunoglobulin (IVIG) against parvovirus B19 Hydrops fetalis, fetal death, and miscarriage → Parvovirus B19 is a TORCH infection (see parvovirus B19 infection during pregnancy). Hepatitis, myocarditis, and aseptic meningitis/encephalitis (rare)

Croup Croup (acute laryngotracheobronchitis) is one of the most common infectious pediatric emergencies seen in winter. Commonly caused by the parainfluenza virus, croup is characterized by inflammation of the larynx and trachea. The clinical presentation varies depending on the severity of airway obstruction, but typically includes a barking cough, hoarse voice, and inspiratory stridor, all of which tend to occur at night. In moderate to severe cases, respiratory distress with subcostal and intercostal retractions occurs. Croup is primarily a clinical diagnosis, although a chest x-ray may be used to support diagnosis; laboratory tests and pulse oximetry help assess the severity of disease. In mild cases, treatment aims at alleviating symptoms and involves cold, moist air, calming the child, and corticosteroids. Moderate to severe cases require racemic epinephrine. Complications are rare: in cases of respiratory insufficiency, supplemental oxygen is necessary or even sedation and intubation. The prognosis of uncomplicated croup is good, with complete recovery occurring within seven days of onset.

Epidemiology Peak incidence: 6 months to 3 years Most common in fall and winter Etiology Most common pathogen: parainfluenza viruses (75% of cases) Second most common pathogen: respiratory syncytial virus (RSV) Other pathogens: adenovirus, influenza virus Pathophysiology Important membrane-bound virulence factors of parainfluenza virus include: Hemagglutinin: binds sialic acid → viral entryNeuraminidase: release and spread of virions Viral infection → inflammation of the upper airway with edema formation and infiltration of inflammatory cells → narrowing of subglottic airway (inspiratory stridor) and increased work of breathing Clinical features Prodromal phase Duration: 1-2 days PresentationRhinitis with nasal discharge and congestionLow-grade feverPossible erythematous pharynx Laryngotracheal inflammation phase Duration: 2-7 days PresentationSymptoms of croup primarily occur during the late evening/night.Mild: seal-like barking cough, hoarseness, and mild inspiratory stridor due to subglottic narrowingModerate: dyspnea at rest, pronounced thoracic retractions, pallor, tachycardia > 160/minSevereUpper airway obstruction can cause pulsus parodoxus.Severe tachydyspnea at rest with increasing respiratory failure, cyanosis, hypoxemia, bradycardia, and altered mental status.Infants may become agitated as a result of breathing difficulties → worsens agitation and obstruction → in severe cases, exhaustion leads to the infant being unable to breathe on his or her own. Diagnostics Croup is primarily a clinical diagnosis, but imaging may be considered in mild cases of suspected croup. Other tests (e.g., pulse oximetry, blood gas analysis) help to assess the severity of disease. Identification of the viral pathogen is rarely necessary. Based on clinical findings (see "Symptoms/clinical findings" above) Pulse oximetry X-ray of chest and neck: helps to verify subglottic narrowing, usually called steeple sign In suspected cases of respiratory insufficiency: blood gas analysis (BGA) If pneumonia or bacterial tracheitis is suspected: CBC PCR: To identify the viral pathogen in tissue (e.g., nasopharyngeal washing) Differential diagnoses Croup (subglotticlaryngitis; laryngotracheitis) Viral: primarily human parainfluenza viruses Slow: 12-48 hours Does not appear toxic Barking Cough Hoarse voice No drooling Steeple sign(subglotticnarrowing on chest x-ray) Mild croup: improvement after cool mist inhalation Moderate to severe croup: improvement after epinephrineinhalation Epiglottitis (supraglottic laryngitis) Bacterial: primarily Haemophilus influenza type B Sudden: 4-12 hours Toxic appearance (infectious state with lethargy, poor perfusion, cyanosis, hypo- or hyperventilation), drooling, upright position with extended neck NO COUGH Muffled voice Thumbprint sign (thickening of epiglottis on lateral neck x-ray) HiB vaccine 2,4,6,12 Laryngeal diphtheria Bacterial: Corynebacterium diphtheriae Initially slow, then sudden onset of symptoms after 4-5 days Toxic appearance, possible swollen neck Barking cough Subglotticnarrowing dTap vaccine Foreign body (FB) aspiration Most FB are radiolucent; focal overinflation of the distal lung may be visible Approx. 16% of FB in larynx or tracheaand 60% in the right lung Removal of FB via rigid bronchoscopy Heimlich maneuver if the child is in respiratory distress and cannot speak or cry Others Asthma/obstructive bronchitis: asthma is characterized by intrathoracic narrowing, which leads to expiratory stridor. Croup, on the other hand, is characterized by extrathoracic narrowing, which leads to inspiratory stridor! Pneumonia: No inspiratory stridor; mainly a productive cough, high fever, rales (bubbling sounds) Laryngomalacia EpidemiologyMost common cause of congenital stridorSymptoms begin within the first 2 months of life and peak at 6-8 months Pathophysiology: congenital abnormality of laryngeal cartilage → increased laxity and collapse of supraglottic structures during inspiration → airway obstruction Clinical featuresUsually happy and thriving infantsInspiratory stridor: worsens in supine position, during crying, upper respiratory tract infections, agitation, and feeding Reflux may be present Failure to thrive and sleep-disordered breathing in severe cases Diagnosis: flexible laryngoscopy: collapse of supraglottic structures during inspiration and omega-shaped epiglottis TreatmentReassurance (resolves by age 2 years in 90% of cases)Supraglottoplasty in severe cases (e.g., severe hypoxemia, apnea, pulmonary hypertension, failure to thrive) Mild croupDecrease infant's anxiety Cool mist inhalationPlacing infant to sleep in an upright positionBreathing cool air at night (especially in the winter) helps to soothe symptomsDexamethasoneReduces airway swelling within 6 hoursLong-lasting effectOral syrup, IV or IM injectionModerate to severe croupPatients with severe croup should always be hospitalizedInhaled racemic epinephrineReduces airway swelling, faster onset than with dexamethasone DexamethasoneHumidified air or oxygen if necessaryIV fluids to prevent dehydrationIntubation is indicated when airway compromise is imminent (required in < 1% of infants with severe croup) Complications Respiratory failure may occur in cases of advanced subglottic narrowing (very rare) Risk of asphyxiation Secondary bacterial infection Pulmonary edema Pneumothorax Pneumomediastinum Cardiac arrest and death Prognosis The prognosis in uncomplicated cases is good, with full recovery. Parents should be aware that croup tends to recur. Most often within a week after recoveryIf croup recurs within the peak incidence age (six months to three years), airway abnormalities should be suspected.If croup recurs outside the peak incidence age, atopic conditions, airway lesions or gastroesophageal reflux should be suspected.

Epiglottitis Epiglottitis is the rapid progressive inflammation of the epiglottis and surrounding supraglottis that historically was primarily caused by Haemophilus influenzae type b (Hib). Acute epiglottitis has become rare following the implementation of the Hib vaccine and most cases now involve other bacteria. Although acute epiglottitis can occur at any age, especially when unimmunized, young children are most commonly affected. Children suffering from epiglottitis typically appear toxic and position themselves in a tripod stance (sitting and leaning forward) in an attempt to improve their airway diameter. The disease is characterized by the acute onset of fever, drooling, sore throat, dysphagia, and in severe cases, respiratory distress accompanied by inspiratory retractions and cyanosis. Impending airway obstruction is also accompanied by a muffled voice and restlessness. Epiglottitis is diagnosed based on the clinical presentation. A lateral cervical x-raymay be considered if the diagnosis is unclear and the child is stable, in which a thumbprint sign may be present. However, appropriate management should not be delayed. Epiglottitis is a medical emergency since severe hypoxia and airway obstruction can lead to cardiopulmonary arrest. Therefore, patients should be closely monitored in a hospital and receive IV antibiotics, while severe cases require immediate intubation. Direct laryngeal examination may be performed in a controlled environment after airway control. Most patients make a full recovery after prompt and adequate treatment.

Epidemiology Peak incidence: 6-12 years (but can occur in any age, including adults, especially when unimmunized) Etiology PathogensTraditionally: Haemophilus influenzae type b (Hib)Most cases now involve: Streptococcus pyogenesStreptococcus pneumoniaeStaphylococcus aureusNon-typable H. influenzae Risk factorsNot immunized against HibImmunodeficiency Pathophysiology Bacteria invades tissue (directly or through hematogenous spreading) of the epiglottis and/or surrounding supraglottic structures (i.e., arytenoids, aryepiglottic folds, and vallecula) → supraglottic inflammation and edema → narrowing of the airway → airway obstruction (partial or complete) Clinical features Acute onset of high fever (39-40 °C or 102-104 °F) Toxic appearance "Tripod" position Sore throat Dysphagia Drooling Muffled voice (i.e., resembling a "hot-potato" voice) with painful speech Respiratory distress (inspiratory retractions, cyanosis) and inspiratory stridor Restlessness and/or anxiety Diagnostics Diagnostic approach Epiglottitis is primarily a clinical diagnosis Consider further investigations In a stable patient with atypical presentation In an unstable patient only after appropriate airway management and control.Investigations should be performed in a controlled environment If there are definitive signs of epiglottitis present → airway management before attempting to visualize the epiglottis and supraglottic structures! Pharyngoscopy (with a tongue blade) FindingsCherry-red epiglottisPooled secretionsInflammation and edema of the supraglottic structures AlternativesFiberoptic nasolaryngoscopyIndirect laryngoscopy (with an endoscope) Soft-tissue lateral neck x-ray Indication: To exclude other diagnoses (e.g., if barking cough of croup is present) or in unclear pharyngoscopy findings FindingsThumbprint sign: enlarged epiglottis and supraglottic narrowing Loss of vallecular air space Differential diagnoses See differential diagnoses of pediatric inspiratory stridor and differential diagnosis of dyspnea Foreign body aspiration Anaphylactic reaction Chemical injury or thermal injury (burns) Laryngitis Peritonsillar abscess or retropharyngeal abscess Treatment Keep child comfortable and as calm as possible If signs of respiratory distress → emergency airway managementMove child to a controlled environment (i.e., operating room)Use a nasotracheal tube with a small diameter to reduce the risk of post‑intubation sequelaeEmergency tracheostomy needs to be considered if intubation fails. Extubation should be performed 2-3 days (at the earliest) after starting antibiotic treatment. IV AntibioticsEmpiric therapy: third-generation cephalosporin (e.g., ceftriaxone) + antistaphylococcal antibiotic against MRSA (e.g. clindamycin), if MRSA is suspectedFollowing cultures of the organism, antibiotics can be chosen according to the culture sensitivities. IV fluid resuscitation if required Prognosis Mortality rate < 1% (in patients without endotracheal intubation ∼10%) Prevention Hib vaccine (see immunization schedule) Postexposure prophylaxisIndication: close contacts without adequate Hib immunization, and immunocompromised individuals regardless of immunizationstatusMedication: rifampicin

Norovirus infection Noroviruses are a frequent cause of viral gastroenteritis in individuals of all ages worldwide. Transmission commonly occurs from person to person, as well as through contact with contaminated surfaces, food, and water. Given their virulence and short incubation period, illnesses caused by noroviruses may quickly lead to outbreaks, which must be reported. The elderly, immunocompromised patients, and those who reside in long-term care facilities are at an increased risk of contracting the illness. The clinical presentation of norovirus infection includes acute-onset vomiting and watery diarrhea. Diagnosis can be confirmed with reverse transcription polymerase chain reaction (RT-PCR). Treatment is supportive and mainly involves fluid replacement therapy.

Epidemiology Peak incidence: November-March (winter months) Community outbreaks (in nursing homes, hospitals, preschools, cruise ships, etc.) are common Elderly and immunocompromised patients are commonly affected. Most common cause of Adult gastroenteritis Severe acute gastroenteritis in children younger than 5 years of ageFoodborne illness Etiology Pathogen: Norovirus is a non‑enveloped RNA calicivirus. TransmissionFecal‑oral route through contaminated food or water, person‑to‑person contact, via airborne droplets, and contact with contaminated surfacesThe virus is highly virulent. Individuals are highly infectious during the acute phase and 24-72 hours following onset of symptoms Clinical features Incubation period: 12-48 hours Nausea and acute-onset vomiting Watery, non-bloody diarrhea Abdominal cramps Symptoms resolve after 48-72 hours. Diagnostics Norovirus should be suspected in potentially exposed individuals if vomiting and/or diarrhea consisting ≥ 2 loose stools occur within a 24‑hour period. Clinical suspicion of norovirus infection should be confirmed with reverse transcription PCR (RT-PCR). Enzyme immunoassays: not a standard procedure due to low sensitivity (∼ 50%) Differential diagnoses Rotavirus infection Bacterial gastroenteritis Food poisoning Treatment Supportive therapyRehydration, if necessary with IV fluids (especially in the elderly and children)If myalgia and/or headache are present: NSAIDs or acetaminophen Prevention Obligation to report Health care providers are required to report all outbreaks. Many cases go underreported, as symptoms are usually mild in healthy individuals → higher chance of further transmission

Acute tonsillitis Acute tonsillitis is an inflammation of the tonsils that frequently occurs in combination with an inflammation of the pharynx(tonsillopharyngitis). It is particularly common in children and young adults and is primarily caused by viruses and group A streptococci(GAS). Acute tonsillitis is characterized by the sudden onset of fever, sore throat, and painful swallowing. Tender, swollen cervical lymph nodes and tonsillar exudates may occur. The disease is normally self-limiting. However, if GAS infection is confirmed via rapid antigen detection test and/or throat culture, treatment with antibiotics (penicillin) should be started to prevent rheumatic fever. Tonsillectomy is an option in recurrent and chronic tonsillitis, although the procedure is associated with a high risk of postoperative bleeding. Peritonsillar abscess and parapharyngeal abscess are serious suppurative complications of acute bacterial tonsillitis and require immediate treatment.

Epidemiology Peak incidenceViral tonsillitis: children < 5 years and young adults [1]Streptococcal tonsillitis: children aged 5-15 years; rare in children aged < 2 years Etiology Acute tonsillitisViral (50-80% of cases): adenovirus, EBV, CMV, HSV, rhinovirus, coronavirus, influenza and parainfluenza viruses, HIV [2][3]Bacterial (15-30% of cases)Streptococcus pyogenes (most common)Rarely, Neisseria gonorrhoeae, Corynebacterium diphtheriae, Mycoplasma pneumoniae [2][3] Recurrent tonsillitis and chronic tonsillitis: polymicrobial infections with aerobic bacteria (typically streptococci, staphylococci, Haemophilus influenzae) and anaerobic bacteria [2] Clinical features Sudden onset of symptoms Red and swollen pharynx, tonsillar exudates [3] Fever, sore throat, dysphagia Painful, swollen cervical lymph nodes Foul breath If viral: headache, earache, nasal congestion, and cough Trismus and changes in voice quality indicate the formation of potentially life-threatening peritonsillar abscess! [4] Diagnostics Diagnosis of acute tonsillitis is primarily clinical but may be further supported by blood tests and confirmed via microbiological testing. Modified Centor score [5] A set of criteria used to estimate the probability that pharyngitis is caused by GAS CriteriaNo cough (1 point)Tender anterior cervical adenopathy (1 point)Fever (1 point)Tonsillar exudates or swelling (1 point) Age3-14 years (1 point)15-44 years (0 points)≥ 45 years (-1 point) ApproachScore ≤ 1: no further diagnostic testing or antibiotic treatment is indicatedScore 2 or 3: rapid antigen detection testing (RADT) and/or throat culture is indicatedScore ≥ 4: empiric antibiotics Microbiological testing [6] Confirmatory tests: rapid antigen detection test and/or throat cultureRapid GAS antigen detection testThroat swab allows for simple and quick detection of GAS infection (highly specific, sensitivity ∼ 70-90%). [5]In children and adolescents, negative test results should be confirmed with throat culture.Throat culture: to identify pathogen and determine antibiotic sensitivity [7] Blood testsInflammatory markers (↑ CRP, ↑ ESR, leukocytosis) may be elevated but are not specific.Antistreptolysin O (ASO) titer ↑ ASO titer indicates a previous infection with GAS.Particularly useful for detecting prior infections in patients presenting with complications (e.g., rheumatic fever)Not recommended for diagnosing acute infection [7] Differential diagnoses Pharyngitis See Etiology section above. Sore throatPharyngeal erythemaMore common in viral pharyngitis: nasal congestion, coryza, and hoarsenessMore common in bacterial pharyngitis: fever, tonsillar exudate, and cervical lymphadenopathyAphthous stomatitis UnknownUlcers on anterior oral mucosaUsually no systemic symptomsHerpangina Coxsackie A virus Herpes-like oral lesions: multiple 1-mm vesicles located on the posterior oropharynx and tonsils; pharyngeal and tonsillar rednessFibrin-covered ulcerations appear in later stagesSore throat and high feverMay occur as a component of hand, foot, and mouth diseaseHerpetic pharyngotonsillitis/herpetic gingivostomatitis HSV-1Multiple small oral lesions located in the anterior oropharynx and lipsFever, sore throat, pharyngeal rednessVincent anginaSynergistic mixed infection with Treponema vincentii and Fusobacterium nucleatumUnilateral ulcers on the pharyngeal tonsilsMild general symptomsDifficulty swallowingFoul breathLudwig anginaMixed infection (Viridans streptococci and anaerobes) [8]Usually arising from an infected mandibular molar, an infection of the upper airways, or acute lingual tonsillitisPredisposing factors: diabetes mellitus, alcohol use disorder, and other immunocompromising conditions [9]Submandibular space infection Fever, mouth pain, stiff neck, difficulty swallowing, trismusAirway obstruction may occur! [8]Oral thrush (fungal tonsillitis) Candida albicans Pseudomembranous stomatitis with white plaquesPharyngeal syphilisTreponema pallidumPrimary syphilis chancre in the posterior pharynx Early stages are often asymptomatic; sore throat may occur. [10]Tonsillitis in infectious mononucleosis Epstein-Barr virus (EBV)Fever, pharyngitis, and enlarged erythematous tonsils with white and gray deposits Generalized lymphadenitisPossible involvement of liver, spleen, and skinTonsillitis in diphtheria (diphtheritic croup) Corynebacterium diphtheriaePseudomembranes Inflammation often exceeds the tonsils; mucosal bleedingAgranulocytic anginaAppears in the context of agranulocytosisTriad of aphthous stomatitis, sore throat, and feverDirty necrosis of pharyngeal tonsils Treatment Acute tonsillitis is typically self-limiting (symptoms usually resolve within 3-4 days without treatment). However, antibiotics are indicated for bacterial infections. [11] Conservative Symptom relief: rest, sufficient fluid intake, analgesics, salt-water gargles [3] Avoid aspirin in children. [12] Antibiotics if infection with GAS has been confirmed [12]Although streptococcal tonsillopharyngitis is usually self-limiting, antibiotics are required to reduce the risk of rheumatic fever. [12] Penicillin V (or aminopenicillin) [13]Most antibiotics are taken for at least 10 days.In patients with penicillin allergies: macrolides (e.g., clarithromycin, azithromycin, erythromycin) [13] Mistakenly treating an EBV infection (infectious mononucleosis) with ampicillin can lead to maculopapular rash. Surgery IndicationsRecurrent and chronic tonsillitisExtreme hypertrophy of the tonsils ("kissing tonsils")A history of peritonsillar abscessTonsillitis that does not respond to antibiotic treatmentTonsillitis in children who meet all of the Paradise criteria except those regarding documentation (see table below) Minimum frequency of sore throat episodes≥ 7 episodes in the past year, OR≥ 5 episodes/year in the past 2 years, OR≥ 3 episodes/year in the past 3 yearsClinical featuresEpisodes are counted if sore throat + ≥ 1 of the following are present: Temperature ≥ 100.9°F (38.3°C)Cervical lymphadenopathy (lymph nodes are tender or > 2 cm in size)Tonsillar exudateCulture positive for group A beta-hemolytic streptococciTreatmentAntibiotics were administered in the conventional regimen for each of the proved/suspected streptococcal episodes.DocumentationEach episode should be reflected in the medical documentation with the description of the clinical features mentioned above ORThere is subsequent observation by the physician of 2 episodes with patterns of frequency and clinical features consistent with the initial history. Procedure Subtotal tonsillectomy: tonsils are partially removed, while the capsule remains [15] Advantage: There is a low rate of postoperative bleeding.Disadvantage: Relapse is possible. [15]Total tonsillectomy: removal of the entire tonsils and capsule Postoperative hemorrhage is a serious complication (occurs in ∼ 5% of cases) NSAIDs (e.g., acetylsalicylic acid) are contraindicated for postoperative pain relief because of the increased risk of bleeding! The pharyngeal tonsils are supplied with blood by the external carotid artery. The main vessels are the ascending palatine artery (a branch of the facial artery), the greater palatine artery (a branch of the maxillary artery), and the ascending pharyngeal artery. Complications Suppurative complicationsPeritonsillar abscessParapharyngeal abscessOtitis mediaSinusitisCervical lymphadenitisMastoiditisInfectious thrombophlebitis of the internal jugular vein (Lemierre syndrome): A severe, potentially fatal condition usually resulting from oropharyngeal infections Characterized by infection of the carotid sheath vessels and bacteremia.Etiology: Most commonly caused by oropharyngeal flora (e.g., Fusobacterium necrophorum).Clinical features: fever, respiratory distress, neck pain, throat pain Nonsuppurative complicationsRheumatic fever Scarlet feverPoststreptococcal glomerulonephritis

Toxoplasmosis Toxoplasmosis is a disease caused by the obligate intracellular parasite Toxoplasma gondii. Transmission occurs either through ingestion of cysts found, for example, in raw meat or cat feces, or from mother to fetus through the placenta. The clinical presentation depends on the patient's immune status: In immunocompetent individuals, 90% of cases are harmless and asymptomatic, with the remaining 10% displaying mild mononucleosis-like symptoms. In immunosuppressed patients (e.g., those who are HIV-positive), infection may result in cerebral toxoplasmosis (headache, confusion, focal neurologic deficits) or toxoplasmic chorioretinitis (eye pain, reduced vision). Treatment is indicated for immunosuppressed patients, infected mothers, congenital toxoplasmosis, and immunocompetent patients with more severe symptoms. The treatment of choice is usually a combination of pyrimethamine, sulfadiazine, and leucovorin (folinic acid), with the exception of new infections during pregnancy, which are treated with spiramycin. For the congenital variant and how to manage infection in pregnant women, see toxoplasmosis during pregnancy.

Epidemiology Prevalence In the US: ∼ 10% of adults In some tropical climates: up to 95% Etiology Pathogen: Toxoplasma gondii, an obligate intracellular, single-celled protozoan Route of transmissionOral ingestion: The oocytes are excreted in the feces of cats (final host) and are orally ingested by other mammals such as humans, hoofed animals, and birds (intermediate hosts). Primary modes of transmission therefore include: Cat fecesRaw or insufficiently cooked meatUnpasteurized milk (especially goat milk)Transplacental transmission: see toxoplasmosis during pregnancyVia organ transplantation or blood transfusion Clinical features Incubation time: 3 days to 3 weeks Immunocompetent patientsMainly asymptomatic (90% of cases)Symptomatic (< 10% of cases): mononucleosis-like symptoms with bilateral cervical adenopathyLifelong immunity following infection Immunosuppressed patients Cerebral toxoplasmosis (the most common neurological AIDS-defining illness)Ocular toxoplasmosis Cerebral toxoplasmosis DescriptionCaused by reactivation of T. gondii in immunocompromised individualsMost common neurological disorder associated with AIDS (considered an AIDS-defining condition) Clinical features (symptomatic usually if CD4 count < 100 cells/μL)FeverHeadacheMental status changesSeizuresFocal neurological deficits Diagnostics CT or MRI with contrast: multiple ring-enhancing lesions (predominantly in the basal ganglia and/or the subcortical white matter)Serology: detection of anti-toxoplasma IgG antibodies PathologyToxoplasma tachyzoites and bradyzoites Chronic inflammation and necrosis of brain tissue Treatment: see "Treatment" below ProphylaxisAdequate HIV treatment (cART) TMP/SMX Ocular toxoplasmosis Chorioretinitis Acute toxoplasmosis (current focal infection): yellow-white retinal lesion, marked vitreous reaction, concomitant vasculitis, defects in the visual field at the site of inflammationPrevious toxoplasmosis (previous focal infection): formation of scars with white atrophic areas and surrounding dark, sharply-defined pigmentationRecurrent focal infection usually develops at old scar areas. Congenital toxoplasmosis is almost always accompanied by the formation of macular scars and corresponding visual impairment. retinochoroiditis juxtapapillaris Diagnostics SerologyIgM antibody test: positive within first week of acute infectionIgG antibody test: positive 2 weeks following infection and remains positive for life CT/MRI of the brain for suspected cerebral toxoplasmosis (see cerebral toxoplasmosis) Treatment Immunocompetent patients usually do not require treatment. Medical therapyIndications Immunosuppression (e.g., HIV)Infected pregnant women (for both pre-existing and new infections)Severe symptoms in immunocompetent patientsFirst choice Spiramycin if maternal infection before the 18th week of pregnancy is suspected/confirmed and infection of the fetus is not suspected/documented (see toxoplasmosis during pregnancy) [6]Combination treatment with pyrimethamine, sulfadiazine, and leucovorin (folinic acid) in all other cases Duration: minimum of 4-6 week

Cytomegalovirus infection Infection with the cytomegalovirus (CMV or human herpes virus 5) is generally asymptomatic in immunocompetent hosts, but can cause mild mononucleosis-likesymptoms. Like all Herpesviridae infections, CMV persists for the lifetime of its host; reactivation may therefore occur. Immunocompromised individuals (e.g., AIDS, post-transplantation) are especially at risk of illness following reactivation or initial infection, which can include severe manifestations such as CMV retinitis(risk of blindness) or life-threatening CMV pneumonia. Treatment with ganciclovir or valganciclovir should therefore begin promptly on clinical suspicion of a CMVinfection.Congenital CMV infection is discussed in another learning card.

Epidemiology Prevalence of CMV infection in the general population: 40-100% Seroprevalence increases with age with more than 90% in individuals > 80 years Etiology Pathogen: cytomegalovirus (CMV, human herpes virus 5, HHV-5) Transmission Blood transfusionsSexual transmissionDroplet transmissionTransplant-transmitted infection (e.g., bone marrow, lungs, kidneys) Pathophysiology CMV binds to integrins → activation of integrins → induction of cellular morphological changes → activation of signal transduction pathways such as FAK (focal adhesion kinase) and apoptotic pathways → cell damage → clinical manifestations depending on the organ/tissue affected. Clinical features CMV infection is usually asymptomatic. Severe manifestations occur in immunocompromised states (e.g., following organ transplantation, AIDS). In immunocompetent patients > 90%: asymptomatic course < 10%: CMV mononucleosisFever, malaise, myalgia/arthralgia, fatigue, headacheLess common: sore throat, cervical lymphadenopathy, hepatomegaly, splenomegalyDifferential diagnosis: infectious mononucleosis caused by EBVUnlike in infectious mononucleosis caused by EBV, a heterophile antibody test (monospot test) is negative in cases of CMV. In immunocompromised patients Among HIV-positive patients, manifestations of CMV disease usually occur when the CD4 count is ≤ 50! One or more of the following clinical manifestations may be present: CMV mononucleosis CMV pneumonia: interstitial pneumonitisEtiology: immunocompromised patients (e.g., following bone marrow transplant or in HIV/AIDS patients with CD4 ≤ 50 cells/mm3) Clinical findings: fever, nonproductive cough, dyspneaDiagnostics: Chest x-ray: diffuse bilateral interstitial infiltratesDetection of CMV in bronchoalveolar lavage fluid or lung tissue samples following biopsyDifferential diagnoses: pneumocystis pneumonia and other viral respiratory infections CMV retinitis: floaters, photopsia, visual field defects Fundoscopy: "pizza-pie" appearance (retinal hemorrhages, fluffy/granular white opacities around retinal vessels resembling cotton-wool spots, retinal detachment)Differential diagnoses: HIV retinopathy, herpes simplex retinitis, varicella zoster retinitis, toxoplasmosis CMV esophagitis and/or CMV colitis: odynophagia, abdominal pain, bloody diarrhea: Endoscopic examination of the GI tract typically shows linear ulcers. Adrenal insufficiency CMV encephalitis: impaired cognitive function, neurological deficits CBC: relative lymphocytosis with > 10% atypical lymphocytes Blood smear: large atypical lymphocytes with intranuclear inclusion bodies that have an owl-eye appearance Monospot (heterophile antibody) test: negative Serological testsActive disease IgM antibodies A four-fold increase in the levels of IgG antibodies Inactive disease: IgG antibodies in the absence of IgM antibodies Direct evidence of viremia: especially useful in immunosuppressed patients PCR to detect CMV DNA in bodily fluidsIndirect immunofluorescence assay: pp-65 CMV antigens Fundoscopy: retinal hemorrhages and cotton-wool spots ("pizza-pie" appearance) Serological tests may be unreliable in immunosuppressed patients! Treatment In immunocompetent patients: No specific treatment is needed. In immunosuppressed patientsOptimize antiretroviral therapy regimen to increase CD4 count above 100 cells/mm3 CMV retinitis Peripheral lesion: valganciclovir Lesions within 1.5 mm of the fovea: valganciclovir, and intravitreal injections of ganciclovir or foscarnet At least 3-6 months CMV colitis/CMV esophagitis Mild disease: valganciclovir Severe disease: ganciclovir or foscarnet 21-42 days CMV pneumonia IV ganciclovir (or IV foscarnet) and IV immunoglobulin (IVIG) therapy Until CD4 count > 100 cells/mm3 and symptoms improve CMV encephalitisIV ganciclovir and IV foscarnet

Granuloma inguinale Granuloma inguinale is a sexually transmitted bacterial disease caused by Klebsiella granulomatis. It is seen most commonly in sexually active individuals between 20 and 40 years of age. Clinically, granuloma inguinale manifests with one or more genital nodules that develop into red, painless ulcers. The regional lymph nodes are typically spared. Diagnosis of granuloma inguinale is based primarily on clinical findings and is confirmed through detection of Donovan bodies (intracytoplasmic macrophages containing bacteria) in ulcer smears or biopsies. Management focuses on antibiotic treatment with azithromycin, which is continued until the ulcers have completely healed. Surgical treatment may be necessary for patients who develop genital pseudoelephantiasis, a complication seen most commonly in women. In these cases, ulcers or scar tissue obstruct lymph drainage and lead to severe localized edema.

Epidemiology Prevalence: endemic to tropical and subtropical countries Incidence: < 100 cases annually in the US Age range: 20-40 years Etiology Pathogen: Klebsiella granulomatis (gram-negative, aerobic, encapsulated) Route of transmissionSexual transmissionAutoinoculation of adjacent skinPerinatal transmission Risk factorsMen who have sex with menUncircumcised menLow socioeconomic status Clinical features Incubation period: highly variable (1 day to 1 year); median time ∼ 50 days Clinical featuresPainless genital lesion: begin as one or more nodules; eventually ulcerate to form large, beefy-red lesions that bleed easily Localization♂: foreskin, coronal sulcus, glans♀: labia minora, cervixRarely presents in the oral cavity or pharynxRegional lymph nodes typically spared Granuloma inguinale (Klebsiella granulomatis) should not be mistaken for lymphogranuloma inguinale (Chlamydia trachomatis serotype L1-L3), which is commonly known as lymphogranuloma venereum! Diagnostics Granuloma inguinale is a clinical diagnosis supported by the presence of Donovan bodies in smears from the lesion. Confirmatory test: demonstration of Donovan bodies in biopsies and/or smears from lesionsIntracytoplasmic cysts filled with deeply staining , safety-pin shaped bodies within macrophages (Pud cells) PCR: if Donovan bodies or not present and to differentiate K. granulomatis from other Klebsiella species K. granulomatis cannot be cultured. Treatment Antibiotics First-line: azithromycinAlternatives: doxycycline, ciprofloxacin, trimethoprim/sulfamethoxazole Surgery: may be necessary for correction of disfiguring genital swellings Complications Genital pseudoelephantiasis (seen especially in women) Bacterial superinfection of the ulcer Neoplastic transformation of the ulcer Osteomyelitis (rare)

Congenital varicella infection

Epidemiology Seroprevalence in the general population is ∼ 95%. Most mothers have been vaccinated, so congenital infection is rare. Pathogen Varicella-zoster virus (VZV) Transmission MotherPrimary infection Airborne dropletsDirect skin contact with vesicle fluidReactivation: usually in immunocompromised individualsSee chickenpox and shingles. Fetus: transplacental transmission from an infected mother Clinical features Congenital varicella syndrome (infection during first and second trimester) Hypertrophic scars (cicatricial skin lesions)Limb defects (e.g., hypoplasia)Ocular defects (e.g., chorioretinitis, cataracts, microphthalmia)CNS defects (e.g., cortical atrophy, seizures, intellectual disability), hydrocephalus Neonatal varicellaMild infection (maternal exanthem > 5 days before birth) Severe infection (maternal exanthem < 5 days before birth): hemorrhagic exanthem, encephalitis, pneumonia, or congenital varicella syndrome (mortality rate of up to 30%) Diagnosis Newborn and motherUsually clinical diagnosis is confirmed by appearance of skin lesions (See chickenpox and shingles.)DFA or PCR of fluid collected from blisters or cerebrospinal fluid (CSF)Serology Fetus: PCR for VZV DNA (in fetal blood, amniotic fluid) and ultrasound to detect fetal abnormalities Treatment For pregnant women or newborns with (severe) infection: acyclovir Administer postexposure prophylaxis in newborns if mother displays symptoms of varicella < 5 days before delivery: IgG antibodies (varicella-zoster immune globulin, VZIG)For other indications for varicella postexposure prophylaxis, see "Prevention" in varicella. Cesarean section if lesions are present at delivery Breastfeeding is encouraged because of the possible protective effect of antibodies in breast milk. Prevention Immunization of seronegative women before pregnancy VZIG in pregnant women without immunity within 10 days of exposure Nationally notifiable condition: Varicella must be reported to the local or state health department

Mumps Mumps is a highly contagious viral infection that is transmitted via airborne droplets. The incidence is now very low in the US because of the combined measles, mumps, and rubella (MMR) vaccine. The condition primarily affects children between the ages of five and fourteen. Classically, it manifests with parotitis, which initially occurs unilaterally, but typically progresses to involve both sides. The lateral cheek and jaw area usually show marked swelling and the ears may protrude. Other symptoms include low-grade fever, malaise, headache, and possible swelling of other salivary glands. The diagnosis of mumps is largely based on clinical findings. Many cases, however, present with nonspecific features and are not easily recognizable as mumps. If possible, diagnosis should be confirmed with laboratory tests. Treatment is symptomatic. Rare complications include orchitis, aseptic meningitis, deafness, and pancreatitis. Immunization offers the best protection against future exposure. Mumps is a self-limiting disease, followed by lifelong immunity. The prognosis in uncomplicated cases is very good.

Epidemiology Sex: ♂ = ♀ for parotitis (however, males are three times more likely to have CNS complications) Peak incidence: 5-14 years of age The incidence in the United States has drastically declined since administration of the MMR vaccine became routine. Etiology Pathogen: Mumps virus; from the family Paramyxoviridae TransmissionAirborne dropletsDirect contact with contaminated saliva or respiratory secretionsContaminated fomites Infectivity: Highly infectiousAffected individuals are contagious ∼ 3 days before and up to 9 days after disease onset (when the parotid glandbecomes swollen).Asymptomatic cases are also contagious! Pathophysiology Nasopharyngeal entry → replication of the virus in the mucous membranes and lymph nodes → viremia and secondary infection of the salivary glands (particularly the parotid gland) → further dissemination possible (lacrimal, thyroid, and mammary glands, pancreas, testes, ovaries, CNS) Clinical features Incubation period: 16-18 days Asymptomatic course in ∼ 20% of cases Nonspecific or predominantly respiratory symptoms in ∼ 50% of cases Prodrome: Duration: 3-4 daysLow-grade fever , malaise, headache Classic course (in ∼ 30% of cases):inflammation of the salivary glands, particularly parotitis Duration of parotitis: at least 2 days (may persist > 10 days)May initially present with local tenderness, pain, and earacheSwelling on one side is initially observed. During the course of disease, both salivary glands are usually swollen. Possible redness in the area of the parotid ductPossible protruding ears Usually self-limiting with a good prognosis (unless complications arise)Chronic courses are rare Diagnostics Laboratory tests, if available, should be conducted to confirm the suspected cases (especially if presentation is atypical or there is a mumps outbreak). Positive serology confirms the diagnosis: IgG and/or IgM Relative lymphocytosis ↑ CRP, ↑ ESR ↑ amylase Differential diagnoses Mumps Possible redness, tenderness and protruding ears Usually bilateral Fever Acute purulent sialadenitis Fever, tenderness, and swelling of the gland Usually unilateral Possible pusdischarge Sialadenosis (sialosis) Non-inflammatory, non-neoplastic swelling of the parotid gland Systemic causes (e.g., alcoholism, diabetes mellitus) Sialolithiasis(salivary stones) Suddenpain while eating Partial swelling of the gland Tumors of the salivary glands Painless swelling of the gland Possible malignant symptoms of infiltrated structures (e.g., facial palsy) ifferential diagnosis of orchitis: epididymitis, testicular torsion Differential diagnosis of aseptic meningitis: meningitis due to other causes (bacterial, other viruses) Symptomatic therapyMedication for pain and fever (e.g., acetaminophen)BedrestAdequate fluid intakeAvoidance of acidic foods and drinksIce packs to soothe parotitisIsolation and post-exposure prophylaxis → see "Prevention" below Complications Orchitis (< 10% of cases; most common complication in post-pubertal males) Primarily unilateral, although bilateral in ∼ 15% of casesSudden onset of fever, nausea, vomitingOn examination: swollen and tender affected testicle(s)May lead to atrophy and, in rare cases, infertility Aseptic meningitis (1-10% of cases): predominantly mild course; usually no permanent sequelae Encephalitis (< 1% of cases)Reduced consciousness, seizuresNeurological deficits: cranial nerve palsy, hemiplegia, sensorineural hearing loss (rare) Acute pancreatitis (< 1% of cases) Vomiting, nausea, upper abdominal pain↑ Lipase in addition to ↑ amylaseDiabetes mellitus type I (delayed complication) Prevention Primary immunization: a live vaccine in combination with measles and rubella vaccine (i.e., MMR) and, if necessary, varicella (MMRV) Via two doses: first dose at 12-15 months, second dose at 4-6 years → immunization schedule Mumps vaccination during the first trimester in pregnancy may lead to embryonal death! Isolate infected patients (up to 5 days after onset of symptoms) Mumps is a reportable disease

Molluscum contagiosum Molluscum contagiosum is a common localized skin infection caused by the molluscum contagiosum virus that often occurs on the trunk, face and genitalia. It is more common in childhood as well as early adolescence, particularly in males, and is usually transmitted at this age via skin contact and autoinoculation. In adults, it is considered a sexually transmitted infection. Lesions appear as smooth, dome-shaped papules with central umbilication. In healthy patients, molluscum contagiosum is generally self-limiting and heals spontaneously after several months. However, in immunosuppressed individuals, lesions can be very large, widespread, and persistent. If treatment is indicated (e.g., for sexually transmitted molluscum contagiosum), cryotherapy with liquid nitrogen is usually the first treatment option.

Epidemiology Sex: ♂ > ♀ Age: most common in childhood (peak incidence < 5 years of age) and early adolescence PrevalenceMore common in warm and humid climates or areas with poor hygieneUp to 18% of HIV-positive patients and up to 33% if CD4 cell count is < 100 cells/μL Etiology Pathogen: a DNA poxvirus (molluscum contagiosum virus) Transmission: Direct skin contact (contact sports, sexually transmitted in sexually active adolescents and adults)Autoinoculation (scratching or touching lesion, e.g., while shaving) Fomites (e.g., on bath sponges/towels) Risk factors: immunosuppression , active atopic dermatitis (in children) , hot and humid climates, crowded living conditions Suspect AIDS if large, persistent, widespread lesions appear on an adult! Clinical features Incubation period: 2-6 weeks Physical examination: single or multiple lesions in healthy patients; especially widespread in immunocompromised patients Nontender, skin-colored, pearly, dome-shaped papules with central umbilicationIndividual lesions may also be painful or pruritic.Usually 2-5 mm in diameterGiant lesions may be > 15 mm in immunocompromised patientsPapules contain a caseous plug. Predilection sites: In children: face , trunk , and extremities (e.g., axilla, antecubital and popliteal fossa)In adults: lower abdomen, groin, genitalia, and proximal thighsChronic follicular conjunctivitis may occur as molluscum contagiosum viral particles spread into the conjunctiva of the eye. Diagnostics Clinical diagnosis Seek out underlying etiologies (i.e., HIV testing) if lesions in adults and/or widespread A biopsy is usually not necessary, but consider in cases of immunosuppression, as the diagnostic differential is wide (see "Differential diagnosis" below). Histology Localized to the epidermis H&E-stained sections demonstrate: Acanthosis (thickened epidermis)Cup-shaped invagination (the epidermis invaginates into the dermis)Molluscum bodies: keratinocytes with eosinophilic intracytoplasmic inclusion bodies containing viral particles Differential diagnoses Cutaneous cryptococcosis Cutaneous histoplasmosis Cutaneous aspergillosis Condyloma acuminatum Condylomata lata Keratoacanthoma Verruca vulgaris Flat warts Treatment Spontaneous remission usually happens within 6-9 months (thus treatment often unnecessary). Consider treatment for sexually transmitted cases, immunocompromised individuals, and/or to reduce autoinoculation or transmission. Cryotherapy is often the first-line treatment for adolescents and adults as it is better tolerated than in children. Curettage Topical cantharidin Podophyllotoxin Topical imiquimod may be used to successfully treat immunocompromised patients with refractory disease, along with antiretrovirals in HIV-positivepatients. Complications Scarring Hypopigmentation Secondary bacterial infections

Prostatitis Prostatitis is an inflammation of the prostate gland that may be of infectious (acute and chronic bacterial prostatitis) or noninfectious origin (chronic pelvic pain syndrome, or CPPS). Acute and chronic bacterial prostatitis are most often caused by Escherichia coli, while in CPPS no causative organism can be identified. Patients with acute bacterial prostatitis typically present with spiking fevers, chills, perineal pain, and symptoms of bladder irritation. The presentation of chronic bacterial prostatitis and CPPS is more subtle, including symptoms of chronic or recurrent urinary tract infections and genitourinary pain. Findings on examination include a tender, boggy prostate in acute bacterial prostatitis, and mildly tender or normal prostate in chronic bacterial prostatitis and CPPS. Diagnostics aim to identify a potential causative organism via urine culture or fractional urine examination. Empirical antibiotic treatment is the primary therapeutic approach for acute and chronic bacterial prostatitis, whereas treatment for CPPS is multimodal, including pharmacological treatment, psychological support, and physiotherapy. Acute bacterial prostatitis can lead to complications (e.g., acute urinary retention, prostatic abscess formation, sepsis) that may require additional treatment, such as suprapubic catheterization or ultrasound-guided abscess drainage.

Epidemiology Very common urologic diagnosis in men < 50 years of age In men, there is an ∼ 8% lifetime risk of developing prostatitis. Bacterial prostatitis (2-5% of cases): primarily affects men ∼ 20-50 years of age Chronic pelvic pain syndrome (90-95% of cases): primarily affects men 40-60 years of age Etiology Pathogenesis Bacterial prostatitis: Gram-negative bacteria, particularly E. coli and other EnterobacteriaceaeEnterococci and other gram-positive cocci Chronic pelvic pain syndrome (CPPS): no detectable causative organism (the exact etiology remains unknown) Risk factors for bacterial prostatitis Other genitourinary tract infections (e.g., urethritis, cystitis, epididymitis) Genitourinary tract interventions (e.g., indwelling catheter, transurethral surgery, prostate biopsy) Voiding dysfunction and bladder outlet obstruction Acute bacterial prostatitis Spiking fevers, chills, malaise Acute dysuria , frequency, urgency, cloudy urine Severe (perineal, pelvic, with defecation) Tender, boggy, swollen Chronic bacterial prostatitis Low-grade fever in some patients Chronic bladder irritation: dysuria, frequency, urgency Erectile dysfunction Possibly bloody semen Mild, possibly stronger or noticable on ejaculation Often normal May be enlarged and tender Chronic pelvic pain syndrome Possibly erectile dysfunction, painful ejaculation, and bloody semen May have symptoms of bladder irritation Moderate, diffuse (lower abdomen, perineum, scrotum, or penis) Usually normal May be slightly tender Diagnostics Clinically suspected bacterial prostatitis is confirmed by detection of bacteria in urinalysis and culture. Chronic pelvic pain syndrome is a diagnosis of exclusion. Laboratory tests Acute bacterial prostatitisUrinalysis using midstream urine (↑ WBC), urine culture, urine Gram stainE. coli is most common pathogen (80% of cases): grows on MacConkey agar as pink colonies (lactose fermenting, gram-negativerod)Blood tests: ↑ inflammatory markers, ↑ PSA Blood cultures if sepsis is suspected Chronic bacterial prostatitisFractional urine examinationFour-glass test (according to Meares‑Stamey) Two-glass test Further diagnostics Urethral swab and culture UltrasonographyTo assess for residual urineTransrectal ultrasonography Uroflowmetry or cystoscopy Treatment Bacterial prostatitis First-line treatment: fluoroquinolones (e.g., ciprofloxacin) or trimethoprim-sulfamethoxazole PO for 6 weeks [19] Suprapubic catheterization in cases of acute urinary retention and persistent fever Chronic pelvic pain syndrome Medical therapyAlpha blockers (e.g., tamsulosin, doxazosin) 5-alpha-reductase inhibitors (e.g., finasteride) Antibiotics NSAIDsAnti-inflammatory phytotherapeutic agents (e.g., cernilton) Supportive therapyPsychological support and treatmentPhysiotherapy Complications Prostatic abscessGenitourinary symptoms similar to acute bacterial prostatitis; prostate fluctuates on rectal examTreatment with antibiotics and transrectal ultrasound-guided drainage Acute urinary retention Pyelonephritis and sepsis Epididymitis

Coxsackie virus infections Coxsackie viruses are a group of RNA viruses with over 20 serotypes; depending on specific viral characteristics, these serotypes are further divided into groups Aand B. Infection is associated with a wide range of symptoms, which are dependent on the exact serotype. Hand, foot, and mouth disease (HFMD) and herpangina are commonly caused by group A coxsackie viruses, while pleurodynia and myocarditis are caused by group B coxsackie viruses. Both groups may cause viral meningitis, conjunctivitis, or flu‑like symptoms. Diagnostic procedures and treatment should be tailored to the specific disease manifestation.

Epidemiology Worldwide distribution Occur in all age groups Highest incidence in infants and young children (< 10 years) Etiology Pathogen: Coxsackie virus Single‑stranded RNA virusOver 20 serotypes, divided into group A and group B coxsackie virusesGenus: EnterovirusFamily: Picornaviridae Route of transmissionAirborne dropletsFecal‑oral route Disease manifestations Coxsackie AHerpanginaHand, foot, and mouth diseaseCharacteristics: highly contagiousClinical presentationGeneral symptoms: fever, reduced general conditionSkin/mucosa Maculopapular and partially vesicular rash on the hands and feetOral ulcersDiagnosis: clinicalTreatment: symptomaticPrognosis: almost always self‑limiting Coxsackie B Myocarditis Pleurodynia Clinical presentationFlu‑like symptomsSudden thoracic and upper abdominal pain caused by irritation of the pleura and muscles Coxsackie A and BConjunctivitisViral meningitisFlu‑like symptoms Coxsackie B is the most common cause of viral myocarditis!

Zika virus infection Zika virus is an arbovirus transmitted by the mosquito Aedes aegypti. The infection can also be transmitted transplacentally and sexually. Since 2015, epidemicoutbreaks of Zika virus infection have occurred in South America, US territories, and in certain southern US states. The infection is typically asymptomatic or results in mild flu-like symptoms. However, this infection has received a lot of attention because it can result in fetal microcephaly when the virus infects pregnant women. Much about this disease is still unknown and it is currently the subject of much study and research. The diagnosis is usually confirmed by PCR and/or serology. Currently, neither a definitive therapy nor a clinically-approved vaccine exist.

Epidemiology Worldwide geographical distributionOutbreaks most commonly occur in tropical and subtropical regions.Before 2015, a few cases were reported in Africa, southeast Asia, and in the Pacific islands Since 2015, epidemic outbreaks have been reported in South America (especially Brazil). Epidemiology in the USThe overwhelming majority of cases (> 25,000) are reported in US territories, most of which occurred in Puerto Rico. Approx. 4000 cases were reported in the continental US, most of which occur in New York, Florida, California, and Texas. Etiology Pathogen: Zika virusGenus: flavivirus, type of arbovirusPositive-sense, single-stranded, enveloped RNA Route of transmissionVector-borne transmission by the mosquito Aedes aegypti (common) Transplacental transmission from the mother to the fetusSexual transmission Clinical features Incubation time: 2-14 days Approx. 80% of cases remain asymptomatic In symptomatic patients, the manifestations are usually mild and last for 2-7 daysLow-grade feverFlu-like symptoms: headache, arthralgia, myalgia, non-purulent conjunctivitis, malaiseMaculopapular, pruritic rash (20% of cases) Possible findings↑ Acute phase reactants (e.g., CRP, ferritin)Leukopenia, thrombocytopenia↑ LDH, ↑ γ-GT Definitive diagnosisDuring the first 7 days of the infection: PCR detects Zika virus RNA in blood and/or urine samplesDuring days 7-28: RT-PCR and/or serologyAfter 28 days: serology confirms Zika virus antibodies Treatment Definitive therapy does not yet exist. Treatment is primarily symptomatic with rest, oral/IV fluids, and/or acetaminophen to relieve fever and pain. Complications Guillain-Barre syndrome During pregnancyCongenital infections can result in microcephaly (craniofacial disproportion) Other congenital manifestations: spasticity (contractures), hyperreflexia, ocular abnormalities (e.g., pigmentary retinal mottling), and sensorineural hearing lossMiscarriage in the case of intrauterine transmission Prevention A vaccine against Zika virus does not exist yet. Vector control and safe sexual practices are the most important public health measure in endemic regions. Individuals traveling to endemic regions should be told to use insect repellents, mosquito nets, and long-sleeved clothing. Pregnant women should be advised against visiting endemic regions. In the case of travel to an endemic region and/or a positive Zika test, the individual should use some form of contraception for the following time periods (even if asymptomatic!): ♀: at least 2 months♂: at least 6 months Zika virus infection is a notifiable disease!

Yellow fever Yellow fever is an acute viral infection caused by the yellow fever virus. Primates are the main reservoir of the virus, which is usually transmitted through bites from infected mosquitoes. Yellow fever is endemic in large parts of South America and Africa. The incubation period is 3-6 days, and the majority of patients remain asymptomatic or experience only mild symptoms. Symptomatic patients initially present with nonspecific symptoms such as sudden-onset fever, malaise, headaches, chills, nausea, and myalgia. Approx. 15% of symptomatic patients progress to the most serious stage of the disease, which can present with life-threatening hemorrhagic fever and organ failure. There is no causal treatment available, making prevention of crucial importance. A single dose of live-attenuated vaccine provides lifelong protection for most individuals.

Epidemiology Yellow fever is endemic in tropical regions of South America and Sub-Saharan Africa. Asia, Europe, North America, and Australia are free of yellow fever (except for occasional imported cases). Etiology Pathogen: yellow fever virusGenus: flavivirus, type of arbovirus Genetics: single-stranded, positive-sense, linear RNA virus Appearance: enveloped, icosahedral TransmissionVectors: mosquitoes (primarily Aedes aegypti )Main reservoir: primates (human and non-human)Different transmission cycles (depending on local circumstances and geography) Clinical features Incubation time: 3-6 days Clinical featuresThe majority of infected individuals remain asymptomatic.In symptomatic patients: classic progression in three stages Period of infection (3-4 days) Sudden onset of high fever (up to 41°C, or 105°F)Headaches, chillsNausea, vomitingPeriod of remission (up to 2 days)Easing of symptoms and decline in feverPeriod of intoxication (only in ∼ 15% of symptomatic patients)Hemorrhage (epistaxis, mucosal bleeding, melena, hematuria, black vomiting)Multiorgan dysfunction (e.g., acute kidney and liver failure)Abdominal pain, severe jaundice Laboratory tests↑ ALT/AST LeukopeniaIn period of intoxication Thrombocytopenia, ↑ PTTSigns of organ failure (see acute liver failure, acute renal failure) Virus detectionPCRELISA Liver biopsyUsed for definitive diagnosis (e.g., postmortem)Must not be done while the patient has an active yellow fever infection May show Councilman bodies (eosinophilic apoptotic globules) Differential diagnoses Influenza Viral hepatitis (e.g., hepatitis A) Other viral hemorrhagic fevers (e.g., Dengue hemorrhagic fever) Malaria Treatment Symptomatic treatment No specific antiviral treatment is availabl Avoid NSAIDs that increase the risk of bleeding (e.g., aspirin, ibuprofen, naproxen) in patients with confirmed or suspected yellow fever infection! Vaccination Indication: recommended for individuals (≥ 9 months) traveling to areas where yellow fever is endemic AdministrationA single dose of live-attenuated vaccine is sufficient for most patients and provides life-long protection (administer at least 10 days before travel). Absolute contraindications (also see general contraindications for vaccination) Infants under 9 months of age Individuals with insufficient immune function (e.g., due to HIV infection or immunosuppressive medication)

Congenital CMV infection

Epidemiology ∼ 1% of live births per year in the US Pathogen Cytomegalovirus Transmission Mother: via CMV-contaminated blood, urine, saliva, and genital secretions Blood transfusionsSexual transmissionDroplet transmissionTransplant-transmitted infection (e.g., bone marrow, lungs, kidneys)See cytomegalovirus infection. Fetus: transplacental transmission from an infected mother Newborn: during birth or postnatal via breastmilk from infected mother Clinical features Subclinical infection (∼ 90%): ∼ 10% go on to develop a late complication (most commonly hearing loss). Symptomatic infection at birth (∼ 10%): ∼ 70-80% go on to develop a late complication. Fetal infectionIncreased risk of fetal demiseIntrauterine growth restrictionOligohydramnios or polyhydramnios, placental abnormalitiesUltrasonographic signs of CMV infection: periventricular calcifications, hyperechogenic foci (bowel and liver, ascites), and hydrops fetalis Sequelae of fetal and newborn infectionCNS findings Abnormalities on brain imaging in 70% of symptomatic infants (e.g., periventricular calcifications)Hydrocephalus, intraventricular hemorrhageMicrocephaly .Sensorineural hearing loss (∼ 30%) Chorioretinitis (∼ 10%)Nonspecific findings (similar to other TORCH infections) Petechiae, purpura (blueberry muffin rash)Hepatosplenomegaly, jaundiceSmall for gestational age (SGA)Seizures, lethargy, poor suckHemolytic anemia, thrombocytopeniaPneumoniaLate complications Hearing loss, vision impairmentPsychomotor retardation, intellectual disabilityDental abnormalities Diagnosis Fetus and newborn: CNS imaging may show hydrocephalus, periventricular calcifications, or intraventricular hemorrhage. Newborn and motherCMV IgM antibodies (blood)Viral culture or PCR for CMV DNA (urine, saliva) FetusViral culture or PCR for CMV DNA (amniotic fluid)CMV IgM antibodies (fetal blood) Differential diagnosis [38] Congenital toxoplasmosisCauses chorioretinitis, hydrocephalus, and intracranial calcificationsIntracranial calcifications in congenital toxoplasmosis typically show ring-enhancement. Treatment FetusSevere anemia: intrauterine blood transfusionsThrombocytopenia: platelet transfusions NewbornSupportive therapy of symptoms (e.g., fluid/electrolyte imbalances, anemia, thrombocytopenia, seizures, secondary infections)Ganciclovir, valganciclovir, or foscarnet Mother: valacyclovir is the only therapy approved during pregnancy; trials with CMV specific hyperimmune globulin ongoing [39] Prevention Frequent hand washing, especially after contact with bodily secretions of small children (e.g., diaper changing) Avoidance of food sharing with children Avoidance of kissing small children on the mouth

Congenital toxoplasmosis

Epidemiology ∼ 1:10,000 live births per year in the US Pathogen Toxoplasma gondii Transmission MotherCat fecesRaw or insufficiently cooked meatUnpasteurized milk (especially goat milk)See "Etiology" in toxoplasmosis. FetusTransplacental transmissionTransmission rate Third trimester: ∼ 70%First trimester: ∼ 15% Clinical features First trimesterIncreased risk of premature birth and spontaneous abortionClassic triad of toxoplasmosisChorioretinitis (a form of posterior uveitis) Diffuse intracranial calcificationsHydrocephalusPossible other nonspecific clinical features Petechiae and purpura (blueberry muffin rash) FeverSeizuresJaundiceHepatosplenomegalyLymphadenopathyPneumonitisThrombocytopenia Second or third trimester: subclinical or mild toxoplasmosis Sequelae of congenital toxoplasmosis EpilepsyIntellectual disabilityVisual disabilities (chorioretinitis → increased risk of retinal lesions , cataracts, and glaucoma) Diagnostics Mother: See "Diagnostics" in toxoplasmosis. Fetus: PCR for T. gondii DNA in amniotic fluid NewbornCT/MRI: intracranial calcifications, hydrocephalus, ring-enhancing lesions T. gondii-specific IgM antibodies (CSF, serum)PCR for T. gondii DNA (CSF, serum)Ophthalmological evaluation: chorioretinitis Treatment Mother: immediate administration of spiramycin Fetus: When confirmed or highly suspected, switch to pyrimethamine, sulfadiazine, and folinic acid. Newborn: pyrimethamine, sulfadiazine, and folinic acid Prevention Avoid raw, undercooked, and cured meats. Wash hands frequently, especially after touching soil (e.g., during gardening). Avoid contact with cat litter. The 4 Cs of congenital toxoplasmosis: Cerebral calcifications, Chorioretinitis, hydroCephalus, and Convulsions!

Congenital herpes simplex virus infection

Epidemiology ∼ 1:3,000-10,000 live births per year Pathogen Mainly herpes simplex virus 2 (HSV-2); in rare cases HSV-1 Transmission MotherPrimary infection: contact with contaminated oral secretions via small skin lesionsReactivation: usually in immunocompromised individualsSee herpes simplex virus infections. Fetus: Transplacental transmission from an infected mother (rare) Newborn: perinatal transmission during birth (∼ 30% transmission rate if mother has not yet undergone seroconversion at time of delivery) Clinical features Intrauterine HSV infection (congenital herpes simplex virus infection) (∼ 5% of cases) Fetal demise, preterm birth, very low birth weight Microcephaly, hydrocephalus, and other CNS defectsMicrophthalmia → chorioretinitisVesicular skin lesions Perinatal and postnatal transmissionSkin, eye, and mouth diseaseVesicular skin lesionsKeratoconjunctivitis → cataracts, chorioretinitisVesicular lesions of oropharynxCNS diseaseMeningoencephalitis (manifesting with fever, lethargy, irritability, poor feeding, seizures, bulging fontanelle)Possibly vesicular skin lesionsDisseminated disease Features similar to those of sepsis, with organ involvement (e.g., liver, CNS, lungs, heart, adrenal glands, kidneys, GI tract)Vesicular skin lesions (may not appear until late in disease course) Diagnosis Mother: typically clinical diagnosis Fetus: The ultrasound may show CNS abnormalities. Newborn (and mother) Standard: viral culture of HSV from skin lesions, conjunctiva, oro/nasopharynx, or rectumAlternative: PCR for HSV DNA (CSF, blood) Treatment Newborn and mother: IV acyclovir or valaciclovir Additionally in newborns: supportive therapy of fluid/electrolyte imbalances, SIRS, septic shock, seizures, secondary infections, etc. Prevention Antiviral therapy (acyclovir) beginning at 36 weeks of gestation for individuals with a known history of HSV lesions Cesarean section in women with active genital lesions or prodromal symptoms (e.g., burning pain) HSV should be considered in infants up to 6 weeks of age with vesicular skin lesions, persistent fever with negative cultures, and/or symptoms of meningitis, encephalitisor sepsis. A high index of suspicion is warranted in neonatal HSV. Skin, eye, and mouth disease has a good prognosis if detected and treated early!

Bartholin gland cyst and abscess The Bartholin glands are located in both sides of the inner labia and serve primarily to produce the mucus that moisturizes the vaginal mucosa. The mucus is secreted into two ducts that appear in the posterior vaginal introitus. A Bartholin gland cyst is usually caused by blockage of the duct as a result of inflammation or trauma; a Bartholin gland abscess occurs when the obstructed duct becomes infected. The most common symptoms are swelling and, in the case that an abscess develops, pain as well as possibly fever. Both Bartholin gland cysts and abscess are clinical diagnoses. First-line treatment includes sitz baths, which may promote spontaneous rupture or resolution of the cyst after a few days. An abscess, however, usually requires incision and must be drained surgically.

Epidemiology ∼ 2% of women are affected at some point in their lives by a Bartholin gland cyst or abscess. Peak incidence: 20-30 years Bartholin gland cyst Pathophysiology: blockage of the duct by inflammation or trauma Clinical features: often asymptomatic but can cause mild dyspareunia DiagnosticsPelvic exam: unilateral, palpable mass in the posterior vaginal introitusBiopsy is indicated if any of the following apply : > 40 years of ageProgressive, solid, and painless mass found during pelvic examNot responsive to treatmentHistory of malignancy in the labia Treatment: Sitz baths to facilitate rupture of the cyst Consider surgery for symptomatic cysts (see "Treatment" of Bartholin gland abscesses below) Bartholin gland abscess Pathophysiology: Bartholin gland or cyst becomes infectedUsually a polymicrobial infection: E. coli (most common), Staphylococcus species, Streptococcus species, N. gonorrheae, C. trachomatis Clinical featuresAcute unilateral pain and tender swellingDyspareuniaPain especially while walking and sittingFever (∼ 20% of cases)Prompt pain relief with discharge (indicates spontaneous rupture of abscess) DiagnosticsPelvic exam: unilateral, tender mass surrounded by edema and erythema in the posterior vaginal introitusPossible culture STD testing at the request of the patient .Consider biopsy to rule out malignancy (see "Diagnostics" of Bartholin gland cyst above) TreatmentIncision and drainage followed by irrigation and packing Fistulization with a Word catheter MarsupializationIndicated for recurring abscessesThe labia minora is cut longitudinally to expose the cyst or abscess. Once the cyst or abscess is displayed, it is slit open longitudinally and drained. The slit edges of the cyst or abscess are then everted and sutured to the slit edges of the labia minora, which forms a new opening to allow free drainage Differential diagnoses Bartholin gland carcinomaEpidemiology: primarily found in postmenopausal womenSymptoms: gradual, solid, and painless enlargement of the Bartholin glandDiagnostics: biopsyTreatment Resection of the lesionIf surgery is not possible or as adjuvant therapy: chemotherapy and radiation Folliculitis Inclusion cysts Leiomyomas Fibroma

Congenital syphilis

Epidemiology ∼ 23:100,000 live births per year in the US Pathogen Treponema pallidum Transmission MotherSexual contact (contact with infectious lesion)See "Etiology" in syphilis. Fetus: transplacental transmission from infected motherIncreased risk of transmission with recent syphilis infection Risk of transmission increases with gestational age Neonate: perinatal transmission during birth Clinical features Early congenital syphilis (onset < 2 years of age) Hepatomegaly and jaundiceRhinorrhea with white or bloody nasal discharge Maculopapular rash on palms and soles Skeletal abnormalities (e.g., metaphyseal dystrophy, periostitis)Generalized lymphadenopathy (nontender) Late congenital syphilis (onset > 2 years of age) Typical facial features: saddle nose, frontal bossing, short maxillaDental findings: Hutchinson's teeth (notched, widely spaced teeth); mulberry molars (poorly developed first molars) Eyes and ears: interstitial keratitis, sensorineural hearing lossSkin: rhagades (perioral fissures), gummasSkeletal: saber shins (anterior bowing of the tibia), painless arthritis in knees and other jointsNeurological: cranial nerve palsies (e.g., CN VIII defect causing deafness), intellectual disability, hydrocephalus Diagnosis Newborn and motherInitial test: RPR or VDRL (serum)Confirmatory test: dark-field microscopy or PCR of lesions or bodily fluids See "Diagnostics" in syphilis. Fetus: repeated ultrasound examinations (placentomegaly, hepatomegaly, ascites, and/or hydrops fetalis) Treatment 14 days of IV penicillin G for both pregnant women and newborns Prevention Maternal screening in early pregnancy Nationally notifiable condition: Congenital syphilis and syphilitic childbirth must be reported to local or state health department. Hutchinson triad: interstitial keratitis, sensorineural hearing loss, Hutchinson teeth

Congenital listeriosis

Epidemiology ∼ 3:100,000 live births per year in the US Pathogen Listeria monocytogenes Transmission MotherContaminated food: especially raw milk productsOther possible sources: fish, meat, and industrially processed vegetables (e.g., ready-made salads)See "Etiology" in listeriosis. FetusTransplacental transmission from an infected motherDirect contact with infected vaginal secretions and/or blood during delivery Clinical features Intrauterine transmissionIncreased risk of premature birth and spontaneous abortionEarly-onset syndrome: granulomatosis infantisepticaSevere systemic infection characterized by disseminated abscesses (may develop in any organ system)Most common findings: respiratory distress and skin lesionsSigns of meningitis may already develop. Transmission during birth or postnatally (via contact with the mother or contaminated environment) Late-onset syndrome (5 days to 3 weeks after birth): Listeria meningitis/encephalitisSee "Neonatal infection and sepsis" in chorioamnionitis, neonatal infection, and omphalitis. Diagnosis Culture from blood or CSF samples (pleocytosis) Treatment IV ampicillin and gentamicin (for both mother and newborn) Prevention Avoidance of soft cheeses Avoidance of potentially contaminated water and food: See "Food and water safety" in food poisoning. Nationally notifiable condition: Listeriosis must be reported to the local or state health department.

Congenital parvovirus B19 infection

Epidemiology ∼ 5% incidence in pregnant women per year in the US Higher prevalence in daycare workers and elementary school teachers Pathogen Parvovirus B19 Transmission MotherMainly via aerosolsRarely hematogenous transmissionSee fifth disease. Fetus: transplacental transmission from infected mother Clinical features Severe anemia and possibly fetal hydrops Fetal demise and miscarriage/stillbirth in approximately 10% of cases (Risk is highest in the first and second trimesters.) Most intrauterine infections do not result in fetal developmental defects. Diagnosis Mother: serologic assays for IgG and IgM against parvovirus B19 Positive IgM and negative IgG: very recent infection → refer to specialist Positive IgM and IgG: acute infection → refer to specialist Positive IgG and negative IgM: maternal immunity → reassurance Negative IgG and negative IgM: no maternal immunity → counseling Fetus PCR for parvovirus B19 DNA (amniotic fluid or blood) Doppler ultrasound of fetal vessels in suspected hydrops fetalis Treatment Intrauterine fetal blood transfusion in cases of severe fetal anemia Prevention Hand hygiene (frequent hand washing) Pregnant women with risk factors for TORCH infection should avoid potentially contaminated workplaces (e.g., schools, pediatric clinics)

Progressive multifocal leukoencephalopathy (PML)

Epidemiology: Develops mainly in patients with severe immunosuppressionAIDS-defining condition (∼ 5% of AIDS patients) Etiology:HIV infection Hematologic and solid cancersInflammatory diseasesPatients are treated with immunosuppressants/-modulators (natalizumab, rituximab). Pathophysiology: past subclinical infection with JC virus (most adults are infected)→ event (e.g., immunosuppression) triggers reactivation → infects oligodendrocytes → viral DNA mutation leads to aggressive replication within brain tissue → destruction of infected oligodendrocytes + demyelination Clinical featuresFocal symptoms SeizuresImpaired vigilanceCognitive disordersBehavioral changes DiagnosticsMRI: disseminated, non-enhancing white matter lesions without mass effectCSF : detection of JC virus DNA in PCR of cerebrospinal fluidBrain biopsy and histology : demyelination of axons and intranuclear inclusions Prognosis: high mortalityPatients without HIV: Median survival is 3 months.HIV patients: One-year survival is ≥ 50% (with sufficient antiretroviral therapy). Treatment: supportive therapy and optimization antiretroviral therapy (to improve immune status)

Immune deficiency

EpidemiologyPrimary immunodeficiency diseases are rare (an exception is selective IgA deficiency).∼ 1-2/1,000 patients are immunodeficient. There are over 50 different forms of immunodeficiency, with the most frequent being: Innate (see the learning card on congenital immunodeficiency disorders for more information): Fanconi anemiaSelective IgA deficiencyWiskott-Aldrich syndromeAtaxia telangiectasiaDiGeorge syndromeAcquired HIV/AIDSIatrogenic immune suppression Clinical findings: The main symptom of a primary immunodeficiency is a pathological susceptibility to infection. The type of susceptibility is characterized by the invading pathogen, localization, course, severity, and number of infections. Not all immune defects are clinically apparent. Antibody deficiency Bruton agammaglobulinemia Variable immunodeficiency syndrome (common variable immunodeficiency, or CVID) Bacterial infections: particularly Staphylococcus, Streptococcus, Haemophilus influenza Enteroviral infection Defective cellular immunity HIV Viral infections Fungal infections (e.g., Candida) Protozoal infections Opportunistic infections

Meningitis Meningitis is a serious infection of the meninges in the brain or spinal cord that is most commonly viral or bacterial in origin, although fungal, parasitic, and noninfectious causes are also possible. Enteroviruses and herpes simplex virus are the leading causes of viral meningitis, while Neisseria meningitidis and Streptococcus pneumoniae are the pathogens most commonly responsible for bacterial meningitis. Rarer forms of bacterial meningitis include tuberculous meningitis and Lyme-associated meningitis. The classic triad of meningitis is fever, headache, and neck stiffness. In infants and young children, the presentation is often nonspecific. Patients may also present with neurological deficits, altered mental status, and seizures, indicating increased intracranial pressure (ICP). Diagnostics include physical examination followed by blood cultures and lumbar puncture. If increased ICP is suspected, a CT of the head should be performed first. Bacterial meningitis requires rapid initiation of empiric treatment. A life-threatening complication of bacterial meningitis (especially meningococcal meningitis) is Waterhouse-Friderichsen syndrome, which is characterized by disseminated intravascular coagulation and acute adrenal gland insufficiency. Viral meningitis typically resolves on its own and has a far less severe course than bacterial meningitis, which is generally fatal if left untreated

Etiology Common causes Otitis media Sinusitis CSF leak after head trauma or neurosurgery Maternal group B streptococcal infection during birth Sepsis Risk factors Immunocompromise (e.g., due to AIDS, asplenia, heavy alcohol use disorder, chronic illness, cancer, sickle cell anemia, old age, pregnancy) Crowded living conditions (e.g., college dormitories, military barracks, retirement homes (listeriosis), kindergartens) Close contact with an infected person NewbornsGroup B streptococcus (most common but incidence decreasing because of screening and prophylaxis during pregnancy)Escherichia coliListeria monocytogenesHaemophilus influenzaeEnterobacter cloacaeInfantsStreptococcus pneumoniae and Neisseria meningitidis (most common)Haemophilus influenzae Listeria monocytogenesGroup B streptococcusChildren and teenagersNeisseria meningitidis (most common)Streptococcus pneumoniaeListeria monocytogenesHaemophilus influenzae if not immunized Enteroviruses (especially coxsackievirus and echovirus)Herpes simplex virus (HSV-2)Mumps virusAdults 20-60 yearsStreptococcus pneumoniae (most common)Enteroviruses (especially coxsackievirus and echovirus)Herpes simplex virus (HSV-2)Adults ≥ 60 yearsStreptococcus pneumoniae (most common)Neisseria meningitidisHaemophilus influenzae if not immunizedGroup B streptococcusE. coliListeria monocytogenesEnteroviruses (especially coxsackievirus and echovirus)Herpes simplex virus (HSV-2)Immunocompromised individualsListeria monocytogenesGram-negative bacilliStreptococcus pneumoniaeCryptococcus spp. (particularly in individuals with HIV)CMV, VZV, HSV, JC virusMycobacterium tuberculosis (tuberculous meningitis)Toxoplasma gondiiPregnant womenListeria monocytogenesStreptococcus agalactiaeHospitalized patients Staphylococci (most frequently S. aureus) [1]Gram-negative bacteria (e.g., Pseudomonas aeruginosa Less common pathogens Bacterial meningitisBorrelia spp. → Lyme meningitisTreponema pallidum → syphilitic meningitis Viral meningitis: often associated with encephalitis (meningoencephalitis) Herpesviruses: HSV1 (meningitis is more commonly caused by HSV2 than HSV1), CMV, EBV, VZVLymphocytic choriomeningitis virus (LCMV)Mumps virusSome arboviruses (e.g., West Nile virus, TBEV in Eurasia)Influenza virusHIV Fungal meningitis CoccidioidesCandida spp.Aspergillus spp. Parasitic meningitis: helminths such as Echinococcus spp. Noninfectious meningitis SarcoidosisTumor metastases (meningeal carcinomatosis and meningeal leukemia)Medication (e.g., NSAIDs) Pathways of infection Most pathogens that cause meningitis colonize the nasopharynx or the upper airways before entering the CNS via: Hematogenous dissemination . [8]Contiguous spread of infections in nose, eyes, and earsRetrograde transport along or within peripheral or cranial nerves Direct infection (e.g., due to trauma or head surgery) [1] Incubation periods Bacterial meningitis: usually 3-7 days [9] Viral meningitis: usually 2-14 day, depending on the type of virus Clinical features Clinical features of bacterial and viral meningitis are similar, although viral meningitis is less acute and usually self-limiting within 7-10 days. Neonates (neonatal meningitis) Often nonspecific and without the classic triad of meningitis Early symptomsLethargyMuscle hypotoniaIrritabilityPoor appetite, vomitingHyperthermia or hypothermiaDyspnea, abnormal breathing patterns (e.g., Biot respiration) [10] Late symptomsFontanelle bulgingHigh-pitched cryingSeizures Children and adults Classic triad of meningitis: fever, headache, and neck stiffness (this triad is often not present in neonates and infants) Altered mental status Photophobia Nausea, vomiting Malaise Seizures Possibly cranial nerve palsies In the case of N. meningitidisMyalgia and, possibly, petechial or purpuric rash (especially in children)Possibly Waterhouse-Friderichsen syndrome Common symptoms of viral meningitis Prodrome with flu-like symptoms Low-grade feverMalaise, fatigueMyalgiaUpper respiratory symptoms (e.g., sore throat)Pharyngitis, herpangina, and/or rash Physical examination [3][11] Signs of meningeal irritationNeck stiffnessKernig sign Brudzinski sign Systemic signs of inflammationFeverHypotensionTachycardia Signs of increased intracranial pressure: e.g., papilledema (< 5% of cases) [12] Signs of underlying infectionsBulging and redness of tympanic membrane: acute otitis mediaSkin manifestations [13]Cutaneous petechiae in meningococcal meningitis: suggestive of meningococcemiaMaculopapular rash in some viral meningitis (e.g., West Nile virus, enterovirus) Subarachnoid hemorrhage can manifest with the classic triad of meningitis but has a more sudden onset and patients often lose consciousness. Blood studies Blood cultures should be performed before antibiotic therapy is started Blood glucose to assess CSF glucose (see table on cerebrospinal fluid analysis in meningitis below) Serum studies ↑ WBCCoagulation studies if disseminated intravascular coagulation is suspected Lumbar puncture (LP) Approach: essential in all patients with suspected meningitis, unless there are signs of increased intracranial pressure (ICP), which include: [16]History of space-occupying CNS lesions, hydrocephalus, CSF shunts, or CNS traumaFocal neurological deficitsAltered mental statusSeizuresPapilledema If LP is contraindicated: initiate empiric antibiotic treatment immediately and conduct CT before LP to rule out ↑ ICP [16] ComplicationsHeadacheDizzinessNauseaHearing loss, tinnitus CSF studies: Gram stain and culture, PCR, and CSF analysis should all be conducted. LAT is not routinely recommended but may be considered if antibioticswere given before the LP. Gram stain and culture to differentiate pathogens [12]Meningococci: gram-negative diplococciPneumococci: gram-positive diplococciListeria: gram-positive rodsHaemophilus influenzae: gram-negative coccobacilliPCR: for bacterial (e.g., meningococcus) and/or viral meningitis (e.g., HSV)Latex agglutination test (LAT; for bacterial antigen detection): enables rapid detection of meningococci, pneumococci, Haemophilus influenzae, and Escherichia coliNo longer recommended as a routine test.Highly specific but sensitivity ranges from 50-90%. Indicated if a patient has received antibiotics prior to the LP (which could cause a culture to be falsely negative)Cerebrospinal fluid analysis in meningitis Normal Clear fluid,No granulocytes, Primarily lymphocytes, Cell count< 5/μL, Opening pressure 50-180 mm H2O Lactate 1.2-2.1 mmol/L Protein15-45 mg/100 mL Glucose40-75 mg/100 mL (∼ ⅔ of blood glucose level) Bacterial meningitis Cloudy, purulent fluid Significant granulocytosis > 1000/μl OP ↑↑ Lactate ↑↑ Protein ↑ Glucose ↓ Viral meningitis Clear fluid Lymphocytosis 10-500/μl OP/Lactate Normal or ↑/Protein Normal or ↑/Glucose normal Tuberculous meningitis Clear fluid with spiderweb coagulum Pleocytosis (predominantly lymphocytes, but also granulocytes and mononuclear cells) 30-300/μl OP/Lactate/Protein high, Glucose low Lyme meningitis Clear fluid Pleocytosis(lymphocytes, mononuclear cells) 10-1000/μl Only OP ↑↑ Cryptococcal meningitis Cloudy Pleocytosis(lymphocytes) 20-200/μl OP/Lactate/Protein high, Glucose low Post-dural puncture headache is the most probable diagnosis in patients complaining of headache, dizziness, hearing loss/tinnitus, and nausea after lumbar puncture. Cerebral imagingCT: possible signs of ↑ ICP (e.g., effacement of the ventricles, herniation)MRT: gelatinous pseudocysts in cryptococcal meningitis (soap bubble appearance) Fundoscopic examination: papilledema if ↑ ICP Tuberculous meningitis Pathogen: Mycobacterium tuberculosis Incubation period: approximately 2-8 weeks Clinical courseSubacute course over several weeks or monthsGradual manifestation with intermittent fever Clinical featuresFocal neurological deficits (e.g., hemiparesis) due to hematogenous dissemination of cranial arteritisCranial nerve deficits Most commonly seen in basal meningitisPredominantly involves the facial nerve and oculomotor nerve DiagnosticsAcid-fast stain and culture of 3 CSF samples ComplicationsCommunicating (malabsorptive) hydrocephalus Pituitary gland insufficiency Treatment: see "Treatment" in tuberculosis Cryptococcal meningitis Pathogen: Cryptococcus neoformans (a type of encapsulated yeast) Risk factorsAIDSExposure to pigeon droppings Clinical course: subacute onset with (low) fever, fatigue, and headaches Clinical featuresSee section on "Clinical features" aboveMeningeal symptoms are often absent DiagnosticsLaboratory studies (CSF and blood)Latex agglutination test detects C. neoformans and cryptococcal antigens Culture (Sabouraud agar)Staining: India Ink (clear halo), mucicarmine (red inner capsule) TreatmentIntrathecally amphotericin B with or without flucytosine (induction therapy lasting 10-14 days)Followed by fluconazole (consolidation therapy lasting 8-10 weeks and maintenance therapy lasting at least 12 months)cART therapy should be delayed for at least 2 weeks after initiation of antifungal therapy. Lyme meningitis See Lyme disease. Tick-borne meningoencephalitis (primarily in Eurasia) Pathogen: tick-borne encephalitis virus (TBEV) TBEVs are part of the Flaviviridae family and occur predominantly in parts of Europe, Russia, and Asia.TBEV is very closely related to the Powassan virus in the US and Russia, which is a rare cause of encephalitis. Route of infection: tick-borneIxodid tick acts as a vector → transmission predominantly in June/July and September/OctoberOccasional transmission via unpasteurized dairy products from infected livestock Incubation period: usually 7-14 days Clinical features:Nearly 90% of cases are asymptomatic.Biphasic course: initial flu-like symptoms and fever, followed (after ∼ 8 days) by a fever-free interval and subsequent increase in temperature, which is associated with the onset of meningoencephalitis Treatment: symptomatic Prognosis:Full recovery is common (particularly in children and adolescents).In symptomatic disease, residual symptoms may occur. Prevention: A vaccine is not available in the US. Active immunization with an inactivated TBEV (inactivated vaccination): Large-scale implementation of this vaccination is not generally recommended.The CDC's Advisory Committee on Immunization Practices (ACIP) recommends the vaccination only for individuals living, traveling, or working in high-riskareas (laboratory staff exposed to TBEV, foresters, etc.). Primary amoebic meningoencephalitis [21] Pathogen: Naegleria fowleri, an amoeba found in warm, still standing freshwater (e.g., ponds, hot springs) Route of infection: via contaminated water entering the nose (e.g., while swimming) → invades the CNS directly via the cribriform plate Clinical features: causes fulminant meningoencephalitis with rapid onset (brain-eating amoeba) Diagnosis: microscopy of CSF shows amoebas Treatment: amphotericin B Prognosis: nearly always fatal Acute bacterial meningitis Management algorithm Blood cultures Lumbar puncture for CSF Gram stain and culture Immediate empirical treatment Empiric treatment IV antibiotics for different patient groups < 1 month: ampicillin PLUS aminoglycoside (e.g., gentamicin) PLUS third-generation cephalosporin (e.g., cefotaxime or ceftriaxone )> 1 month to < 50 years: vancomycin PLUS third-generation cephalosporin (e.g., cefotaxime or ceftriaxone)> 50 years: vancomycin PLUS ampicillin PLUS third-generation cephalosporin (e.g., cefotaxime or ceftriaxone)Immunocompromised: vancomycin PLUS ampicillin PLUS cefepime OR meropenemHospital-acquired: vancomycin PLUS ceftazidime OR cefepime OR meropenem Possibly dexamethasone: only beneficial in some cases In adults: when pneumococcal meningitis is strongly suspected or confirmedIn children: for suspected or confirmed HiB meningitis Doxycycline (during tick-bite season in endemic areas only!) Acute viral meningitis Symptomatic therapy only For severe cases of HSV, EBV, and VZV meningitis, consider antiviral therapy with acyclovir (IV or PO). Complications Neurologic Most common: sensorineural hearing loss (transient or permanent) Focal neurological deficits [31] Seizures Cognitive impairment Spasticity or paresis Cerebral edema and elevated ICP Communicating hydrocephalus Cerebrovascular disease Rare: brain abscess, subdural empyema, arteritis (risk of cerebral infarction and cerebral venous sinus thrombosis), ventriculitis, cerebritis Waterhouse-Friderichsen syndrome Epidemiology: predominantly affects small children and asplenic individuals Description: acute primary insufficiency of the adrenal gland most commonly caused by adrenal hemorrhageDangerous complication of a number of diseases but most commonly associated with meningococcal meningitisRarer causes include DIC, endotoxic shock, and septicemia due to other pathogens (e.g., S. pneumoniae) Pathophysiology: coagulopathy triggered by endotoxins, which often leads to hemorrhagic necrosis of the adrenal glands Clinical featuresFeverMyalgiaNonblanching, petechial rash (mostly on trunk and legs); in severe cases, even purpura fulminans with extensive necrosis of the skinSevere malaiseHypotension or even shockFindings of disseminated intravascular coagulationFindings of acute adrenal gland failureRespiratory failure TreatmentEmpiric antibiotic treatment (see section on "Treatment" above)Parenteral fluid therapy and management of disorders of sodium balanceCoagulopathy treatment Prognosis: fatal without treatment and often fatal even with treatment, particularly if associated with meningococcal infection (> 40% mortality rate) [32] Prognosis Bacterial meningitisFatal if left untreatedPrognosis in treated patients depends on age, overall condition, immune status and the pathogen(s) involved. Viral meningitisResolves spontaneously in the majority of casesResidual symptoms such as sensorineural hearing loss, epilepsy, and cognitive deficits are rare. Fungal meningitisAssociated with neurological sequelae and a high mortality rateTreatment adherence is very important to avoid relapse. Prevention Preexposure prophylaxis: For meningococcal vaccination (a polysaccharide conjugate vaccine), 11-12 and 16 Postexposure measures in bacterial meningitis [35]Postexposure vaccination: may be considered if the particular serogroup is known and available as a vaccinePostexposure chemoprophylaxis Drugs of choice: rifampin, ciprofloxacin, or ceftriaxoneIndicated for all individuals exposed to an index case (close contacts) if caused by: [11][20]N. meningitidis (e.g., rifampin, ciprofloxacin, or ceftriaxone)H. influenzae (e.g., rifampin)Postexposure prophylaxisDrugs of choice (monotherapy)AdultsRifampinCiprofloxacinCeftriaxoneInfants, children, and adolescentsRifampinCeftriaxonePregnancyCeftriaxone Miscellaneous Notifiable disease: Any probable or confirmed cases of meningococcal meningitis or meningitis due to Haemophilus must be reported to the CDC.

Sepsis Sepsis is an acute life-threatening condition characterized by organ dysfunction due to a dysregulated immune response to infection. The previously widely used term "systemic inflammatory response syndrome" (SIRS) is now considered outdated because its criteria were too simplified. Initial infection is generally bacterial and commonly of respiratory, genitourinary, gastrointestinal, dermatological, or soft tissue origin. Risk factors include immunocompromise, chronic comorbidities (e.g., diabetes mellitus), young or old age, and lengthy or invasive medical care. Patients may present with fever, tachycardia, confusion, and signs of the primary infection. Organ dysfunction is determined using a sequential organ failure assessment (SOFA) score that considers multiple parameters, but may be quickly evaluated and assumed if two of the following findings are present: tachypnea, hypotension, and altered mental status. Diagnostic workup focuses on determining the responsible pathogen via cultures and identifying the source of infection (e.g., via imaging, ECG, lumbar puncture). Laboratory findings are largely nonspecific. Prompt, aggressive treatment is vital to survival and consists of resuscitation, empiric antibiotic therapy, and control of the infectious source.

Etiology Common primary infections: respiratory , genitourinary, gastrointestinal, skin, and soft tissue infections PathogensBacterial: gram positive bacteria (most common in the US), gram negative bacteriaFungal, viral, or parasitic infection (rare) Risk factorsAge: < 1 year or > 75 yearsPrimary comorbidities (diabetes mellitus, cirrhosis, community acquired pneumonia, bacteremia (presence of bacteria in circulation), alcoholism)Immunosuppression (neutropenia, corticosteroid treatment)Intensive care or prolonged admission (nosocomial infections)Recent antibiotic or corticosteroid treatmentInvasive medical devices (e.g., endotracheal tubes, intravenous lines, urinary catheters) Classification 2015 criteria and SOFA classification (The third international consensus definitions for sepsis and septic shock, Sepsis-3) Sepsis: acute and life-threatening organ dysfunction due to abnormal host response to infection Organ dysfunction: an acute change in total SOFA score ≥ 2 points Infection: may be confirmed (via culture) or suspected Septic shock consists of the following parameters: Sepsis +Significant circulatory, metabolic, and cellular abnormalities +Requiring vasopressor therapy to maintain a mean blood pressure of ≥ 65 mmHg and presence of increased lactate levels > 2 mmol/L (18 mg/dL) in the absence of hypovolemia The term "severe sepsis" is no longer used Quick SOFA criteria (qSOFA): to predict mortality in adult patients with suspected infection Positive if ≥ 2 of the following are present: Altered mental status (Glasgow Coma Scale < 15) [8] Respiratory rate: ≥ 22 breaths per minuteSystolic BP: ≤ 100 mmHgIf positive then the patient should be assessed for organ dysfunction via the SOFA score. Respiration PaO2/FiO2 (mmHg) ≥ 400 < 400 < 300 < 200 with respiratory support < 100 with respiratory support Coagulation Platelets x 103/mm3 ≥ 150 < 150 < 100 < 50 < 20 Liver Bilirubin (mg/dL) < 1.2 1.2-1.9 2.0-5.9 6.0-11.9 > 12.0 Cardiovascular systemMAP ≥ 70 mmHg MAP< 70 mmHg Dopamine < 5 or dobutamine(any dose)* Dopamine > 5.1-15, Epinephrine ≤ 0.1, or norepinephrine ≤ 0.1* Dopamine > 15, Epinephrine > 0.1, or norepinephrine > 0.1* Central nervous systemGlasgow Coma Scale 15 13-14 10-12 6-9 < 6 Renal systemCreatinine (mg/dL) or urine output (mL/d)< 1.2 1.2-1.9 2.0-3.4 3.5-4.9 or < 500> 5.0 or < 200 MAP ⅓ systolic pressure + ⅔ diastolic pressure Pathophysiology Sepsis is the state of a hyperinflammatory systemic reaction Local activation of inflammatory mediators (complement system, mast cells, macrophages) results in vessel dilation and further release of proinflammatory cytokines (esp. TNFα, IL-1)Generalized endothelial disruption → capillary leak → generalized edema due to a shift of intravascular fluid and albumin into the surrounding tissueIntravascular hypovolemia → excessive triggering of the extrinsic coagulation cascade → disseminated intravascular coagulation(DIC) and microvascular thrombosisDecreased oxygen utilization and tissue ischemia → widespread cellular injury → organ dysfunction (commonly multisystem) Clinical features Patients typically present with a poor overall condition and generalized edema (capillary leak). Fever , chills, and diaphoresis Tachycardia Tachypnea Features of organ dysfunction (see SOFA score) CNS impairment: altered mental statusCardiovascular failure: hypotensionCoagulopathy → disseminated intravascular coagulation → petechiae, purpuraLiver failure: jaundiceKidney failure: oliguriaRespiratory failure: symptoms of acute respiratory distress syndrome (ARDS) Additionally in septic shockSevere hypotension (< 65 mmHg)Initially warm skin and normal capillary refill time (warm shock) → cold cyanotic, pale, or mottled skin with prolonged capillary refill time (cold shock) Features of the primary infection Diagnostics Identify the responsible pathogenPerform Gram stain and cultures of blood and urine Depending on symptoms, consider other body fluids for culture: e.g., sputum (if coughing), stool (if diarrhea is present), pus (soft tissue infection). Identify the infectious focusImaging Lumbar puncture if suspected CNS infectionEchocardiography if suspected endocarditis Assess organ dysfunctionCoagulation abnormalities (see disseminated intravascular coagulation): ↑ prothrombin time, ↑ activated partial thromboplastin time, ↓ antithrombin III, later ↑ D dimerAbnormal liver function: hyperbilirubinemia, ↑ INR, ↑ ALT, ↑ ASTAdrenal insufficiency (e.g., ACTH stimulation test)Impaired kidney function: ↑ BUN and ↑ creatinine Nonspecific infectious parametersCBCAnemia Leukocytosis or eventual leukopenia Thrombocytopenia → early prognostic marker of 28 day mortality due to septic shockProcalcitonin ↑ CRP ↑ Serum lactate Hyperglycemia (plasma glucose > 140 mg/dL or 7.7 mmol/L) in the absence of known diabetes Treatment Immediate resuscitation (respiratory and circulatory support)Intubation and mechanical ventilation may be required if the following is present: respiratory insufficiency, dyspnea, persistent hypotension, or poor peripheral perfusionFluid resuscitation (hypotension and hypoperfusion)Vasopressors (catecholamines) may be necessary when patients remain hypotensive despite fluid resuscitation (e.g., norepinephrine) Empiric antibiotic treatment: begin immediately after blood cultures have been drawn, preferably within 1 hour after recognition Treat for MRSA until ruled out: vancomycin or linezolid/daptomycin in combination with either: Piperacillin/tazobactam, cefepime, or carbapenems if Pseudomonas infection is likely3rd generation cephalosporin (e.g., ceftriaxone or cefotaxime) if Pseudomonas infection is unlikelyAntifungal treatment in cases of documented fungemia (presence of a fungus in the bloodstream) Control infectious sourceRemove any foreign bodies Surgically drain abscesses or perform debridement on infectious woundsManage any complications of surgery (e.g., ileus, peritonitis, anastomotic insufficiency, osteomyelitis) Reassess the success of the therapeutic management every 48-72 hours Other therapy considerations Glucocorticoids (e.g., prednisone or dexamethasone): if there is an increased risk of cerebral edema Insulin-based control of blood glucose levels: control of stress-induced hyperglycemia results in a shorter length of stay in the ICU, even in non-diabetic patients Complications Critical illness polyneuropathyDefinition: axonal injury, particularly to the motor neurons, as a sequela of sepsis and multiple organ dysfunctionClinical featuresPredominantly distal, symmetrical, flaccid paralysis of the extremities with muscle atrophy; may affect the diaphragmAbsent or reduced reflexesDysesthesias in a glove-and-stocking distribution may be presentPreservation of cranial nerve functionMay be associated with critical illness myopathy : flaccid quadriparesis (proximal > distal); facial muscle weakness, sensation normal, tendon reflexes normal or ↑Diagnosis: typical clinical features, sepsis, and electrophysiological evidence of motor and sensory neuropathy Electromyography (EMG): spontaneous activity (e.g., fibrillations)Nerve conduction studies: normal velocity, reduced amplitudeTreatment: no specific treatment available, usually gradual spontaneous resolution (weeks to months)

Pneumonia Pneumonia is a respiratory infection characterized by inflammation of the alveolar space and/or the interstitial tissue of the lungs. In industrialized nations, it is the leading infectious cause of death. Pneumonia is most commonly transmitted via aspiration of airborne pathogens (primarily bacteria, but also viruses and fungi) but may also result from the aspiration of stomach contents. The most likely causal pathogens can be narrowed down based on patient age, immune status, and where the infection was acquired (community-acquired or hospital-acquired). Pneumonia is classified based on clinical features as either typical and atypical; each type has its own spectrum of commonly associated pathogens. Typical pneumonia manifests with sudden onset of malaise, fever, and a productive cough. On auscultation, crackles and bronchial breath sounds are audible. Atypical pneumonia manifests with gradual onset of unproductive cough, dyspnea, and extrapulmonary manifestations. Auscultation is usually unremarkable. Some patients may present with elements of both types. Diagnostics include blood tests for inflammatory parameters and pathogen detection in blood, urine, or sputum samples. Chest x-ray in cases of typical pneumonia shows opacity restricted to one lobe, while x-ray in atypical pneumonia may show diffuse, often subtle infiltrates. Together with the characteristic clinical features, newly developed pulmonary infiltrate on chest x-ray confirms the diagnosis. Management consists of empiric antibiotic treatment and supportive measures (e.g., oxygen administration, antipyretics).

Etiology Community-acquired pneumoniaTypical pneumoniaStreptococcus pneumoniae (most common) Also the most common pathogen in nursing home residentsHaemophilus influenzae , Moraxella catarrhalisKlebsiella pneumoniae Staphylococcus aureus Atypical pneumoniaBacteria Mycoplasma pneumoniae (most common in the ambulatory setting)Chlamydophila pneumoniae Chlamydophila psittaciLegionella pneumophila → legionellosisCoxiella burnetii → Q feverFrancisella tularensis → tularemiaViruses RSVInfluenza virusesCMVAdenovirus Hospital-acquired pneumonia Gram-negative pathogensPseudomonas aeruginosaEnterobacteriaceaeStaphylococci (Staphylococcus aureus) Streptococcus pneumoniae Lobar pneumoniaMost commonly S. pneumoniaeLess commonlyLegionellaKlebsiellaH. influenzae BronchopneumoniaS. pneumoniaeS. aureusH. influenzaeKlebsiella Interstitial pneumoniaAtypical pathogensMycoplasma pneumoniaeChlamydophila pneumoniaeChlamydophila psittaci (primarily transmitted by parrots) LegionellaViruses (e.g., RSV, CMV, influenza, adenovirus) Cryptogenic organizing pneumoniaNoninfectious Pneumonia in immunocompromised patientsEncapsulated bacteria Pneumocystis jirovecii → Pneumocystis jirovecii pneumoniaAspergillus fumigatus → aspergillosisCandida species → candidiasisCytomegalovirus (CMV) → CMV pneumonia Pneumonia in newbornsEscherichia coliStreptococcus agalactiae (Group B streptococcus)Streptococcus pneumoniaeHaemophilus influenzae Recurrent pneumonia Uncommon organisms (e.g., Nocardia, Coxiella burnetii, Aspergillus, Pseudomonas aeruginosa) Risk factors Old age and immobility of any cause Chronic diseasesPre-existing cardiopulmonary conditions (e.g., bronchial asthma, COPD, heart failure)Acquired or congenital abnormalities of the airways (e.g., bronchiectasis, space-occupying lesions, cystic fibrosis) Immunosuppression (e.g., HIV infection, diabetes mellitus, cytostatic therapy, alcoholism, immunosuppressive therapy, malnutrition) Smoking Impaired airway protection → aspirationAlteration in consciousness (e.g., stroke, seizure, anesthesia, drugs, alcohol)Dysphagia Environmental factorsCrowded living conditions (e.g., prisons, homeless shelters)Toxins (e.g., solvents, gasoline) Cryptogenic organizing pneumoniaSpecific medications (e.g., amiodarone, bleomycin) Chronic inflammatory disorders (e.g., rheumatoid arthritis) Classification Pneumonia can be classified according to etiology, location acquired, clinical features, and the area of the lung affected by the pathology. EtiologyPrimary pneumonia: no apparent pre-existing conditions that may predispose to pneumoniaSecondary pneumoniaBronchial asthma, COPD, heart failure, cystic fibrosisViral upper respiratory tract infections with bacterial superinfectionAnatomical abnormalities such as tubercular caverns, bronchial tumors, or stenosis (postobstructive pneumonia)Aspiration pneumonia Location acquiredCommunity-acquired pneumonia (CAP): pneumonia that is acquired outside of a healthcare establishmentHospital-acquired pneumonia (HAP): nosocomial pneumonia, with onset > 48 hours after admissionVentilator-associated pneumonia (VAP): pneumonia occurring in patients who are on mechanical ventilation breathing machines in hospitals (typically in the intensive care unit)Healthcare-associated pneumonia (HCAP): pneumonia that is acquired in healthcare facilities (e.g., hospital, nursing homes, hemodialysis centers, and outpatient clinics); this terminology is no longer recommended but is included for historical purposes. [4][5] Clinical features (see "Clinical features") Typical pneumoniaPneumonia featuring classic symptoms; typical findings on auscultation and percussionManifests as lobar pneumonia or bronchopneumoniaAtypical pneumoniaPneumonia with less distinct classical symptoms and often unremarkable findings on auscultation and percussionManifests as interstitial pneumonia Area of lung affected by the pathology (see "Pathophysiology") Lobar pneumonia: pneumonia affecting one lobe of a lungMultilobar pneumonia refers to the involvement of multiple lobes in a single lung or both lungs.Panlobar pneumonia involves all the lobes of a single lung.Bronchial pneumonia: pneumonia affecting the tissue around the bronchi and/or bronchiolesInterstitial pneumonia: pneumonia affecting the tissue between the alveoliCryptogenic organizing pneumonia (formerly known as bronchiolitis obliterans organizing pneumonia): a noninfectious pneumonia of unknown etiology characterized by the involvement of the bronchioles, alveoli, and surrounding tissue Pathophysiology Routes of infection Most common: microaspiration (droplet infection) of airborne pathogens or oropharyngeal secretions Aspiration of gastric acid (aspiration pneumonitis) , food, or liquids Hematogenous dissemination (rare) Pathogenesis Failure of protective pulmonary mechanisms (cough reflex, mucociliary clearance , alveolar macrophages ) Pathogen infiltrates pulmonary parenchyma → interstitial and alveolar inflammation Impaired alveolar ventilation → ventilation/perfusion (V/Q) mismatch with intrapulmonary shunting (right to left) Hypoxia due to increased alveolar-arterial oxygen gradient Hypoxia is worsened when the affected lung is in the dependent position, as perfusion to the dependent lung is better compared to the nondependent lung.In the case of a large unilateral pulmonary abscess, it may be helpful to position the patient so that the affected lung is in the dependent position in order to prevent pus from filling the unaffected lung. Pattern of involvement Lobar pneumoniaClassic (typical) pneumonia of an entire lobe; primarily caused by pneumococciCharacterized by inflammatory intra-alveolar exudate, resulting in consolidationCan involve the entire lobe or the whole lung Congestion (day 1-2)Parenchymal partial consolidationRed-purpleAlveolar lumens with serous exudate, bacteria, and rare inflammatory cellsRed hepatization (day 3-4)Parenchymal consolidationRed-brownDry and firmLiver-like consistencyReversible Alveolar lumens with exudate rich in fibrin, bacteria, erythrocytes, and inflammatory cellsAlveolar walls thickened Gray hepatization (day 5-7)Uniformly grayLiver-like consistencyAlveolar lumens with suppurative exudate (neutrophils and macrophages)Erythrocytes and most bacteria have been degraded.Alveolar walls thickened Resolution (day 8 to week 4)Gradual aeration of the affected segmentEnzymatic fibrinolysisMacrophages remove the suppurative exudate. Bronchopneumonia: mostly commonly a descending infection that affects the bronchioles and adjacent alveoli; usually involves the lower lobes or right middle lobe; manifests as typical pneumonia [8]Primarily caused by pneumococci and/or other streptococciNecrotizing bronchopneumonia and pneumatocele are caused by Staphylococcus aureus and are often preceded by an influenza infection.Characterized by acute inflammatory infiltrates that fill the bronchioles and the adjacent alveoli (patchy distribution)Usually affects ≥ 1 lobe Interstitial pneumonia: interstitial inflammation, typically caused by mycoplasma and viral infections; manifests as atypical pneumoniaCharacterized by a diffuse patchy inflammation that mainly involves the alveolar interstitial cellsBilateral multifocal opacities are classically found on chest x-ray.Often has an indolent course (walking pneumonia) Miliary pneumonia: multiple small infiltrations caused by hematogenous dissemination (e.g., of tuberculosis) Cryptogenic organizing pneumonia: characterized by inflammation of the bronchioles and surrounding structures Typical pneumonia Typical pneumonia is characterized by a sudden onset of symptoms caused by lobar infiltration. Severe malaise High fever and chills Productive cough with purulent sputum (yellow-greenish)Crackles and decreased bronchial breath sounds on auscultationEnhanced bronchophony, egophony, and tactile fremitusDullness on percussion Tachypnea and dyspnea (nasal flaring, thoracic retractions) Pleuritic chest pain when breathing, often accompanying pleural effusion Pain that radiates to the abdomen and epigastric region (particularly in children) Suspect bacterial pneumonia in immunocompromised patients with acute high fever and pleural effusion! Atypical pneumonia Atypical pneumonia typically has an indolent course (slow onset) and commonly manifests with extrapulmonary symptoms. Nonproductive, dry cough Dyspnea Auscultation often unremarkable Common extrapulmonary features include fatigue, headaches, sore throat, myalgias, and malaise. Diagnostics Pneumonia is a clinical diagnosis based on history, physical examination, laboratory findings, and CXR findings. Consider microbiological studies and advanced diagnostics based on patient history, comorbidities, severity, and entity of pneumonia. [14] Laboratory studies Routine CBC, inflammatory markers: ↑ CRP, ↑ ESR, leukocytosis ↑ Serum procalcitonin (PCT): Procalcitonin is an acute phase reactant that can help to diagnose bacterial lower respiratory tract infections. [5]PCT can be used to guide antibiotic treatment but should not be used to decide if antibiotic therapy is necessary on its own. [5][15][16]PCT levels ≥ 0.25 mcg/L correlate with an increased probability of a bacterial infection.Low PCT level after 2-3 days of antibiotic therapy can help facilitate the decision to discontinue antibiotics. [16] ABG: ↓ PaO2 [14] BMP, LFTs Any admitted patientMRSA nares swab (PCR and/or culture)Any patient being treated empirically for MRSA or P. aeruginosa Blood cultures (2 sets)Sputum culture and gram stainSevere CAPHAPVAPBlood cultures (2 sets)Sputum culture and gram stainPneumococcal urinary antigenLegionella pneumophila urinary antigen Consider Chlamydia pneumoniae respiratory PCR. Influenza seasonInfluenza nasal swab (NAAT) Consider respiratory virus panel nasal swab (NAAT). Chest x-ray (posteroanterior and lateral) Indications: all patients suspected of having pneumoniaFindings may include: Lobar pneumoniaOpacity of one or more pulmonary lobesPresence of air bronchograms : appearance of translucent bronchi inside opaque areas of alveolar consolidationBronchopneumoniaPoorly defined patchy infiltrates scattered throughout the lungsPresence of air bronchograms Atypical or interstitial pneumoniaDiffuse reticular opacityAbsent (or minimal) consolidationParapneumonic effusion A new pulmonary infiltrate on chest x-ray in a patient with classic symptoms of pneumonia confirms the diagnosis. Chest CT without contrast Indications Inconclusive chest x-rayRecurrent pneumonia Poor response to treatment Advantages: more reliable evaluation of circumscribed opacities, pleural empyema, or sites of consolidationFindings may include: [17]Localized areas of consolidation (hyperdense)Air bronchogramsGround-glass opacitiesPleural effusion/empyema: hyperdense fluid collection, split pleura signNodules: large , peribronchial , disseminated Advanced diagnostics BronchoscopyIndications Suspected mass (e.g., recurrent pneumonia)Need for pathohistological diagnosis (e.g., biopsy of a central mass discovered on CT)Inconclusive results on CTPoor response to treatment Diagnostic thoracentesisIndications: consider if pleural effusion is present to evaluate for pleural empyema [18][14]Findings: see "Diagnostics" and parapneumonic effusion in pleural effusion. Criteria for hospitalization Every patient should be assessed individually and clinical judgment is the most important factor. The pneumonia severity index (PSI) and the CURB-65 score are tools that can help to determine whether to admit a patient. CURB-65 score [19]Confusion (disorientation, impaired consciousness)Serum Urea > 7 mmol/L (20 mg/dL)Respiratory rate ≥ 30/minBlood pressure: systolic BP ≤ 90 mm Hg or diastolic BP ≤ 60 mm HgAge ≥ 65 yearsInterpretationEach finding is assigned 1 point.CURB-65 score 0 or 1: The patient may be treated as an outpatient.CURB-65 score ≥ 2: Hospitalization is indicated.CURB-65 score ≥ 3: Consider ICU level of care. CRB-65 score (if serum urea is not known or unavailable) CRB-65 score of 0: The patient may be treated as an outpatient.CRB-65 score of ≥ 1: Hospitalization is recommended. Criteria for ICU admission The decision of whether to admit a patient to the ICU should be based on clinical judgment. The IDSA/ATS criteria for severe CAP can be used to help triage patients with CAP and guide empiric antibiotic treatment decisions Empiric antibiotic therapy for community-acquired pneumonia Previously healthy patients without comorbidities or risk factors for resistant pathogens Monotherapy with one of the following: AmoxicillinDoxycyclineA macrolide (only in areas with a pneumococcal macrolide resistance < 25%)AzithromycinClarithromycin Patients with comorbidities or risk factors for resistant pathogens Combination therapyAn antipneumococcal β-lactam: Amoxicillin-clavulanateCefuroximeCefpodoximePLUS one of the following:A macrolideAzithromycinClarithromycinDoxycycline Monotherapy: with a respiratory fluoroquinolones GemifloxacinMoxifloxacinLevofloxacin Duration of treatment5 days of therapy is usually sufficient for CAP that is treated in the outpatient setting.Any patient being treated in a primary care setting should be re-examined after 48-72 hours to evaluate the efficacy of the prescribed antibiotic. Additional considerations: Knowing local resistance patterns of S. pneumoniae to macrolides is critical when deciding on an empiric antibiotic regimen. Inpatient Nonsevere CAP/non-ICU treatment Combination therapyAn antipneumococcal β-lactam: Ampicillin-sulbactamCeftarolineCeftriaxoneCefotaximePLUS one of the following:A macrolideAzithromycinClarithromycinDoxycycline Monotherapy: with a respiratory fluoroquinolone GemifloxacinMoxifloxacinLevofloxacin Severe CAP/ICU treatment Combination therapyAn antipneumococcal β-lactam: Ampicillin-sulbactamCeftarolineCeftriaxoneCefotaximePLUS one of the following: A macrolideAzithromycinClarithromycinDoxycyclineA respiratory fluoroquinolone MoxifloxacinLevofloxacin Alternative for patients with a penicillin allergy: AztreonamPLUS a respiratory fluoroquinoloneMoxifloxacinLevofloxacin) Risk factors for Pseudomonas aeruginosa Combination therapyAn antipneumococcal, antipseudomonal β-lactam:Piperacillin-tazobactamCefepimeCeftazidimeMeropenemImipenem-cilastatinPLUS one of the following: A macrolideAzithromycinClarithromycinDoxycyclineA respiratory fluoroquinoloneLevofloxacinMoxifloxacin Alternative for patients with a penicillin allergy: AztreonamPLUS a respiratory fluoroquinoloneMoxifloxacinLevofloxacin) Risk factors for MRSA Addition of one of the following antibiotics with MRSA activityVancomycinLinezolid Duration of therapy5-7 days is usually sufficient.Consider longer courses in patients with one of the following: Patient not responding to treatmentSuspected or concern for MRSA or P. aeruginosa infectionConcurrent meningitisUnusual pathogens (e.g., Burkholderia pseudomallei, fungal infection) Additional considerationsIf aztreonam is used instead of a β-lactam antibiotic (e.g., for penicillin allergy), the addition of MSSA coverage (e.g., a fluoroquinolone) is necessary.Anaerobic coverage is not routinely recommended for suspected aspiration pneumonia (unless lung abscess or empyema is suspected). [5]Corticosteroids are not routinely recommended as adjunct therapy. Empiric antibiotic therapy for hospital-acquired pneumonia Patients not at high risk for mortality and without risk factors for MRSA infection MonotherapyAn antipneumococcal, antipseudomonal β-lactamImipenemMeropenemCefepimePiperacillin-tazobactamOR levofloxacin Patients not at high risk for mortality but with risk factors for MRSA infection Combination therapyOne of the following antibiotics with MRSA activity:LinezolidVancomycinPLUS one of the following: An antipneumococcal, antipseudomonal β-lactamPiperacillin-tazobactamCefepimeCeftazidimeMeropenemImipenemA fluoroquinoloneLevofloxacinCiprofloxacin )Aztreonam Patients at high risk for mortality Patients with structural lung disease (e.g., cystic fibrosis, bronchiectasis) Combination therapyOne of the following antibiotics with MRSA activity:VancomycinLinezolidPLUS any two of the following (avoid combining two β-lactams):An antipneumococcal, antipseudomonal β-lactamPiperacillin-tazobactamCefepimeCeftazidimeMeropenemImipenemA fluoroquinoloneLevofloxacinCiprofloxacinAn aminoglycosideAmikacinGentamicinTobramycinAztreonam Duration of treatmentEmpiric antibiotic therapy should be narrowed and/or de-escalated as soon as feasible.Seven days of therapy are usually sufficient. [4] Additional considerations: Resistance patterns can vary widely; local antibiograms should be considered when starting empiric treatment. Empiric antibiotic therapy for ventilator-associated pneumonia [4] Recommended combination therapyAn antipneumococcal, antipseudomonal β-lactamAztreonamImipenemMeropenemCeftazidimeCefepimePiperacillin-tazobactamPLUS one of the following antibiotics with MRSA activity: VancomycinLinezolidPLUS one of the following: A fluoroquinoloneLevofloxacinCiprofloxacinAn aminoglycosideAmikacinGentamicinTobramycinA polymyxinColistinPolymyxin B Duration of treatment: Seven days of therapy are usually sufficient. [4] Additional considerations: Risk factors for multi-drug resistant organisms (e.g., presence of structural lung disease, recent IV antibiotic therapy, local resistance patterns) should be considered when deciding on an empiric regimenEmpiric antibiotic therapy for ventilator-associated tracheobronchitis is not routinely recommended. Supportive therapy Sufficient rest (not absolute bed rest) and physical therapy Hydration with PO fluids or IV fluids (see IV fluids) Treat hypoxemia. Supplemental oxygen as needed for hypoxiaSee also airway management and ventilation. Incentive spirometer Antipyretics, analgesics as needed (e.g., acetaminophen) Expectorants and mucolytics Antitussives (e.g., codeine) Pathogen-specific pneumonia Mycoplasma pneumonia [12][13]EpidemiologyOne of the most common causes of atypical pneumoniaMore common in young childrenOutbreaks may occur in schools, colleges, prisons, and military facilities.Clinical featuresSee atypical pneumonia.Generalized papular rash; erythema multiforme [23]DiagnosticsSubclinical hemolytic anemia: associated with elevated cold agglutinin titers (IgM)Interstitial pneumonia, often with reticulonodular pattern on chest x-rayTreatment: macrolides, doxycycline, and fluoroquinolones Legionnaires' disease Pneumocystis pneumonia Tuberculosis Primary influenza pneumonia Various viral infections (e.g., respiratory-syncytial-virus, hantavirus, adenovirus, CMV) SARS Ornithosis Pseudomonas aeruginosa: causes ventilator-associated pneumonia Aspiration pneumonia Definition: Aspiration is the inhalation of foreign material into the respiratory tract. It most commonly occurs after instrumentation of the upper airways or esophagus (e.g., upper GI endoscopy) or secondary to vomiting and regurgitation of gastric contents. Aspiration pneumonitisAspiration of gastric acid that initially causes tracheobronchitis, with rapid progression to chemical pneumonitisMay cause ARDS in extreme cases Risk factors Altered consciousness: alcohol, sedation, general anesthesia, strokeApoplexy and neurodegenerative conditions Gastroesophageal reflux disease, esophageal motility disordersCongenital defects (e.g., tracheoesophageal fistula) Pathogens: mixed infections with anaerobic organisms are common (e.g., Klebsiella spp.) Clinical findingsImmediate symptoms: bronchospasms , crackles on auscultation, hypoxemia with cyanosisLate symptoms: fever, shortness of breath, cough with foul-smelling sputum DiagnosisArterial blood gas analysis (↓ PaO2, pH < 7.35, PaCO2 > 45 mm Hg)Radiologic imaging: The lung region in which the infiltrates are seen depends on the patient's position on aspiration. Supine position: superior segment of the right lower lobe (most common site of aspiration)Standing/sitting: posterior basal segment of the right lower lobeRight lateral decubitus position: posterior segment of the right upper lobe or right middle lobe ManagementIf secondary to extubation: Immediate (re)intubation with administration of 100% O2Endotracheal suction with microbiological analysis of bronchial secretionsAntibiotic treatment that covers anaerobes (e.g., ampicillin-sulbactam, carbapenems, or clindamycin) Regular monitoring: arterial blood gas, radiologic imaging Prevention: Optimize treatment and/or prophylaxis of underlying causes to reduce the risk of aspiration (e.g., elevation of the head of the bed). Complications Parapneumonic pleuritisFibrinous pleuritis: inflammation → increased vessel permeability → fibrin-rich exudate deposited on the serosal surface of the pleuraMay manifest with pleuritic chest pain and friction rubAnalgesics can be used for relief of symptoms. Parapneumonic pleural effusion (common) Pleural empyema Sepsis Respiratory failure, ARDS Lung abscess Lung abscess Definition: a localized collection of pus and necrotic tissue within lung parenchyma caused by microbial infection Risk factorsPredisposition to aspiration due to reduced level of consciousness (see risk factors for "Aspiration pneumonia" above)Bronchial obstruction (e.g., lung cancer, foreign body aspiration, bronchial stenosis)Immunocompromised statePneumonia PathogensMost commonly: mixed infections caused by anaerobic bacteria that colonize the oral cavity (e.g., Peptostreptococcus, Prevotella, Bacteroides, Fusobacteriumspp.)Less commonly: monomicrobial lung abscess caused by S. aureus, Klebsiella pneumoniae, Streptococcus pyogenes, Streptococcus anginosus Clinical findings: indolent presentation with symptoms that evolve over weeks to months FeverCough with production of foul-smelling sputumAnorexia, weight lossNight sweatsHemoptysis DiagnosisGram stain, culture, and sensitivity of expectorated sputum Radiologic imaging (x-ray or CT): irregular rounded cavity with an air-fluid level that is dependent on body position (most commonly in the right lung) Upright position: right lower lobeRecumbent position: right upper or middle lobe ManagementAntibiotic treatment that covers anaerobes (e.g., ampicillin-sulbactam, carbapenems, or clindamycin )If medical therapy fails, percutaneous catheter drainage or surgical resection (e.g., segmentectomy or lobectomy) may be considered. Prognosis Mortality increases with age. The mortality risk can be evaluated with the CURB-65 score. Score 0: ∼ 1%Score 1-2: ∼ 10%Score 3: ∼ 14%Score 4: ∼ 40% HAP is associated with a mortality rate of > 20%. Prevention Pneumococcal vaccination Influenza vaccination Smoking cessation

Epididymitis Epididymitis is an inflammation of the epididymis that is commonly associated with genitourinary tract infections. The typical presentation involves gradual onset of pain and swelling of the affected side of the scrotum as well as a positive Prehn sign. Epididymitis is a clinical diagnosis, but testicular torsion should be excluded by ultrasound because it has a similar presentation and is a surgical emergency. Treatment involves prompt empiric antibiotic therapy, scrotal elevation, and nonsteroidal anti‑inflammatory therapy to prevent abscessformation and possible infertility.

Etiology Epididymitis is an inflammation of the epididymis. , usually as a result of an infection. In most cases, the epididymis and testes are affected simultaneously, resulting in epididymo-orchitis. Urinary tract infectionsMost common cause among older males and childrenPathogens: E. coli (most common), Proteus mirabilis, Klebsiella pneumoniae, PseudomonasSexually transmitted infectionsMost common cause among young males (usually < 35 years of age)Pathogens: Chlamydia trachomatis (common), Neisseria gonorrhoeae (common), Treponema pallidum, Trichomonas vaginalis, Gardnerella vaginalis Chronic epididymitis (> 6 week course of disease) Recurrent and/or untreated acute epididymitisTuberculosis (usually associated with renal tuberculosis)Rare, non-infectious causes: Amiodarone-induced epididymitisAutoimmune diseases (e.g., Behcet's disease) Clinical features Unilateral scrotal pain and swelling , which develops over several days and radiates to the ipsilateral flank Positive Prehn sign: reduced pain when the affected hemiscrotum is elevated Scrotal skin overlying the epididymis may appear red, shiny, and edematous. Low-grade fever (especially among children) Symptoms of lower urinary tract infection (e.g., dysuria, frequency, urgency), including urethritis (urethral discharge) Chronic epididymitisRecurrent bouts of scrotal painSwelling is minimal when compared to acute epididymitisThickened epididymis Diagnostics Primarily a clinical diagnosis Laboratory findingsUrinalysis (pyuria, bacteriuria) and urine culture if a UTI is suspected Urethral swab for culture and nucleic acid amplification testing (Chlamydia, Gonorrhea) if a STI is suspectedCBC: leukocytosis Scrotal ultrasoundIndicated To rule out testicular torsion if this is not possible based on history and physical examIf an abscess is suspected Findings in epididymitis: enlarged epididymis, increased blood flow Differential diagnoses See differential diagnosis of scrotal pain. Hydrocele Varicocele Inguinal hernia Treatment Empiric antibiotic therapy based on likely pathogens (until the causative organism is known) Suspected UTI (with enteric organisms): fluoroquinolones (e.g., ofloxacin or levofloxacin)Suspected STI: (with chlamydia or gonorrhea) ceftriaxone and doxycycline, or (in the case of Chlamydia, Gonorrhea, and entericorganisms ) ceftriaxone and a fluoroquinolone Scrotal elevation, ice packs, and NSAIDs If an abscess develops: surgical drainage Chronic epididymitisNSAIDs and prolonged antibiotic therapyIf symptoms persist: epididymectomy and/or orchidectomyIf tuberculosis is suspected: anti-tuberculous therapy Complications Epididymal abscess Testicular infarction Infertility

Endophthalmitis Endophthalmitis is a rare, potentially sight-threatening inflammation of the vitreous humor (vitritis) that may be infectious (bacterial/fungal infection) or noninfectious (sterile). Infectious endophthalmitis can have either an exogenous (following ocular surgery/penetrating trauma) or endogenous (hematogenous spread) etiology. Staphylococcal/streptococcal infection after cataract surgery is the most common cause of exogenous bacterial endophthalmitis. Fungal endophthalmitis is often caused by Candida and is more common in immunocompromisedindividuals. Endophthalmitis may present either acutely with sudden, deep ocular pain and rapidly progressive loss of vision or indolently (chronic endophthalmitis). Clinical features include conjunctival hyperemia, corneal haziness, hypopyon, and decreased visual acuity. Vitreous infiltrates are seen on slit lamp examination. Diagnosis is often clear on history and ocular examination. In doubtful cases, ultrasound of the eye and gram stain and culture of the vitreous humor is indicated. Infectious endophthalmitis is treated with intravitreal injection of either antibiotics (vancomycin with ceftazidime/amikacin) or antifungals (amphotericin B/voriconazole). Surgical removal of the vitreous humor (vitrectomy) is done in sight-threatening cases. Patients with noninfectious endophthalmitis usually resolve completely with topical steroids alone. Untreated infectious endophthalmitis can progress to cause panophthalmitis, corneal rupture, and permanent vision loss.

Etiology Infectious endophthalmitis Causative organismBacteria: coagulase-negative staphylococci (most common), S. aureus, streptococci, B. cereus (in posttraumatic endophthalmitis) Fungi: Candida (most common), mold (Aspergillus, Mucor, and Fusarium species) Route of entryExogenous (direct inoculation) Intraocular surgeries/injections Postcataract surgery (most common cause)After glaucoma surgery; corneal transplant; intravitreal injections Penetrating trauma (less common) Endogenous (hematogenous spread) Presence of a distant infectious focus → bacteremia/fungemia → seeding of the vascular choroid by the organism → spreadof infection to the retina and vitreous Noninfectious endophthalmitis (sterile) An inflammatory reaction to drugs injected into the vitreous Usually resolves completely without intravitreal antibiotics/vitrectomy Acute endophthalmitis Usually bacterial Postoperative endophthalmitis usually develops within a week of surgery. Infection by less virulent bacteria (or fungi) can cause endophthalmitis up to 6 weeks after surgery. Severe, deep-seated, dull ocular pain Acute loss of vision Features of sepsis may be present (in endogenous endophthalmitis). Chronic endophthalmitis Usually fungal Less virulent bacteria Insidious Ocular pain is usually absent/appears late. Gradually progressive loss of vision Floaters (fungal endophthalmitis) Exogenous endophthalmitis Conjunctival hyperemia and chemosis out of proportion to the surgical/traumatic insultHazy cornea (due to edema)Hazy aqueous chamber or hypopyon Endogenous endophthalmitis: The above signs do not develop/develop until late in the course of the disease In both types Relative afferent pupillary defectDecreased visual acuity Diagnostics Slit lamp examination of the eye Indicated in all patients with endophthalmitis. Cornea: edematous/hazy Aqueous chamber: hazy; hypopyon Vitreous chamber: inflammation (cells and protein); white and fluffy infiltrates (snowball appearance) in fungal endophthalmitis Fundoscopy Indicated in all patients with endophthalmitis. Loss of the red reflex (due to chorioretinitis) Roth's spots may be seen in patients with endogenous endophthalmitis due to infective endocarditis, and occasionally in fungal endophthalmitis. Bacterial endophthalmitis: nonvisualization of retinal vessels Fungal endophthalmitis: creamy white retinal nodules Ultrasound of the eye (B-scan) Indicated if the vitreous cannot be seen on slit lamp examination (e.g., due to a hazy cornea/aqueous chamber) Findings: hyperechogenicity of the vitreous (due to inflammation), thickened chorioretinal membrane Gram-stain and culture of aqueous and/or vitreous humor The aqueous and/or vitreous humor can be extracted through a fine needle and cultured. Indicated in doubtful cases Workup for primary source of infection For patients with endogenous endophthalmitis Blood cultures: should be done in all patients with endogenous endophthalmitis When an infectious source is unknown, the following tests are indicated: Urine culture to rule out UTIECHO to rule out infective endocarditis (suspect in IV drug abusers or patients with prosthetic heart valves)Abdominal USG to rule our liver abscess (suspect in patients with DM, hepatobiliary disease), etc. Treatment Intravitreal drug administrationBacterial endophthalmitis: empirical intravitreal antibiotic administration in all cases (vancomycin and ceftazidime/amikacin) Mold endophthalmitis or sight-threatening candida endophthalmitis: intravitreal antifungal administration (amphotericin B or voriconazole) Systemic antifungal administration (IV fluconazole or voriconazole): early disease due to Candida , all patients with endogenous fungal endophthalmitis Pars plana vitrectomy: in patients with sight-threatening endophthalmitis Sterile endophthalmitisMild/early disease: topical steroidsSevere inflammation: treat as bacterial endophthalmitis Early initiation of treatment (within hours) is critical to preserve eyesight! Complications Panophthalmitis Corneal perforation Phthisis bulbi Glaucoma Permanent loss of vision

Septic arthritis Septic (infectious) arthritis is a bacterial infection of the joint space. Contamination occurs either via the bloodstream, iatrogenically, or by local extension (e.g., penetrating trauma) and patients with damaged (e.g., patients with rheumatoid arthritis) or prosthetic joints have an increased risk. Patients usually present with an acutely swollen, painful joint, limited range of motion, and a fever. Suspected infectious arthritis requires prompt arthrocentesis for diagnosis. In addition to the immediate broad-spectrum antibiotic therapy, surgical drainage and debridement may be necessary to prevent cartilage destruction and sepsis.

Etiology Mechanism of infectionHematogenous spread (most common)From a distant site (e.g., abscesses, wound infection, septicemia)Disseminated infection (e.g., gonorrhea)Direct contaminationIatrogenic (e.g., joint injection, arthrocentesis, arthroscopy)Trauma (e.g., open wounds around the joint, penetrating trauma)Contiguous spread (e.g., septic bursitis, osteomyelitis) Risk factorsProsthetic implantInterventions (e.g., intra-articular injections)Underlying joint disease, especially rheumatoid arthritis Immunosuppressed stateDiabetes mellitusAge > 80 yearsChronic skin infectionsIV drug use Causative organismsStaphylococcus aureus - most common, in adults and children > 2 years and arthritis caused by invasive procedures StreptococciS. epidermidisH. influenzae N. gonorrhea Gram-negative rods esp. E. coliand P. aeruginosa M. tuberculosis and atypical mycobacteria B. burgdorferi (Lyme disease) Clinical features Acute onset Joint involvementUsually monoarticular Most commonly affected joints: knees; followed by hip, wrists, shoulders, and ankles Classical triad of fever, joint pain, and restricted range of motion Joint may be swollen, red, and warm Prosthetic joint infection Etiology [4]Early onset (< 3 months of placement) : most commonly S. aureusDelayed onset (3-12 months of placement) : coagulase-negative staphylococci, particularly S. epidermidisLate onset (> 12 months of placement) : most commonly S. aureus Clinical findingsUsually prolonged, low-grade course Minimal swelling, with or without a sinus that drains pusCan present acutely (see "Clinical features" above) Diagnostic findingsConventional x-ray: loosening of the prosthesis, periosteal reactionsFor other diagnostic tests see "Diagnostics" below TherapyRemoval of the prosthesis (usually) and administer IV antibiotics for 6-8 weeksReimplantation of the prosthesis following antibiotic treatment Bacterial coxitis (septic arthritis of the hip) Uncommon condition that requires urgent treatment to avoid destruction of the joint Etiology: S. aureus and group A streptococcus account for the majority of cases Clinical findingsJoint pain (may be referred to the groin or knee); patients present with flexion and external rotation of the hip → alleviates pain by decreasing intraarticular pressureSee also "Clinical features" above For diagnostics and therapy, see respective sections below. Bacterial coxitis is an orthopedic emergency! Gonococcal arthritis See purulent gonococcal arthritis and arthritis-dermatitis syndrome. Gonococcal arthritis is the most common form of arthritis in sexually active young adults! In a young, sexually active adult presenting with classic symptoms of septic arthritis, gonococcal infection must be ruled out! Lyme disease See Lyme arthritis. Migratory large joint. Diagnostics If septic arthritis is suspected, arthrocentesis should be conducted for synovial fluid analysis. Imaging (e.g., X-ray, MRI) may be indicated to assess potential underlying diseases or differential diagnoses. Ultrasound-guided arthrocentesis: Definitive diagnosis requires detection of bacteria in the synovial fluid.To conduct synovial fluid analysis, gram stain, and culture↑ Synovial fluid WBC and dominance of polymorphonuclear (PMN) cellsCell count: > 50,000 WBC/μl (neutrophil predominant) points to septic arthritis (can be as low as > 10,000 in early disease).Fluid appears yellowish-green and turbidSynovial fluid culture and gram stain is positive in most patients with bacterial arthritis.Also alleviates pain by decreasing intraarticular pressure Laboratory tests↑ CRP/ESRBlood culture: at least 2 sets of blood cultures to rule out a bacteremic origin Imaging: to look for signs of underlying osteomyelitis and concurrent joint disease and rule out possible differential diagnoses (see "Differential diagnosis" below) Ultrasound: effusion, edema of the surrounding soft tissue, possible empyemaX-ray: unremarkable early in the course of septic arthritis; osteolysis usually becomes visible after 2-3 weeks.MRI or scintigraphy for early detection MRI provides early evidence of infectious involvement of the surrounding soft tissueScintigraphy is used for detection or exclusion of polyarticular involvement Differential diagnosis based on synovial fluid analysis findings Synovial fluid analysis: comprises a group of tests that examine joint (synovial) fluid to aid in definitively establishing the specific types of arthritis. Normal synovial fluidTransparentClear and viscous WBCs/μl (PMN %) < 200 (< 25%)Nearly equal to bloodNegativeNone Noninflammatory arthritis TransparentYellow and viscous WBCs/μl (PMN %) 200-2000 (< 25%)Nearly equal to bloodNegativeCalcium phosphate crystals (apatite): ∼ 60% of osteoarthritis cases Inflammatory (RA, SLE, gout, pseudocout) Translucent-opaqueYellow and watery WBCs/μl (PMN %) > 2,000 (≥ 50%)Lower than bloodNegativeMonosodium urate crystals: goutCalcium pyrophosphate crystals: pseudogout Septic OpaqueYellow or green with variable viscosity WBCs/μl (PMN %) > 50,000 (≥ 75%)Early:WBCs/μl (PMN %) > 10,000 (≥ 75%)Much lower than bloodUsually positiveNone Hemorrhagic CloudyReddish with variable viscosity WBCs/μl (PMN %) 200-2,000 (50%-75%)Nearly equal to bloodNegativeNone Further differential diagnoses to consider Viral arthritis Etiology: parvovirus B19, hepatitis B virus, hepatitis C virus, rubella virus, HIV PathophysiologyDirect invasion of the virus (e.g., rubella, enteroviruses)Immune complex formation (e.g., hepatitis B, hepatitis C, parvovirus) Clinical findingsSymmetric involvement of multiple small jointsSudden onsetPossibly accompanied by rash and feverUsually no destruction of the joint DiagnosticsHistory and clinical findings are the mainstay of establishing a diagnosisSerology: antibodies against the suspected virusSynovial joint analysis: very variable (can be normal or inflammatory) Not routinely used since viral isolation is usually not successfulFor other diagnostic tests, see "Diagnostics" above Therapy: supportive treatment only (usually self-limited; see also learning cards on hepatitis B, hepatitis C, rubella, and parvovirusB19-associated arthritis) Fungal arthritis Etiology: Histoplasma species, Sporothrix schenckii, Blastomyces species, Coccidioides species Clinical findings: very variable with acute and chronic courses, often with symptoms of disseminated infection (e.g., pulmonary symptoms) DiagnosticsSynovial fluid analysis may show normal, inflammatory, or septic findingsSynovial fluid culturePossibly serologic studies: positive antibodies against the pathogen (e.g., in coccidioidal arthritis) See "Overview of fungal infections" in the General mycology learning card for additional information Non-infectious arthritis Acute onset, monoarticular arthritisGoutPseudogoutReactive arthritisJoint trauma Acute or sub-acute onset polyarthritisSee section on differential diagnoses of inflammatory arthritis in learning card on rheumatoid arthritis Treatment Initial management Following arthrocentesis and culture, simultaneous empiric antibiotic therapy (based on the Gram stain) and evacuation of purulentmaterial should be performed. Empiric antibiotic regimensGram-positive cocci: VancomycinGram-negative cocci: CeftriaxoneGram-negative bacilli: 3rd generation cephalosporin (e.g., ceftazidime), cefepime, piperacillin-tazobactam, or carbapenemSuspected pseudomonas infection (e.g., IV drug users): IV ceftazidime plus an IV aminoglycoside (e.g., gentamicin)No organism on gram stain but strong suspicion for bacterial septic arthritis: IV vancomycin plus either ceftazidime, cefepime, or an aminoglycoside Start serial drainage with lavage Sometimes debridement (arthroscopic or open approach) is necessary Further management Tailor antibiotics to gram stain, culture and susceptibility results when available (see table below) Continue antibiotic therapy at least ≥ 2 weeks Continue serial drainage as needed Immobilization + NSAIDs for pain relief and to reduce inflammation Follow-up: Physiotherapy should be initiated early to prevent contracture of both the joint and its capsule S. aureus and other gram-positive cocciPenicillinase-resistant penicillinesOxacillin, nafcillinCefazolinMRSA: VancomycinGram-negative cocciAminoglycosidesCeftriaxoneGram-negative rodsCeftazidime, cefepimeN. gonorrheaIV ceftriaxoneChlamydiaDoxycycline Treatment of children ≤ 3 months: oxacillin + gentamicinIf high risk of MRSA (i.e., prolonged ICU stay) → replace oxacillin with vancomycin > 3 months: nafcillin + cefazolinIf high risk of MRSA + signs of sepsis → replace nafcillin with vancomycinIf high risk of MRSA without signs of sepsis → replace nafcillin with clindamycin Complications Joint destruction Osteomyelitis Sepsis Children: growth arrest

Otitis externa Otitis externa (OE) refers to inflammation of the external auditory canal, which is most often the result of a local bacterial infection. Risk factors for OE include injury to the skin of the external auditory canal and/or exposure to water. OE is characterized by ear pain, discharge, and tragal tenderness. Otoscopy may reveal a furuncle (localized OE) or a red, edematous external auditory canal (diffuse OE). OE is primarily a clinical diagnosis. Treatment involves keeping the external auditory canal dry and administering fluoroquinolone and hydrocortisone ear drops. Systemic antibiotic therapy is usually indicated in immunosuppressed and/or diabetic patients who are at risk of a more severe variant called malignant otitis externa (MOE). MOE, which is almost always caused by Pseudomonas aeruginosa, may present with facial nerve palsy and is potentially fatal because it spreads rapidly to the base of the skull. Immediate referral and treatment with systemic antipseudomonal antibiotics are indicated.

Etiology Most cases of otitis externa are infectious in origin. PathogensBacterial infections (most common cause of otitis externa)Pseudomonas aeruginosa (∼ 40% of cases), commonly from swimming activitiesStaphylococcus aureus, Proteus mirabilis, Escherichia coliFungal infections (less common): Aspergillus (accounts for 90% of all fungal otitis externa), CandidaViral infections (rare): Herpes zoster, Influenza virusesRisk factorsInjury to the skin of the external auditory canal (e.g., cleaning, insertion of foreign objects such as hearing aids or earplugs, excessive itching)Increased moisture in the external auditory canal (e.g., swimming, humid climate) Non-infectious forms of otitis externa are less common and include seborrheic otitis externa (which is associated with seborrheic otitis externa), eczematous otitis externa (a hypersensitivity reaction to pathogens or topical antibiotics), and neurodermatitis (caused by compulsive/psychogenic scratching). Clinical features SymptomsSevere ear pain, particularly at nightOtorrheaIntense itching in the external auditory canal SignsThe tragus is tender to touchPulling up and back on the auricle causes painConductive hearing lossOtoscopic findingsLocalized OE: FuruncleDiffuse OE: Edematous and reddened external auditory canal Subtypes and variants Malignant otitis externa (necrotizing otitis externa) Definition: necrotizing inflammation of the external auditory canal EtiologyPathogen: Pseudomonas aeruginosa (95% of cases)Risk factors: Elderly patients with poorly controlled diabetesImmunosuppression Clinical featuresSevere ear pain Red and swollen periauricular soft tissueOtorrheaConductive hearing lossOtoscopic findings: granulation tissue at the transition between the cartilaginous and the osseous part of the ear canal ComplicationsFacial nerve palsyOsteomyelitis of the skull base → extradural abscess, venous sinus thrombosis, paralysis of other cranial nerves DiagnosticsImagingCT scan to identify bone destructionMRI to identify intracranial extension (e.g., venous sinus thrombosis, cranial abscess)Gallium-67 scan in order to monitor response to treatmentBiopsy: distinguishes malignant otitis externa from a tumor and helps optimize treatment TreatmentPrompt IV antibiotic therapy for several weeks First-line: high-dose ciprofloxacin Second-line: other antipseudomonal antibiotics (e.g., piperacillin-tazobactam, ticarcillin, cefepime, ceftazidime)Surgical debridement is indicated for abscess drainage and removal of bony sequestrumTopical antibiotic treatment (see "Therapy" below) Prognosis: The mortality rate is high even with appropriate antibiotic therapy Diagnostics Otitis externa is primarily a clinical diagnosis. Check blood glucose levels to rule out diabetes Culture and sensitivity tests are not routinely performed; they may be indicated if antibiotic treatment is not effective. Fungal otitis externa should be suspected when symptoms do not resolve with local and/or systemic antibiotic therapy (especially among immunocompromised and diabetic patients)! Treatment Topical treatmentAntibiotic eardrops (typically ofloxacin, ciprofloxacin, or gentamycin) Topical hydrocortisone to control itching and inflammationAural toilet: clean the external auditory canal and keep it dry using an ear wick and/or astringents (e.g., mixture of isopropyl alcoholand acetic acid) Systemic treatment: oral ciprofloxacinIndications ImmunosuppressionDiabetes mellitusSevere otitis externa with cellulitis of the face and neckTopical administration of antibiotics is not possible (e.g., severe edema of the external auditory canal) or is ineffective. NSAIDs for pain relief

Candidiasis Candida albicans is the most common cause of candidiasis and appears almost universally in low numbers on healthy skin, in the oropharyngeal cavity, and in the gastrointestinal and genitourinary tracts. In immunocompetent individuals, C. albicans usually causes minor localized infections, including thrush (affecting the oral cavity), vaginal yeast infections (if there is an underlying pHimbalance), and infections of the intertriginous areas of skin (e.g., the axillae or gluteal folds). More widespread and systemic infections may occur in immunocompromised individuals (e.g., neonates, diabetics, and HIV patients), with the esophagus most commonly affected (candida esophagitis). Localized cutaneous candidiasis infections may be treated with topical antifungal agents (e.g., clotrimazole). More widespread and systemic infections require systemic therapy with fluconazoleor caspofungin.

Etiology Pathogen Most common: Candida albicans (C. albicans)C. albicans is a type of oval, budding yeast (see general mycology)Forms hyphae and long pseudohyphaeUbiquitous on healthy skin, as well as in the oropharyngeal cavity, gastrointestinal tract, genitourinary tract, and vagina Risk factors Immunosuppression is the main risk factor for infection.HIVDiabetes mellitusCertain patient groups (e.g., ICU, transplant patients, surgical patients, and neonates) Imbalance in local floraMedications: antibiotics, steroids, cytostatic agents, immunosuppressive therapy↑ Estrogen levels during pregnancy Hematologic malignancies (e.g., acute myeloid leukemia, multiple myeloma) Compromised skin Excessive moistureLocal lesions (e.g., elderly with dentures, burns) Smoking cigarettes Candida albicans appears almost universally in low numbers on healthy adults but can cause disease in certain high-risk patients, especially those that are immunocompromised! Pathophysiology Local infection: imbalance in local flora (e.g., triggered by antibiotic use) → local overgrowth of C. albicans → local mucocutaneous infection (e.g., oropharyngeal infection, vaginitis) Systemic infection: local mucocutaneous infection → breach of skin/mucosal barrier or translocation (IV catheterisation, ascending infection in pyelonephritis, or resorption via GIT) → direct invasion of bloodstream (candidemia) → spread to visceral tissues → disseminated organ infection (e.g., pyelonephritis, endocarditis) ocal mucocutaneous Oropharyngeal (oral thrush)Pseudomembranous candidiasisWhite plaque in the oral cavity that can be scraped off, giving way to red, inflamed, or bleeding areas. Cottony feeling in the mouth, loss of taste, and in some cases pain while eatingFissuring at the mouth corners Skin and nail infections: erythematous patches and satellite lesions Intertriginous areas Digital web spaces (erosio interdigitalis blastomycetica) Paronychia and onychomycosisDiaper dermatitis: typically in infantsPeak incidence: 3-4 months of ageDevelops as a result of prolonged wetness and diaper occlusionChronic candidal diaper dermatitis should raise suspicion of diabetes mellitus type 1 Candida esophagitisAIDS-defining illness and in patients with hematologic malignanciesOften presents together with oral thrush (but may occur on its own)Retrosternal pain on swallowing (odynophagia)Differential diagnosis: CMV esophagitisHerpes simplex virus esophagitisDrug-induced esophagitis (e.g., doxycycline, tetracycline, and clindamycin) Vaginal yeast infection Systemic candidiasis Candidemia: symptoms may vary from fever to sepsis (hard to distinguish from bacterial sepsis) Infiltration of organs may occur either directly (e.g., ventriculoperitoneal shunt in meningitis) or hematogenous Infiltration of any organ Chorioretinitis Diagnostics A suspected diagnosis based on clinical appearance requires confirmation with additional tests. KOH test (potassium hydroxide smear) on a wet mount preparation of scrapings or smears (best initial test): budding yeasts, hyphae, and pseudohyphae Blood or tissue culture (best confirmatory test) Candida spp. form yeast cells and pseudohyphae at 20-25°CCandida albicans forms germ tubes at 37°C Endoscopy (with or without biopsy) Indications Immunocompetent individuals with odynophagiaCandida infection not responsive to oral fluconazole therapyFindings: white mucosal plaque-like lesions Local mucocutaneous Topical antifungal agents: e.g., clotrimazole, miconazole, ketoconazole, nystatin for 7-14 days Vaginal yeast infection: either topical antifungal agents (e.g., clotrimazole cream) 3-14 days or a single dose of oral fluconazole Esophageal candidiasisFirst-line: oral or IV fluconazole for 14-21 daysAlternatives if treatment fails: oral or IV voriconazole, or IV echinocandins (e.g., caspofunginor micafungin) Systemic treatment IndicationsImmunocompromised patientsHematological infiltration or organ involvement Drug of choice: IV caspofungin or micafungin (echinocandins) for 2 weeks after resolution of symptoms and documented clearance of C. albicans AlternativesFluconazole: in patients not critically ill and if a resistance is unlikely MOA: inhibition of yeast cytochrome p450 enzyme 14-alpha demethylase, which inhibits cell membrane formation Lipid formulation amphotericin B: because of toxicity, only indicated if there is intolerance, limited availability, or resistance to alternatives

Brucellosis Brucellosis is a zoonotic infection caused by different species of Brucella, a genus of gram-negative bacteria. The most common vectors of the disease are cattle, sheep, goats, and pigs. Transmission occurs through ingestion of infected animal products, contact with infected animals, or inhalation of bacteria. Although brucellosis is a major public health concern in many countries, it has become rare in the United States as result of animal health policies. Brucellosis manifests with flu‑like symptoms. However, hepatomegaly, splenomegaly, lymphadenopathy, and focal organ infection (e.g., osteomyelitis, endocarditis, spondylitis) may also occur. Recommended treatment is a combined regimen of doxycycline and rifampin.

Etiology Pathogen: Brucella spp. are facultative intracellular gram-negative coccobacilli TransmissionContaminated food, esp. raw/unpasteurized dairy products or meatContact with infected animals Risk factors: occupational or recreational exposure to infected animals and animal products, e.g., farmers, veterinarians, hunters, slaughterhouse workers, laboratory personnel Clinical features Incubation period: ∼ 2-4 weeks GeneralFlu-like symptomsHigh, potentially undulant fever Painful lymphadenopathy Localized infection Arthralgias, low back pain → osteoarticular infection (e.g., osteomyelitis, spondylitis)Epididymal and testicular tenderness, flank pain → genitourinary infection (e.g., epididymo-orchitis, pyelonephritis)Murmurs, friction rubs, tachycardia → cardiac infection (e.g., endocarditis, myocarditis) Diagnostics Laboratory studies: may show anemia, neutropenia; mild elevation of liver enzymes Serology: serum agglutination, ELISA Confirmatory test: Blood cultureLymph node or bone marrow biopsy specimen and culture Treatment Antibiotic therapyFirst-line therapy: doxycycline and rifampinSecond-line therapy: doxycycline and streptomycin Prevention Obligation to report: According to the CDC, brucellosis is a nationally notifiable disease.

Pneumocystis pneumonia Pneumocystis jirovecii pneumonia (PCP), previously known as Pneumocystis carinii pneumonia, is an opportunistic fungal lung infection occurring almost exclusively in immunocompromised individuals. In 50% of cases, PCP is the first manifestation of AIDS (acquired immune deficiency syndrome), but it may be caused by other immunodeficiency disorders. PCP should be suspected in patients with a history of progressive dyspnea and a dry cough with resistance to standard antibiotictreatment. Signs that support this diagnosis include a CD4 count < 200/μL, an increased beta-D-glucan level, and diffuse bilateral infiltrates on chest x-ray. Management of PCP includes high-dose trimethoprim/sulfamethoxazole (TMP/SMX), treatment of the underlying immunodeficiency disorder, and steroids in the case of severe respiratory insufficiency.

Etiology Pathogen: P. jirovecii (previously P. carinii); ubiquitous fungus Route of transmission: airborne Risk factorsHIV Infection CD4 count: usually < 200/μLPoor compliance with PCP prophylaxis or HAARTHistory of PCP infectionPrimary immunodeficiency disorders e.g., Severe combined immunodeficiency disorderHyper IgM syndromes) Malignancy (e.g., leukemia, non-Hodgkin lymphoma)Immunosuppressive treatment (e.g., chronic glucocorticoid therapy) indicated in Stem cell or organ transplantationConnective tissue disorders (e.g., systemic lupus erythematosus)Vasculitides (e.g., polyarteritis nodosa)Malnutrition Clinical features Symptoms typically have a gradual onset (days to weeks) and include: Low-grade fever and malaiseDyspnea and non-productive coughFatigue, weight loss, chills May progress to fulminant respiratory failure Can be asymptomatic Diagnostics If PCP is suspected based on the history and clinical examination, oxygen saturation, the CD4+count, the beta-D-glucan level should be measured and a CXR conducted. If the CXR is inconclusive, a high-resolution CT scan can be obtained. The diagnosis should generally be confirmed via microscopic identification of P. jirovecii from respiratory secretions. Clinical examination Chest auscultationBilateral crackles and rhonchiUnremarkable auscultatory findings are possible in the early stages of disease. Pulse oximetry: oxygen saturation < 90 % at rest (worsens with exertion) PCP is often misdiagnosed as atypical pneumonia or bronchitis because of the persistent cough and similar auscultatory findings. Laboratory tests CD4 count: typically < 200/μL ↑ Beta‑D‑glucan Confirmatory test: microscopic identification of P. jirovecii in specimen obtained via bronchoalveolar lavage or induced sputum, with methenamine silver staining and immunofluorescence Staining enables visualization of disc-shaped P. jirovecii cysts with central spores Imaging Chest X‑rayTypically symmetrical, diffuse interstitial infiltrates extending from the perihilar regionMay sometimes be normal High-resolution CTIndicated if PCP is still suspected in a patient with a normal CXRHigh sensitivity for PCP; a negative scan thus suggests the diagnosis of PCP is unlikely Acute Infection Treatment of choice: high‑dose TMP/SMX for up to 3 weeks Glucocorticoids: add in the case of severe respiratory insufficiency (either PaO2 < 70 mmHg or arterial‑alveolar oxygen gradient ≥ 35 mmHg). Alternatives if allergic to TMP/SMX or treatment of choice is ineffective Mild/moderate disease Oral trimethoprim + dapsoneOral atovaquoneOral primaquine + clindamycinModerate/severe disease Oral primaquine + IV clindamycinIntravenous pentamidine (monotherapy) PCP prophylaxis IndicationPrimary prophylaxis: CD4‑cell count below 200/μl (e.g., AIDS, bone marrow suppression due to cytotoxic therapy, or primary immunosuppressive disorders)Secondary prophylaxis: to prevent recurrence in patients with AIDS or other immunocompromising conditions ImplementationLow‑dose TMP/SMX Alternative (e.g., if allergic to TMP/SMX): oral dapsone or oral atovaquone Complications Respiratory failure Bullous formation with risk of rupture → secondary pneumothorax Pleural effusion Prognosis PCP was formerly the most common cause of death in HIV‑positive patients during the early years of the HIV epidemic. The introduction of HAART (highly active antiretroviral therapy) and TMP/SMX prophylaxis in patients with a CD4 count < 200/μl has significantly improved the long-term outcome of the disease.Despite adequate prophylaxis, PCP infection may lead to death in patients presenting with severe symptoms (e.g., respiratory failure).

Scabies Scabies is a parasitic skin infestation caused by the Sarcoptes scabiei var. hominis (S. scabiei) mite, which is primarily transmitted via direct human-to-humancontact. The female scabies mite burrows into the superficial skin layer, causing severe pruritus, particularly at night. Primary lesions commonly include erythematous papules, vesicles, or burrows. Treatment involves topical medical therapy (e.g., permethrin) and decontamination of all clothing and textiles.

Etiology Pathogen: Sarcoptes scabiei var. hominis TransmissionHighly contagiousTypically via direct physical contact Risk factors: crowded living conditions (e.g., institutions such as nursing homes, child care facilities, and prison Pathophysiology The fertilized, female mite tunnels into the superficial skin layer (stratum corneum), forming burrows in which she lays her eggs and deposits feces (scybala). After 2 months, the female parasite dies on site. Following a period of 3 weeks, the larvae mature into adult mites, maintaining the infestation cycle. The excretions of the mites and their decomposing bodies contain antigens which cause an immunological response (see type IV hypersensitivity reaction), presenting as severe pruritus and excoriations. Incubation period: approximately 3-6 weeks following infestation. Intense pruritus at night Burning sensation Skin lesionsElongated, erythematous papules Burrows of 2-10 mm in length Scattered vesicles filled with clear or cloudy fluidExcoriations, pustules, and secondary infection Predilection sites Wrists (flexor surface)Medial aspect of fingersInterdigital folds (hands and feet)Male genitalia (e.g., scrotum, penis) All other intertriginous areas of the skin (anterior axillary fold, buttocks)Periumbilical area or waistAdditionally in children, elderly persons, and immunosuppressed patients: scalp, face, neck, under the nail, palms of hands, and soles of feet Diagnostics Typical history and skin lesions on clinical examination (see "Symptoms/clinical findings" above) Environmental diagnosis (direct contact with infected persons) Detection of mites, larvae, ova, or mite fecesRevealed in dermoscopy Microscopic examination of the skin Skin scraping and histology Scabies may be mistaken for eczema, especially as the topical use of glucocorticoids initially alleviates symptoms! Treatment Medical therapy: topical application of a scabicidal agent Drug of choice: permethrin 5% lotion Mechanism of action: inhibition of voltage-gated sodium channels in the mite → delayed repolarization of neurons → paralysis and death of the miteAlternatives Lindane 1% lotion: in the case of treatment failure or side effects Mechanism of action: blocks GABA channels → neurotoxicity in the miteOral ivermectin: especially indicated in large outbreaks or severe forms of scabiesSymptomatic treatment of pruritusOral antihistaminesPossible topical corticosteroid (e.g., hydrocortisone) if severe General measuresWash all textiles (e.g., clothing and bedding) Complications Bacterial superinfection Infection with β-hemolytic streptococcus is a serious complication.

Urinary tract infections Urinary tract infections (UTIs) are classified based on location as upper or lower UTIs, and based on presentation as complicated or uncomplicated. In particular, infection of the bladder is known as cystitis. UTIs are most commonly caused by Enterobacteriaceae, especially Escherichia coli. Women are at high risk of contracting UTIs due to a shorter urethra and the proximity of the anal and genital regions. Other risk factors include sexual intercourse, indwelling urinary catheters, pregnancy, and abnormalities of the urinary tract. Patients present with suprapubic pain, dysuria, urinary urgency and frequency. In typical presentations, clinical diagnosis is often possible and can be supported with findings of pyuria on urinalysis or positive leukocyte esterase and nitrites on a urine dipstick test. Further evaluation with urine culture and/or imaging may be required for patients with complicated cystitis. First-line empiric treatment options for uncomplicated cystitis include trimethoprim-sulfamethoxazole, nitrofurantoin, and fosfomycin. Pregnant women with cystitis should be screened and treated for asymptomatic bacteriuria.

Etiology Pathogens Bacteria: usually caused by an ascending bacterial infection from the urethraEnterobacteriaceae (gram-negative rods)Escherichia coli: in ∼ 80% of UTIsProteus mirabilis: urease-producing → causes alkaline urine with an ammonia smellKlebsiella pneumoniaeEnterobacter speciesOthers Staphylococcus saprophyticus Enterococci (e.g. Enterococcus faecalis) Ureaplasma urealyticum Viruses: Adenoviruses can cause hemorrhagic cystitis in children and immunocompromised patients. Yeast: rare; usually Candida species Abacterial, interstitial cystitis Predisposing factors Female sex: Women are anatomically predisposed because their urethra is shorter and the anal and genital regions are in close proximity, making it more likely that bacteria might spread from the anal region and colonize the vagina. Sexual intercourseBacteria may enter the urethra from the genital and anal regions, hence the term honeymoon cystitis.Diaphragm and spermicide use disturbs the vaginal flora, further increasing the risk of UTIs. Catheter-associated urinary tract infection (CAUTI): caused by indwelling urinary catheters; most common cause of iatrogenic or nosocomial urinary tract infection Host-dependent factorsStructural or functional abnormalities of the urinary tract (e.g., BPH, vesicoureteral reflux, urinary bladder diverticulum, neurogenic bladder, calculi or stones)PregnancyDiabetes mellitusImmunocompromiseUncircumcised malesChronic constipation in toddlers Classification Location Upper UTI : pyelonephritis Lower UTI : cystitis (most common location of UTIs), urethritis Type Asymptomatic bacteriuria: presence of significant bacteriuria without symptoms Uncomplicated UTIImmunocompetent, premenopausal women that are neither pregnant nor have any condition that predisposes them to an increased risk of infectionor failed therapy (see list below) Complicated UTIAny condition or comorbidity that may predispose a patient to an increased risk of infection or failed therapy such as:Male patientPregnant womenChildren or postmenopausal womenPresence of any significant functional or anatomical abnormalities (e.g., BPH, obstruction, stricture)History of urological pathologies (e.g., neurogenic bladder, kidney cysts, stones)History of impaired renal function or renal transplantationDiabetes mellitusImmunocompromise (e.g., transplant recipients, HIV/AIDS)Recent history of any instrumentation (e.g., cystoscopy)Recent placement of any medical devices (e.g., urinary catheter, nephrostomy tubes, or stents)Infection with a resistant uropathogen or recent antibiotic useUTI that spreads beyond the bladder (sepsis, pyelonephritis, prostatitis) Recurrent UTI ≥ 2 infections/6 monthsor≥ 3 infections/year Nosocomial urinary tract infectionFourth most common nosocomial infectionMost commonly caused by indwelling urinary catheters (see catheter-associated urinary tract infection in "Etiology") Clinical features Dysuria, frequency, urgency Suprapubic pain Gross hematuria may be present Fever is usually absent in lower UTIs; therefore, fever and flank pain should be taken as a sign of more serious infection, such as pyelonephritis. Diagnostics Clinical Clinical diagnosis in healthy women with a typical presentation In patients with an atypical presentation, urinalysis is the most important diagnostic test for cystitis. Laboratory tests Dipstick urine test Best initial test Findings indicative of UTIPositive leukocyte esterase Positive nitrites Urine pH may be > 7 (alkaline) in Proteus mirabilis infections Urinalysis with microscopy Confirmatory test Required in children and adolescents Clean-catch midstream specimen is necessary to avoid contamination with vaginal or skin flora. Straight catheterization of the bladderor suprapubic aspiration can also be performed if a clean catch cannot be obtained without contamination (e.g., in children who are not toilet trained.) Diagnostic criteria for UTIPyuria: ≥5-10 WBC/high power field (hpf) Bacteriuria: presence of bacteria on Gram stain (most commonly, gram-negative rods) Leukocyte casts should be absent in lower UTIs. Urine culture Diagnostic criteria for UTISignificant bacteriuria defined as ≥ 105 colony forming units (CFU)/mL serves to confirm a UTI. Any bacteriuria in urine from a suprapubic aspiration of the bladder is abnormal. Indications Patients with the following characteristics or risk factors: Patients with complicated UTIAge older than 65 yearsUse of a diaphragmRecent use of antibioticsSuspected cystitis with the following characteristics: Duration of symptoms greater than 7 daysHigh suspicion of cystitis with a non-diagnostic urinalysisRecurrent UTIsSuspicion of pyelonephritis or urosepsis Diagnostic imaging Indication: complicated cystitis, suspicion of structural abnormalities Ultrasound: allows urinary retention to be ruled out; may also show signs of pyelonephritis (see "Diagnostics" of pyelonephritis) Children <24 months with a urinary tract infection should undergo renal ultrasound in case there is a kidney or urinary tract abnormality Cystoscopy: evaluates for unusual findings on urinalysis, stones, reflux, urinary obstruction, polyps or malignancies, and interstitial cystitis CT: investigates possible urinary tract pathologies, such as stones, obstruction, tumors, cysts, and trauma Intravenous pyelogram (IVP): to look for structural abnormalities, mainly obstructions Differential diagnoses Interstitial cystitis (painful bladder syndrome) Description: rare, chronic, noninfectious cystitis with an unknown etiology that causes suprapubic pain and scarring of the bladderwall Clinical findingsSuprapubic pain or discomfortRelieved by voiding and worsened by bladder filling (most common feature)Other exacerbating factors include sexual activity, exercise, alcohol use, and prolonged sittingUrgency and frequencySymptoms for at least 6 weeks DiagnosisClinical diagnosis after exclusion of other diagnosesUrinalysis with microscopy: required to exclude other diagnoses TherapyBehavior modification (first-line): avoid triggers, fluid management based on symptoms, bladder training Oral medications (second-line): Amitriptyline is most commonly used and works as an analgesic and antidepressant.Invasive procedures in the bladder (third-line) Other differential diagnoses Tuberculous cystitis (see urogenital tuberculosis) Drug-induced cystitis (e.g., cyclophosphamide, NSAIDs) or radiation-induced cystitis Other diseases of the bladder (e.g., urolithiasis, bladder cancer, foreign objects) Vaginitis Pelvic inflammatory disease (PID) Prostatitis Urethritis with sexually transmitted infections (Neisseria gonorrhoeae, Chlamydia trachomatis, etc.), Candida, or irritants Trauma Structural abnormalities of the urethra, e.g., diverticula or strictures Treatment Antibiotic therapy of uncomplicated UTIs Principles of therapy Empiric treatment can be given for uncomplicated cystitis; local resistance patterns should guide the choice of empiric therapy. Persistent symptoms after 48-72 hours of antibiotic therapy suggest possible complicated cystitis or necessitate that empiric therapybe changed. Phenazopyridine, a urinary analgesic, can be used for dysuria for 1-3 days. First-line treatment for acute uncomplicated cystitis in nonpregnant women Trimethoprim-sulfamethoxazole (TMP-SMX)Should be avoided in areas with high resistance (> 20%) or in patients who have used it within the last 3 months (unless the pathogen is susceptible to TMP-SMX on culture) Nitrofurantoin: avoid if patient has renal insufficiency or if pyelonephritis is suspected Fosfomycin: avoid in suspected pyelonephritis Second-line treatment Fluoroquinolones (e.g., ciprofloxacin, levofloxacin) Oral cephalosporins (e.g., cefpodoxime, cefdinir) Penicillins (e.g., amoxicillin-clavulanate) If treatment fails or symptoms worsen, the patient may be treated for complicated cystitis. Antibiotic therapy of complicated UTIs Treatment is extended to 7 days in complicated cystitis. Must be able to reach the prostate in men sufficiently ; therefore, substances such as fosfomycin and nitrofurantoin are not treatment options.Treatment failure or recurrent UTIs in men warrant a urological workup. Antibiotics of choice Fluoroquinolones (e.g., ciprofloxacin, levofloxacin)Cephalosporin, fosfomycin, nitrofurantoin, and trimethoprim-sulfamethoxazole are only used if the pathogen is susceptible. Therapy in pregnant women See treatment of cystitis in pregnant women. Treatment of recurrent infections Chemoprophylaxis can be given to patients with > 2 UTIs per year.Postcoital prophylaxis or at the onset of initial symptoms with a single dose of TMP-SMXContinuous prophylaxis with low-dose TMP-SMX for 6 months. Complications Pyelonephritis and perinephric abscess Epididymitis Prostatitis Prevention Increased fluid intake Postcoital voiding Intermittent straight catheterization is preferred in patients with neurogenic bladder. Intermittent catheterization, instead of the placement of an indwelling catheter, also reduces catheter-associated UTIs Prophylaxis in recurrent urinary tract infections (see "Treatment of recurrent infections" above) UTI during pregnancy Pathogenesis: Pregnancy may increase the risk of recurrent bacteriuria and UTIs due to urinary stasis (caused by increased progesterone), ureteral smooth muscle relaxation and dilation, increased pressure on the bladder from the uterus, and immunosuppression Asymptomatic bacteriuriaScreening for asymptomatic bacteriuria is recommended for all pregnant women in the first trimester. Diagnostic criteria for asymptomatic bacteriuria on urine culture: two consecutive urine samples with the same pathogen with > 105 CFU/mLTreatment is always required for asymptomatic bacteriuria in pregnancy because asymptomatic bacteriuria is more likely to lead to pyelonephritis in pregnant women than in nonpregnant women.Treatment is tailored to urine culture and susceptibilityTreatment options include Beta-lactam antibioticsFosfomycinTMP-SMX, nitrofurantoin Follow-up culture is required. Treatment of UTIs in pregnant womenUncomplicated UTIObtain urinalysis and urine cultureEmpiric treatment options Aminopenicillins such as amoxicillin-clavulanateOral cephalosporins (e.g., cefpodoxime)FosfomycinAlternatives (especially during the 2nd and 3rd trimesters): TMP-SMX, nitrofurantoinAntibiotic therapy is tailored when urine culture and susceptibility results become available. Many antibiotics that are acceptable therapy for UTIs in nonpregnant patients are contraindicated during pregnancy (see pharmacotherapy during pregnancy).Complicated UTI: hospitalization and administration of intravenous antibiotic (also see pyelonephritis in pregnancy) Follow-up culture is required. Complications: preterm labor, low birth weight, ↑ perinatal mortality UTI in children and adolescents DiagnosisUrinalysis and urine cultureCriteria for diagnosis includes both a positive urinalysis (pyuria and/or bacteriuria) and urine culture (> 50,000 CFU/mL).A clean-catch urine sample may be obtained if the child is toilet trained. If not trained, a straight catheterization is necessary.Indicated in patients with suspected UTI that fulfill one of the following criteria: Females and uncircumcised males of < 24 months of age with one of the following risk factors: either fever of unknown source or of duration > 24 hours, history of UTI, ill appearance, suprapubic tenderness, or nonblack raceCircumcised boys < 24 months of age with at least two of the above risk factorsChildren older than 24 months with a suspected UTI based on urinary symptoms (see "Clinical features" section)Any febrile infant or child with an abnormal urinary tract or family history of urinary tract diseaseRenal and bladder ultrasoundIndications:Infants aged 2-24 months with a febrile UTIChildren with either treatment failure, abnormal voiding, abdominal mass, recurrent UTI, or poor likelihood of follow-upVoiding cystourethrography (VCUG) Indications: abnormal ultrasound (hydronephrosis, obstruction, scarring, or masses), abnormal voiding pattern, or recurrent UTI TreatmentTreatment principles in children are similar to adultsEmpiric therapyFirst-line: second- or third-generation cephalosporin (cefdinir, cefixime, cefpodoxime)Alternative: TMP-SMX, first-generation cephalosporin

Viral hemorrhagic fevers Viral hemorrhagic fevers (VHFs) are a group of viral infections caused by viruses from five different families: Arenaviridae, Bunyaviridae, Filoviridae, Flaviviridae, and Paramyxoviridae. The most well-known VHFs are Lassa fever, Hantavirus syndromes, Ebola virus disease, Dengue hemorrhagic fever, and yellow fever. Transmission of VHFs occurs via contact with their animal or insect reservoirs or vectors (e.g., rodents, mosquitoes, ticks). Human-to-human transmission is also possible, e.g., via bodily fluids. VHFs predominantly occur in tropical and subtropical regions. Clinical features of VHFs vary but often include an initial nonspecific flu-like illness that progresses to multisystem hemorrhage. VHFs are diagnosed via antibody detection (e.g., IgG, IgM), PCR, or immunohistochemistry. Treatment is typically supportive, but antivirals may be used in some cases (e.g., ribavirin in Lassa fever). Case fatality rates vary greatly between VHFs but can be up to 90%. Vaccines are licensed internationally for yellow fever only, so prevention primarily consists of infection control measures.

Etiology Pathogens are enveloped RNA viruses from the following families: Arenaviridae, Bunyaviridae, Filoviridae, Flaviviridae, Paramyxoviridae TransmissionReservoir hosts or vectors such as rodents, mosquitoes, and ticksDirect contact Inhalation of infected particles Contact with infectious material Human-to-human transmission Airborne droplets Contact with blood or other bodily fluids ArenaviridaeLassa virusLassa feverWest Africa (e.g., Liberia, Sierra Leone, Guinea) Ingestion/inhalation of rodent urine or droppings from reservoir hosts of the virus: the multimammate rat Contact with bodily fluids of other infected animals or humans1-21 daysOnly ∼ 1% of infections are fatalMortality rate in those requiring hospitalization: 15-20%None internationally licensed Bunyaviridae Hantaviruses(especially Sin Nombre virus for HCPS) Hantavirus cardiopulmonary syndrome(HCPS)North and South America Contact with infected rodent reservoir hosts or ingestion/inhalation of their blood, urine, droppings, or saliva 1 -8 weeks35-45% in severe cases (bilateral infiltrates on chest x-ray)Mild cases are not fatal. None internationally licensed Hemorrhagic fever with renal syndrome(HFRS)Asia, Korea, Russia, Europe Highest annual incidence in China Contact with infected rodent reservoir hosts or ingestion/inhalation of their urine, droppings, or saliva Up to 15% NairovirusCrimean-Congo hemorrhagic feverSoutheastern Europe, Africa, Middle East, Asia Tick bites from Ixodid tickreservoir hosts Contact with infected animal or human bodily fluids 1-13 daysUp to 80%None internationally licensed Rift valley fever virusRift valley feverEastern and Southern Africa (e.g., Kenya, Tanzania, Somalia) Sporadic cases also reported throughout Africa and the Middle East Contact with infected livestock (i.e., bodily fluids)Mosquito bites 2-6 days< 1% of patients develop the hemorrhagic feverform, which has a case fatality rate of ∼ 50%.None internationally licensed FiloviridaeEbola virus Ebola virus diseaseSub-Saharan Africa Contact with bodily fluids of infected people, nonhuman primates (e.g., gorillas, chimpanzees, monkeys), or fruit bats Direct contact with fomites increases the likelihood of nosocomial spread.2-21 daysHigh mortality rate(∼ 50%) Recombinant vesicular stomatitis virus-Zaire Ebola virus (rVSV-ZEBOV) vaccine (approved in the US in December 2019) Marburg virusMarburg hemorrhagic feverAfrica (e.g., Uganda, Zimbabwe, the Democratic Republic of the Congo) Contact with the reservoir host of the virus, the African fruit bat Contact with bodily fluids of infected individuals or animals 5-10 days25-90%None internationally licensed FlaviviridaeDengue virusDengue hemorrhagic feverWorldwide in tropical regions of Central and South America, the Caribbean, Africa, and Asia Mosquito bites 4-10 days2-5%Dengue vaccine(CYD-TDV; approved in the US in May 2019) Yellow fever virusYellow feverTropical regions of South America and sub-Saharan Africa Mosquito bites 3-6 days30-60% of those who develop severe infection (The vast majority of infections are asymptomatic or very mild.) Single-dose live-attenuatedvaccine for individuals traveling to areas where yellow fever is endemic Clinical features of VHFs vary depending on which virus is involved. Onset may be acute (e.g., Ebola virus disease) or insidious (e.g., Lassa fever) and often includes the following: Initial flu-like illness Headache, dizzinessConjunctivitisHigh feverLymphadenopathySore throat Myalgia, arthralgiaRash Weakness, fatigue, prostration Gastrointestinal symptoms (abdominal pain, diarrhea, nausea, vomiting) Severe VHF with bleeding diathesis: develops in a variable number of cases, depending on the causative pathogen Diffuse hemorrhage including:Bloody diarrhea, hematuria, hematemesis, melenaMucosal bleedingPetechiae, ecchymosesHypovolemic shock and multiorgan failureSepsisDICMeningoencephalitis Diagnostics ApproachDiagnosis of VHF during the early stages is difficult because the symptoms are nonspecific.If clinical and laboratory features are consistent with the condition, further studies should be conducted to confirm the diagnosis. Medical historyA detailed travel history to endemic regions is essential!History of exposure to a potential source of infection (e.g., rodents, mosquitoes, ticks) General laboratory studiesCBCElectrolytes, BUN/creatinine, liver function testsUrinalysisCoagulation studies Confirmatory testsGenerally performed by specialized reference laboratories; presumptive positive results must be confirmed by the CDC. Serology: IgM and/or rising levels of IgG antibodies detected using enzyme-linked immunosorbent assay (ELISA) or other diagnostic assays Reverse transcription-polymerase chain reaction (RT-PCR)Immunohistochemistry Differential diagnoses Malaria Meningococcal septicemia or other types of sepsis Leptospirosis Typhoid fever Q fever Influenza Shigellosis Rickettsial infection (e.g., Rocky Mountain spotted fever) Acute leukemia Idiopathic thrombocytopenic purpura Thrombotic thrombocytopenic purpura Treatment Supportive treatmentManagement of fluids and electrolyte balance Maintenance of blood pressure and oxygenation Analgesics for pain and feverBlood products in patients with severe thrombocytopenia, coagulopathy, hemorrhage Medical treatment: Ribavirin may be used in some cases (e.g., Lassa fever Prevention Avoid contact with blood, body fluids, or tissue from infected reservoirs or humans Avoid travel to endemic areas In suspected cases Immediate notification of local health authorities and the CDC of any suspected cases of VHFStrict isolation of infected patients and their contacts with disinfection and sterilization measuresWear appropriate personal protective equipment (e.g., impermeable gown, gloves, respiratory protection, rubber boots). Reportable disease Probable, suspected, or confirmed cases of VHFs are notifiable conditions to local and state health authorities, as well as the CDC National Notifiable Disease Surveillance System. Hantavirus infection There are two notable syndromes that can develop from a hantavirus infection: hantavirus cardiopulmonary syndrome (HCPS) and hemorrhagic fever with renal syndrome (HFRS) Epidemiology: See "Overview of viral hemorrhagic fevers" above. Clinical features History of rodent or rodent urine exposure (e.g., picnicking in a park)Prodromal/febrile phase (∼ 2-7 days upon onset of illness): clinical features of VHF (see above)Syndrome-specific features HCPS: Cardiopulmonary phase (∼ 2-7 days following prodromal/febrile phase) with lung infiltration (pulmonary edema) and, in severe cases, development of acute respiratory distress syndrome (ARDS) Dry coughIn severe cases: rapidly developing shock, coagulopathy, pulmonary edemaTachycardia, hypotensionDyspneaHFRS: group of clinical syndromes of acute interstitial nephritis occurring mainly in Europe and Asia Signs of renal failure Hypotension Diagnostics: If clinical and laboratory features are consistent with the condition, further studies should be conducted to confirm the diagnosis. Laboratory studies HCPS: triad of left shift, thrombocytopenia, abundance of immunoblastsHFRSCBC: thrombocytopenia, leukocytosisBMP: ↑ serum creatinineUrinalysisProteinuriaHematuriaConfirmatory studies Serology: IgM and/or rising levels of IgG antibodies detected using enzyme-linked immunosorbent assay (ELISA) or other diagnostic assays Reverse transcription-polymerase chain reaction (RT-PCR) Immunohistochemistry ManagementSupportive care (e.g., ICU admission, early intubation, supplementary oxygen) For HFRS: ribavirin Prognosis: See case fatality rate

Urethritis Urethritis is an inflammation of the urethral mucosa that may be caused by various pathogens, most notably C. trachomatis, N. gonorrhea, and M. genitalium. Transmission primarily occurs as a result of unprotected sexual intercourse and it is especially prevalent in young, sexually active men. Patients typically present with urethral discharge, dysuria, and/or itching of the urinary meatus, although asymptomatic infections are common. Diagnostics include urine dipstick (pyuria, positive leukocyte esterase), staining of a urethral sample, and nucleic acid amplification testing of first-void urine. In gonococcal urethritis, Gram staining of the urethral swab demonstrates gram-negative diplococci and patients are treated with ceftriaxone and azithromycin; otherwise patients are treated with azithromycin or doxycycline for nongonococcal urethritis. Evaluation and treatment of all recent sexual partners is necessary to prevent recurrent infections.

Etiology Typically a sexually transmitted infectionGonococcal urethritis (GU): Neisseria gonorrhoeae Nongonococcal urethritis (NGU) [1]Chlamydia trachomatis (most common) Mycoplasma genitalium Trichomonas vaginalisGram-positive cocciHerpes simplex virus types 1 and 2 Adenovirus Coinfection is also common Most common in young, sexually active men Risk factorsUnprotected sexual intercourseMultiple sexual partnersHistory of other sexually transmitted infections Clinical features Dysuria Burning or itching of the urethral meatus Urethral discharge: purulent , cloudy, blood-tinged, or clear Initial hematuria General symptoms (e.g., fever, chills, or myalgia) are uncommon in urethritis and should raise suspicion for complications (see "Complications" below). Diagnostics Confirming urethritisUrine dipstick of first-void urine: pyuria (≥ 5-10 WBC per high power field ) or positive leukocyte esteraseUrethral smear: ≥ 2 leukocytes per oil immersion field Identifying the causative pathogenGram stain of urethral swab or discharge : Gram-negative diplococci: GU Otherwise NGUNucleic acid amplification testing (NAAT) of first-void urine without prior precleaning of the urethra for N. gonorrhea and C. trachomatis Offer to test for HIV, syphilis, and hepatitis B. Dysuria with urethral discharge and no organism on Gram staining of a urethral specimen suggest urethritis by C. trachomatis or M. genitalium! Differential diagnoses Because coinfection with other genitourinary tract infections is possible, the presence of one infection does not rule out urethritis. Acute cystitis Epididymitis Prostatitis Treatment The initial therapy is usually empiric and, according to prior distinction based on microscopic urethral specimen evaluation, divided into either a GU or NGU regimen. Nongonococcal urethritis: single dose azithromycin or doxycycline PO for seven daysGonococcal urethritis: single dose of ceftriaxone IM and azithromycin PO If T. vaginalis infection is suspected: metronidazole Patients should refrain from sexual activity for 1 week after initiation of therapy. All sexual partners from the 2 months prior to diagnosis should be notified, evaluated for urethritis, and offered empiric treatment. Repeat NAAT 3-6 months after completion of therapy. Complications Other genitourinary tract infections, e.g., cystitis, epididymitis, prostatitis, cervicitis, pelvic inflammatory disease Urethral stricture or stenosis Infertility Disseminated gonococcal infection Reactive arthritis Prevention Barrier protection during sexual intercourse Chlamydia and gonorrhea are reportable diseases.

Pyelonephritis Pyelonephritis is an infection of the renal pelvis and parenchyma that is usually associated with an ascending bacterial infection of the bladder. It occurs more commonly in females and risk factors include pregnancy and urinary tract obstruction. Patients typically present with flank pain, costovertebral angle tenderness, fever, and other features of cystitis (e.g., dysuria, frequency). Urinalysis reveals leukocyturia and bacteriuria. Urine cultures should be taken in all patients before initiating treatment to identify the pathogen and possible antibiotic resistance. Treatment depends on the drug sensitivities of the offending pathogen and the patient's clinical profile (e.g., possible comorbidities). Early empiric antibiotic treatment is essential to avoid renal complications and urosepsis.

Etiology Usually associated with an ascending bacterial infection of the bladder (cystitis) PathogensMost commonly Enterobacteriaceae (gram-negative rods) Escherichia coli (∼ 75-90% of cases) Pseudomonas aeruginosaKlebsiella pneumoniaeProteus mirabilisGram-positive bacteria (e.g., Enterococcus faecalis, Staphylococcus aureus)Candida infection (esp. in immunocompromised patients) is possible Risk factorsMost common in women because they have shorter urethrasPregnancyUrinary tract obstructionForeign bodies (e.g., catheters or other urologic instrumentation)Anatomical abnormalities (e.g., benign prostatic hyperplasia, vesicoureteral reflux, nephrolithiasis, ureteral strictures)CystitisRecent administration of antibiotics (possible antibiotic resistance)Immunosuppression (e.g., HIV, diabetes)Acute kidney injury Clinical features High fever, chills Flank pain, costovertebral angle tenderness (usually unilateral, may be bilateral) Dysuria as well as other symptoms of cystitis (e.g., frequency, urgency) Weakness, nausea, vomiting (diarrhea may also be present) Possible abdominal or pelvic pain Subtypes and variants Chronic pyelonephritis [4][5] Consequence of recurrent or persistent acute pyelonephritis Predisposing factorsVesicoureteric refluxUrinary tract obstruction (e.g., nephrolithiasis, neurogenic bladder) Clinical featuresNonspecific (mild fever, anorexia, malaise)Abdominal or flank pain DiagnosticsUrinalysis: pyuria, proteinuria, WBC castsImaging (ultrasound, intravenous urogram): corticomedullary scarring (mainly upper pole), blunt/clubbed renal calyces Biopsy: thyroidization of the kidney (see ''Pathology'') TreatmentTreat the underlying causeAntibiotics Long-term antibiotics (e.g., oral trimethoprim-sulfamethoxazole or nitrofurantoin) may be necessary). Diagnostics Laboratory tests UrinalysisPyuria (→ positive esterase on dipstick test), leukocyturia, WBC casts Bacteriuria (→ positive nitrites on dipstick test) Microhematuria Blood↑ Inflammatory markersNormal or ↑ renal function parameters Urine culture and blood culture Urine and blood cultures should be ordered before initiating empiric antibiotic therapy! Imaging Generally not necessary for diagnosis CT abdomen: modality of choice Indications History of nephrolithiasisUnusual urinary findings (e.g., gross hematuria)Complicated pyelonephritis (e.g., obstruction, sepsis)No response to therapy within 2 daysFindings Hemorrhage, nephrolithiasis or urolithiasis, abscess or anatomical obstructionAlterations in renal parenchymal perfusion or contrast excretion Alternative imagingIndication: if the patient has contraindications to IV contrast agents or CT is not availableRenal ultrasound of the kidney and bladderUrinary obstruction, calculi, or abscess Diffuse corticomedullary junctionMRI abdomenIntravenous pyelogram (IVP)Retrograde cystourethrogram to diagnose vesicoureteral reflux Pathology Destructive interstitial nephritisPurulent inflammation of the interstitium with destruction of the parenchyma, the renal tubules, and in some cases the renal pelvisRenal tubules infiltrated with neutrophils Chronic pyelonephritisChronic inflammatory changes such as rough scarring at the junction of the cortex and medullaBlunted calyces from recurrent urinary refluxEosinophilic casts in the tubules (so called "thyroidization of the kidney") Xanthogranulomatous pyelonephritisLipid laden foamy macrophages and multinucleated giant cells seen on histologyLarge, irregular, yellow masses appear throughout the kidney on gross examinatio Differential diagnoses Other UTIs See differential diagnoses of acute abdomen. Treatment While uncomplicated pyelonephritis usually only requires outpatient treatment, complicated pyelonephritis requires hospitalization. Pyelonephritis is considered complicated if any of the following is present: Urinary tract abnormalities (e.g., obstruction, indwelling catheter) Recent surgery to the urinary tract Renal impairment Immunosuppression and/or severe comorbidities Sepsis High-risk patient despite uncomplicated clinical picture (e.g., elderly) Uncomplicated pyelonephritis Outpatient treatment Encourage the patient to drink adequate amounts of fluids. Oral treatment is often preceded by a single dose of ceftriaxone or gentamicin. First-line: oral fluoroquinolones (e.g., ciprofloxacin for 7 days) Second-line: oral trimethoprim-sulfamethoxazole for 14 days If there is no response within 48 hours, then check urine culture results and change treatment accordingly. Repeat urine culture 2-4 days after completion of the antibiotic course. Complicated pyelonephritis Hospitalization and adequate IV resuscitation First line: IV fluoroquinolones (e.g., ciprofloxacin) for 10-14 days Second-line Aminopenicillins + beta-lactamase-inhibitors (e.g., IV ampicillin/sulbactam); possibly in combination with an aminoglycosideEmpiric broad-spectrum cephalosporins (e.g., IV ceftriaxone); possibly in combination with an aminoglycosideCarbapenem (e.g., IV meropenem or imipenem)Monobactam (e.g., IV aztreonam) in the event of a penicillin allergy Check blood culturesIf negative, change to oral antibiotics once the patient has been afebrile for at least 24 hours.If positive, treat with IV antibiotics for 2-3 weeks. In contrast to antibiotic treatment with most cephalosporins, empiric therapy with ciprofloxacin also covers infections with enterococci. Complications Urosepsis Perinephric abscess Papillary necrosis Emphysematous pyelonephritis Renal abscess Recurrent bacterial pyelonephritis If recurrence is caused by the same organism despite adequate treatment, then prolong the course of antibiotics for 6 weeks.If a new pathogen is identified, change antibiotic accordingly and treat for 2 weeks. Atrophic kidneys End-stage renal disease (ESRD): if both kidneys are affected, the patient has a single kidney, or the other kidney has been damaged by a different pathology Special patient groups Pyelonephritis in pregnancy [3] The risk of pyelonephritis is increased during pregnancy . In as many as one-third of asymptomatic bacteriuria cases in pregnant women will progress to pyelonephritis if left untreated. One of the most common complications of pregnancy, with potentially severe consequences for both mother and fetus. Treatment Hospitalization + IV broad-spectrum third-generation cephalosporins (e.g., ceftriaxone) If severe (immunocompromised or poor urine output): IV ticarcillin-clavulanate or piperacillin-tazobactam (see antibiotics during pregnancy) Do not use fluoroquinolones or trimethoprim/sulfamethoxazole in pregnant women!

Acute bronchitis Acute bronchitis is a self-limiting lower respiratory tract infection (RTI) characterized by inflammation of the bronchi. In more than 90% of cases, it is caused by a virus. Acute bronchitis usually follows an upper RTI and presents with cough, sometimes in combination with sputum, runny nose, chest pain, headache, and malaise. The diagnosis is made on the basis of clinical symptoms. Important differential diagnoses include bronchiolitis, a very similar disease that often leads to respiratory distress in infants, and pneumonia, which is also a serious complication of acute bronchitis. Chronic bronchitis affects the same anatomical structure but has a very different clinical picture (see COPD). Management of acute bronchitis consists of adequate hydration and possibly NSAIDs for symptomatic relief. Antibiotics are frequently and unnecessarily prescribed as part of treatment; however, they are not indicated unless the patient is at risk for secondary bacterial infection.

Etiology Viruses (> 90% of cases)Influenza A and BParainfluenzaAdenovirusRSVRhinovirusCoronavirus Bacteria Environmental etiologies The etiology of acute bronchitis is viral in > 90% of cases! Clinical features Cough> 5 daysResolves in 2-3 weeksSputum (∼ 50% of cases), especially as infection progresses [4] Runny nose and sore throat (likely symptoms of the preceding or simultaneous URI) Chest pain and dyspnea Headache Malaise Myalgias Fever (uncommon) ddx pneumonia, influenza bronchitis Diagnostics Acute bronchitis is a clinical diagnosis Auscultatory findings Wheezing Rhonchi Coarse crackles Further workup is indicated if pneumonia is suspected Differential diagnoses See bronchiolitis See differential diagnosis of acute cough For cough persisting ≥ 8 weeks, see differential diagnosis of chronic cough Treatment Rest and adequate hydration NSAIDs Antibiotics: generally not recommended! Possible indications: patient groups with increased risk of bacterial infection (e.g., smokers, the elderly, patients with lung disease) and patients with suspected differential diagnosis (see "Differential diagnosis" above) Antitussives, expectorants, and bronchodilators are generally not recommended, but may be considered under specific circumstances (e.g., wheezing in older children). rognosis Generally self-limiting Groups at increased risk for complications: elderly, immunocompromised patients, patients with pre-existing lung conditions

Cutaneous fungal infections

EtiologyClinical featuresDiagnosisTreatmentDermatophytesPathogens: Trichophyton, Microsporum, and EpidermophytonRisk factors: profuse sweating, obesity, diabetes, immunocompromisedTinea capitis(head): scalingand hair lossTinea corporis(body): ring-shaped, pruritic lesions with central clearing and elevated borders on an erythematousbaseTinea cruris(groin): usually spares the scrotumTinea manuum(hand), tinea pedis (foot): pruritic lesions in interdigital spaces, on the soles of the feet or as vesiclesOnychomycosis(nails): thick, opaque nailsBest initial: KOHshowing hyphaeConfirmatory: fungal cultureWood lamptest for tinea capitisBest initial: topical antifungal(e.g., clotrimazole)Hair or nailinvolvement: oral griseofulvin Tinea versicolor(pityriasis versicolor)Pathogen: Malassezia furfurRisk factors: hot or humid weather conditionsSmall, hyperpigmentedor hypopigmented macules on chest and back; may coalesce to form patches Best initial: KOHshowing short hyphaeand spores that have a "spaghetti and meatballs" appearanceTopical and/or oral antifungalmedications (e.g., seleniumsulfide shampoo)

Inherited fever syndromes

Familial Mediterranean fever (FMF) Description: A hereditary autoinflammatory disorder characterized by recurrent, self-limiting fever attacks, serositis, and often other inflamed tissue. Patients do not experience any symptoms between attacks. Epidemiology: mostly limited to individuals of eastern Mediterranean descent ; most common inherited fever syndrome Genetics: an autosomal-recessive mutation in the MEFV gene on chromosome 16 Clinical presentation: can vary greatly All patients experience fever attacks lasting 1-3 days that recur over weeks to months.Most patients (95%) experience abdominal pain and arthralgia (75%).Other manifestations Chest pain (40%): due to peritonitis and sometimes pericarditisScrotal pain: due to inflammation of the tunica vaginalisMyalgiaErysipeloidThe disorder often goes undiagnosed in patients with mild to moderate symptoms.Patients often have an appendectomy scar from a past episode of FMF that was mistaken for acute appendicitis. Complication: AA amyloidosis Therapy: Prevention of acute episodes and progression to AA amyloidosis through inhibition of granulocyte function by colchicine. Other hereditary fever syndromes Hyper-IgD syndrome TNFα reception-associated periodic syndrome

Fever

Fever is defined as an elevation of normal body temperature, which can vary based on a number of factors (e.g., the time of day, geographical location, degree of exertion). In general, fever is defined as a temperature > 38°C (100.4°F). Fever is a nonspecific symptom that may be caused by infectious and noninfectious conditions, including malignancies, systemic rheumatic diseases, and drug reactions. History and physical examination alone are often sufficient to diagnose uncomplicated infectious causes of fever (e.g., URI, gastroenteritis). Laboratory tests and imaging should be guided by the pretest probability of the differential diagnoses. Antipyretics and tepid sponging may be used to decrease body temperature, but treatment of the underlying cause is the main goal when managing febrile patients. See also neutropenic fever. Laboratory studies Routine CBC with differential Blood glucose BMP LFTs Coagulation studies (e.g., INR, PTT) Urinalysis with microscopy In patients with suspected SIRS or sepsis Blood gas analysis Serum lactate Procalcitonin assay ESR/CRP Blood cultures (at least 2 sets) Additional cultures from other sites as indicated Chest x-ray Cultures should be obtained before initiating empiric antibiotic therapy, if possible without delaying the administration of antibiotics.

Cephalosporins

First generation cephalosporins PECK DrugsOral: cephalexinIV, IM: cefazolin Clinical useGram-positive cocciProteus mirabilisE. coliKlebsiellaCefazolin is used to prevent surgical wound infections (perioperative prophylaxis) Second generation cephalosporins HEN PECK DrugsOral: cefaclor, cefuroxime (axetil)IV: cefoxitin, cefotetan, cefuroxime Clinical useGram-positive cocciH. influenzaEnterobacterNeisseriaProteus mirabilisE. coliKlebsiellaSerratia Third generation cephalosporins DrugsOral: cefiximeIV: ceftriaxone , cefotaxime, ceftazidime, cefoperazoneIM: ceftriaxone Clinical useSevere gram-negative infections that are resistant to other beta-lactams (e.g., Enterobacteriaceae) Ceftazidime and cefoperazone are effective against Pseudomonas. Ceftriaxone (good CNS penetration) is used in disseminated Lyme disease, meningitis, gonorrhea, and for perioperative prophylaxis against wound infection Fourth generation cephalosporins Drugs: IV cefepime Clinical useGram-negatives (including Pseudomonas)↑ Activity against gram-positives (particularly Staphylococcus)Severe life-threatening infections (including nosocomial) SepsisPneumoniaSevere urinary or biliary tract infectionsIntra-abdominal infections (including peritonitis) Fifth generation cephalosporins Drugs: IV ceftaroline Clinical useGram-positive bacteria (including MRSA)Gram-negative bacteria (but not effective against Pseudomonas)Complicated skin and soft tissue infections Cephalosporins can be LAME because they don't act against Listeria, Atypical organisms (Chlamydia, Mycoplasma), MRSA , and Enterococci! Adverse effects Hypersensitivity (potential cross-reactivity in patients with penicillin allergies) Autoimmune hemolytic anemia Vitamin K deficiency → increased bleeding tendency Some cephalosporins may cause a disulfiram-like reaction when consumed with alcohol (flushing, tachycardia, hypotension). Can lower seizure threshold Increase the nephrotoxicity of aminoglycosides

Antifungal Antimetabolites

Flucytosine(oral) Converted to 5-fluorouracilby fungal cytosine deaminase, which then inhibits DNAand RNAsynthesis Monotherapy: select cases of non-life-threatening infections such as genitourinary candidainfections that are not covered by alternative drugs Combination with amphotericin B: systemic fungal infections (especially cryptococcal meningitis) Use with extreme caution in patients with renal impairment Avoid during pregnancy and breastfeeding Hepatic injury Renal failure Gastrointestinal (e.g. nausea) Bone marrow suppression with pancytopenia

Food poisoning

Food poisoning, or foodborne illness, occurs following the ingestion of food or water contaminated with bacteria, bacterial toxins, viruses, parasites, or chemical substances. According to the Centers for Disease Control and Prevention (CDC), an estimated 1 in every 6 people in the US is annually affected with a foodborne illness. Risk factors include the cross-contamination of food, as well as improper handling and storage. In addition, immunocompromised individuals are at an increased risk of infection. Common pathogens attributed to food poisoning include Norovirus, Salmonella, Clostridium perfringens, Campylobacter jejuni, Staphylococcus aureus, and Escherichia coli. Incubation periods depend on the cause, and range from a few hours to days. The clinical presentation associated with food poisoning varies, but typical symptoms include diarrhea, nausea, vomiting, and abdominal cramping. Various laboratory tests (e.g., stool analysis, blood tests) help confirm the suspected diagnosis. Young children and the elderly are at greater risk for developing complications related to food poisoning and must be closely monitored. For most patients, supportive care, including fluid replenishment, is sufficient.

Empiric antifungal therapy for neutropenic fever

For low-risk patients, empiric antifungal therapy is not routinely recommended. For high-risk patients, consider empiric antifungal therapy in the following situations: Persistent or recurrent fever after 4 days of intravenous antibiotic therapy and expected duration of neutropenia > 7 days Reassessment does not yield a cause.Clinically unstable and suspected fungal infection (e.g., positive galactomannan, 1,3-β-d-Glucan assay, and/or imaging concerning for invasive fungal infection) Choose one of the following for empiric antifungal therapy regimens: Caspofungin Micafungin Anidulafungin Voriconazole Amphotericin B Patients who received antifungal prophylaxis should be switched to a different agent effective against molds (e.g., from voriconazole to amphotericin B). Additional considerations Empiric antiviral treatment: only recommended for patients with clinical or laboratory evidence of active viral disease and in patients with possible influenzaexposure. G-CSF or GM-CSF: Use is not routinely recommended. [1] Indications for indwelling catheter removal in patients with suspected CLABSI: [1]Bacteremia with S. aureus, P. aeruginosa, fungi, or mycobacteria Diagnosis of septic thrombosisTunnel or port pocket site infectionEndocarditisSepsis with hemodynamic instabilityBloodstream infection that persists despite > 72 hours of appropriate antibiotic therapy. Supportive care IV fluids Antipyretic therapy Pain management Antiemetics

Skin and soft tissue infections Skin and soft tissue infections comprise a group of heterogeneous conditions that primarily develop as a result of pathogens infiltrating the skin via minor injuries. Most skin infections are caused by Staphylococcus, but they may also be caused by Streptococcus or mixed infections in select cases. Risk factors include diabetes mellitus, immunodeficiency, and chronic edema. Skin and soft tissue infections primarily present as painful, warm, erythematous skin lesions. Systemic symptoms, such as fever and malaise, may also occur. Elevated inflammatory markers in the blood support the clinical diagnosis. Imaging may be considered to establish the extent and localization of infection. Treatment includes antibiotic therapy and immobilization of the affected area while severe cases and abscesses require surgery (debridement or incision and drainage). With the exception of necrotizing fasciitis, the majority of cases respond well to treatment and have a favorable prognosis. In the event of generalization, sepsis and spread of infection to local and distant sites may result.

General Cardinal signs of inflammationRubor = rednessCalor = heatTumor = swelling/edemaDolor = painFunctio laesa = loss of function Risk factorsDiabetes mellitusImmunodeficiency (e.g., alcoholism, HIV infection) Chronic lymphedema Circulatory disorders: arteriovenous insufficiency, chronic edema, stasis ObesityLocal skin defects (e.g., tinea pedis) ComplicationsLocal spread of infectionSystemic involvement with fever and possible sepsisSpread of infection to distant sites (see staphylococcal infections; streptococcal infections) Treatment of skin and soft tissue infections Management principlesAntibiotic treatmentSupportive measuresBed rest Pain reliefSurgeryIncision and drainageSurgical debridement Moderate: Systemic signs of infection, e.g., elevated temperature, tachycardia, tachypnea, elevated WBC Severe: Nonpurulent infections are considered severe if: previous oral antibiotic treatment failed; systemic signs of infections or signs of deep infection (eg., bullae, skin sloughing, signs of organ dysfunction) occur; or infections develop in immunocompromised patients. Purulent infections are considered severe if incision and drainage plus oral antibiotic treatment fail, or systemic signs of infection occur, or infection develops in immunocompromised patients. Nonpurulent infections (erysipelas, cellulitis, necrotizing fasciitis) Oral antibiotics: penicillin V or cephalosporin or dicloxacillin or clindamycin IV antibiotics: penicillin or ceftriaxone orcefazolin or clindamycinSurgical debridement (with culture and sensitivity testing) Empiric antibiotic treatment: vancomycin PLUSpiperacillin/tazobactam Purulent infections (furuncle, carbuncle, abscess) Incision and drainage Incision and drainage Empiric antibiotic treatment: TMP/SMXor doxycycline Incision and drainage Empiric antibiotic treatment covering MRSA: vancomycin or daptomycin or linezolid ImpetigoStaphylococcus aureus (bullous and nonbullous) or Streptococcus pyogenes (nonbullous)Superficial epidermisHighly contagious superficial infection with honey yellow crustsBullae formation common in staphylococcal infection Staphylococcal scalded skin syndrome(generalized form of impetigo)Exotoxin of Staphylococcus aureusSuperficial epidermisErythematous rashFeverHeals completely ErysipelasGroup A streptococcusSuperficial dermis and lymphatic vesselsSharply demarcated, erythematous skin lesion CellulitisStaphylococcus aureus (purulent cellulitis)Group A streptococcus (non-purulent cellulitis)Deep dermis and subcutaneous tissueRapidly spreading infection; erythematous skin lesion with indistinct marginsMay present with or without purulent exudate Skin abscessStaphylococcus aureus Deeper layers of the skinWalled-off infection with a collection of pus FolliculitisStaphylococcus aureus; Pseudomonas aeruginosa Hair follicleLocalized papules and pustules on the base of hair follicles, usually with a central hair Necrotizing fasciitisMixed infection: Group A streptococci + anaerobic bacteriaSuperficial fasciaSevere, rapidly progressive infection with necrosis; crepitus, bullae, and purple skin discolorationHigh risk of systemic complications; high mortality Skin involvement (from superficial to deep): impetigo (superficial epidermis), erysipelas (superficial dermis and lymphatic vessels), cellulitis (deep dermis and subcutaneous tissue), necrotizing fasciitis (superficial fascia). Folliculitis Definition: localized inflammation of the hair follicle (or sebaceous glands) EtiologyInfectious causes: primarily Staphylococcus aureus; gram-negative bacteria (e.g., Pseudomonas aeruginosa), Candida albicans or Malassezia (particularly M. furfur) Noninfectious causes: ingrown hair, friction, follicular trauma or occlusion Clinical features: tender papules and/or pustules at the site of hair follicles Differential diagnosis: ecthyma, acne vulgaris ComplicationsFuruncle: deep folliculitis beyond the dermis with abscess formation in the subcutaneous tissueCarbuncle: confluent folliculitis; abscess and skin necrosis may be present TreatmentSupportive measures: hygiene, antibacterial soap, warm compressesFirst line: topical mupirocinSystemic antibiotic treatment is generally not necessary For furuncle and carbuncle: see treatment of skin and soft tissue infections Special formsFacial furuncleRisk of a cavernous sinus thrombosis and meningitis Furuncle is to be left untouched; no speaking or chewing permittedTreatment with high-dose antibiotics (e.g., flucloxacillin) until spontaneous drainage occursHot tub folliculitis: pseudomonal folliculitis that appears 8-48 hours after exposure to contaminated water; usually a self-limiting condition that does not require antibiotic treatment Skin abscess Definition: an accumulation of white-yellow pus that contains proteins, leukocytes (esp. neutrophils), bacteria, and cellular debris and is located in the dermisand subcutaneous tissue Pathogen: most commonly caused by Staphylococcus aureus (depending on the location and local bacterial colonization) Clinical features: classic signs of inflammation; pain usually relieved after rupture or drainage DiagnosisLaboratory analysis: ↑ inflammatory markersUltrasonography: presentation of a hypoechoic superficial massCulture of abscess contents: identify pathogen Treatment: see treatment of skin and soft tissue infections Complications: recurrent infections Special formsScrotal abscess: subcutaneous collection of pus in the scrotal region, which usually occurs as a result of inflamed hair follicles (ingrown hair follicle; iatrogenic Complication: Fournier gangreneDifferential diagnoses: neoplasia of the testis, infected hydrocele, genital warts Erysipelas Definition: a superficial skin infection involving the upper dermis, with lymphangitis and lymphadenitis Pathogen: group A Streptococcus (Streptococcus pyogenes) Pathophysiology: entry via minor skin injury (rhagades, athlete's foot, ulcers, blisters, insect bites) → infection of the upper dermis and spread via superficiallymphatic vessels Clinical featuresLocation: lower limbs (80% of cases), faceTender, sharply demarcated skin lesion; raised in comparison to surrounding noninfected skin Erythema, edema, and warmth The erythematous lesion may form bullae. These bullae may occasionally become hemorrhagic.Lymphangitis : Red streaks radiating from the skin lesion, extending along the course of the lymphatic vessels, and lymphadenitis (swollen, tender regional lymph nodes) may be present.Systemic symptoms: fever, chills, nausea, headaches, muscle and joint pain DiagnosisPrimarily a clinical diagnosisInspect skin for lesions as potential portals of entryRapid progression and systemic symptoms of infections may indicate more severe forms of skin infection (e.g., necrotizing fasciitis, toxic shock syndrome) Laboratory findings: Leukocytosis↑ CRP, ↑ ESR Treatment: see treatment of skin and soft tissue infectionsElevation of the affected limbs Complications Recurrent erysipelasThrombophlebitisAbscessCellulitisNecrotizing fasciitis LymphedemaSystemic complications: sepsis, endocarditis, streptococcal toxic shock syndrome, poststreptococcal glomerulonephritis, acute rheumatic fever, multiple organ failure The most common point of entry for the pathogen is a small skin lesion (e.g., interdigital tinea pedis). Cellulitis Definition: rapidly spreading local infection of the deep dermis and subcutaneous tissue PathogenStreptococcus pyogenes (group A Streptococcus): causes nonpurulent cellulitisLess common: Staphylococcus aureus : causes nonpurulent or purulent cellulitisPasteurella multocida (gram-negative, encapsulated coccobacillus): secondary to dog and cat bites Pathophysiology: portals of entry may be a minor skin injury (e.g., fungal foot infections), or the infection may be secondary to a systemic infection Clinical featuresErythematous, painful skin lesion with poorly defined marginsPasty consistency of the affected region LymphadenitisSystemic symptoms: fever, chills, confusionPossibly purulent exudate DiagnosisPrimarily a clinical diagnosisLaboratory findings: leukocytosis, ↑ CRP, ↑ ESRWound and blood culture: identify pathogen; rule out bacteremiaUltrasonography: rule out occult abscessMRI: distinguish cellulitis from osteomyelitis Treatment: see treatment of skin and soft tissue infectionsElevation of the affected limbsTreat fungal foot infections if present to prevent recurrent cellulitisSee treatment of skin and soft tissue infections ComplicationsRecurrent cellulitis in 20-50% of cases Skin abscess formationOsteomyelitisSepsisIn orbital cellulitis: blindness, cavernous sinus thrombosis, intracranial abscess Special formsOrbital cellulitis; periorbital (preseptal) cellulitisLudwig angina ecrotizing fasciitis DefinitionRapidly progressive infection resulting in extensive necrosis of superficial fascia and overlying subcutaneous fat that can develop into a life-threateningcondition within hoursA type of necrotizing soft tissue infection (NSTI) Pathogen: Although necrotizing fasciitis is also known as flesh-eating disease, the causative bacteria do not consume flesh; rather, they release toxins that damage the surrounding tissue. Frequently mixed infection (with aerobic and anaerobic gram-negative bacteria)Aerobes: group A StreptococcusAnaerobes: e.g., Bacteroides spp., Peptostreptococcus spp.Monomicrobial infection with group A Streptococcus is referred to as streptococcal gangrene. Clinical featuresLocal findings: Infection first spreads along the fascia before spreading to the superficial cutaneous tissue. Local findings may, therefore, be unremarkable and disproportionate to the pain.Initially Diffuse rednessSwellingExtreme tendernessLater stages Crepitus: due to the production of methane and CO2 by bacteriaPurple skin discolorationBullae formationSkin necrosisLoss of sensation in the affected area Systemic symptoms: fever, chills, acute illnessFournier gangrene: necrotizing fasciitis of the external genitals; mixed infection with facultative pathogens (E. coli, Klebsiella, Enterococcus) and anaerobic bacteria; infection spreads rapidly to the anterior abdominal wall, gluteal muscles, and, in men, the scrotum and penis DiagnosisLaboratory analysis: leukocytosis, ↑ CRP, ↑ ESR, ↑ CK, hyperglycemia, ketoacidosisImaging (X-ray, MRI): detect subcutaneous accumulation of air;determine extent of infection Treatment: see treatment of skin and soft tissue infectionsMonitoring in an intensive care unitImmediate extensive surgical debridement with tissue culture and histopathology (confirmatory test) ComplicationsSepsis; (urosepsis in Fournier gangrene) Disseminated intravascular coagulationOrgan dysfunction (e.g., acute kidney injury)Severe necrosis requiring amputation of limbThe mortality rate has been reported to range between 20% and 80%! Differential diagnosesGas gangrene: caused by Clostridium perfringensCellulitis: no involvement of fascia Necrotizing fasciitis is a life-threatening condition! If necrotizing fasciitis is suspected, radiographic imaging should not, under any circumstances, delay surgical treatment! Ecthyma gangrenosum Definition: an ulcerative lesion extending into the dermis that develops in the setting of bacteremia Pathogen: Pseudomonas aeruginosa (not pathognomonic but is the most common causative organism) Pathophysiology: Classically develops in patients with P. aeruginosa bacteremia who are immunocompromisedBacteria invade vasculature, causing septic vasculitis and cutaneous necrosisVirulence factors destroy tissue: Exotoxin A: inhibits elongation factor 2, impairing protein synthesisElastase: degrades elastin in blood vessel wallsPhospholipase C: breaks down cell membranesPyocyanin: produces damaging reactive oxygen species Clinical featuresRapid progression (within 12-18 hours) of painless red macules → induration, development of pustules, vesicles, and/or bullae → crusted ulcersCan involve skin or mucous membranes; anogenital and axillary areas most commonly involvedCan be solitary or multiplePatients typically also systemically ill (e.g., septic shock) Diagnosis: primarily a clinical diagnosis Treatment: see treatment of skin and soft tissue infections

Dermatophyte infections Dermatophyte infections, also known as tinea, are the most common fungal infections of the skin, hair, and nails. The term "dermatophyte" refers to fungal species that infect keratinized tissue, and includes members of the Trichophyton, Microsporum, and Epidermophyton genera. Tinea are classified based on their location (e.g., tinea pedis occurs on the feet and tinea capitis on the scalp). Children and immunocompromised individuals are more likely to contract tinea infections, especially tinea capitis. However, people of all ages may suffer from tinea pedis or tinea unguium. The clinical features of dermatophyte infection include pruritus, scaling, and erythema. The best initial test for the diagnosis of dermatophyte infection is potassium hydroxide (KOH) preparation, which allows segmented hyphae to be seen on microscopy. Generally, the treatment for dermatophyte infections is topical antifungals. Oral antifungals (e.g., terbinafine, griseofulvin) are always used in tinea capitis and are also used for severe, refractory cases of other kinds of tinea. Concomitant tinea infections in household members or pets should be treated as well. Tinea versicolor, despite its name, is not caused by dermatophytes and is discussed in another learning card.

General Definition: skin, hair, and nail infections caused by dermatophytes Pathogen: Dermatophytes are fungi that infect keratinized tissue and belong to the Trichophyton (most common), Microsporum, and Epidermophyton genera. Risk factors Diabetes mellitusImmunocompromise (e.g., HIV)Poor circulation, peripheral arterial diseaseMaceration of skin (e.g., in athletes) LocationFoot: Tinea pedisHands: Tinea manuumBody: Tinea corporisScalp: Tinea capitisNails: Tinea unguiumInguinal area: Tinea cruris Diagnosis of dermatophyte infections Best initial test: KOH preparation, possibly with fungal stain, showing segmented hyphae Confirmatory test: fungal culture Wood's light: yellow-green fluorescence of Microsporum species Treatment of dermatophyte infections Topical antifungalsIndication: dermatophyte infections other than tinea capitisAgents: e.g., terbinafine 1% for 1 week, azoles Systemic antifungal therapyIndications Tinea capitisFailed topical treatmentImmunocompromised patientsExtensive spreadSome cases of tinea unguium Agents: terbinafine, itraconazole, fluconazole, and griseofulvin Because topical treatments are unable to penetrate the hair shaft, systemic therapy with oral antifungals such as griseofulvin or terbinafine is necessary in tinea capitis! Chemical and surgical treatments for onychomycosisChemical removal of nail (e.g., with high dose urea or potassium iodide)Surgical removal of the nail is indicated if systemic therapy is not effective. Examination and treatment of members of the household and pets Tinea pedis (athlete's foot) Definition: dermatophyte infection of the foot EpidemiologyAffects adults and adolescentsMost common tinea infection Predisposing factorsClosed, tight footwearPublic showers Clinical features by type Interdigital (most common): chronic, pruritic, erythematous scaling and erosions between the toesMoccasin: hyperkeratotic thickening of skin on soles of feetVesicular: pruritic or painful vesicular lesions and erythema, often on the medial foot Diagnosis and treatment: See the overview of dermatophyte infections above. Complication: secondary bacterial superinfection (e.g., erysipelas) PreventionFoot powders and open shoes in warm, humid weatherAntifungal treatment of shoesFootwear for public showers Tinea corporis (ringworm) Definition: dermatophyte infection affecting a location other than feet, scalp, nails, and groin Predisposing factorsContact with infected individuals or animalsMoist environments (e.g., public swimming pool facilities) Clinical presentationInitially round, pruritic, erythematous plaque that grows centrifugallyDevelops into round, pruritic plaque with central clearing and a scaling, raised border Diagnosis and treatment: See the overview of dermatophyte infections above. Tinea capitis Definition: dermatophyte infection affecting the scalp Epidemiology: mainly occurs in children Clinical presentation: Round, pruritic scaly plaques with broken hair shafts or alopecia in affected areasMay mimic seborrheic dermatitis Kerion: severe form of tinea capitis characterized by a deep, boggy plaque with pustuleformationPostauricular lymphadenopathy Diagnosis and treatment: See the overview of dermatophyte infections above. PreventionAvoid sharing combs and hats with infected individuals.Antifungal treatment of contaminated objectsEvaluation and treatment of household contacts and pets PrognosisUsually good; hair regrows completelyProtracted infection and kerion may result in permanent alopecia. inea unguium (onychomycosis) Definition: fungal infection of the nail PathogenMostly dermatophytes (most commonly T. rubrum) Rarely yeast and molds Clinical presentation: discolored (white, gray, or yellow) and brittle nails Diagnosis and treatment: See the overview of dermatophyte infections above Tinea cruris (jock itch) Definition: fungal infection of the inguinal area Clinical presentation: Pruritic erythematous plaque that grows centrifugallySimilar to tinea capitis but often without central clearingScaling, raised borderSpares the scrotum Diagnosis and treatment: See the overview of dermatophyte infections above. Differential diagnoses Impetigo Seborrheic dermatitis Tinea versicolor Herald patch (→ pityriasis rosea) Cutaneous candidiasis Erythrasma Contact dermatitis Psoriasis

Herpes simplex virus infections Herpes simplex virus infections may be caused by two virus genotypes: herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2). Worldwide seroprevalence is high, with antibodies detectable in over 90% of the population. Of these cases, approx. 60% are caused by HSV-1. The most common infections are labial and genital herpes, which present with painful ulcerations. Two further conditions, seen especially in children, are herpetic gingivostomatitis and herpetic whitlow. While herpetic gingivostomatitis is characterized by painful lesions of the oral and pharyngeal mucosa, herpetic whitlow causes blisters on the fingers with pronounced regional lymphadenopathy. In individuals with underlying dermatological conditions, infection with HSV can cause eczema herpeticum, resulting in painful erosions spread diffusely over the head and upper body. However, the majority of primary infections remain asymptomatic, while recurrent infections present with the typical manifestations. The diagnosis of HSV infections is usually confirmed through viral cultures, but may also be based on detection of HSV DNA in PCR, or multinucleated giant cells in Tzanck smears. Treatment consists mainly of topical or oral acyclovir; IV administration may be needed in critical cases, such as HSV infection in immunocompromised patients.

General information Prevalence: More than 90% of the world's population over the age of 40 carries HSV. TypesHerpes simplex virus type 1 (HSV-1), human herpes virus type 1 (HHV-1)Herpes simplex virus type 2 (HSV-2), human herpes virus type 2 (HHV-2) TransmissionDirect contact with mucosal tissue or secretions of another infected personInfection with HSV-1 usually acquired in childhood via saliva Type of infectionPrimary infection Mostly asymptomatic (up to 80% of cases, but virus is still shed)If symptomatic, the infection is often sudden and severeReactivation of infection Frequency and severity vary individually; symptoms are usually less severe than in primary infection.Often at the same site as primary infection Pathophysiology Inoculation: The virus enters the body through mucosal surfaces or small dermal lesions. Neurovirulence: The virus invades, spreads, and replicates in nerve cells. Latency: After primary infection, the virus remains dormant in the ganglion neurons (e.g., trigeminal, sacral ganglion) Reactivation: triggered by various factors (e.g., immunodeficiency, stress, trauma) → clinical manifestations Dissemination: infection spreads to unusual sites (e.g., lungs, gastrointestinal tract, eyes)May occur in pregnant patients or patients with severe immunodeficiency (e.g., malnutrition, recipients of organ transplants, patients with AIDS) Labial herpes (herpes labialis) Pathogen: mostly HSV-1 (HSV-2 in 10-20% of cases) Most common recurrent HSV-1 infection in adults Clinical featuresProdromal symptoms (∼ 24 hours): pain, tingling, burning Recurring, erythematous vesicles that turn into painful ulcerations (primarily affecting the oral mucosa and lip borders) Differential diagnosesShingles (Herpes zoster)Aphthous ulcersHerpanginaHand, foot, and mouth diseaseCandidiasisSyphilitic chancre or chancroid Genital herpes (herpes genitalis) Pathogen: HSV-2, HSV-1 (less common) Incubation period: 2-7 days Clinical findingsMost patients are asymptomatic Genitals: redness, swelling, tingling, pain, pruritusPossibly unusual vaginal dischargePainful lymphadenopathy in the groin areaAfter several days, "punched-out" lesions may appear that later ulcerate.Lesions may appear as single or disseminated, painful red bumps or white vesicles.They are typically located on or around the genitals and anus.Recurrence is common. For genital herpes during pregnancy, see congenital herpes simplex virus infection Herpetic gingivostomatitis Etiology: severe manifestation of an (often primary) HSV-1 infection Mainly in children (∼ 1-6 years), but also immunocompromised patients (e.g., agranulocytosis, HIV) Clinical featuresProdrome (fever, malaise) often mistaken for teething in children. Pharyngitis, cervical lymphadenopathyGingivitis; erythema and painful ulcerations on perioral skin and oral mucosa, especially on the inner cheek, soft palate, and tongue Differential diagnosesThe same as for labial herpes Herpetic pharyngotonsillitis: pharyngitis and tonsillitis caused by HSV-1 Eczema herpeticum Also known as Kaposi varicelliform eruption (KVE) Pathogen: most commonly HSV-1 and HSV-2 Etiology: associated with preexisting skin conditions, most often atopic dermatitis Clinical featuresFever, malaise, lymphadenopathyExtensive disseminated and painful eruptions on the head and upper body : erythematous skin with multiple, round, umbilicated vesicles that may progress to punched-out erosions Herpetic whitlow Pathogen: HSV-1 in 60% of cases; HSV-2 in 40% of cases (in the adult population) EtiologyDirect contact with infected secretions through a break in the skin, e.g., torn cuticleMain groups: Children (via sucking of thumb/fingers (may have a history of labial herpes)Health care workers exposed to oral secretions (e.g., dentists) Incubation period: 2-20 days Clinical featuresPossibly history of fever and malaiseInfection of the dermal and subcutaneous tissueOne or more fingers involved (especially the thumb and index fingers); mostly found on terminal phalanxFeeling of pain, tingling, and burning in infected finger; edemaGrouped, non-purulent vesicles on an erythematous base for up to 10 daysVesicles may rupture or ulcerateAxillary and epitrochlear lymphadenopathy Differential diagnoses: paronychia, cellulitis, felon Surgical treatment is not indicated because it may cause severe complications (e.g., bacterial superinfection, systemic spread, herpes encephalitis)! Other HSV infections Herpes simplex encephalitis Herpes conjunctivitis Viral keratitis Congenital herpes simplex virus infection Herpes esophagitisEpidemiology: typically occurs in patients who are immunocompromised. Clinical features: odynophagia, dysphagia, and retrosternal chest painDiagnostics: see "Diagnostics" and "Treatment" below; endoscopy shows superficial ulcers in the upper or mid esophagus in the absence of plaques Erythema multiforme Diagnostics Diagnosis is primarily based on clinical features, with confirmation through the following tests: Light microscopy findings on a Tzanck smear Multinucleated giant cells (non-specific)Eosinophilic intranuclear Cowdry A inclusion bodies (non-specific)Results available within 1 hourUnable to differentiate between HSV-1 and HSV-2 Viral culture: gold standard for definitive diagnosis; results available in 48 hours PCR: detects HSV RNA; identification of virus genotype Direct fluorescent antibody test : identification of the virus genotype Serum antibody testing: shows primary seroconversion Treatment Depending on the site, type, and severity of HSV-1 infection, antiviral drugs are administered either topically or systemically. In most cases of recurrent infection, topical and/or symptomatic treatment is sufficient. Antiviral treatment EffectDecrease in duration and severity of infection (most effective if therapy is initiated within 72 hours of onset of infection) Reduction of viral sheddingHowever, recurrence cannot be prevented. AgentsFirst-line: oral acyclovir for mild diseaseIn severe cases or immunocompromised patients → IV acyclovir Topical may be helpful if used early In case of acyclovir-resistant HSV-1: foscarnetValacyclovirPenciclovirFamciclovir Duration: 7-10 days Prophylaxis: indicated in the case of frequent or severe relapses; in patients with prodromal symptoms Long-term suppressive therapy with (val)acyclovir Early treatment of herpes infections is essential to prevent complications because antiviral drugs only inhibit the virus during its replication phase! Symptomatic treatment IV fluids Barrier creams to avoid lip adhesion in cases of lesions on the lips Pain relief (oral or IV) Antipyretics Antibiotics for bacterial superinfection (e.g., amoxicillin, clindamycin) Prevention Use of condoms, gloves Consider isolation of hospitalized patients with shedding lesions

Conjunctivitis Conjunctivitis (pinkeye) is a very common inflammation of the conjunctiva (the mucus membrane that lines the inside of the eyelids and the sclera). It is most commonly caused by viruses or bacteria but can also have noninfectious (e.g., allergic) causes. It is also commonly associated with corneal inflammation (then referred to as keratoconjunctivitis). Conjunctivitis is the most common cause of ocular hyperemia. Other classic features are burning, foreign body sensation, excessive tearing, and photophobia. Additionally, in infectious conjunctivitis, general signs of viral or bacterial infection (e.g., fever) may be seen, while itching is particularly common in allergic conjunctivitis. Dry eye is a hallmark feature of keratoconjunctivitis sicca. In most cases, local pharmacologic therapy with anti-infective,anti-inflammatory and/or antiallergic agents is sufficient. However, bacterial conjunctivitis can lead to blindness in newborns; therefore, strict and rapid treatment and prevention is vital. Surgical intervention is only rarely useful or necessary (e.g., correction of eyelids).

General signs and symptoms of conjunctivitis Conjunctival injection: conjunctival hyperemia with dilatation of blood vessels → ocular hyperemia and reddening Discharge and crust formation Chemosis: edema of eyelids and/or conjunctiva. Burning or foreign-body sensation Photophobia Itching (most intense in seasonal allergic conjunctivitis) BacterialViralGeneralUsually unilateralThick purulent discharge (yellow, white or green)Reduced vision and risk of blindness (if cornea is involved)Extraocular signs of bacterial infection See additional features of certain causes below ViralBilateral (usually begins with one eye and spreads to the other within a few days) Clear, watery discharge (with mucoid component) . Increased lacrimation (epiphora) Usually normal vision Conjunctival folliclesSmall raised, yellowish-white hyperplasia of lymphatic tissue, usually with peripheral (rather than central) vascularizationParticularly on the palpebral and bulbar conjunctiva Extraocular/general signs of viral infection : e.g., fever, lymphadenopathy (e.g., preauricular node), pharyngitis See additional features of certain causes below Viral conjunctivitis EpidemiologyMost common type of conjunctivitisIncidence rises during the late fall and early spring Etiology: adenoviruses (most common), herpes simplex virus (HSV), varicella-zoster virus (VZV), picornavirus, molluscum contagiosum, HIV (highly contagious), measles, zika Epidemic keratoconjunctivitis ("pinkeye") Pathogen: specific adenovirus subtypes Transmission: direct contact, fecal-oral route, or contaminated water (e.g., swimming pools) Pharyngoconjunctival fever (PCF) Pathogen: adenovirus 3 Transmission: direct contact, fecal-oral route, or contaminated waterHerpes simplex conjunctivitisPathogen: usually HSV-1 in children (most common) and adults (HSV-2 infection may occur in neonates)Transmission: close personal contact with inoculation into conjunctiva Clinical featuresSee "Clinical features" aboveEpidemic keratoconjunctivitisSudden onset, fulminant course (lasts 7-21 days)Subconjunctival and petechial hemorrhageEyelid ecchymosisMultifocal epithelial punctate keratitis → anterior stromal keratitis Unilateral preauricular lymphadenopathyIncreased lacrimationSevere cases Membrane or pseudomembrane formation → conjunctival scarringAnterior uveitisVision loss (rare)Pharyngoconjunctival fever: fever, pharyngitis, acute follicular conjunctivitis (unilateral or bilateral), tender preauricular lymphadenopathyHerpes simplex conjunctivitisVesicular blepharitisDendritic epithelial keratitis of cornea or conjunctivaEndothelialitis, trabeculitis, or uveitis DiagnosisClinical diagnosis + history of upper respiratory infection, if presentConjunctival smear and cultures (or viral isolation) if symptoms are recurrent/chronic TreatmentAdenovirus: usually supportive (application of cold and moist compresses, artificial tears) Herpes simplex: topical antiviral (e.g., ganciclovir)Topical antibiotics if bacterial superinfection is suspected Prognosis: usually self-limiting Prevention: disinfect hands and instruments, avoid sharing towels, shaking hands, or touching eyes Bacterial conjunctivitis General Etiology: Staphylococcus aureus (most common in adults), Streptococcus pneumoniae, Haemophilus influenzae, Pseudomonas, Haemophilus, and Moraxella catarrhalis Clinical features: see "Clinical features" above DiagnosisClinical diagnosisConjunctival scrapings and culture (or PCR) required if persistent or severe disease (i.e., multiple or large corneal lesions), if the diagnosis is uncertain, and in newborn conjunctivitis Treatment: Topical broad-spectrum antibiotics (e.g., erythromycin or trimethoprim-polymyxin B) Special recommendations in newborn conjunctivitisNeisserial and chlamydial infections require systemic treatment PreventionProper hygieneTreatment of pregnant women and prophylaxis in newbornsPublic health programs (e.g., mass treatment) Neisserial conjunctivitis EtiologyPathogen: Neisseria gonorrhoeaeRoute of infection (highly contagious) Young, sexually active adults: direct contact to contaminated secretions (e.g., from the genitalia to the hand to the eye)Newborns: perinatally Clinical featuresSee "Clinical features" above; hyperacute conjunctivitis with marked eye swelling and profuse purulent dischargeAlso preauricular lymphadenopathy Diagnosis: gram stain shows intracellular gram negative diplococci Treatment: IV or IM ceftriaxone plus oral azithromycin with saline irrigation (topical antibiotics may also be considered) N.gonorrhoeae infection is an ocular emergency that can lead to keratitis, perforation, and blindess without prompt treatment! Trachoma (Granular conjunctivitis) EtiologyInfection with Chlamydia trachomatis type A-CRoute of infection: direct (human-to-human contact with eyes or nose) or indirect (flies or towels) contact EpidemiologyMost common cause of blindness due to chronic scarring worldwide Predominantly affects young children and women Clinical features: see "Clinical features" aboveCan be divided into two stages which may occur simultaneously Active phase : conjunctival follicles (with eventual involution forming Herbert pits), inflamed upper tarsal conjunctivaCicatricial phase : chronic/recurring inflammation in both eyes → conjunctival scarring → progressive conjunctival shrinkage → corneal ulcers and opacities, superficial neovascularization with cellular infiltration (corneal pannus), entropion, trichiasis Diagnosis: clinical diagnosis Treatment/PreventionAntibioticsDrug of choice: single oral dose azithromycin Alternative: topical tetracycline (for six weeks) Surgical intervention (eyelid correction in trichiasis)Hygienic measures (particularly facial cleanliness) and environmental improvement (e.g., supply of clean water) Prognosis: good (if treated early) Inclusion conjunctivitis (paratrachoma) Epidemiology: more common in industrialized countries EtiologyPathogen: Chlamydia trachomatis types D-KRoute of infection: sexually , perinatally, or via swimming pools, Clinical features: see "Clinical features" above Conjunctival folliclesPapillary hypertrophy Corneal pannusPreauricular lymphadenopathy Treatment/prevention: oral azithromycin, erythromycin, or doxycycline Newborn conjunctivitis Chemical conjunctivitis Usually due to silver nitrateexposure Usually first day Mild conjunctivalinjections Flush eyewith saline Neonatal gonococcal conjunctivitis N. gonorrhoeae 2-7 days Profuse purulent ocular drainage, pronounced eyelid swelling Cultures and gram stain (on blood, chocolate agar, and conjunctivalscrapings) or PCR IV or IM 3rd generation cephalosporin (e.g., ceftriaxone or cefotaxime)for both mothers and newborns. Ceftriaxone is contraindicated in premature neonates, neonateswith hyperbilirubinemia , and in neonates requiring calcium-containing IV solutions (e.g., parenteral nutrition) Prenatal maternal screening and systemic antibiotic treatment Crede prophylaxis for newborns (topical erythromycin or tetracycline) Chlamydial conjunctivitis C. trachomatis;serotypes D-K 5-14 days Watery/mucopurulent ocular discharge, eyelid swelling Cultures and gram stain (on blood, chocolate agar, and conjunctival scrapings) or PCR Newborns: oral erythromycin or azithromycin Mother and at-risk contacts: oral azithromycin or amoxicillin (for 1 week) Prenatal maternal screeningand systemic antibiotictreatment Viral conjunctivitis Herpes simplex virus 2 Less commonly, other viruses Within 14 days Nonpurulent ocular discharge, corneal ulceration, periocular vesicles PCR Systemic acyclovirplus topical drugs (e.g., vidarabine) for 14-21 days Proper hygiene Keratoconjunctivitis sicca (dry eye disease) Definition: disease of the eye surface caused by underproduction or changes in the composition of lacrimal fluid or by increased evaporation EpidemiologyVery common in the US, especially > 40 years♀ > ♂ EtiologyEnvironmental factors Often associated with blepharitis (inflammation of the edge of the lid)Primary and secondary Sjögren's syndromeDisorders of the lid positioning or ↓ blink rate (e.g., cranial nerve lesions V or VII)Medication: systemic or local Vitamin A deficiencyContact lenses Clinical features General signs and symptoms of conjunctivitisDry eyes (paradoxically, excessive tearing is also possible )Blurred visionEntropion or ectropion DiagnosisPrimarily a clinical diagnosis Slit-lamp examinationConjunctival injection (usually symmetric and bilateral)Punctate epithelial erosions (superficial punctate keratitis)Epithelial filaments on the corneal surface (filamentary keratitis)Also see Sjögren's syndrome TreatmentAvoid triggers (e.g., dry air) or change environment (e.g., use of humidifiers)Patient education on eyelid hygieneMedical therapyArtificial tears and ocular lubricantsIf symptoms persist despite above therapy Topical corticosteroids and/or cyclosporineTopical or systemic Omega-3 supplementation Topical or systemic tetracyclines (for meibomitis or rosacea)Moisture chamber spectacles Surgical (if symptoms persist despite above medical therapy) Punctal occlusion (after inflammation controlled) Correction of eyelid abnormalities.

Chagas disease Chagas disease (American trypanosomiasis) is an infectious disease caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), which is typically transmitted by triatomine bugs of the reduviid family. Chagas disease is endemic to Central and South America and most cases that occur in the US are reported in immigrants from endemic regions. Patients present initially with fever, swelling at the site of inoculation of triatomine feces, and generalized lymphadenopathy. These symptoms resolve within a few weeks, and the patient enters an asymptomatic latent phase, which may last for 10-20 years. Eventually, 10-30% of all infected patients enter a chronic phase and develop symptoms of Chagas cardiomyopathy and/or gastrointestinal disease characterized by achalasia and progressive dilation of the colon. The disease is diagnosed by thin and thick peripheral smears in the acute phase and by serological tests in the chronic phase. Chagas disease patients are treated with the antitrypanosomal drugs benznidazole and nifurtimox. Supportive therapy is required for Chagas cardiomyopathy and gastrointestinal disease. Treatment of Chagas disease is most effective when initiated early (in the acute phase).

Global statisticsPrevalence: 8-10 million infected individuals; endemic in Central and South America Prevalence in the US: > 300,000 infected individuals Pathogen: Trypanosoma cruzi Route of infectionVector transmission by numerous triatomine species of the reduviid family ("kissing bug") Life cycle of T. cruzi in the triatomine insectIngestion of the trypomastigote form of T. cruzi by the triatomine insect occurs during a blood meal.Transformation of the trypomastigotes into epimastigotes in the midgut and transformation of into metacyclic trypomastigotes in the hindgut occurs after 8-10 days.Metacyclic trypomastigotes are shed in feces. Life cycle of T. cruzi in the human host Metacyclic trypomastigotes enter cells that are located in the vicinity of the wound site and/or mucosal membranes (e.g. conjunctiva). Within the cells, the metacyclic trypomastigote is converted into an amastigote, which then multiplies within the infected cell by binary fission. Intracellular amastigotes transform into trypomastigotesBoth trypomastigotes and amastigotes are released into the blood stream by lysis of the infected cell. Trypomastigotes can reinfect host cells and perpetuate the cycle within the host. The parasite causes immune-mediated tissue damage as a result of cross-reaction with T. cruzi antigens. Incubation period: 1-2 weeks Acute phase (lasts ∼ 8-12 weeks) Fever, malaise, loss of appetiteCutaneous manifestations Chagoma: inflammatory edema at the bite site (usually in the face)Romana sign: unilateral painless edema of the eyelids and periocular tissue Generalized lymphadenopathy and hepatosplenomegalyRarely (∼ 1% of cases): myocarditis, meningoencephalitis Indeterminate phasePatient enters an asymptomatic latent phase.Patients in the indeterminate phase are serologically positive but do not develop signs and symptoms associated with the chronic phase. Chronic phase (develops after ∼ 10-20 years) Chagas cardiomyopathyConduction disorders: right bundle branch block (RBBB) Biventricular dilative cardiomyopathy → heart failureMural thrombi → strokeGastrointestinal tractDamage to the submucosal and myenteric plexus → inability to relax lower esophageal sphincter and impaired gut motility → progressive dilation of the esophagus and colonMegaesophagus and achalasia: dysphagia, weight loss, regurgitationMegacolon: abdominal pain, chronic constipation Confirmatory testsAcute phase Best initial test: direct visualization of T. cruzi trypomastigotes in thin and thick peripheral blood smears PCR to detect T. cruzi DNA Indeterminate and chronic phase: serological assays to detect IgG antibodies against T. cruzi Additional testsRegular ECG monitoring Patients with symptoms or ECG signs of Chagas cardiomyopathy → see "Diagnostics of dilated cardiomyopathy"Patient with symptoms of GI involvement: barium radiography, endoscopy, and manometry (also see "Diagnostics" in achalasia) Antitrypanosomal therapy Treatment against Chagas disease is most effective when initiated early (in the acute phase). First-line: benznidazole Second-line: nifurtimox Supportive therapy Chagas cardiomyopathySee "Therapy of dilated cardiomyopathy"Patients with severe cardiomyopathy: heart transplantation Gastrointestinal disease Megaesophagus: see "Therapy" in achalasiaMegacolon: High fiber diet with adequate fluid intake, laxatives, and/or rectal enemas to treat constipationPatients with persistent constipation, fecalomas, sigmoid volvulus: rectosigmoidectomy (with either retrocecal interpositioning or end-to-side low colorectal anastomosis) Instructions for people traveling to or working in endemic regionsUse insect repellents and insecticide-treated bed nets.Avoid sleeping in poorly constructed houses with thatched roofs and cracked walls. Public health measuresScreening of blood donors Screening of neonates born to infected mothers Vector control methods such as insecticide spraying and reduviid-proof housingFood hygiene

Treatment of multiresistant pathogens The increased use of antibiotics in hospital settings has led to a greater antibiotic resistance of some bacterial strains. The treatment of infections caused by these strains is difficult since common broad spectrum antibiotics are ineffective and use of alternative drugs is necessary. Therefore, prophylaxis involves both preventing the spread of the causative pathogen as well as treating asymptomatic carriers.

Gram-positive MRSA: Resistance to All beta-lactam antibiotics (penicillins, cephalosporins, and carbapenems) Further potential resistance to Aminoglycosides MacrolidesLincosamidesQuinolones MRSA Treat with: Vancomycin Linezolid Quinupristin/dalfopristinDaptomycinTigecycline Vancomycin-resistant enterococci Resistance to: (VRE)Vancomycin (possibly also teicoplanin) Numerous further resistances to MacrolidesMost penicillinsQuinolonesAminoglycosidesTetracyclines VRE Treat with: Linezolid Quinupristin/dalfopristin Tigecycline Daptomycin Gram-negative ESBL pathogens (Extended-spectrumβ-lactamase) Resistance to Penicillins Cephalosporins Multidrug resistant gram-negative bacteria (MDRGNor MDRGNB) MDRGN Main substances Broad spectrum penicillinsCephalosporins (groups 3and 4) Carbapenems Fluoroquinolones MDRGN: carbapenems If the MDRGN is resistant to all four antibiotic groups: colistin, linezolid, tigecycline (last resort antibiotics) Pseudomonas aeruginosa Resistance to Most penicillins Cephalosporin groups 1, 2, and 3(a)Macrolides MDRGN Piperacillin + tazobactam Group 3b cephalosporins(ceftazidime) Carbapenems All options are potentially combinable with an aminoglycoside If the MDRGN is resistant to all four antibiotic groups → give last resort antibiotics according to antibiogram (e.g., colistin )

Common bacterial pathogens in neutropenic fever

Gram-positiveCoagulase-negative staphylococciStaphylococcus aureus, including MRSAViridans group streptococciStreptococcus pneumoniaeStreptococcus pyogenes Gram-negativeEscherichia coliKlebsiella speciesEnterobacter speciesPseudomonas aeruginosaCitrobacter speciesAcinetobacter speciesStenotrophomonas maltophilia Treatment Empiric antibiotic therapy should be initiated immediately after two sets of blood cultures have been obtained Low-risk patients who can tolerate oral intake and have a caregiver, telephone, and access to transportation may be treated with oral antibiotics on an outpatient basis. High-risk patients require admission and broad-spectrum IV antibiotics to avoid sepsis and life-threatening complications Once the patient is clinically stable and/or a source has been determined, consider narrowing antibiotics If fever persists, reassess for fungal or viral infection and adapt treatment accordingly. Neutropenic fever is an emergency! Mortality risk increases if no empirical antibiotic therapy has been initiated after one hour.

Benzofurans

Griseofulvin(oral) Bind to keratin and interfere with microtubulefunction, which disrupts fungal mitosis Oral treatment of tinea infections(e.g., tinea pedis) Narrow range of efficacy Important contraindications: porphyria, hepatic failure Avoid during pregnancy and breastfeeding Hepatotoxicity Rashes and severe skin reactions (e.g., Stevens-Johnsonsyndrome) Urticaria Carcinogenic Teratogenic Induces cytochrome P-450 → ↓ concentration of many drugs metabolized by P-450 (e.g., warfarin)

Fever Differential diagnoses by affected system

HEENTOtitis media Otitis externa Mastoiditis Epiglottitis Sinusitis Pharyngitis LaryngitisAbscess (e.g., peritonsillar or retropharyngeal) Ludwig angina Trauma Malignancy Pulmonary URI, Bronchitis, Pneumonia, Pulmonary abscess, Empyema, Pulmonary tuberculosis, Q fever, Loeffler syndrome, Acute schistosomiasis, Leptospirosis, Middle East respiratory syndrome, Acute histoplasmosis, Acute coccidioidomycosis, Psittacosis, Melioidosis, Pulmonary embolism, Pulmonary infarction, Pleuritis, Pneumonitis (e.g., chemical pneumonitis), ARDS, Diffuse alveolar hemorrhage,Lung cancer, E-cigarette or vaping-associated lung injury (EVALI) CardiovascularInfectious endocarditis Marantic endocarditis Pericarditis Myocarditis Aortitis Acute myocardial infarction Pericarditis Myocarditis Vasculitides Postmyocardiotomy syndrome Dressler syndrome Abdominal Peritonitis, SBP, Acute cholangitis, Acute cholecystitis, Appendicitis, Diverticulitis, Hepatitis, Pyelonephritis, Intra-abdominal abscess, Infectious colitis, Gastroenteritis, Acute pancreatitis, Pancreatic cancer, Colon cancer, Inflammatory bowel disease, Mesenteric carcinomatosis Urologic/PelvicTubo-ovarian abscess, Fournier gangrene, Urinary tract infection, Pyelonephritis, Epididymitis, Acute prostatitis,STI, PID, TTP-HUS, Retained products of conception, Toxic shock syndrome, Prostate cancer, Cervical cancer, Endometrial cancer, RCC, AIN, Vasculitides Neurologic/psychiatric Typhus Poliomyelitis Rabies Japanese encephalitis West Nile encephalitis Tick-borne encephalitis Meningococcal meningitis Eosinophilic meningitis Trypanosomiasis Angiostrongyliasis Brain abscess Intracranial hemorrhage Stroke Cavernous sinus thrombosis Hypothalamic dysfunction Anti-NMDA encephalitis Factitious fever CNS lymphoma NMS Skin and soft tissue/bone/lymphatic ErysipelasCellulitisAbscessNecrotizing fasciitisHerpes virus infectionLymphangitisVasculitidesCat scratch fever Scarlet fever Osteomyelitis Thrombophlebitis Lymphangitis Mycosis fungoides Vasculitides DRESS Sweet syndrome Sarcoma RheumatologicSeptic arthritisSeptic bursitisLyme diseaseChikungunya feverDengue feverZika virusParvovirusRoss River virusRubellaMycobacterial infectionRheumatoid arthritisJuvenile idiopathic arthritisSLEGoutPseudogoutReactive arthritisTraumatic arthritis Hematologic HIV infection CMV infection Mononucleosis Malaria Leukemia Lymphoma Multiple myeloma Myelodysplastic syndromes Thrombosis Autoimmune hemolytic anemia Transfusion reaction EndocrineSubacute thyroiditisThyroid stormAcute adrenal insufficiency

Fever Further diagnostic testing to consider based on suspected localization of symptoms

HEENTRapid strep testThroat cultureCT scan of the head, face, and/or neck with IV contrast PulmonarySputum culture Legionella urinary antigenRespiratory viral panelS. pneumoniae urinary antigenAFB smear microscopy Procalcitonin Chest x-ray CT chest with IV contrast Bronchoscopy Thoracentesis CardiovascularTroponin ECGTTE and/or TEE CTA chest AbdominalStool culture,Stool ova and parasites,Stool leukocytes,C. difficile toxin PCR,Viral PCR Abdominal ultrasound,X-ray abdomen,CT abdomen/pelvis with oral and IV contrast, Paracentesis Urologic/pelvic Urine culture,Urinary PCR for N. gonorrhoeae and C. trachomatis,Urethral, vaginal, and or cervical PCR for N. gonorrhoeae and C. trachomatis PCR,Urethral microscopy and culture,Serum RPR, TPPA, Transabdominal pelvic ultrasonography,Transvaginal ultrasonography, Testicular ultrasonography Neurologic/psychiatricESR, CRP Toxicology screenLumbar puncture with CSF analysis (glucose, protein, cell count, gram stain, culture, viral PCR) CT brain MRI brain Brain biopsy Skin and soft tissue/bone/lymphaticGram stain and culture of any exudate CT with IV contrast MRI Skin biopsy Bone biopsy Rheumatologic ANA,ANCAs,Rheumatoid factor,dsDNA,Uric acid level, See also antibody diagnosis of autoimmune diseases., Arthrocentesis with joint aspiration analysis (cell count, gram stain, culture, microscopy) HematologicPeripheral blood smearHIV serology test HIV PCR Peripheral flow cytometryLyme IgM and IgGParvovirus B19 IgM and IgGEBV IgM, IgG, and DNA PCREhrlichiosis IFA and/or PCRAnaplasmosis IFA and/or PCRBone marrow biopsy EndocrineTSH with free T3, T4 Serum cortisol, ACTH (morning) Thyroid gland ultrasoundCT abdomen with contrast

Herpes virus infections Human herpesviruses (HHV) are a large family of DNA viruses that remain dormant in a host following primary infection. An overview of the eight subtypes known to cause various diseases (ranging from asymptomatic to fatal disease courses) in humans is provided below.

HHV-1Herpes simplex virus 1(HSV-1)Seroprevalence: ≥ 90% in adultsAntivirals may be indicated (see acyclovir)After primary infection, the virus remains dormant in nerve ganglia (typically trigeminal).SalivaRespiratory secretionsHerpes labialis Herpetic gingivostomatitis Herpes simplex encephalitis (adults and older children) Eczema herpeticum Herpetic whitlow [1][2] ; most commonly seen in children and healthcare workers who come into contact with saliva (i.e. dentists)HSV keratitis HSV conjunctivitis HHV-2Herpes simplex virus 2(HSV-2)Seroprevalence: 10-30% in adultsAntivirals may be indicated (see acyclovir)After primary infection, the virus remains dormant in nerve ganglia (typically sacral).Sexual intercoursePerinatalGenital herpes Eczema herpeticum Congenital herpes simplexHerpes simplex encephalitisHerpetic whitlow HHV-3Varicella zoster virus(VZV)Seroprevalence: up to 90%Antivirals may be indicated (see acyclovir).Vaccinations are widely used to prevent VZVinfections in children.Respiratory secretionsVesicular fluidPrimary infection: chickenpox (varicella) Reactivation: shingles (zoster) Congenital varicella syndromeViral encephalitisPneumonia HHV-4Epstein-Barr virus(EBV)Seroprevalence: ≥ 65% in children[3]Oncogenic potential: can immortalize and transform host B cellsUses CD21 receptor to cause infection in B cellsSalivaRespiratory secretionsInfectious mononucleosis Oral hairy leukoplakia Burkitt's lymphoma Nasopharyngeal carcinoma HHV-5Cytomegalovirus (CMV)Seroprevalance: ∼ 40% in children in the US Morphologic features of infected cells: "Owl-eye appearance" Antivirals may be indicated (see ganciclovir, foscarnet, and fomivirsen).Uses integrins to cause infectionCongenitalSexual intercourseTransfusions, transplantsSalivaUrineCongenital CMV infectionHeterophile-negative mononucleosis Cytomegalovirus infections CMV retinitisCMV pneumoniaCMV esophagitis HHV-6/HHV-7 Virus spreads early. To be determined Roseola (also called sixth disease, roseola infantum or exanthema subitum) HHV-8Kaposi's sarcoma-associated virus (KSHV)Seroprevalence: < 10% in the US Seroprevalence is higher in men who have sex with men (MSM) and HIV-positive patients. Sexual intercourseKaposi's sarcoma

HIV-associated ocular manifestations

HIV retinopathyCaused by a microvascular disorderFundoscopic findings Small cotton-wool spotsMicroaneurysmsRetinal hemorrhagesTend to self-resolve without progressionNot painfulVision usually unaffectedVariable Herpes simplex keratitisHistory of HSV infection is commonSlit-lamp examination: dendritic corneal lesionsFundoscopic findings are normalPainful and watery eye(s)Blurry visionVariable Varicella zoster retinitisRareFundoscopic findings: retinal necrosis (starting from the periphery) PainfulSevere loss of visionVariable Cytomegalovirus retinitisFundoscopy findings Hemorrhages (red spots)Perivascular white opacities resembling cotton-wool spots (larger than HIV retinopathy!)"Pizza pie" appearance: combination of red spots on white opacitiesRetinal detachmentNot painfulVision initially unaffectedVision loss occurs if the retina detaches or the posterior pole (optic nerve or macula) is affected.< 50/μL Toxoplasma retinitisFundoscopic findings: raised yellow-white cottony lesions (distribution of the lesions not related to vessels)PainfulVisual impairment< 100/μL

Hand disinfection

Hand disinfection vs. hand washingHand disinfection decreases transient skin flora more effectively and dehydrates the skin to a lesser extent compared to handwashing. Washing with soap should be kept to a minimum. E.g., before work, before surgical hand disinfection, in obvious soiling, after contact with a patient infected with spore-forming bacteria (e.g., Clostridium difficile).Use of skin care products is recommended to prevent skin irritation (e.g., during breaks, after work). Hygiene regulationsFingernails should be cut short. Artificial nails should not be worn.No jewelry on the hands and forearmsSpecial rub-in technique for hygienic hand disinfectionApply a sufficient amount of disinfectant onto dry skin.Attention should also be paid to the fingertips, thumbs, and the spaces between the fingers. Wall-mounted dispensers are preferred to pocket-sized sanitizers. Hygienic hand disinfection Aim: decrease the number of pathogens in transient skin flora IndicationBefore and after contact with each patientBefore work, before and after breaks, as well as before (self-protection) and after going to the bathroom.Before handling medication, syringes, and infusionsAfter removing contaminated gloves Substances: alcohol and phenol mixtures ProcedureDisinfection → minimum contact time: 30-60 sIf desired, the hands may be subsequently washed. Surgical hand disinfection Aim: Decrease the number of pathogens in transient and resident skin flora. Indication: before every surgical procedure Substances: alcohol and phenol mixtures ProcedureScrubbing of hands and forearms Disinfectants may have a decreased efficacy after contact with soap → thoroughly rinse off the remaining soap.Disinfection of hands and forearms → minimum contact time: 1.5-5 min (depending on disinfectant used)

Systemic fungal infections

HistoplasmosisPathogen: Histoplasma capsulatumRisk factors: AIDSand other immunocompromisedpatients, exposure to bird or bat droppings, especially in Mississippi and the Ohio river valley AIDS-defining illness if disseminated or extrapulmonaryOften asymptomaticFlulike illness: fever, weight loss, erythema nodosum, hepatosplenomegaly, lymphadenopathy, nonproductive coughThe presence of ulcerative oral lesions is specific for histoplasmosisChest x-ray: diffuse nodular densities, focal infiltrate or cavity, or lymphadenopathyBest initial: positive urine and serum polysaccharide antigen testSilver stain of biopsy or bronchoalveolar lavage showing macrophages filled with dimorphicfungus with septate hyphaeCulture (blood, sputum, bone marrow, lymph node, liver)Liver biopsy: demonstrates disseminated disease with the presence of fungal organisms in the yeast-stage of development. Mild disease: supportive therapyChronic cavitation: oral itraconazole > 1 yearSevere pulmonary or disseminated disease: IV amphotericin B/liposomal then oral itraconazole Coccidioidomycosis(valley fever) Pathogen: Coccidioides immitisRisk factors: travel to Southwestern United States, California AIDS-defining illness if disseminated or extrapulmonaryFlu-like illness or pneumonia: fever, cough, night sweats, anorexia, chest pain, and dyspneaExtrapulmonary: CNS (e.g., meningitis), skin (desert bumps), and joints (desert rheumatism)Serology: increased IgM (increases within 2 weeks of infection and disappears after 2 months); increased IgG at 1-3 monthsChest x-ray: normal or infiltrates/lymphadenopathy/pleural effusionKOH or culture (sputum, wound exudate, joint effusion) showing large spherules containingendosporesIV amphotericin B (severe infection)Alternative: itraconazole ParacoccidioidomycosisPathogen: ParacoccidioidesspeciesParacoccidioides brasiliensisParacoccidioideslutziiRisk factors: travel to South and Central AmericaInfected patients often asymptomaticAcute pneumoniaPainful nasal, pharyngeal, and laryngeal mucosal ulcerationsLymphadenopathy(usually cervical)Can disseminate → extrapulmonary manifestations (including verrucousskin lesions)KOH/calcofluor staining on smears or silver/PAS-staining on tissue biopsy: budding yeast with "captain's wheel" formationCultures have a low sensitivity.ItraconazoleSevere or refractory cases: amphotericin B Blastomycosis Pathogen: Blastomyces dermatitidis Risk factors: travel to Southeastern and Central US Pneumonia Extrapulmonary: can disseminate to the skin (verrucouslesions and granulomatous nodules) and bones KOH or culture (confirmatory) of sputum, urine, or body fluids showing: yeast form (at body temperature or > 37°C): broad-based budsMold form (at room temperature): circular fungal cells with filamentous hyphae Local infection: fluconazole and itraconazole Systemic infection: IV amphotericin B Other fungal infections Sporotrichosis (Rose gardener disease) EtiologyPathogen: Sporothrix schenckiiRisk factor: traumatic injury to the skin while gardening (e.g., thorn prick) Clinical featuresPustules and ulcers with ascending lymphangitisDisseminated disease: pneumonia, meningitis DiagnosticsFungal culture (sputum, pus, biopsy tissue) showing dimorphic, cigar-shaped yeastSeptate hyphae, rosette-like clusters of conidia at the tips of the conidiophores TreatmentOral itraconazole or potassium iodideDisseminated: IV amphotericin B

Human papillomavirus infection The human papilloma virus (HPV) causes infections of the skin and mucous membranes. The locations and specific manifestations of infection depend on the type of virus and its mode of transmission. Many HPV strains are already spread during infancy and childhood through direct skin-to-skin contact and may remain dormant, while others (especially HPV-1, HPV-2, and HPV-4) can cause common warts (verruca vulgaris). Other strains are sexually transmitted (especially in young adults) and can be further divided into low-risk and high-risk HPV types. Low-risk types (especially HPV-6 and HPV-11) can cause benign anogenital warts(condylomata acuminata) and papillomatous nodules in other genital (e.g., squamous intraepithelial lesions of the cervix) or non-genital (e.g., oral warts, respiratory papillomatosis) mucosal areas. Infection with oncogenic high-risk HPV types (especially HPV-16 and HPV-18) may lead to malignant disease. These high-riskstrains account for more than 70% of cervical cancers and can also cause genital, oral, and oropharyngeal squamous cell cancers. Risk factors for infection include skin damage, immunocompromise, early first sexual intercourse, and frequent change of sexual partners. Most HPV infections are asymptomatic and self-limiting, although pruritus, tenderness, and bleeding may occur. Diagnosis is often based on the physical exam alone, but can be confirmed with diagnostic tests (e.g., the acetic acid test), particularly in asymptomatic HPV infections of the cervix. Treatment of condylomas includes the use of local ointments, cryotherapy, and electrocoagulation. However, surveillance is important since recurrence rates are high and malignant transformation is possible. Prevention includes education about safe sexual practices and the proper use of condoms, as well as vaccination of all boys and girls at 11-12 years of age.

Human papillomavirus Double-stranded, circular, non-enveloped DNA virus with an icosahedral capsid Low-risk types 6 and 11Anogenital warts (condylomata acuminata)Mild cervical cell abnormalitiesTumors of non-genital mucosal membranes (e.g., respiratory tract, oral cavity, esophagus, eye) High-risk types 16, 18, 31, and 33Cervical cancer (responsible for 70% of cases) High risk of anogenital, oral, and oropharyngeal squamous cell carcinomaPathomechanism: Inactivation of tumor suppressor genes (HPV-16: E6 gene product inactivates TP53 gene; HPV-18: E7 gene product inactivates Rb gene) HPV types 1, 2, and 4: cause skin warts, such as common warts (verruca vulgaris) and plantar warts (myrmecias) Route of transmission Transmission occurs between two epithelial surfaces. Close personal contact: cutaneous wartsSexual contact: anogenital lesions Risk factors Damaged skin/mucous membranes Immunodeficiency Additional risk factors for genital/mucosal HPV infections include: Unprotected sexNumber of lifetime sexual partnersEarly age at first sexual activityUncircumcised males Anogenital manifestations Epidemiology Most common sexually transmitted infection (STI) Approx. 50% of new infections affect individuals between 15-24 years of age. PrevalenceIn the US: ∼ 79 millionWorldwide: 12% of women with normal cervical cytology test positive for HPV Incidence: ∼ 14 million annually in the US Sex: ♀ > ♂ (1.4:1) Genital intraepithelial neoplasms Cervical intraepithelial neoplasia (CIN) and cervical cancer Vulvar intraepithelial neoplasia (VIN) and vulvar cancer Vaginal intraepithelial neoplasia (VAIN) and vaginal cancer Squamous cell carcinoma of the penis Anal cancer Condylomata acuminata (anogenital warts) HPV types 6 and 11: responsible for ∼ 90% of genital warts Location♀: vulvar, cervix, urethra (rare), anal region♂: glans penis, foreskin, urethra, anal region DiagnosisVisual inspectionApplication of 5% acetic acid turns lesions white (not a specific finding) Clinical findingsExophytic, cauliflower-like lesions Often asymptomatic; may cause pruritus, tenderness, or bleeding in rare cases Treatment Pharmacotherapy: local cytostatic treatment (e.g., 5-fluorouracil, trichloroacetic acid, podophyllin, salicylic acid) or immune response modifiers (e.g., imiquimod, interferon alpha)Cryotherapy: freezing external warts with CO2, N2O, or N2 In case of numerous warts: curettage, laser surgery, or electrocoagulation Flat condylomata Particularly HPV types 3 and 10 Flat, white-brown, slightly elevated, scattered plaques in the anogenital region Differential diagnosis: condylomata lata (usually flat, smooth, and moist) in syphilis Treatment Curettage or laser surgeryRegular checks are necessary because of the high risk of malignancy Bowenoid papulosis Transitional stage between a genital wart and Bowen disease (a squamous cell carcinoma in situ) Most commonly HPV-16 Multiple, flat, red-brown pigmented papules on the external genitalia (particularly the penile shaft, glans, foreskin, vulva, and perianal region) Treatment Re-examination every 3-6 months (lesions often regress spontaneously)If persistent: local destructive therapy (see "Treatment" of condylomata acuminata above) followed by surveillance (annual examinations), since lesions may recur Malignant transformation occurs in 2.6% of cases. Giant condylomata (Buschke-Löwenstein tumor) Primarily HPV types 6 and 11 Exophytic, verrucous, locally invasive squamous cell carcinoma without a tendency to metastasize Surgical excision Nonanogenital manifestations Epidemiology Most common in infancy, childhood, and adolescence Prevalence: ∼ 7-12% in the US Sex: ♀ = ♂ Common warts (verruca vulgaris) Particularly HPV types 1, 2, and 4 Skin-colored or whitish, rough, scaly papules or plaques (sometimes with a cauliflower-like appearance) on the elbows, knees, fingers, and/or palms Often asymptomatic but may cause tenderness (depending on the location) and pruritus → scratching → bleeding Treatment Initially watchful waiting (most skin warts regress within 2 years)Topical agents (e.g., salicylic acid), cryotherapy, or surgical interventions Plantar warts Particularly HPV types 1, 2, and 4 Rough, hyperkeratotic lesions on the sole of the foot Often grow inwardly and cause pain while walking Nonanogenital mucosal manifestations HPV types that cause mucosal manifestations in the genital area may also lead to non-anogenital mucosal manifestations, such as: Oral warts and oropharyngeal carcinomas Laryngeal papillomaDefinition: benign tumor of the laryngeal epithelium caused by HPV infection of the throat; associated with strains 6 and 11Clinical features: voice changes (e.g., hoarseness) and, in more severe cases, airway obstruction; white, exophytic cauliflower-like lesions located in the larynx, trachea, and on the vocal cords Laryngeal carcinoma Respiratory papillomatosis and squamous cell carcinoma (SCC) of the lung Conjunctival papillomas and conjunctival carcinoma Flat warts (verruca plana) Particularly HPV types 3 and 10 Multiple small, flat patches or plaques Localization: face, hands, and shins KoilocytesPathognomonic of an infection with HPVDysplastic squamous cells characterized by well-defined, clear, balloon-like, perinuclear halo and hyperchromasia Differential diagnoses See genital lesions Benign tumors, e.g., fibroids, papillomatous dermal nevi Malignant tumors, particularly squamous cell carcinomas Prognosis High rate of recurrence Infection with high-risk types may transition to precancerous or malignant lesions after several years. Prevention Education about possible risk factors and effective preventive measures, such as: HPV vaccination: All boys and girls should be vaccinated at 11-12 years of age. Use of condoms Condoms decrease the risk of infection, but do not provide full protection, as uncovered areas may still be infected. Pregnancy Vertical transmission to the fetus is rare but may lead to: Laryngeal papillomatosis → airway obstructionConjunctival papillomatosis Treatment/Prevention Vaccination should be avoided during pregnancy.Trichloroacetic acid is preferred; cryotherapy and surgical interventions are also safe. Cesarian section is indicated if the birth canal is obstructed by large genital warts.

Immunoglobulin types

IgMPentamerLargest antibody , located on the surface of B cells as a monomer and circulating as pentamer (with J chain)Formed early (evidence of recent infection)Activates complement Blood group antibodiesImmune response (early reaction) antibodies, e.g., anti-HBc (hepatitis C core) IgM antibody IgGMonomerMost abundant immunoglobulin in blood serumDelayed formation during the course of infection (IgM-IgG switch); ensures long‑termimmunityTiter determination for follow‑up: high affinity and specificityCan be free-floating in serum or bound to the surface of lymphocytesThe only immunoglobulin that can cross the placenta and thus convey passive immunityto the childActivates complementOpsonization of bacteriaNeutralization of viruses and toxinsRhesus antibodies Immune response (late reaction) antibodies, e.g., anti‑Hbc IgGAllergy: mediation of type II hypersensitivity, type III hypersensitivity IgAMonomer or dimerMonomer in circulation and dimer when secretedMost abundant immunoglobulin in the body but has a low serum concentrationFound especially on mucosal surfaces and in bodily fluids Prevents binding of pathogens to host cellsSecretory component protects IgA from proteases (e.g., in the gastrointestinal tract)IgA antibodies to tissue transglutaminase are present in gluten‑sensitiveenteropathy (celiac disease)Important in defense against intestinal infections (e.g., giardiasis)Selective IgA deficiency IgEMonomerDefense against parasitesBinds to mast cells → cross-linking → release of histamine (involved in allergic diseases)Binds to basophilsAllergy: mediation of immediate‑type reaction (type I hypersensitivity - e.g.., anaphylaxis) IgDMonomerLocated on the surface of mature B lymphocytesFunction is incompletely understood

Azoles CNS penetration of fluconazole: "FLU through the blood-brain barrier" Voriconazole is the drug of choice for inVasive aspergillosis.

Imidazole derivatives Clotrimazole(topical, oral) Miconazole(topical, oral) Broad spectrum of efficacy Inhibit fungal cytochrome P450, which decreases fungal synthesis of ergosterolfrom lanosterol Primarily topical fungal infections Oropharyngeal candidiasis Vaginal candidiasis Dermatophyte infections Miconazole for tinea versicolor Broad spectrum of efficacy Local burning, reaction, and/or pruritus Ketoconazole(topical, oral) Primarily nonfungal: Psoriasis Hypercortisolism (e.g., Cushing syndrome) Fluconazole(oral, IV) Voriconazole(oral, IV) Fluconazole Drug of choice for cryptococcal meningitis (in AIDS patients) Candidiasis (all forms) CoccidioidomycosisHistoplasmosis/blastomycosis Voriconazole(oral, IV) Voriconazole: drug of choice for invasive aspergillosis Itraconazole(oral) Particularly effective in dermatophytosis (e.g., onychomycosis) Oropharyngeal/esophageal candidiasis Histoplasmosis Blastomycosis Coccidioidomycosis Allergic bronchopulmonary aspergillosis Sporotrichosis Broad spectrum of efficacy Pregnancy and breastfeeding Fluconazole: avoid during pregnancy and breastfeeding Itraconazole: weigh risks during breastfeeding Important contraindications Cardiac arrhythmias (e.g., prolonged QT)Severe cardiac insufficiencyAvoid cross-reactions with drugs metabolized by cytochrome P-450 Use with caution in patients with:Renal dysfunctionHepatic dysfunction If given orally, discontinue PPIs, as they require a low pH to be absorbed Hepatotoxicity Inhibits cytochrome P-450 → ↑ concentrationof many drugs metabolized by P-450 (e.g., warfarin, simvastatin, cyclosporine, theophylline etc.) Gastrointestinal upset Gynecomastia QT prolongation → torsade de pointes Hypokalemia Additionally in ketoconazole Adrenal cortexinsufficiency Topical use: local burning, reaction, and/or pruritus Additionally in voriconazoleDose-dependent, reversible visual disordersPhotosensitivity

Immunoglobulins

Immunoglobulins (antibodies) have two functional parts: the Fc region and the Fab region. The two enzymes papain and pepsin can be used to identify the different functional parts. Fc regionContains the constant regionFormed by heavy (H) chainsDetermines the antibody isotype (e.g., IgA, IgG, IgM)Binds complement (IgG, IgM)Binds various immunological cells, such as macrophages, to stimulate phagocytic or cytotoxic activityContains the carboxy terminalHas many carbohydrate side chains Fab regionContains the variable/hypervariable regionFormed bylight (L) chains and heavy chains (H) Recognizes and binds to antigens via epitopeDetermines the idiotype, which is specific for one antigen only

Isolation precautions

In healthcare facilities, implementing isolation precautions prevents contact-, airborne-, or droplet-mediated pathogen transmission. Contact precautionsUsed for the care of patients with drug-resistant pathogens (e.g., MRSA, VRE), enteric infections (e.g., Clostridium difficile, Escherichia coliO157:H7), scabies, impetigo, and draining abscessesIncludes performing hand hygiene and wearing gloves and gowns when getting into the patient's room (even when direct contact with the patient or infected material is not expected).Patients should be kept in isolation or in cohort Medical equipment should be dedicated to a single patient. If not possible, disinfect before reuse. Droplet precautionsUsed for the care of patients with suspected or confirmed infection with pathogens that spread with droplets, such as Neisseria meningitidis, Bordetella pertussis, influenza, parainfluenza, adenovirus, Haemophilus influenzae type b, Mycoplasma pneumoniae, and rubellaPatients should be kept in isolation or in cohort. Includes wearing masks within a distance of 3- 6 feet from the patient and masking patients during transportImplement hand hygiene after contact with respiratory secretions. Airborne precautionsUsed for the care of patients with suspected or confirmed tuberculosis (TB), measles, varicella, smallpox, and severe acute respiratory syndrome (SARS) infectionsPatients should be kept in a private room with negative air pressure; the door of the isolated room must remain closed.Individuals must wear a respirator when entering the room.Minimize transport of patients and mask them if it is mandatory.Implement hand hygiene after contact with respiratory secretions. Prevention of cathether-associated urinary tract infection Avoiding unnecessary catheterization Using sterile technique during catheter placement Cleaning the catheter surrounding area with soap and water suffices for maintenance. Prompt removal when the catheter is no longer needed Using clean intermittent catheterization in patients with neurogenic bladder: In this technique, the catheter is immediately removed after bladderdrainage and gets either discarded (single-use catheter) or cleaned (reusable catheter). Prevention of intravascular catheter-related infections (e.g., central venous line infection) Implementing hand hygiene and strict aseptic technique during insertion Using a cap, mask, long-sleeved sterile gown, sterile gloves, and a sterile full body drape Preparing skin with chlorhexidine and alcohol before inserting the catheter Systemic anticoagulation and antibiotics may be considered in oncology patients who require long-term central venous access. Changing dressings regularly

Antibiotic Contraindications

InfantsChloramphenicol < 8 yearsTetracyclinesEthambutol is relatively contraindicated in children. < 18 yearsFluoroquinolones Pregnant womenAll trimestersTetracyclinesFluoroquinolonesErythromycinClarithromycinStreptomycinOnly in the last trimesterSulfonamidesChloramphenicolLimited data on safety (use with caution, i.e., when benefits outweigh risks) AminoglycosidesVancomycinAzithromycinClindamycinTrimethoprimRifampinPyrazinamideConfirmed safe: penicillins, cephalosporins, INH, ethambutolFor more details, see pharmacotherapy during pregnancy. Breastfeeding womenSulfonamidesTetracyclinesMetronidazoleFluoroquinolonesNitrofurantoin Renal failureAbsolutely contraindicated: tetracyclinesRelatively contraindicatedAminoglycosidesCephalosporinsFluoroquinolonesConfirmed safe: penicillins, macrolides, vancomycin, metronidazole, INH, rifampin Hepatic failureNo antibiotic is absolutely contraindicated.Relatively contraindicatedChloramphenicolErythromycinFluoroquinolonesMetronidazoleRifampinIsoniazidConfirmed safe: penicillins, cephalosporins, ethambutol, aminoglycosides

Immunizations for travel

Japanese encephalitis vaccine (JE)2 doses, 28 daysapartShould be completed at least one week before exposureBooster if last dose ≥ 1 year ago2 monthsSoutheast Asia Recommended for travelers or US citizens living in endemic areas during periods of JE transmission There is currently no efficacy data available for the vaccine. Yellow fever vaccine1 dose; at least 10 days before departure9 monthsAfrica, Central and South AmericaRecommended for all travelers or US citizens living in risk areasMany African and South American countries require proof of vaccination from incoming travelers.One dose provides lifelong protection. Rabies vaccine3 doses: day 0, 7, and either 21 or 28 (depending on vaccine)Provides protection within ∼ 2 weeksnoneRabies is endemic on all continents except Antarctica. However, several countries are considered rabies-free. May be recommended for travelers visiting countries with a high occurrence of animal rabiesand low availability of antirabies biologics (e.g., countries in Africa, South America, and Southeast Asia)Depends also on planned activities (e.g., caving, wildlife work in rabies-epizootic areas)After being bitten by a mammal (e.g., dog, cat, monkey) persons who have been previously vaccinated should get 2 more doses of rabies vaccine (days 0 and 3). Rabies immune globulin is not required. Typhoid and paratyphoid fever vaccineInactivated typhoid vaccine: 1 doseAt least 2 weeksbefore travelingBooster dose every 2 yearsLive typhoidvaccine: 4 doses; day 0, 3, 5, 7); At least 1 weekbefore travelingBooster dose every 5 yearsInactivated typhoidvaccine: 2 years of ageLive typhoidvaccine: 6 years of ageCommon in most developing countries, especially in Southern AsiaRecommended for travelers with exposure to potentially contaminated foods and beverages Persons with intimate exposure to a chronic carrier of Salmonella typhiThe vaccine can only prevent illness in about ¾ of cases. Meningococcal vaccine Children at 2 months of age: MenACWY-CRMas a 4-doseseries at 2, 4, 6, and 12 monthsof age Children at 7-23 months of age: MenACWY-CRMor MenACWY-Das a 2-doseseries Travelers 2-56 years: 1 doseMenACWY-CRMor MenACWY-D Travelers > 56 years: 1 dose of meningococcal polysaccharidevaccine(groups A, C, Y, W combined) 2 monthsSub-SaharanAfrica A quadrivalent meningococcal conjugate vaccination (e.g., MenACWY-CRM or MenACWY-D; protects against serogroups A, C, W, and Y) is recommended for persons traveling or residing in hyperendemic or epidemiccountries who are in close contact with natives.Travelers aged ≥ 2 years going to Saudi Arabia on a pilgrimage to Mecca are required by the Saudi government to provide proof of vaccination with a quadrivalent meningococcal vaccine in the last 3 years. Documentation of 2 doses of a meningococcal vaccine against serogroup A is required for travelers aged 3 months to 2 years.

Fever Differential diagnoses by associated finding

JaundiceAcute viral hepatitis Yellow feverMalariaLeptospirosisAcute cholangitisPyogenic abscess Bradycardia Typhoid fever Brucellosis Leptospirosis Lyme disease Viral myocarditis Endocarditis Malaria Babesiosis Ehrlichiosis Anaplasmosis Q fever Rash Bacterial infection MeningococcemiaLeptospirosisLymphangitisCellulitisErysipelasTyphoid feverRocky Mountain spotted feverAcute rheumatic feverInfectious endocarditisViral infection MeaslesRubellaMononucleosisEnteroviral encephalitisDengue feverChikungunya feverZika feverAcute HIV infectionHSV infectionShinglesNoninfectious causes Drug feverSLERheumatoid arthritisSarcoidosisCrohn diseaseBehcet disease EosinophiliaParasitic infections StrongyloidiasisSchistosomiasisTrichinellosisDrug feverDRESS LeukopeniaTyphoid feverTyphusChikungunya infectionZika feverAcute HIV infectionViral hemorrhagic feversDengue feverLassa feverEbola feverCrimean-Congo hemorrhagic feverHanta feverYellow fever AnemiaMalariaParvovirus infectionSickle cell diseaseAnaplasmosis

Nosocomial infections Overview of multiresistant pathogens

Methicillin-resistant Staphylococcus aureus (MRSA) Resistance: developed by forming a modified penicillin-binding protein (PBP) that inhibits binding to beta-lactam antibiotics, thereby decreasing their bactericidal effect Occurrence: asymptomatic colonization of the nasal mucosa estimated at 0.5-5% of the population Measures to curb MRSA Hygiene measures: hand disinfection, protective clothing (gown, mask) , disinfection of patient rooms Patient isolation, if necessary cohort isolation MRSA eradication in asymptomatic carriersMupirocin nasal ointment, antiseptic solution for skin/hair contamination (e.g., chlorhexidine) Extended-spectrum beta-lactamase-producing bacteria (ESBL) Resistance: Bacteria produce beta-lactamases that have a broad spectrum and are thus able to cleave penicillins, cephalosporins, and, in isolated cases, carbapenems. Common pathogens: particularly gram-negative bacteria (e.g., Enterobacteriaceae such as Klebsiella, Escherichia coli)Associated with nosocomial urinary tract infections and healthcare-associated pneumonia Isolation in separate rooms required Vancomycin-resistant enterococci (VRE) Definition: bacterial strains of the genus Enterococcus that are resistant to the antibiotic vancomycin (e.g., E. faecalis , E. faecium) Resistance: acquisition of van genes → alteration of peptidoglycan synthesis pathway → inhibits binding of vancomycin to peptidoglycan Multidrug-resistant gram-negative bacteria (MDRGNB) Definition: A pathogen is termed as MDRGN when resistance is demonstrated to at least three antibiotic classes (see "Treatment of multiresistant pathogens" below). Hospital hygiene and prevention of infectionSuspected cases: no isolationIn cases of pathogen detection Basic hygiene measures in normal areas sufficient Isolation in risk areas Infections caused by Pseudomonas aeruginosa CharacteristicsPseudomonas aeruginosa has a high natural resistance to antibioticsBlue-green color (e.g., blue-green sputum or pus)Sweet, sickly odorTypically found in damp environments Diseases: pneumonia, severely infected wounds, urinary tract infections, otitis externa ("swimmer's ear"), keratitis

Mycobacterium avium complex (MAC) infection

Mycobacterium avium complex (MAC) infection Epidemiology: Most frequent opportunistic bacterial infection in AIDS patientsAIDS-defining condition Pathogenesis: Occurs usually only if CD4 count < 50/μLInfection occurs via gastrointestinal or respiratory epithelium → Bacteria may remain confined to area of entry (localized) or spread via the lymphatic system and the blood (disseminated). Clinical featuresNight sweats, fever, weight lossLymphadenopathyAbdominal pains, diarrheaAnemia, leukocytosis Diagnostics: Confirmed by isolation of MAC from blood, bone marrow, lymph nodes, or other tissue or body fluidsAcid-fast bacilli staining and culture TherapyMacrolide (clarithromycin or azithromycin) plus ethambutolRifabutin may be added in some cases Prophylaxis: azithromycin, clarithromycin, or, in select cases, rifabutin Indicated if the CD4+ T-cell count is < 50 cells/μL in patients who are not on cARTNo longer recommended in patients who are immediately started on effective cART

Penicillins

Natural penicillins DrugsPenicillin G (benzylpenicillin) IV: crystalline penicillin GIM: procaine penicillin G, benzathine penicillin GOral penicillin V (phenoxymethylpenicillin) Clinical useGram-positive aerobes (especially S. pyogenes, S. pneumoniae) Gram-negative cocci (especially Neisseria meningitidis)Spirochetes (especially Treponema pallidum)Branching gram-positive anaerobe (Actinomyces) Adverse effects: hemolytic anemia, seizures Anti-staphylococcal penicillins Drugs (oral or IV) NafcillinDicloxacillinOxacillinMethicillin Special characteristics: Intrinsically beta-lactamase resistant through the addition of bulky side chains (e.g., isoxazolyl) Clinical use: gram-positive aerobes, especially S. aureus (non-MRSA) Adverse effects: interstitial nephritis Development of resistance: due to alteration of binding site of penicillin-binding proteins → reduced affinity → pathogen is not bound or inactivated by β-lactam (one of the main virulence factors in MRSA) Aminopenicillins DrugsOral or IV amoxicillin (± clavulanate)IV or IM ampicillin (± sulbactam) Structures are similar to penicillin, therefore are susceptible to beta-lactamase degradation. Clinical use: broader spectrum of activity than penicillinSome gram-positive aerobes and gram-negative bacilli H. pyloriH. influenzaeE. coliListeriaProteusSalmonellaShigellaSpirochetesEnterococci Adverse effects DiarrheaPseudomembranous colitisDrug-induced rash when treating patients with infectious mononucleosis AmOxicillin is administered Orally, while amPicillin is administered via a Prick! Ureidopenicillins DrugsIV piperacillin (+ tazobactam) Clinical use: extended spectrum Gram-negative bacilliEspecially PseudomonasAlso anaerobes, i.e., Bacteroides fragilisGram-positive aerobes Carboxypenicillins DrugsIV ticarcillinIV carbenicillin Intrinsically beta-lactamase resistant Clinical use: extended spectrum gram-negative bacilli, especially Pseudomonas

Neutropenic fever

Neutropenic fever is an oncologic emergency common in patients receiving chemotherapy. A decrease in a patient's absolute neutrophil count (ANC) can lead to potentially life-threatening infections, and the risk of serious infection is directly associated with the extent and duration of neutropenia. Because the immune response is impaired in neutropenia, symptoms can be mild and even a low-grade temperature (38°C) should be considered a fever. Initial workup should consist of peripheral and, if applicable, central line blood cultures; further investigation is guided by localization of clinical signs. Empiric antibiotic therapy should be started within the first hour of onset to minimize mortality risk. Treatment should be adjusted as soon as further findings are available. Neutropenia: ANC < 500/μL OR expected to decrease to < 500/μL within 48 hours Fever: single oral temperature ≥ 38.3°C (101°F) OR ≥ 38°C (100.4°F) for at least 1 hour Laboratory studies CBC with differential Blood cultures x 2 sets (at least) Culture from any suspected site of infection Urinalysis with reflex urine culture BMP LFTs Serum lactate Blood glucose ESR/CRP Procalcitonin Type and screen Coagulation studies (e.g., INR, PTT) Imaging [1] CXR for patients with respiratory symptoms Further imaging (e.g., CT) should be guided by history and clinical findings.

Low Risk Neutropenic Fever Fluoroquinolones should only be considered for treatment in patients not previously taking a fluoroquinolone for prophylaxis. If the patient develops a neutropenic feverwhile on a fluoroquinolone, they should be treated as high-risk and started on an antipseudomonal beta-lactam.

No penicillin allergy and not taking fluoroquinolone prophylaxis One of the following fluoroquinolonesCiprofloxacinLevofloxacinPLUS amoxicillin-clavulanate Penicillin allergy and not taking fluoroquinolone prophylaxisOne of the following fluoroquinolonesCiprofloxacinLevofloxacinPLUS clindamycin Taking fluoroquinolone prophylaxisNo longer low-risk, proceed to high-risk recommendations.

High Risk Neutropenic Fever Any recurrent fever should be considered a new episode of infection.

No penicillin allergyMonotherapy with one of the following antipseudomonal beta-lactams: Piperacillin-tazobactam CefepimeMeropenemImipenem-cilastatinPenicillin allergy and not taking fluoroquinolone prophylaxisCiprofloxacinPLUS clindamycinPenicillin allergy and taking fluoroquinolone prophylaxisAztreonamPLUS vancomycinSuspected necrotizing or intraabdominal infection ADD anaerobic coverage, e.g., metronidazoleRisk factors for MRSAand/or a complication associated with a high risk of MRSA infection ADD vancomycinRisk factors for VREADD one of the following (instead of vancomycin): LinezolidDaptomycinRisk factors for ESBLUse one of the following carbapenems (instead of cephalosporin or penicillin): MeropenemImipenem-cilastatinRisk factors for CPEADD one of the following: Polymyxin B [6]ColistinTigecycline [7]

Nosocomial infections

Nosocomial infections, also known as hospital-acquired infections, are newly acquired infections that are contracted within a hospital environment. Transmission usually occurs via healthcare workers, patients, hospital equipment, or interventional procedures. The most common sites of infection are the bloodstream, lungs, urinary tract, and surgical wounds. Though any bacteria may cause a nosocomial infection, there is an increasing incidence of multidrug-resistant (MDR) pathogens causing hospital-acquired infections. This rise can be explained by indiscriminate use of antibiotics and lacking hygiene measures, especially among medical staff. Commonly seen multidrug-resistant pathogens include methicillin-resistant Staphylococcus aureus (MRSA), extended-spectrum beta-lactamase-producing bacteria (ESBL), and vancomycin-resistant enterococci (VRE). The choice of antibiotic for treating infections with these pathogens is based on the individual resistance profile and often requires additional strict isolation methods for the patient.

Amebiasis Amebiasis is an infectious disease caused by the anaerobic protozoan Entamoeba histolytica. Transmission usually occurs via the fecal-oral route (e.g., via contaminated drinking water) when traveling in an endemic region. Depending on its manifestation, amebiasis is termed either intestinal or extraintestinal. After an incubation period of one to four weeks, symptoms such as loose stools with mucus and fresh blood in combination with painful defecation develop. In extraintestinal amebiasis, amebic abscesses(mostly a single liver abscess in the right lobe of the liver) may form, resulting in pain as well as a feeling of pressure in the right upper quadrant (RUQ). Important diagnostic steps include stool analysis and liver ultrasound to assess extraintestinal amebiasis. Treatment consists of paromomycin to destroy intestinal amebae and metronidazole for invasive disease. Image-guided needle aspiration may be indicated in cases involving complicated liver abscesses.

Occurence: E. histolytica is very common in tropical and subtropical regions (e.g., Mexico, Southeast Asia, India) and affects more than 50 million people worldwide. Amebic infection is relatively rare in the US. Men and especially immunocompromised individuals have a higher risk of developing liver abscesses. Pathogen: Entamoeba histolytica, a protozoan TransmissionFecal-oralAmebic cysts are excreted in stool → contaminate drinking water or foodTransmission may also occur through sexual contact.Infection typically occurs following travel to endemic regions such as the tropics and subtropics. StagesCyst stage: Cysts are very resilient (even against gastric acid) and are able to survive outside the host for months.Vegetative stage: trophozoite formation Trophozoites can produce proteolytic enzymes that allow them to invade the intestinal submucosa. They can then enter the bloodstream where they consume erythrocytes and disseminate to target tissues like the liver via the portal system. Incubation period Intestinal amebiasis: 1-4 weeks Extraintestinal amebiasis: a few weeks to several years Clinical courses Intestinal amebiasis (dysentery)Loose stools with mucus and bright red bloodPainful defecation, tenesmus, abdominal pain, cramps, weight loss, and anorexiaFever in 10-30% of cases and possible systemic symptoms (e.g., fatigue)High risk of recurrence, e.g., through self-inoculation (hand to mouth)A chronic form is also possible, which is clinically similar to inflammatory bowel disease. Extraintestinal amebiasisMostly acute onset of symptoms; subacute courses are rareIn 95% of cases: amebic liver abscess, usually a solitary abscess in the right lobeFever in 85-90% of cases (compared to amebic dysentery) RUQ pain or pressure sensationChest pain, pleuralgiaDiarrhea precedes only a third of all cases of amebic liver abscesses. In 5% of cases: abscesses in other organs (e.g., especially the lungs; in rare cases, the brain), with accompanying organ-specificsymptoms Diarrhea precedes only a third of all cases of amebic liver abscess! Always consider amebiasis when a patient presents with persistent diarrhea after traveling to a tropical or subtropical destination! Travel history Intestinal amebiasisStool analysisMicroscopic identification of cysts or trophozoites in fresh stool Trophozoites often contain ingested erythrocytesThe following tests confirm the microscopic findings (important since E. histolytica and Entamoeba dispar are morphologically identical ): EIA or copro-antigen ELISA (antigens found in feces)Molecular methods: e.g., PCRStool microscopy is not sensitive, especially in later phases, so at least three stool samples should be examined before reporting a negative result. Extraintestinal amebiasisSerological antibody detectionLiver function testsALP, AST, ALT, bilirubin slightly elevatedImaging: shows a solitary lesion, typically in the right lobeUltrasound: hypoechoicCT/MRI Asymptomatic intestinal amebiasisNo treatment in endemic areasIn nonendemic areas: a luminal agent such as paromomycin or diloxanide to eradicate the infection Symptomatic intestinal amebiasis and invasive extraintestinal amebiasisInitial treatment with a nitroimidazole derivative such as metronidazole or tinidazole to eradicate invasive trophozoitesFollowed by a luminal agent (e.g., paromomycin or diloxanide) to eradicate intestinal cysts and prevent relapse Invasive procedures Aspiration: ultrasound or CT-guided puncture of complicated abscesses at risk for perforationIndications: Localized in the left lobe Pyogenic abscessMultiple abscessesFailure to respond to pharmacotherapy Surgical drainage: should generally be avoided, but may be indicated for inaccessible abscesses or ruptured abscesses in combination with peritonitis To ensure successful treatment, the patient's stool must be analyzed regularly! Intestinal amebiasis Fulminant or necrotizing colitis Toxic megacolon → colon rupture Ameboma Fistula formation (e.g., rectovaginal) Extraintestinal amebiasis Secondary infection → pyogenic abscess Abscess rupture → peritonitis Dissemination, possibly resulting in a brain abscess Direct extension to the pericardium or pleura Food and water hygiene Unpeeled fruits or vegetables should not be consumed if there is a potential risk of contamination by Entamoeba histolytica cysts (e.g., endemic region with low hygiene standards). Even chlorinated water can contain high concentrations of amebae; therefore, water should be boiled before use.

Osteomyelitis Osteitis and osteomyelitis are infections of the bone and bone marrow, respectively. Because these terms are often used interchangeably in clinical settings, both conditions will be referred to as osteomyelitis here. Staphylococcus aureus accounts for the majority of acute osteomyelitis cases; however, there are a number of other pathogens associated with this condition. How the pathogen enters the bone determines the type of osteomyelitis: hematogenous and exogenous forms exist. Hematogenous osteomyelitis is caused by seeding from a remote source and is most common among IV drug users and children. Exogenous osteomyelitis is more common in adults and results from direct inoculation through trauma (posttraumatic osteomyelitis) or contiguous spread from infected adjacent tissue (contiguous osteomyelitis due to, e.g., diabetic foot, contaminated prosthetic device). Osteomyelitis may be either acute or chronic and presents with general signs of local inflammation, including swelling, pain, redness, and warmth. Systemic signs, such as fever and chills, are more indicative of an acute infection. Diagnosis of clinically suspected cases is supported via laboratory tests, biopsy, and/or imaging. The treatment of choice for hematogenous osteomyelitis is IV antibiotics. Surgery may be necessary to remove necrotic bone, abscesses, infected foreign bodies, or fistulae. While osteomyelitis in adults often assumes a chronic course and requires prolonged treatment, children typically make a quick and full recovery.

Osteitis: general term for inflammation of the bone Osteomyelitis: infection of the bone marrowAcute form: develops within days or weeksChronic form: develops slowly (over months or years) and is associated with avascular bone necrosis and sequestrum formation (necrotic bone fragment that has become detached from the original bone) Epidemiology Hematogenous osteomyelitis: More common in children and adolescents (> 50% of cases occur in children ≤ 5 years)Vertebral osteomyelitis (a form of hematogenous osteomyelitis) occurs mainly in adults aged > 50 years Exogenous osteomyelitis: more common in adults Etiology Routes of infection Hematogenous osteomyelitis: most commonly due to a single pathogenHematogenous dissemination of pathogen Exogenous osteomyelitis: usually due to multiple pathogens Posttraumatic: infection following deep injury (penetrating injury, open fractures, severe soft tissue injury)Contiguous: spread of infection from adjacent tissueSecondary to infected foot ulcer in diabetic patientsIatrogenic (e.g., postoperative infection of a prosthetic joint implant) Risk factors LocalPoor tissue perfusion Open fracturesSevere soft tissue injury (poor tissue perfusion) SystemicImpaired immunocompetence (e.g., immunosuppression, HIV infection, neoplastic diseases) Systemic diseases (e.g., diabetes mellitus, atherosclerosis)IV drug use Microbial: highly virulent pathogens Staphylococcus aureusChildren and adultsStaphylococcus epidermidisDiabetic patients with foot ulcers and pressure ulcersPatients with prosthetics StreptococciDiabetic patients with foot ulcers and pressure ulcersNeonates and infantsPseudomonas aeruginosaIV drug usersPlantar puncture wounds (especially if wearing rubber-soled footwear) Enterobacteriaceae SalmonellaSickle cell anemia patientsKlebsiellaPatients with UTIs or a history of UT instrumentation Fungal pathogensImmunocompromised patients IV drug users Mycobacterium tuberculosisSee tuberculous spondylitis Acute osteomyelitis Onset: usually gradual, over several days Chief complaint: pain at the site of infection, possibly related to movement Possible localized findings: point tenderness, swelling, redness, warmth Possible systemic findings: malaise, fever, chills Common localization of hematogenous osteomyelitis: Infants: long bone metaphysis, jointsChildren: long bone metaphysis, joint infection very rareAdults: vertebral involvement is most common Chronic osteomyelitis Onset: usually following a prior episode of osteomyelitis; may last for months Chief complaint: recurrent pain Possible findingsSwelling, rednessLocal sinus tract formation, perhaps draining pus Vertebral osteomyelitis Definition: osteomyelitis of the vertebrae Pathophysiology: hematogenous seeding of a distant infectious focus → infection of the vertebral bone → contiguous spread to the intervertebral discs (and adjacent vertebrae) Discitis refers to the infection of the vertebral disc Classification according to the underlying pathogenPyogenic vertebral osteomyelitis> 50% of cases are caused by Staphylococcus aureus.Also Enterobacteriaceae, Pseudomonas, StreptococciTuberculous spondylitis (Pott disease): a coinfection with HIV is common Clinical features: often latent, nonspecific symptoms Chief complaint: back/neck painNot relieved with rest Worse with activity and at nightsTenderness over the spinous process of the affected vertebra (even on light touch)Possibly feverProtective posture, increased muscle tone → extension contracture DiagnosticsAssess patient for clinical features and history suggestive of vertebral osteomyelitisInitial work-up: see flowchart Blood culturesInflammatory markersX-ray imaging (anterior-posterior and lateral views) Often inconclusive in the first 2 weeks of infection Initial narrowing of intervertebral spaces and end plate sclerosisProgressive kyphosis, vertebral body squaring, and development of block vertebraContrast-enhanced MRI: the most sensitive diagnostic study for vertebral osteomyelitisFindings Disruption of vertebral structure, fusion of vertebral bodies and discs Contrast enhancement Gallium scan if MRI is contraindicated (metal foreign body implants) → detects sites of infection CT-guided needle aspiration biopsy (confirmatory test): culture and histologyRequired to confirm the diagnosisEnables appropriate antibiotic selection based on the culture results.Not recommended in patients with neurologic compromise or sepsis. TreatmentBed rest and immobilization of the affected vertebral segment; spinal orthosis required in severe casesAntibiotic treatment (IV administration, for weeks or months) Immediate empiric therapy if the patient presents with signs of neurologic compromise and/or sepsisPathogen-directed therapy once blood culture results are available (see "Treatment" below) Tuberculosis treatment: if mycobacterium tuberculosis is the underlying pathogenCT-guided catheter drainage of paravertebral abscessSurgery Indications: spinal instability, neurological deficits, cord compression, large epidural or paravertebral abscess, refractory osteomyelitis Debridement; stabilization of collapsed vertebrae/spinal instabilities with or without interbody fusion ComplicationsAbscess formationPsoas abscess : abscess formation in the psoas muscle, causing pain and swelling in this regionPrevertebral abscess formation in the cervical spine can be life threatening → risk of tracheal compression and airway obstruction Symptoms: neck pain, difficulty swallowing, difficulty breathing, and possible respiratory failureVertebral collapse and spinal instability → cord compression → paraplegia Diagnostics Clinical approach Suspect osteomyelitis in patients with focal symptoms (point tenderness) accompanied by nonspecific signs and symptoms of inflammation. Initial work-up includes blood cultures, inflammatory markers, and x-ray imaging. Rule out possible primary sources of infection and/or sites of dissemination (e.g., dental infection, furuncle, and urinary tract infections)! Laboratory tests Inflammatory markers↑ CRP, ↑ ESRPossible leukocytosis Blood cultures: microbiological testing Imaging X-ray: Early stages (< 2 weeks of symptoms onset): typically no pathological findingsLater stages: bone destruction, sequestrum formation, periosteal reactions MRI: the most sensitive diagnostic study; shows signs of inflammation ≤ 5 days after onset of infection → cortical destruction, bone marrow inflammation, soft tissue involvement Skeletal scintigraphy: visualizes areas of bone with increased bone turnover Radionuclide-labeled leukocyte scintigraphy: detects sites of infection or inflammation Sonography: assess soft tissue involvement Biopsy (confirmatory test) Bone biopsy: MRI/CT-guided needle or open biopsy + gram staining, culture, and histologyIndication: should be performed whenever feasible, before administering antibioticsDetects both osteonecrosis and the pathogen → confirms the diagnosis and helps guide more specific therapy Differential diagnoses Septic arthritisInfection of the joint; in contrast to osteomyelitis, involvement of the metaphysis is rareMay occur secondary to osteomyelitis in infants Bone tumors (e.g., Ewing sarcoma, osteoid osteoma) Avascular bone necrosis Benign bone tumors (e.g., bone cyst) Treatment Conservative Bed rest and immobilization of the affected extremity Antibiotic treatment 4-6 weeks Initial empiric antibiotic treatment In adultsIV Vancomycin PLUSAntipseudomonal cephalosporins (ceftazidime, cefepime) OR antipseudomonal fluoroquinolones (ciprofloxacin, levofloxacin) In children< 3 months of ageIV 3rd generation cephalosporin (cefotaxime) PLUS An antistaphylococcal agent (nafcillin, oxacillin)OR vancomycin or clindamycin if MRSA is likely > 3 months of ageIV Nafcillin/oxacillin OR cefazolinVancomycin OR clindamycin if MRSA is likely Pathogen-directed IV antibiotics (according to bone biopsy findings) Methicillin-susceptible S. aureus (MSSA)IV Nafcillin/oxacillin, OR 1st or 2nd generation cephalosporin (cefazolin, cefuroxime)MRSA or S. epidermidisIV VancomycinGram-negative pathogens (including Pseudomonas)Antipseudomonal cephalosporins (ceftazidime, cefepime) OR antipseudomonal fluoroquinolones (ciprofloxacin, levofloxacin Secondary osteomyelitis (e.g., prosthetic joints or foreign bodies)Rifampicin in addition to the antibiotic regimen Surgical IndicationOsteomyelitis refractory to antibiotic treatment → debridement of necrotic bone and tissue Abscess → drainage Post-traumatic osteomyelitis → debridement and fracture management (e.g., external fixator) Infected prosthetic joint or foreign body → removal Revascularization in case of poor wound healing due to Peripheral artery disease Complications InfectiousAbscessSequestrumPyarthrosis: infiltration of nearby joints MechanicalProgressive destructionPathological fractures and complications → pseudarthrosis, abnormal bone healing Course: recurring/chronic cases In children: growth impairment Prognosis Acute osteomyelitisQuick, full recovery is common in children receiving appropriate antimicrobial treatment → > 95% of cases resolve completely. Acute osteomyelitis in adults often relapses and transforms into chronic osteomyelitis. Chronic osteomyelitisDifficult to cure, often requires repeated surgical and antibiotic treatment (over years to decades) In patients with diabetes or vascular insufficiency, the probability of complete resolution is particularly low.

Sinusitis Sinusitis is an inflammation of the mucous membrane of the paranasal sinuses. It rarely occurs without concurrent inflammation of the nasal mucosa (rhinitis) and is therefore commonly referred to as rhinosinusitis. Sinusitis affects about one in eight adults in the United States, resulting in about 30 million diagnoses annually. While the etiology is typically viral, it may also be bacterial or fungal (especially in immunocompromised patients). The condition is usually self-limiting, but if it lasts longer than 12 weeks it is considered chronic. The primary symptoms are purulent rhinorrhea and facial pain (particularly when leaning forward). Antibiotic therapy is only indicated if a bacterial superinfection is suspected. Imaging and endoscopy is reserved for cases that persist or worsen despite initial antibiotic therapy. Local extension of the disease may occur in cases that are complicated or that have not received adequate treatment, potentially resulting in frontal bone osteomyelitis, meningitis, or brain abscess.

Pansinusitis: inflammation of all sinuses on one or both sides Acute sinusitis: inflammation of the sinuses for < 4 weeks Subacute sinusitis: progressive symptoms of sinus inflammation occuring over 4-12 weeks; represents a transition from acute to chronic infection Chronic sinusitis: persistent symptoms of sinus inflammation > 12 weeks Recurrent acute sinusitis: four or more separate episodes of acute sinusitis that occur within 1 year, with at least 8 weeks of symptom resolution between episodes Rhinosinusitis: simultaneous inflammation of the nasal mucosa and sinuses Epidemiology Sinusitis is one of the most commonly diagnosed conditions in the USA, affecting an estimated 35 million individuals per year. Peak incidence: early fall to early spring Sex: ♀ > ♂ Etiology PathogensViral (most common): rhinovirus, coronavirus, adenovirus, influenza, and parainfluenza virusesBacterial: particularly S. pneumoniae, H. influenzae, M. catarrhalis, S. aureus, E. coli, and Klebsiella. Fungal: Aspergillus, Rhizopus oryzae Route of transmission: droplet transmission, particularly in winter months Risk factorsPreexisting viral upper respiratory tract infection (URTI): most commonVentilation disorders of the sinuses Hypertrophy of nasal turbinates, nasal polyps, deviation of nasal septumImpairments of ciliary function such as cystic fibrosis, primary ciliary dyskinesia, Wegener granulomatosis, allergic inflammation , and immunodeficiencyConcha bullosa (also known as a middle turbinate pneumatization) Foreign body lodged in the nasal cavity (particularly seen in children).Odontogenic infection: leads to unilateral maxillary sinusitisRhinitis: spread of pathogens via nasal mucosaBronchial asthmaAnalgesic (NSAIDs, aspirin) intolerance Pathophysiology Sinusitis is triggered by three factors: obstruction of sinus drainage pathways (sinus ostia), ciliary impairment, and altered mucus quantity and quality → stasis of secretions inside the sinuses → proliferation of various pathogens → sinusitis Recurrent, untreated/complicated acute sinusitis may lead to chronic sinusitis. Clinical Features acute sinusitis Fever (∼ 50% of cases), headaches, general malaise, myalgia Facial pain or pressure, erythema, and swelling over the affected area due to inflammation Maxillary sinuses: over the cheeks (mimics dental pain) Frontal sinuses: lower foreheadEthmoidal sinuses: nasal bridge and/or between the eyes or retro-orbital pain Sphenoid sinuses: located in the sphenoid bones near the optic nerve and pituitary gland. These are the most posterior sinuses. Transillumination may show opacification. Rhinitis Sneezing, nasal congestion, rhinorrhea, and post-nasal drip Hyposmia/anosmia Acute viral rhinosinusitis Occasionally, acute otitis media (earache) Other manifestations of URTI such as pharyngitis (sore throat, cough) Acute bacterial rhinosinusitis Persistent symptoms ≥ 10 days without clinical improvement OR ≥ 3 initial days of severe symptoms, fever (> 39°), facial pain, or purulent nasal discharge OR Symptoms initially improve and then worsen after 5-6 days(double worsening) Fungal rhinosinusitis Non-invasiveAllergic fungal: features of asthma and other atopicmanifestationsFungal mycetoma: unilateral complaints; usually involves the maxillary sinus Invasive Acute fulminant rhino-orbital-cerebral mucormycosis: epistaxis and dark ulcers on the septum, palate and turbinates; acutely ill with altered mental status Chronic rhinosinusitisMay present acutely without improvement of symptoms or insidiously over months to years≥ 2 of the following: Mucopurulent drainage (anterior, posterior, or both)Nasal congestionFacial painAnosmia or hyposmiaAND inflammation as suggested by: Purulent mucus or edema in the middle meatus/anterior ethmoidal area during anterior rhinoscopyPolyps in the nasal cavity/middle meatusImaging showing inflammation of the paranasal sinuses (see "Diagnostics" below) Allergic fungal: See "Fungal rhinosinusitis" above. Chronic rhinosinusitis with nasal polyps: See nasal polyps. Chronic rhinosinusitis without nasal polyps: anatomical abnormalities (septal deviation, tumors), dental disease Acute bacterial rhinosinusitis should be suspected in patients with a pre-existing viral URTI and symptoms that do not improve after 10 days or worsen after initial improvement! Subtypes and variants Nasal polyps Definition: benign lesions of the nasal mucosa or paranasal sinuses due to chronic mucosal inflammation Risk factorsChronic rhinosinusitisCystic fibrosis (CF)Aspirin exacerbated respiratory disease (AERD; aspirin or NSAID induced): triad of asthma, chronic sinusitis with polyps, and bronchospasm . Clinical featuresPostnasal dripBilateral nasal obstructionFrequently impaired olfactory function (from hyposmia to anosmia)Fever and severe facial pain are uncommon. Special form: choanal polyp Definition: isolated, soft nasal polyp that originates in the mucous membrane of the maxillary sinus (rarely in ethmoidal cells) and grows from the middle nasal meatus into the nasopharynxClinical features: nasal obstruction or features of sinusitisTreatment: complete endoscopic excision Differential diagnosis: nasal papilloma DiagnosisNasal cytology for eosinophiliaEvaluate for associated conditions (e.g., sweat chloride test for CF)Nasal endoscopy: bilateral grey polypoid mucosa hypertrophy CT: determines the exact location and extent of polyps; also useful to exclude other causes of nasal obstruction TreatmentTopical or systemic glucocorticoidsResection of polyps if symptomatic despite medical therapy but recurrence is common Primary ciliary dyskinesia Definition: rare autosomal recessive disorder characterized by absent or dysmotile cilia caused by a defect in the dynein arm of microtubules Clinical featuresChronic productive coughRecurrent otitis, sinusitis, and nasal polypsBronchiectasisConductive hearing lossDisplaced heart sounds better heard on the rightInfertility in men due to decreased sperm motility as a result of defective flagellaReduced fertility in women (and rarely ectopic pregnancy) due to defective cilia in fallopian tubesKartagener syndrome: classic triad of situs inversus, recurrent sinusitis, and bronchiectasis DiagnosisNasal nitric oxide test: reduced nasal nitric oxide (screening test)Genetic tests for dynein arm mutationsChest x-ray: bronchiectasis, dextrocardia, and situs inversus (suggests Kartagener syndrome) Electron microscopy: abnormal cilia Treatment: depends on individual clinical presentation and course Kartagener syndrome is a subtype of primary ciliary dyskinesia characterized by the triad of situs inversus, chronic sinusitis, and bronchiectasis! Diagnostics Diagnosis of acute cases is usually established clinically. However, imaging or endoscopy should be considered if symptoms fail to improve within 7 days of diagnosis or worsen during the initial management of acute bacterial rhinosinusitis. Laboratory tests: to determine underlying condition if suspected (e.g., nasal cytology allergic rhinitis, HIV test, sweat chloride test for cystic fibrosis) Imaging X-ray of sinuses (poor sensitivity): decreased transparency of sinus, air-fluid levels may be seen CT of sinuses (imaging modality of choice) Soft tissue swelling, mucoperiosteal thickening, and air-fluid levelsBony erosions and extension in cases of invasive mucormycosis infectionFungus balls in the case of chronic aspergillosis infectionMRI may be considered to confirm soft tissue extension in invasive disease. Nasal endoscopy Mucosal erythema and edema, with sinus ostia and nasal passages blocked by dischargeNecrotic mucosa in the case of invasive mucormycosis infectionBiopsy and culture may be performed (hyphae in fungal disease, eosinophils in allergic sinusitis). A clinical diagnosis of chronic sinusitis should be confirmed with objective documentation of sinonasal inflammation, which may be accomplished using anterior rhinoscopy, nasal endoscopy, or computed tomography! Treatment Viral infection Uncomplicated viral sinusitis is usually self-limiting. Topical, intranasal steroids (fluticasone, beclomethasone) Nasal, saline lavage Decongestive nose drops to relieve pain and blockage (e.g., oxymetazoline) In the case of confounding allergyAntihistamines (loratadine, fexofenadine, chlorpheniramine)Avoid exposure to irritants: cigarette smoke, dust, molds, and chemical irritants Bacterial infection Acute First-line antibiotic therapy: amoxicillin, with or without clavulanate for 5-10 days Alternative for adult patients with penicillin allergy: doxycycline, levofloxacin or moxifloxacinSecond-line antibiotic therapy is indicated in patients who fail to respond within 72 hours, have persistent symptoms beyond 10-14 days, or may be exposed to highly resistant organisms: levofloxacin, moxifloxacin, or clindamycinIntranasal corticosteroids may be used as an adjunct in patients with a history of allergic rhinitis.The use of intranasal or oral decongestants/antihistamines is not recommended. Chronic Broad-spectrum aminopenicillin+ beta-lactamase inhibitor (drug of choice) Alternatively: second generation cephalosporin, e.g., cefuroxime Underlying conditions should be treated (e.g., asthma, cystic fibrosis, immunocompromised state, ciliary dyskinesia, anatomical obstructions) Fungal infection Surgical debridement of necrotic tissue and removal of anatomical obstructions (e.g., mycetoma or allergic mucin and debris) Antifungal therapy (amphotericin B) Treatment of immunocompromising condition Complications Local spreadMucoceles Osteomyelitis, especially of the frontal bone (also known as Pott's puffy tumor): subperiosteal abscess with local pain and edemathat requires antibiotic treatment and surgery Spread to the orbitPreseptal/orbital cellulitis Orbital abscessCavernous sinus thrombosis Intracranial spreadSubdural abscess: most commonMeningitisBrain abscess Systemic complicationsBacteremia/sepsisPneumoniaMultiple organ failureUntreated chronic sinusitis can lead to life-threatening complications, as may be seen in patients with cystic fibrosis. Orbital and intracranial necrotic spread is especially common in invasive fungal sinusitis!

Vaccination

Passive immunization Mechanism of actionPreformed antibodies are injected and provide protection against a specific pathogen.Antibodies degrade and titers decrease over time → only temporary protection IndicationAcute, post-exposure elimination of a pathogenCommonly performed for rubella virus, rabies virus, hepatitis B virus, zoster virus, tetanus toxin, botulinum toxin, and to prevent rhesus incompatibility Application: Vaccines are available for intramuscular as well as for intravenous injection. CombinationSimultaneous vaccination: ≥ 1 vaccine administered on the same day, but in different syringes and at different anatomical locations Two different passive vaccines may be administered simultaneously.An inactivated active and a passive vaccine may be administered simultaneously (e.g., in acute hepatitis A, hepatitis B, rabies, or tetanusinfection).After administration of a passive vaccine against a specific pathogen, a live vaccine against the same pathogen should not be administered for at least 3 months. To Be Healed Rapidly: Passive vaccination (preformed antibodies) after exposure to Tetanus, Botulinum, Hepatitis B and Rabies in unvaccinated individuals. Active immunization General informationIn active immunity, the body's immune system reacts to the presence of antigens by producing antibodies.In general, a combination of different active vaccinations is possible.Immunity usually lasts for years or even a lifetime. Classification:Live attenuated vaccinesInactivated vaccinesWhole vaccinesFractional vaccinesProtein-basedPolysaccharide-based Current vaccination recommendations for the US can be found in the immunization schedule.

Aspergillosis Aspergillosis is the collective term for diseases caused by mold species in the genus Aspergillus. Aspergillus spores are ubiquitous but do not usually cause infection in immunocompetent individuals. Risk factors for Aspergillus infection include immunosuppression (e.g., HIV, hematologic malignancies, transplant recipients) and underlying pulmonary conditions (e.g., cavernous tuberculosis, COPD). Infections may be localized, causing asymptomatic pulmonary aspergilloma, or symptomatic, complicated infiltrates (e.g., with cavitation, fibrosis, or necrosis). In immunocompromised patients, invasive aspergillosis is common, which manifests as severe pneumonia and septicemia with potential involvement of other organs. In patients with pre-existingbronchopulmonary conditions (e.g., asthma, cystic fibrosis), Aspergillus may cause allergic bronchopulmonary aspergillosis (ABPA), which presents with asthmatic symptoms or sinusitis. Elevated serum IgE levels and eosinophilia indicate a fungal infection. Tissue biopsy followed by histopathology and culture are used to confirm the diagnosis. Medical treatment for aspergillosis infection includes voriconazole, caspofungin, or amphotericin B. An aspergilloma, on the other hand, must be surgically removed. ABPA is primarily managed with glucocorticoid therapy. Immunocompromised patients should receive prophylactic posaconazole.

PathogenAspergillus, a genus including over 200 speciesMost common: Aspergillus fumigatus , Aspergillus flavus Transmission: airborne exposure to mold sporesAspergillus spores are ubiquitous indoors, as they enter with the normal flow of air.The spores can also settle on easily accessible sources of nutrition (e.g., water), dust, cellulose (e.g., in wallpaper), and indoor plants Aspergillus spores may also be found in intensive care units Risk factorsDestructive pulmonary pathology → Chronic pulmonary aspergillosisScar tissue or lung cavities (e.g., from tuberculosis) COPD, emphysemaSevere immunosuppression (e.g., HIV, neutropenia) → invasive aspergillosisPre-existing bronchopulmonary conditions (e.g., asthma or cystic fibrosis) → ABPA Allergic bronchopulmonary aspergillosis (ABPA) Chronic exposure to Aspergillus can lead to allergic bronchopulmonary aspergillosis (ABPA) LungsAsthmatic symptoms (e.g., shortness of breath, wheezing)Productive cough with brown bronchial mucous casts Sinusitis without tissue infiltrationFungus ball in the paranasal sinuses with symptoms of chronic rhinosinusitisMay progress in immunocompromised patients (see invasive aspergillosis) Nonspecific symptoms: weight loss, chronic fatigue; irritation of the skin, mucus membranes, and eyes Chronic pulmonary aspergillosis Possible clinical manifestationsAspergilloma: opportunistic infection of a pre-existing cavitary lesion (e.g. from previous tuberculosis)Aspergillus nodule Cavitary pulmonary aspergillosisChronic necrotizing pulmonary aspergillosisSubacute and semi-invasive form of chronic pulmonary aspergillosis characterized by localized, slowly progressive, inflammatory destruction of lung tissue. Clinical featuresPossibly asymptomatic (may be an incidental finding on chest x-ray)Weight loss, fatigueCough, hemoptysis, shortness of breathRecurrent pneumonia caused by superinfectionsSigns of an underlying lung pathology (e.g., digital clubbing in tuberculosis) Invasive aspergillosis Lungs: pulmonary aspergillosisMost common form of invasive aspergillosisDry cough; in severe cases, hemoptysis, fever, pleuritic chest pain, septic shockFrequently occurs in conjunction with bacterial superinfections Mucous membranes in sinusesAspergillus sinusitis with invasion of the surrounding tissueInvasion into the orbit → reduction of visual acuity, painful exophthalmos, chemosisInvasion into the skull → CNS involvement, venous sinus thrombosis Disseminated infection Invasive aspergillosis mostly infects the bronchioles of the lungs, but can also manifest as a disseminated infection (e.g., in skeletal, cutaneous, or neurological tissue)! Diagnostics ABPA History of asthma or cystic fibrosis Positive Aspergillus antigen skin test OR ↑ IgE levels Laboratory tests: ↑ ESR and eosinophilia Tissue biopsy followed by histopathology and culture → Positive findings (e.g. presence of monomorphic, septate hyphae that branch at acute angles, as seen on silver or PAS stained samples) confirm the diagnosis of aspergillosis infection. X-ray and CT: parenchymal opacities; features of bronchiectasis Chronic pulmonary aspergillosis AspergillomaX-ray and CTMonad sign: a peripheral air crescent around a fungus ball in a pre-existing lung cavityRadiological evidence of a mobile fungus ballThe mobility of the fungus ball is demonstrated by moving the patient from a supine position to a prone or lateral recumbent position.The upper lobe is mostly affected because of the increased concentration of oxygenLaboratory tests: positive sputum culture or positive Aspergillus IgG serology Aspergillus noduleX-ray and CT: multiple nodulesLaboratory tests: positive biopsy result or positive Aspergillus IgG serology Cavitary pulmonary aspergillosisX-ray and CT: one or more cavities with or without aspergillomaLaboratory tests: positive Aspergillus IgG serology Invasive aspergillosis Initial work-upChest CTMultiple nodulesHalo sign: hemorrhagic ground glass opacities around nodulesSickle-shaped air crescents around the fungal colonySerum assaysPositive galactomannan antigen test Positive 1,3-β-D glucan test If CNS infection is suspected: cranial MRI Confirmatory test: positive culture and/or histopathological evidence of invasive aspergillosisSpecimen collectionBronchoalveolar lavage via bronchoscopy In patients with peripheral nodular lesions on imaging: endobronchial lung biopsy via bronchoscopy or CT-guided percutaneous biopsy FindingsPAS or Gomori methenamine silver stain: septate hyphae branching dichotomously at 45° Positive Galactomannan antigen test Differential diagnoses Aspergillosis Pathogen: Aspergillus species Aspergillus fumigatusAspergillus flavus Risk factors: chronic granulomatous infection ABPA: associated asthma or CF; causes bronchiectasis and eosinophilia Pulmonary aspergilloma(especially after Tb infection): chronic cough, hemoptysis Invasive aspergillosis: fever, cough, respiratory distress Endocarditis ABPA: eosinophilia, ↑ IgE, pulmonary infiltrates on chest x-ray or CT Pulmonary aspergilloma: x-rayor CT shows mobile fungus ball; serologyis positive for Aspergillus IgG Invasive aspergillosis: silver/PAS-stainingon tissue biopsy: 45° angle branching septate hyphae with fruiting bodies ABPA: oral prednisone if severe; itraconazole if recurrent Pulmonary aspergilloma: lobectomy for massive hemoptysis Invasive aspergillosis: IV voriconazole Coccidioidomycosis(Valley fever)Pathogen: Coccidioides immitisRisk factors: travel to SouthwesternUnited States, California Often asymptomaticAcute pneumonia: fever, chest pain, cough, arthralgia, dyspnea, and night sweatsCan disseminate → extrapulmonary: CNS (e.g., meningitis), skin (e.g., erythema nodosum or erythema multiforme), and bonesSerology: increased IgM ; increased IgG at 1-3 monthsKOH staining on smears: dimorphic fungus and spherules filled with endospores Confirmatory: cultureIV Amphotericin B(severe infection)Alternative: itraconazole ParacoccidioidomycosisPathogen: Paracoccidioidesspecies Paracoccidioides brasiliensisRisk factors: travel to South and Central AmericaInfected patients often asymptomaticAcute pneumoniaPainful nasal, pharyngeal, and laryngeal mucosal ulcerationsLymphadenopathy(usually cervical)Can disseminate → extrapulmonary manifestations (including verrucousskin lesions)KOH staining on smears : budding yeast with "captain's wheel" appearance Cultures have a low sensitivityItraconazoleSevere or refractory cases: amphotericin B BlastomycosisPathogen: Blastomyces dermatitidisRisk factors: travel to East states of Mississipi River andCentral America Infected patients often asymptomaticPneumonia with flulike symptoms Can disseminate → extrapulmonary manifestations (verrucous skin lesions, lytic bone lesions, genitourinary involvement , CNS lesions )KOH staining on smears : broad-baseddimorphic fungus Confirmatory: cultureLocal infection: fluconazole and itraconazoleSystemic infection: IV amphotericin B HistoplasmosisPathogen: Histoplasma capsulatumRisk factors: AIDS, exposure to bird or bat droppingsespecially in Mississippi and Ohio river valleys Infected patients often asymptomaticAcute pneumoniaCan disseminate → extrapulmonary manifestationsBest initial: positive urine and serum polysaccharideantigen testSilver/PAS-stainingon bronchoalveolar lavage or biopsy: macrophages filled with Histoplasma(dimorphic funguswith septate hyphae) Confirmatory: culture Mild disease: supportive therapyChronic cavitation: oral itraconazole > 1 yearSevere pulmonary or disseminated disease: amphotericin B/liposomal then itraconazole CryptococcosisPathogen: Cryptococcus neoformansRisk factors: AIDS, exposure to pigeon droppingsInfected patients often asymptomaticIsolated pneumoniais possibleExtrapulmonary: cryptococcalmeningoencephalitisor brain abscess: headache, fever, signs of increased intracranial pressure, confusion, absent meningeal signsLP India ink stain: positive cryptococcalantigen (also in blood) Fungal culture: ∼10 μm yeastwith thick polysaccharidecapsule and narrow, unequal budding IV amphotericin B and flucytosine followed by oral fluconazoleMaintenance therapy: fluconazole (until symptoms resolve and CD4 > 100/mm3 for at least 1 year)Serial therapeutic LPs for ↑ intracranial pressure CandidiasisPathogen: CandidaalbicansRisk factors: antibiotics, ↑ estrogen during pregnancy, entry point (e.g., wound)Pulmonary involvement in severe immunosuppressionExtrapulmonary:Oral and esophageal thrushVulvovaginitisSkin infectionDisseminated disease: sepsis, meningitis, multiple abscesses, endocarditisKOH staining on scrapings or smears: budding yeasts, hyphae, and pseudohyphae Confirmatory: culture (blood or tissue)Vaginal (uncomplicated): topical azoleOral: nystatin; if refractory oral fluconazoleEsophagitis: oral fluconazole, caspofunginSuperficial skin candidiasis: topical antifungalsSystemic: fluconazole, caspofungin, or amphotericin B Pneumocystis pneumoniaPathogen: P. jirovecii(previously P. carinii) Risk factors: AIDS(especially if CD4count < 200/μl)Pneumocystis pneumonia (PCP): fever, exertional dyspnea, nonproductive cough, weight loss, impaired oxygenationChest x-ray or CT: Diffuse, bilateral ground-glass opacitiesSilver stain and immunofluorescence on bronchoalveolar lavage (or lungbiopsy if sputum is negative): disc shaped-yeasts Cannot be culturedHigh-dose TMP-SMX(treatment and prophylaxis) or clindamycin + primaquinePrednisone (moderate to severe hypoxemia)Prophylaxis: CD4< 200 cells/mm3 Treatment ABPA Avoid aspergillus exposure Glucocorticoids Consider adding itraconazole In addition, in the presence of sinusitis: Endoscopic drainageSurgical resection of nasal polyps Pulmonary aspergillosis Asymptomatic patients without disease progression do not require treatment, but regular follow-up with imaging and Aspergillosis antibody titer tests are nonetheless absolutely necessary. AspergillomaDefinitive treatment: surgical resection (e.g., lobectomy) of the aspergilloma Antifungals (e.g., oral itraconazole or voriconazole) should be used preoperatively and postoperatively Aspergillus nodule: antimycotic treatment Invasive aspergillosis Treatment of choice: IV voriconazoleAlternatives If voriconazole monotherapy fails: consider combining with caspofunginIf voriconazole is not tolerated: IV amphotericin B or IV isavuconazole, followed by oral itraconazoleSecond-line treatment: IV caspofungin oral posaconazole HIV-infected patients: HIV antiretroviral therapy should be initiated as soon as possible or adjusted after consulting an HIV specialist Protective measures: to improve the immune status of the patient

Echinococcosis Human echinococcosis, also known as hydatidosis or hydatid disease, is a parasitic disease caused by small tapeworms of the genus Echinococcus. The two most common forms of hydatidosis are cystic echinococcosis (CE), caused by E. granulosus, and alveolar echinococcosis (AE), caused by E. multilocularis. Infection occurs by ingesting Echinococcus eggs, most commonly via hand-to-mouthtransmission or through food, water, or soil contaminated with feces. Following a long incubation period, infection with E. granulosustypically results in the formation of a single liver cyst (hydatid cyst), which may be asymptomatic or cause upper abdominal pain and other GI complaints. In contrast, infection with E. multilocularis resembles a hepatic malignancy that invades and destroys the surrounding tissue, which can lead to complications such as portal hypertension, cholangitis, jaundice, and even cirrhosis. Other extrahepatic manifestations may also occur as a result of metastasis to distant sites. Because of its malignant nature, AE is more difficult to treat and has a much higher mortality rate than CE. Treatment for both diseases consists of antihelminthic agents (e.g., albendazole or mebendazole), often in combination with surgical intervention

Pathogens: Echinococcus tapewormsEchinococcus granulosus causes CEEchinococcus multilocularis causes AE TransmissionHand-to-mouthFrom the fur of definitive hosts (e.g., petting a dog or cat) Contaminated dirt (e.g., dog feces)Fecal-contaminated food or water (e.g., wild berries, mushrooms) Life cycle Definitive hosts: foxes, dogs, and cats Intermediate hosts: hoofed animals (e.g., sheep, goats, camels, horses, cattle, and pigs) Humans are accidental hosts (e.g., sheep farmers) The definitive host consumes hydatid cysts from an intermediate host → adult tapeworms develop and inhabit the small intestine → tapeworms produce eggs that are shed through stool, contaminating the ground → eggs are ingested by intermediate hosts → eggs hatch within the intestine and penetrate the intestinal wall → travel through the bloodstream and lymphatic system → liver or other organs → hydatid cysts Cystic echinococcosis Up to 50 years Single hepatic cyst (hydatid cyst) Hepatomegaly → RUQ pain Malaise, nausea, vomiting Lung involvement in 25% of cases → chest pain, cough, dyspnea, hemoptysis Involvement of other organs is rare Alveolar echinococcosis Hepatic cystHepatomegaly → RUQ painMalaise, weight loss, nausea, vomiting Cyst that invades and destroys the liver and surrounding tissue Portal hypertension, cholestatic jaundice, cholangitisBudd-Chiari syndromeLiver cirrhosisMay resemble hepatocellular carcinoma Primary involvement of other organs is very rare (< 1% of cases) Metastasis to other organs (especially lungs, brain, spleen) in ∼ 13% of cases Diagnostics Suspected echinococcosis is generally confirmed via ELISA and ultrasonography. Laboratory tests (nonspecific; low diagnostic value): mild eosinophilia, leukopenia or thrombocytopenia, liver function abnormalities Serology: positive ELISAFalse negatives are common. ImagingUltrasonographyCystic echinococcosis: unilocular, anechoic, smooth, well-defined hepatic cyst with or without daughter cystsPossibly daughter cysts and hyperdense internal septa Eggshell calcifications within the cyst wall may be visible Alveolar echinococcosis: lesions with irregular, poorly defined margins, central necrosis, and irregular calcifications within the cyst and cyst wall CT scan: indicated for further evaluation of cysts Alveolar echinococcosis usually not well-defined, but shows infiltration of the liver and surrounding tissueBest test for evaluating extrahepatic cysts Cystic echinococcosis Observation: inactive cyst with heterogeneous hypoechoic/hyperechoic contents, or solid, calcified wall Medical therapy: may be considered as the sole treatment for cysts < 5 cmDrug of choice: albendazole Alternative drugs: mebendazole, praziquantel Ultrasonography/CT-guided percutaneous drainageShould only be done in combination with medical therapy (albendazole) SurgeryGoal: resect the whole cyst to prevent spillage of its content Indications: > 10 cm, complicated cysts Follow-up: Because relapse is common, patients should be closely monitored via imaging for up to five years. Any invasive procedure (drainage or surgery) of hydatid cysts should be performed with the utmost care to prevent spillageof cyst contents, which could cause life-threatening anaphylactic shock and/or secondary seeding of infection! Alveolar echinococcosis Curative resection followed by at least 2 years of treatment with albendazole to prevent a potential relapse Palliative care if surgery is not possible or unsuccessful: see "Medical therapy" above Follow-up for at least 10 years Prognosis Cystic echinococcosis: the long-term outcome depends on organ manifestation Alveolar echinococcosis: 90% of patients die within 10 years if left untreated. However, patients who receive treatment have a life expectancy only 2-3 years lower than the general population.

Lice infestation There are three species of lice that affect humans: Pediculus humanus capitis (head louse), Pediculus humanus corporis (body louse), and Pthirus pubis (pubic or crab louse). All are obligate, stationary ectoparasites that feed solely on human blood. Affected individuals most commonly present with pruritus; although early stages of infestation and mild cases may be asymptomatic. Detection of lice or nits (louse eggs) on the body or clothes usually confirms the diagnosis. Treatment includes topical pediculicides as well as nonpharmacologic measures (e.g., machine washing and drying contaminated clothing/sheets). Secondary skin infections from scratching may occur in all forms of pediculosis (lice infestation). The body louse acts as a vector for louse-borne diseases, including epidemic typhus, trench fever, and relapsing fever.

Pediculosis capitis (head lice infestation) Parasite: Pediculus humanus capitis (∼ 3 mm in length) Transmission: direct head-to-head contact or sharing hair accessories, bedding, or clothing Epidemiology: most common in children (affects 1% of school-aged children in North America) Clinical features: may be asymptomatic initially and in mild cases; scalp/neck pruritus DiagnosisDetection of nymphs and adult lice on the scalp or hair (often visible with the naked eye)Confirmation with microscopy of a hair shaft or Wood's lamp examination (nits fluoresce and appear pale blue) Treatment10-minute topical application of pediculicides followed by mechanical removal with a fine-toothed comb (repeat application after 10 days) First-line: 1% permethrin shampoo or pyrethrinAlternative therapies (i.e., in permethrin resistant areas): malathion shampoo, topical ivermectin, benzyl alcohol, and spinosadClean combs, hair brushes, and hair accessories of lice and nits (i.e., soak in hot water for 5-10 minutes)Machine wash and dry bedding, clothes, etc. (≥ 55°C (≥ 131°F) for 30 minutes.); alternatively, dry clean or store in a sealed plastic bag for 2 weeks.Children with head lice should receive prompt treatment but can continue attending school.People in close contact with affected individuals should be screened for infestation. Complications: secondary skin infections from scratching and skin break-down The presence of nits alone does not indicate active infestation! Pediculosis corporis (body lice infestation) Parasite: Pediculus humanus corporis (∼ 3-5 mm in length) Transmission: direct head-to-head contact or sharing hair accessories, bedding, or clothing Epidemiology: most common in people living in crowded, unsanitary living conditions (e.g., homeless) Clinical features: pruritus is the chief complaint; puncta from fresh bites, linear excoriations, and postinflammatory hyperpigmentation (typically at the waist, neck, and axilla) Diagnosis: detection of lice or nits in clothing (especially at the seams) with the naked eye, on microscopy, or Wood's lamp examination TreatmentWarm bathing and changing into new clothesTopical pediculicides when nits are detected on body hair (e.g., permethrin)Machine wash and dry bedding, clothes, etc. (≥ 55°C (≥ 131°F) for 30 minutes); alternatively, dry clean or store in a sealed plastic bag for 2 weeks. ComplicationsSecondary skin infectionsEpidemic typhus, trench fever, and relapsing fever Pediculosis pubis (pubic lice infestation) Parasite: Pthirus pubis (also known as the crab louse; often referred to as "crabs" because of its crab-like appearance; ∼ 1.5 mm in length Transmission: usually sexual contact (can also be transmitted via infested towels or bedding) Epidemiology: most common in teenagers and young adults Clinical featuresPruritus in the pubic area is common; can also occur in the perianal and axillary region.Maculae ceruleae (pale blue-purple macules ) in patients with chronic infection Diagnosis: identification of louse or nits in pubic hair with the naked eye, during microscopy, or Wood's lamp examination Treatment10-minute topical application of pediculicides (e.g., 1% permethrin cream or pyrethrin); reevaluate after 9-10 days, and repeat treatment if lice are found)Machine wash and dry bedding, clothes, etc. (≥ 55°C (≥ 131°F) for 30 minutes); alternatively, dry clean or store in a sealed plastic bag for 2 weeks.Screen for other STIs and treat sexual partners to prevent reinfection Louse-borne diseases Trench fever (five-day fever) [5] Definition: a type of louse-borne relapsing fever caused by Bartonella quintana Etiology: Bartonella quintanaTransmission: feces of infected body louse (vector) Epidemiology: most commonly affects people who are at risk of body louse infestation (e.g., homeless) Clinical featuresRecurrent fever episodes that last ∼ 5 daysNonspecific, flu-like symptoms (malaise, headache, nausea, vomiting)Bone pain, splenomegaly, and maculopapular rash of the trunk may occur Diagnosis: isolation of Bartonella confirms the diagnosis Bartonella is difficult to grow on cultureSerology testing or PCR are often necessary Treatment: doxycycline and gentamicin Epidemic typhus Definition: an exanthematous typhus fever caused by Rickettsia prowazekii Etiology: Rickettsia prowazekiiTransmission: feces of infected body louse (vector) Epidemiology: extremely rare in the US; occurs in Rwanda, Ethiopia, Asia, and rural parts of South America [6] Clinical features [6]Abrupt onset of fever, severe headache, malaise, myalgia, abdominal pain, and nauseaAfter 4-5 days: maculopapular or petechial rash that spreads from the trunk to the extremities DiagnosisSerologyPositive Weil-Felix reaction Treatment: doxycycline or chloramphenicol Louse-borne relapsing fever Definition: a louse-borne infection caused by Borrelia recurrentis (not to be confused with tick-borne relapsing fever) Etiology: Borrelia recurrentis Epidemiology: most common in areas affected by overcrowding, war, refugee camps Clinical featuresRecurring episodes of high fever (39-43°C) lasting 3-6 days followed by an afebrile period of 7 daysOther symptoms include headache, arthralgia, nausea, confusion, macular rash DiagnosticsConfirmatory test: detection of Borrelia recurrentis in peripheral blood smear, bone marrow, or CSF with Wright or Giemsa stainCulture is difficultLaboratory studies: normocytic anemia, thrombocytopenia , ↑ ESR TreatmentDoxycycline or ceftriaxoneChildren and pregnant woman: amoxicillin and cefuroxime [7]

Antivirals against both hepatitis B and C

Pegylated interferon-αand interferon-α Antiviral and immunomodulatory effect via intercellular and intracellular mechanisms : inhibits viral protein synthesis, promotes the breakdown of viral RNA, and induces the increased expression of MHC class I molecules Flu-like symptoms Bone marrow suppression CNS Depressive mood Seizures Induction of autoantibodies Myopathy Monotherapy in acute hepatitis C and chronic active hepatitis B As a combination treatment in chronic hepatitis C Contraindications Decompensated cirrhosis, Psychiatric conditions, Pregnancy, Autoimmune conditions, Leukopenia or thrombocytopenia

Chickenpox Chickenpox (varicella) is a primary infection caused by the varicella-zoster virus (VZV) that occurs most frequently during childhood. The disease is highly contagious, with transmission taking place via airborne droplets or, less frequently, through direct skin contact with vesicle fluid. Chickenpox occurs only once, as VZV antibodies persist for life. In addition to fever, patients present with a highly pruritic rash covering the entire body (including the scalp). The rash is characterized by macules that rapidly develop into papules and then vesicles with an erythematous base before forming crusts. The simultaneous manifestation of the exanthem's different stages is a hallmark of the disease. In immunocompetent individuals, chickenpox resolves after about six days. Clinical diagnosis is made on the basis of the characteristic rash, although further tests may be necessary in atypical or complicated cases. Chickenpox is usually a self-limiting disease and only requires symptomatic treatment, which includes topical agents for pruritus. Antiviral therapy (e.g., acyclovir) may be indicated in high-risk groups in which a severe course is expected (e.g., adults and immunosuppressed patients). Complications are more common in high-risk groups and during pregnancy. Congenital chickenpox syndrome can lead to malformations with potentially fatal consequences. As a result of VZV persistance in ganglion cells, reactivation of the virus may occur when the immune system is compromised, presenting as shingles(herpes zoster). Routine vaccination against chickenpox is generally recommended. The first dose can be administered at the age of 12-15 months, while the recommended age for the second dose is 4-6 years of age.

Primarily occurs in children Before vaccines were widely introduced, ∼ 90% of all children had been infected by the age of 15. Pathogen: varicella-zoster virus (VZV), a human herpesvirus type 3 (HHV-3) TransmissionAirborne dropletsDirect skin contact with vesicle fluidTransplacental InfectivityHighly contagious2 days before and up to 5 days after the onset of exanthem (or until all the pustules have formed crusts) Incubation period: 2 weeks (10-21 days) Prodromes1-2 days prior to the onset of exanthemPresents with constitutional symptoms (e.g., fever, malaise)More common with primary infection in adults (less typical in children, in which rash is often the first sign of infection) Exanthem phase Duration: ∼ 6 days PresentationWidespread rash starting on the trunk, spreading to the face, scalp, and extremities Simultaneous occurrence of various stages of rash: erythematous macules → papules → vesicles filled with a clear fluid on an erythematous base → eruption of vesicles → crusted papules → hypopigmentation of healed lesionsSevere pruritusFever, headache, and muscle or joint pain Clinical diagnosis is made on the basis of the characteristic rash, although further tests may be necessary in atypical or complicated cases (e.g., older or immunosuppressed patients and pregnant women). Best initial test: Tzanck smear: Smear of vesicle fluid shows multinucleated giant epithelial cells with eosinophilic bodies. Best confirmatory test: PCRMaterial: vesicle fluidAmniotic fluid, chorionic villi, or fetal blood may be used in suspected fetal infection. Viral culture Serology: IgG detection with enzyme-linked immunosorbent assay (ELISA) (to determine exposure and immunity) Treatment Symptomatic Pruritus: topical applications (e.g., calamine lotion or pramoxine gel) and, in more severe cases, oral antihistamines(e.g., cetirizine) Antiviral therapy IndicationImmunosuppressed individualsPrimary infection in adults and in unvaccinated adolescents ≥ 13 yearsIndividuals on long-term salicylate therapy (e.g., aspirin) Administration: within 24 hours of onset of rash Drug of choice: acyclovir (or also: valacyclovir, famciclovir) Complications Skin Bacterial superinfection (including impetigo, phlegmon, necrotizing fascitis), which often leads to scarring and is managed with antibiotics Reactivation of latent VZV results in shingles (herpes zoster) Scarring Central nervous system Acute cerebellar ataxia (∼ 0.1% of cases) → good prognosis, mainly self-limiting after several weeks Encephalitis (very rare) → cramps, coma, poor prognosis Lungs Pneumonia (viral or bacterial) Fetus (chickenpox during pregnancy) Congenital varicella syndrome Reye syndrome is a complication that develops in the course of viral infections such as chickenpox in association with salicylateuse! Prognosis In healthy children, chickenpox infection generally has a benign course and heals without any consequences. Residual scarring may occur because of excessive scratching or bacterial superinfection. Immunosuppressed individuals are at a greater risk of the disease taking a generalized or even fatal course. Chickenpox immunization Vaccine: live, attenuated vaccine Primary immunizationThe CDC recommends two doses of the vaccine: first dose at 12-15 months of age ; second dose at 4-6 yearsof age (may be given earlier, but must be at least three months after the first dose) A combined measles, mumps, rubella, varicella (MMRV) vaccine is available. Catch-up vaccinationTwo doses of varicella vaccine recommended for all children without evidence of immunity between the ages of 7-18After 18 years of age: Individuals in close contact to individuals at high risk of infection (e.g., caretakers of immunocompromisedpatients)Individuals at high-risk of exposure to infected individuals (e.g., childcare employees)Before patients undergo immunosuppressive therapy or organ transplantationSeronegative women of child-bearing ageIndividuals with severe neurodermatitis Postexposure prophylaxis of chickenpox Postexposure prophylaxis may prevent disease onset or significantly mitigate the course of the disease. Active immunization (live, attenuated vaccine) Indications: > 12 months of age, asymptomatic, non-immune and immunocompetent patient following exposureImplementation: within 5 days following exposure Passive immunization (varicella-zoster immune globulin, or VZIG) Indications: Pregnant women with no evidence of immunityImmunosuppressed individuals with no evidence of immunityNewborn infants, if the mother was infected 5 days before or up to 2 days after birthPremature babies > 28 weeks if the mother has no evidence of immunity< 28 weeks regardless of mother's immunity statusInfants < 1 year of ageImplementation: within 10 days following exposure (ideally within 4 days after exposure) Mandatory reporting Chickenpox is listed among the infectious diseases designated by the CDC as nationally notifiable.

Collection of zoonotic diseases Zoonotic diseases are infections that are transmitted from animals to humans. While animals may transmit infection directly, they usually serve as hosts for a pathogen that is then transmitted to humans by a vector (e.g., ticks, fleas). Zoonoses are usually endemic to certain geographical regions, and peaks in incidenceoften correlate with the life cycle of the transmitting vector. Common diseases include Q fever, Rocky mountain spotted fever, endemic typhus, ehrlichiosis, and babesiosis. Although these conditions differ in their exact presentation, symptomatic cases typically present with fever, flulike symptoms, and possibly skin rashes. In some cases of fulminant disease, there may be complications such as disseminated intravascular coagulation, shock, and organ failure. Most zoonoses are treated with antibiotics and respond well to treatment.

Q fever Definition: notifiable zoonotic disease with cattle, sheep, and goats as the primary reservoir Pathogen: Coxiella burnetii (gram-negative, intracellular) EpidemiologyWorldwide occurrence160-170 cases of acute Q fever per year in the US70% of cases occur in men Peak incidence from April to June Route of transmissionInhalation of aerosols from the secretions of infected livestock or animals about to give birth Ingestion of raw milk produced by infected animals Risk groups: slaughterhouse workers, farmers, shepherds, veterinarians Pathophysiology: development of antigens Phase I antigens: seen when C. burnetii is highly infectious Phase II antigens: seen when C. burnetii is less infectious Antigenic shift essential to differentiating acute Q fever from the chronic variant (see below Type of Q feverAcute Q feverChronic Q fever Incubation period2-6 weeksMonths to yearsClinical features∼ 50% of cases are asymptomatic.Sudden onset of flulike symptoms, which last for 1-2 weeksHigh-grade fever, chills, malaise, myalgiaHeadache/retro-orbital pain, photophobiaRhinitis, pharyngitis, laryngitisNausea, vomiting, diarrheaAtypical pneumonia: generally mild with nonproductive cough and feverHepatitis, possibly hepatomegaly without jaundicePregnancy: ↑ risk of spontaneous abortion, intrauterine growth retardation, intrauterine fetal death, and premature deliveryOnly develops in 1-5% of individualsLow-grade feverCulture-negative endocarditis Culture-negative osteomyelitis DiagnosticsSerology via IFA (best initial test)Anti-phase II antibody IgG titers ≥ 200 and IgM titers ≥ 50In cases of negative IFA but high clinical suspicion, perform PCR on serum or tissue samples before administering antibiotics.Anti-phase I antibody IgG titers > 800 or persistently high levels of anti-phase I antibody 6 months after completing therapyAdditional findings↑ Liver enzymes , leukocytosis, thrombocytopeniaChest x-ray: round opacities in patients with atypical pneumoniaTreatmentFirst-line: doxycycline for 2 weeksSecond-line: macrolides (e.g., azithromycin)First-line: doxycycline and hydroxychloroquine for ≥ 18 months Second-line: rifampin and doxycycline/ciprofloxacinValve repair may be required in the case of endocarditis.PreventionAvoid consuming unpasteurized milk products Rocky Mountain spotted fever (RMSF) Pathogen: Rickettsia rickettsii (aerobic, gram-negative, obligate intracellular bacteria ) Epidemiology: Rocky mountains, southeastern, and south central US Reservoir: dogs, rodents, ticks Route of transmission: bite of Dermacentor variabilis (dog tick) Clinical features (incubation period ∼ 7 days, or 2-12 days)Fever, headache, myalgia, malaise, conjunctivitis, nausea, and abdominal painBlanching macular rash (90% of cases): begins on wrists and ankles → spreads to trunk, palms, and soles → becomes petechial and/or hemorrhagic in 50% of cases Hepatomegaly, splenomegalyNoncardiogenic pulmonary edema with ARDS Diagnosis: empiric diagnosis based on clinical and epidemiological features Treatment: doxycycline Typhus Endemic typhus (also known as murine typhus) Definition: An exanthematous typhus fever caused by Rickettsia typhi Etiology: Rickettsia typhi Transmission: via vector: rat and cat fleas Epidemiology: occurs worldwide, mainly warm coastal regions, southern US Clinical featuresIncubation period: 8-16 daysFever, severe headache, malaise Maculopapular or petechial rash erupts on the trunk → spreads to extremities No eschar (scab at site of flea bite) DiagnosisSerology (four-fold rise in antibodies)Positive Weil-Felix reactionA diagnostic test for rickettsial infections, whereby suspensions of proteus antigens (OX 19, OX 2, or OX K) are mixed with a patient's serum.Agglutination occurs in the serum of patients infected with Rickettsia. Treatment: doxycycline, chloramphenicol Ehrlichiosis Pathogen: Ehrlichia chaffeensis, Ehrlichia ewingii (intracellular, gram-negative bacteria) Epidemiology: southeastern and south central US, mid-Atlantic States Reservoir: white tail deer Route of transmission: bite of the lone star tick (Amblyomma americanum) → infection of monocytes and macrophages Clinical infection (incubation period of 1-2 weeks)Fever, headaches, malaise, myalgiasSimilar to RMSF, but usually without a rash ("spotless" RMSF)Possibly neurologic symptoms (altered mental status, stiff neck, clonus)May cause renal failure and GI bleeding DiagnosisLeukopenia, thrombocytopenia, elevated serum transaminasesWright-Giemsa stain of blood smear: detection of morulae inside the infected monocytesSerology via IFA: IgG Ehrlichia titer Treatment: PO doxycycline or tetracycline Babesiosis Pathogen: Babesia species, especially Babesia microti (protozoan parasites) EpidemiologyWorldwide occurrence; endemic in the Northeast, Northwest, and upper Midwest of the USSeasonal distribution: most cases in July and August when tick populations reach their peak Route of transmissionNatural reservoir: wild animals (especially rodents), cattleTransmission to humans via tick bites: Ixodes scapularis (black-legged deer tick) Clinical features (incubation period of 1-6 weeks)Most cases asymptomatic or mild, but may be severe or even fatal Flulike symptoms (fever, malaise, myalgia, headache)Hemolytic anemia with dark urine and icterusMild splenomegaly and hepatomegalySevere infection may lead to DIC, ARDS, congestive heart failure, splenic rupture, and death.Clinical features similar to malaria infections DiagnosticsLaboratory findings: signs of hemolytic anemia, thrombocytopenia, normal WBC or mild leukopenia, ↑ transaminases, and alkaline phosphataseConfirmatory test: Giemsa stain reveals thin blood smear intraerythrocyte rings with a maltese cross.PCR, serologyCoinfection with other tick-borne pathogens (e.g., Borrelia, A. phagocytophilum) should be considered TreatmentAtovaquone and azithromycin for mild diseaseQuinine and clindamycin for severe infections Plague Pathogen: Yersinia pestis Epidemiology: western US (as scattered cases in rural areas) Reservoir: prairie dogs, squirrels, rodents Route of transmission: flea bites Clinical featuresBubonic plague (most common): sudden onset of fever, headache, myalgias, chills, and painful swollen lymph nodes (buboes) → may progress to sepsis, pneumonia, and meningitisSepticemic plague: signs and symptoms of sepsis, abdominal pain, possible shock, DICPneumonic plague : rapidly progressing pneumonia with possible respiratory failure and shock Diagnostics: cultures with Wayson stain taken from buboes, blood, or sputum → shows bipolar staining of bacteria (appearance of "closed safety pin") TreatmentDo not delay treatment for diagnosis!Isolation with droplet precautions until pneumonic plague is ruled outFirst-line: IV gentamicin or fluoroquinolones for 10-14 daysSecond-line: doxycycline, tetracycline

Fever Differential diagnoses by risk factors

Recent international travel TuberculosisMalariaDengueLeptospirosisTyphoid feverTyphusViral hemorrhagic feversEbola feverMarburg hemorrhagic feverLassa feverCrimean-Congo hemorrhagic feverChikungunya feverYellow feverQ feverAmebiasisZika feverRat-bite fever Lymphogranuloma venereumVisceral leishmaniasis HIV infectionPrimary HIV infectionSecondary infections (see HIV-associated conditions) MycobacteriaPneumocystis jiroveciiCMV ToxoplasmosisAspergillosisCryptococcosisHistoplasmosisDrugs Drug-induced feverImmune reconstitution inflammatory syndromeMalignancies Non-Hodgkin lymphomaHodgkin lymphomaPrimary CNS lymphoma Trauma/stress Hematoma Fracture Extreme sports Heatstroke Thromboembolism Fat embolism Post-operative fever Drug exposure Drug-induced fever Antibiotics (Trimethoprim-sulfamethoxazole, beta-lactam antibiotics, sulfonamides, amphotericin B, isoniazid), Antiepileptics, Antidepressants, Antipsychotics, Antiarrhythmics ( Procainamide, quinidine), Antihistamines, Antiemetics, NSAIDs (aspirin), Meperidine, Sulfa-containing laxatives, Diuretics(furosemide, captopril, hydralazine, hydrochlorothiazide), Allopurinol, Erythromycin, Heparin, Methyldopa, Neuroleptic malignant syndrome, Serotonin syndrome, Malignant hyperthermia, Transfusion reaction Inherited fever syndromeFamilial Mediterranean feverHyper-IgD syndromeTNF receptor-1-associated periodic syndromeSchnitzler syndromeMuckle-Wells syndrome Autoimmune disease Rheumatoid arthritis, Juvenile idiopathic arthritis, Polymyalgia rheumatica, Vasculitides, SLE, Still disease, Behcet disease, Sarcoidosis, Crohn disease, Ulcerative colitis, Antiphospholipid syndrome, Transplant rejection

Antivirals against hepatitis C Protease inhibitors used to treat HIV end in "navir." Protease inhibitors used to treat HCV end in "previr." These drugs are always used in combination; none is approved as monotherapy.

Ribavirin Guanosine analog (nucleoside inhibitor): competitive inhibition of IMPdehydrogenase → prevents synthesis of guanine nucleosides Hemolytic anemiaSeverely teratogenicGastrointestinal symptomsCombination treatment in hepatitis C for all HCVgenotypes Viral hemorrhagic fever RSV bronchiolitis Direct acting antivirals (DAAs) GlecaprevirNS3/4A protease inhibitors: inhibit NS3/4A (an HCV serine proteaserequired for viral replication)HeadacheFatigueNauseaChronic hepatitis Cinfection (all genotypes) GrazoprevirHeadacheFatigueNauseaChronic hepatitis Cinfection (genotypes 1a, 1b, and 4) ParitaprevirHeadacheFatigueNauseaInsomniaAstheniaPruritusAllergic skin reactionsChronic hepatitis Cinfection (genotype 1 or 4) SimeprevirPhotosensitivityRashFatigueHeadacheAbdominal painDiarrheaChronic hepatitis Cinfection VoxilaprevirHeadache Fatigue Diarrhea Nausea Chronic hepatitis Cinfection (all genotypes) Non-nucleoside NS5A polymerase inhibitors Daclatasvir inhibition of the viral NS5A phosphoprotein → prevents HCV RNA replication Headache Fatigue Nausea Anemia Chronic hepatitis Cinfection (genotype 1, 3, or 4) Elbasvir Headache Fatigue Nausea Chronic hepatitis Cinfection (genotype 1 and 4) LedipasvirHeadacheFatigueDiarrheaChronic hepatitis Cinfection(genotypes 1a and 1b) Ombitasvir Headache Diarrhea Fatigue Nausea Insomnia Asthenia Pruritus Skin reactions Chronic hepatitis Cinfection(genotypes 1a, 1b, and 4) Pibrentasvir Headache Fatigue Nausea Diarrhea Chronic hepatitis Cinfection (all genotypes) VelpatasvirHeadacheFatigueDiarrheaChronic hepatitis Cinfection (all genotypes) Non-nucleoside NS5B polymerase inhibitors: Dasabuvir Inhibition of NS5B (a RNA-dependent RNA polymerase) → prevents HCV replication Fatigue Headache Insomnia Pruritus Asthenia Nausea Chronic hepatitis Cinfection(genotypes 1a and 1b) SofosbuvirHeadacheFatigueChronic hepatitis Cinfection (all genotypes) Contraindication for sofosbuvir: severe renal insufficiency

Antimycobacterial drugs Compare drugs below with tuberculosis therapy for an overview

Rifamycins The 4Rs' of rifampin: RNA polymerase inhibition, Ramping up of cytochrome P450 activity, Red or orange colored urine, and Rapid developement of resistance if used alone DrugsOral or IV rifampin (rifampicin)Oral rifabutin Mechanism of actionObstruct bacterial protein synthesis by inhibiting bacterial DNA-dependent RNA-polymerase, thus preventing transcriptionBactericidal CNS penetration: only when meninges are inflamed Route of elimination: biliary Clinical useMycobacteriaTuberculosisIn combination with dapsone and clofazimine: leprosyHaemophilus influenzae type b prophylaxisGram-negative coccobacillus that can cause life-threatening acute epiglottitis in children Meningococcal prophylaxis Adverse effectsHarmless orange discoloration of body fluids (e.g., urine, tears)Flulike symptoms (fever, arthralgia and in severe cases hemolytic anemia, thrombocytopenia, renal failure) HepatotoxicityResistance develops rapidly if used as monotherapy CYP induction (CYP3A4, CYP2C9) ContraindicationsHepatic failure (relative contraindication)Pregnancy (relative contraindication) Isoniazid (INH) Mechanism of actionPrevents cell wall synthesis by inhibiting the synthesis of mycolic acid Bacterial catalase-peroxidase converts isoniazid into its active metabolite.Decreased expression of catalase-peroxidase confers bacterial resistance.Bactericidal CNS penetration: variable (20-100% of serum concentration) Route of elimination: renal Clinical use: treatment and prophylaxis of M. tuberculosis; first-line monotherapy for latent TB Adverse effects: HepatotoxicityDrug-induced systemic lupus erythematosusVitamin B6 deficiency : Peripheral neuropathy due to S-adenosylmethionine accumulationSideroblastic anemia, aplastic anemia, thrombocytopeniaOptic neuropathy ContraindicationsHepatic failure (relative contraindication)Pregnancy (relative contraindication) INH Injures Neurons and Hepatocytes! Neurotoxicity and lupus may be prevented by supplementing with pyridoxine (vitamin B6)! Pyrazinamide Mechanism of actionNot completely understood. Bactericidal CNS penetration: only when meninges are inflamed Route of elimination: renal Clinical use: M. tuberculosis Adverse effectsHyperuricemia → goutHepatotoxicity ContraindicationsHepatic failure (relative contraindication)Pregnancy (relative contraindication) NOTES Ethambutol Mechanism of actionPrevents cell wall synthesis by inhibiting arabinosyltransferase Bacteriostatic CNS penetration: only when meninges are inflamed Route of elimination: primarily renal Clinical useM. tuberculosisM. avium-intracellulare Adverse effectsOptic neuritis, retrobulbar neuritis → ↓ visual acuity and red-green color-blindness→ can result in irreversible blindnessResistance develops rapidly if used as a monotherapy. ContraindicationsChildren (relative contraindication) Dapsone Mechanism of actionPrevents synthesis of folic acid by acting as a competitive antagonist of para-aminobenzoic acid (PABA)Bactericidal or bacteriostatic Route of elimination: mostly renal Clinical useM. lepraeAlternative to TMP/SMX for the prophylaxis of P. jiroveci pneumoniaAlternative to sulfadiazine + pyrimethamine for toxoplasmosisIn combination with pyrimethamine as an alternative to standard therapy for chloroquine-resistant malaria Adverse effectsMethemoglobinemiaTriggers hemolytic anemia in G6PD-deficient patientsGastrointestinal side effectsPeripheral neuropathy ContraindicationsPatients with G6PD deficiency

Roseola infantum Roseola infantum (exanthem subitum, three-day fever) is a viral exanthematous infection caused by the human herpes virus 6 (HHV-6; in rare cases, HHV-7) that mainly affects infants and toddlers. Infection is characterized by high fever, which ends abruptly after three to five days, followed by the sudden appearance of a maculopapular rash. The rash generally appears mainly on the trunk, but sometimes spreads to the face and extremities, and fades within two days. Roseola infantum is a self-limiting condition that is only treated symptomatically. Febrile seizures are a possible complication of infection; however, most patients recover from these seizures without any adverse outcome.

Roseola infantum Epidemiology Most frequent in infants and young children Peak incidence: 6 months to 2 years Etiology PathogenHHV-6 (and in rare cases HHV-7)Humans are the sole hosts. Route of transmission: droplet infection Incubation period: 5-15 days Clinical features Febrile phase Duration: 3-5 days FeverAbrupt onset of high fever, in some cases > 40ºC (104ºF) Frequent cause of emergency room visits for febrile illness Cervical, postauricular, and/or occipital lymphadenopathy Inflamed tympanic membranes Nagayama spots: papular enanthem on the uvula and soft palate Other possible symptoms: Mild upper and lower respiratory symptoms (pharyngitis, cough, etc.) Vomiting and/or diarrheaConjunctivitis and edema of the eyelid Exanthem phase Duration: 1-3 days Characteristic presentation: subsequent sudden decrease in temperature and development of a patchy, maculopapular exanthemRose-pink in color; blanches upon pressureNonpruritic (DDx: drug allergy!)Originates on the trunk; sometimes spreads to the face and extremities Diagnostics Usually a clinical diagnosis Laboratory tests Differential diagnoses Classic pediatric exanthem diseases Drug reactions Meningitis Treatment Symptomatic treatment (e.g., fluids and possibly acetaminophen to reduce fever) Complications Febrile seizures (in up to 15% of cases), usually without sequelae Meningoencephalitis (very rare) Prognosis Very good prognosis; self-limiting disease The virus persists lifelong in its host → reactivation of latent virus or reinfection may occur later in life (especially if individuals become immunocompromised)

Inflammatory diarrhea Typical pathomechanism of inflammatory diarrhea: pathogen enters gastrointestinal tract → inflammation → mucosal damage → barrier defect → diarrhea. Bacteria or cytotoxins damage the colonic mucosa → blood in stool and fever WBC positive (fecal polymorphonuclear leukocytes) Blood present

Salmonella (100s of strains, including S. enteritidis and S. typhimurium)Poultry/eggsChicken products: eggs, raw chicken6-48 hSalmonella gastroenteritis: supportiveAntibiotics are not recommended! Campylobacter jejuni Most common bacterial organism pathogen responsible for foodborne gastroenteritis in the USPoultryFecal-oralDays Supportive treatment with fluids and electrolytesErythromycin or azithromycin in severe casesResistance to penicillin, ciprofloxacin, fluoroquinolonesShigella dysenteriaeSecond most common association with hemolytic-uremic syndrome (HUS)Fecal-oralDays Fluoroquinolones, azithromycin, TMP-SMXDo not use ampicillin as some Shigella strains may be resistant!Yersinia enterocoliticaContaminated milk, porkDays SupportiveFluoroquinolones,TMP-SMX, 3rd generation cephalosporins in severe casesVibrio (usually parahaemolyticus) ShellfishUndercooked seafood16-72 hoursSupportiveDoxycycline, fluoroquinolones in severe cases Enterohemorrhagic Escherichia coli (EHEC) O157:H7: most common pathogenic strain; associated with HUSUndercooked meat; most common association with hemolytic-uremic syndrome (HUS)Non-disinfected water; contaminated food, such as unpasteurized dairy products (milk, soft cheese) or apple ciderFecal-oral3-4 days(range: 24 h to 10 days)SupportiveAntibiotics are contraindicated because they increase the risk of HUSClostridium difficileRecent antibiotic use

Contraindications for vaccination

Severe, acute illness: e.g., infection with fever > 38.5°C (> 101.3°F) Previous adverse reaction related to a vaccination: e.g. anaphylaxis Severe allergies to components of a vaccine: e.g., egg white in some live vaccines (e.g., yellow fever) Live vaccinations are not recommended forPregnant individualsImmunodeficient individuals Special contraindicationsRotavirus vaccine: severe combined immunodeficiency (SCID), history of intussusception , uncorrected GI tract malformation (e.g., Meckel's diverticulum)Hepatitis B: infant weighing less than 2 kgTetanus: Guillain-Barré syndrome within 6 weeks after a previous dose of tetanus toxoid-containing vaccinePertussis-containing vaccines: known anaphylactic reactions, encephalopathy within 7 days following previous vaccination, progressive or unstable neurologic disorder (e.g., coma, uncontrolled seizures, or progressive encephalopathy) Precautions: fever > 40.5°C (> 105°F), shock-like state within 48 hours following the previous vaccination, seizure within 3 days following previous vaccination, inconsolable crying > 3 hours following the previous vaccination

Immunoglobulin properties

SpecificityRequires antigensOccurs by somatic hypermutation and affinity maturationAlterations take place in the variable region.Normal response to antigenic stimulation: B lymphocytes with varying immunoglobulin alleles (i.e., polyclonal proliferation)Malignant lymphocyte proliferation: predominance of B lymphocytes with a single immunoglobulin variable domain (i.e., monoclonal proliferation)Class switching (e.g., IgA, IgM, IgG)Alterations take place in the sequence of the heavy chain constant domain. DiversityDoes not require antigensRandom recombination of certain genes during B cell maturation in bone marrowLight chain: VJ genesHeavy chain: V(D)J genesTerminal deoxynucleotidyl transferase (TdT) randomly adds nucleotides to the DNA.Recombination of light chains with heavy chains occurs randomly.

Food poisoning Types

Staphylococcal food poisoning Pathogen: Staphylococcus aureusGram-positive bacteriumSome strains produce heat-stable enterotoxins that cause staphylococcal food poisoning. [1] Transmission: ingestion of preformed toxins in contaminated food [1] CharacteristicsTypically involves a short latency period; resolution of symptoms after 24-48 hours Bacteria proliferate in inadequately refrigerated food (canned meats, mayonnaise/potato salad, custards).[2] Incubation period: 1-4 hours Clinical findings: nausea, vomiting, abdominal discomfort, diarrhea Treatment: supportive[2]Antibiotics are unnecessary Bacillus cereus infection Pathogen: Bacillus cereus, a heat-stable, spore-forming bacterium that produces two different enterotoxins Transmission: The bacterium grows in heated food that cools down too slowly or is improperly refrigerated. Reheated rice is a common source of infection.[1] Incubation period and clinical findingsEnterotoxin I (emetic form): 30 min to 6 h after ingestion → nausea and vomitingEnterotoxin II (diarrheal form): 6-15 h after ingestion → watery diarrhea for 24-48 h Treatment: Supportive[3 Histamine fish poisoning (Scombroid) Transmission: ingestion of contaminated, inadequately refrigerated fish (e.g., fish cakes) Clinical findingsAfter 5 min to 1 h: fever, vomiting, diarrhea, erythema/flushing, urticaria, and oral burning sensation Treatment: Symptoms usually resolve within 48 hours. Antihistamines may be administered in severe cases.

Predominantly Vomiting Food Poisoning Commonly due to delayed gastric emptying caused by changes to gastric motility.

Staphylococcus aureus (Enterotoxins cause the symptoms) Canned meats, mayonnaise/potato salad, custards 1-3 h Supportive Bacillus cereusReheated rice, food kept warm but not hot Vomiting: 30 min to 6 h Diarrhea: 6-15 h Supportive Noroviruses (e.g., Norwalk)(Vomiting more common in children) Fecal-oral 12-48 hSupportive

Infective endocarditis Infective endocarditis (IE) is an infectious inflammation of the endocardium that affects the heart valves. The condition is a result of bacteremia, which is most commonly caused by dental procedures, surgery, distant primary infections, and nonsterile injections. IE clinically presents with either an acute or subacute course. Acute disease is usually caused by Staphylococcus aureus and causes rapid endocardium destruction. Subacute progression is most commonly caused by viridans streptococci species and generally affects individuals with pre-existing damage to the heart valves, structural heart defects, or the presence of prosthetic valves. Unlike acute disease, in which patients develop symptoms over a period of hours to days, subacute disease is associated with a progression of symptoms over weeks to months. Clinical features include constitutional symptoms (fatigue, fever/chills, malaise) in combination with signs of pathological cardiac changes (e.g., new or changed heart murmur, heart failure signs) and possibly manifestations of subsequent damage to other organs (e.g., glomerulonephritis, septicembolic stroke). Diagnosis is made based on the Duke criteria, whose main features include positive blood cultures and evidence of endocardial involvement in echocardiography. Initial treatment of IE consists of empiric IV antibiotic therapy, which is then adapted to blood culture results and continued for four to six weeks. Prophylaxis is only administered in specific circumstances, e.g., in patients with preexisting heart conditions undergoing dental or surgical procedures. If left untreated, infective endocarditis can be fatal within a few weeks.

Staphylococcus aureus (45-65%) Most common cause of acute IE for all groups (including IV drug users and patients with prosthetic valves or pacemakers/ICDs) Affects previously healthy valves Usually fatal within 6 weeks (if left untreated) Viridans streptococci (30%): S. sanguinis, S. mutans, S. mitis Most common cause of subacute IE, especially in predamaged native valves (mainly the mitral valve) Common cause of IE following dental procedures Produce dextrans that facilitate binding fibrin-platelet aggregates on damaged heart valves Staphylococcus epidermidis IE transmitted via infected peripheral venous catheters Common cause of subacute IE in patients with prosthetic heart valves or pacemakers/ICDs Enterococci, especially Enterococcus faecalis (< 10%) Multiple drug resistance Common cause of IE following nosocomial urinary tract infections (UTIs) Following gastrointestinal or genitourinary procedures Streptococcus gallolyticus (S. bovis) S. gallolyticus is associated with colorectal cancer If S. gallolyticus is detected, colonoscopy is indicated Gram-negative HACEK group (Haemophilus species, Aggregatibacter actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Kingella kingae) Physiological oral pharyngeal flora (∼ 3% of cases of IE) In patients with poor dental hygiene and/or periodontal infectio Candida species Aspergillus fumigatus Causes IE in immunosuppressed patients Causes IE in IV drug abusers Cause of IE after cardiosurgical interventions Coxiella burnetii Bartonella species Gram-negative pathogens responsible for culture-negative endocarditis Demographics Male sexAge > 60 years Preexisting conditionsPrevious IEPredamaged or prosthetic heart valvesCongenital heart defectsNeed for chronic hemodialysisImpaired immune function (e.g., HIV infection) BacteremiaInfected peripheral venous catheters, surgery, dental procedures Non-sterile venous injections (e.g., IV drug abuse)Bacterial infections of various organs (e.g., UTIs, spondylodiscitis) Pathophysiology Pathogenesis: localized infection or contamination → bacteremia → bacterial colonization of damaged valve areas → formation of fibrin clots encasing the vegetation → valve destruction with loss of functionPreexisting valvular endothelial damage or prosthetic valves predispose to bacterial colonization, especially of those that cause subacute IE Frequency of valve involvement: mitral valve > aortic valve > tricuspid valve > pulmonary valveThe tricuspid valve is the most commonly affected valve in IV drug users (associated with Pseudomonas, S. aureus, and Candida). Clinical consequencesBacterial thromboemboli from bacterial vegetation → vessel occlusion with infarctionsFormation of immune complexes and antibodies against tissue antigens → glomerulonephritis, Osler nodes Acute bacterial endocarditis Acute onset Rapid, fulminant progression (days to weeks) More severe constitutional symptoms (e.g., high fever) Most common: S. aureus (associated with large vegetations that can destroy the valves) Others: group A hemolytic streptococci, S.pneumoniae, N.gonorrhoeae Native healthy valves Subacute bacterial endocarditis Insidious onset Slow progression (weeks to months) Less severe constitutional symptoms (e.g., low feverpossible, often absent) Most common: viridans streptococci species (small vegetations) Others: nonenterococcal group D streptococci and enterococci Native previously injured or congenitally defect valves Prosthetic valve endocarditis Early-onset: < 60 days after surgery Late-onset: ≥ 60 days after surgery Early onset: S. epidermidis or S. aureus (most common) Late onset: streptococci and S. aureus (most common) Prosthetic valves Constitutional symptoms Fever and chills (∼ 90% of cases), tachycardia General malaise, weakness, night sweats, weight loss Dyspnea, cough, pleuritic chest pain Arthralgias, myalgias Cardiac manifestations New heart murmur development or change to a preexisting one Mitral valve regurgitation → holosystolic murmur, loudest at the heart's apex, and radiates to the left axillaTricuspid valve regurgitation → holosystolic murmur; loudest at the left sternal border ; seen in IV drug users and concomitant HIV infection, immunosuppressed patients, and patients with central venous cathetersAortic valve regurgitation → early diastolic murmur; loudest at the left sternal border Signs of progressive heart failure (e.g., dyspnea, edema) Signs of acute cardiac decompensation (pulmonary edema) Arrhythmias Suspect perivalvular abscess in patients with infective endocarditis who develop a new conduction abnormality (e.g., a third-degree atrioventricular block) Extracardiac manifestations These manifestations are mainly caused by bacterial microemboli and/or the precipitation of immune complexes . Petechiae; especially splinter hemorrhages (hemorrhages underneath fingernails) Janeway lesionsSmall, non-tender, erythematous macules on palms and solesMicroabscesses with neutrophilic capillary infiltration and areas of hemorrhage caused by septic microemboli from valve vegetations Osler nodesPainful nodules on pads of the fingers and toesCaused by immune complex deposition Roth spots: round retinal hemorrhages with pale centers Signs of acute renal injury, including hematuria and anuria (due to renal artery occlusion or glomerulonephritis) Splenomegaly and possible LUQ pain Neurological manifestations (e.g., seizures, paresis): due to septic embolic stroke, hemorrhages, meningitis, encephalitis, and/or abscess. Signs of pulmonary embolism (e.g., dyspnea): typically caused by septic emboli resulting from tricuspid valve involvement Possible arthritis Diagnostics Laboratory studies Best initial test: multiple blood cultures Coxiella burnetii and Bartonella spp. commonly have negative cultures Leukocytosis (with left shift), ↑ ESR, ↑ CRP Echocardiography Detects valve vegetations , new valvular regurgitation, abscess, dehiscence of prosthetic valve Transthoracic echocardiography (TTE) usually performed first (sensitivity: ∼ 75%) Transesophageal echocardiography (TEE) to confirm findings; higher sensitivity (> 90%) than TTE Only negative findings on transesophageal echocardiography (TEE) can reliably rule out endocarditis, as transthoracic echocardiography (TTE) is not sensitive enough! (Modified) Duke criteria The Duke criteria help to diagnose infective endocarditis. To confirm the diagnosis, one of the following requirements must be met: Two major criteriaOne major and three minor criteriaFive minor criteria Major diagnostic criteriaTwo separate blood cultures positive for typical pathogens (see "Etiology" above)Evidence of endocardial involvement in echocardiographyValve vegetation or abscess or new dehiscence of artificial valvesA new valvular regurgitation (worsening of a pre-existing murmur is not sufficient) Minor diagnostic criteriaPredisposition: underlying heart disease or IV drug abuseFever ≥ 38°C (100.4F)Vascular abnormalities Immunologic disorder Microbiology Pathogenesis Acute disease (leading to valve insufficiency, septic embolic infarcts, tendinous cord rupture) Erosion → fibrin deposits on valvesUlcerationPerforation → adaptation of valve edges not possible Chronic disease (leading to valve insufficiency and valve stenosis) Erosion → reorganization of fibrin layerGranulation tissue → valve scarring/fibrosisCalcification → thickened and/or shortened tendinous cords Differential diagnoses Noninfective endocarditis (nonbacterial thrombotic endocarditis) Description: rare, noninfectious form of endocarditis due to sterile platelet thrombus formation on the heart valves (usually mitral and aortic valves) EtiologyMost commonly associated with underlying trauma (e.g., catheters), malignancy, hypercoagulable states, previous rheumatic fever, chronic infections (e.g., TB, pneumonia, osteomyelitis), or autoimmune conditions (systemic lupus erythematosus, rheumatoid arthritis, antiphospholipid syndrome, etc.)A nonbacterial thrombotic endocarditis with verrucous vegetations in a patient with systemic lupus erythematosus is also referred to as Libman-Sacks endocarditis. Clinical featuresValves and cardiac function are rarely impaired.Compared to infectious endocarditis, vegetations are easily dislodged and embolization is common, leading to hemorrhages under the nails, skin, and retina; most patients are asymptomatic until embolization occurs DiagnosticsNegative blood culturesEchocardiography: findings of valve vegetationsDefinitive diagnosis can only be made pathologically: findings show sterile vegetations on either surface of the valve that are composed of immune complexes, mononuclear cells, and thrombi interwoven with fibrin strands Treatment: anticoagulation with heparin and treatment of the underlying condition Prosthetic valve thrombosis EtiologyOccurs if insufficient anticoagulatory therapy after valve replacement Usually affects mechanic valvesRare if anticoagulation is adequatePresence of a cardiac defect raises the risk of recurrent endocarditis Clinical courseSigns of acute heart failureLeft heart failure: dyspnea and coughRight heart failure: edema and jugular venous distentionDeterioration of general condition, cardiac arrhythmias, cerebral emboli (stroke) Diagnostics: transesophageal echocardiography Treatment: anticoagulation and fibrinolysis, surgical valve replacement Treatment Empirical therapy Native valves Initial intravenous empiric antibiotic treatment with vancomycin → adapt intravenous antibiotics according to resistogram results from blood cultures The duration of treatment depends on the patient's profile, the pathogen's resistances, and the patient's response to treatment. 4-week treatment Drug of choice: penicillin GAlternatives: ampicillin, IV ceftriaxone, IV vancomycin 2-week treatment regimens Drug of choice: gentamicin + penicillin GAlternative: gentamicin + ceftriaxone Prosthetic valves Generally the same antibiotic regimen as for native valves, but longer duration (at least 6 weeks) Exceptions for staphylococciMethicillin-susceptible: nafcillin (or oxacillin, cefazolin) + rifampin + gentamicinMethicillin-resistant: vancomycin + rifampin + gentamicin IV drug users Intravenous empiric antibiotic treatment with vancomycin After confirmation of a susceptible pathogen IV nafcillin (2 weeks)PO cloxacillin (2 weeks) Indications for surgery: congestive heart failure, uncontrolled infection, systemic embolization, prosthetic valve, fungal endocarditis If infective endocarditis is suspected: 1. Obtain blood cultures → 2. Start empiric antibiotic therapy → 3. adapt the therapy according to culture results. Targeted therapy HACEK organisms Drug of choiceFirst-line: 3rd or 4th generation IV cephalosporin (e.g., ceftriaxone, cefotaxime)Second-line : ampicillin-sulbactam , IV fluoroquinolone Duration of therapyNative valve infectious endocarditis: 4 weeksProsthetic valve endocarditis: 6 weeks Prevention Endocarditis prophylaxis: Indicated for high-risk patients undergoing procedures with risk of bacteremia Regimens Usually PO amoxicillin (administer 1 hour before procedure)Patients who are unable to take oral medication: IV ampicillinPatients with penicillin allergy: PO clarithromycin or azithromycin

Watery diarrhea Food Poisoning Typical pathomechanism of watery diarrhea: pathogen or toxin enters gastrointestinal tract → binds epithelial cells, sometimes damaging microvilli → ↑ secretion or ↓ absorption of hydrophilic molecules or electrolytes (e.g., NaCl) → ↑ intestinal water due to osmosis → diarrhea. Enterotoxin or bacterial invasion shifts water and electrolyte excretion/absorption in proximal small intestine → watery diarrhea Clinical featuresMild-moderate: abdominal pain, diarrheaSevere: tachycardia, hypotension, fever, bloody or profuse watery diarrhea, and metabolic acidosis WBC negative No blood

Staphylococcus aureusInadequately refrigerated food Clostridium perfringensEnterotoxins cause the symptomsReheated meat dishesUndercooked meat and raw legumes6-24 hSupportiveAntibiotics are not recommended Enterotoxic Escherichia coli (ETEC) Heat-labile toxininduces diarrheaMost common cause of traveler's diarrheaRecent travel (e.g., Asia, Africa, the Middle East, Mexico, Central, and South America) Undercooked meat, endogenousFecal-oral9 h to 3 daysSupportiveFluoroquinolones Listeria monocytogenesCheese, deli meats, coleslaw, hot dogs, unpasteurized milk1-2 daysImmunocompetent patients: ampicillinImmunocompromised patients: ampicillin + gentamicin Vibrio choleraeProfuse secretory diarrhea Enteric viruses (adenovirus, norovirus, rotavirus) Norovirus: diarrhea more common in adults Fecal-oral Adenovirus: 4-5 days, Norovirus: 12-48 h, Rotavirus: 1-3 days, Supportive, Vaccine (rotavirus) Cryptosporidium Fecal-oral5-7 days Immunocompetent patients: self-limiting; nitazoxanide may be shorten the durationImmunocompromised patients: Antiretroviral therapy to elevate the CD4 cell count/restore the immune system is essential prior to eradication with antiparasitic drugs. Cyclospora (Cryptosporidiumcyclospora cayetanensis)Fecal-oral5-7 daysSupportiveTrimethoprim-sulfamethoxazole (TMP-SMX) Intestinal tapewormsLarvae in undercooked pork/beef, raw freshwater fish6-8 weeksAsymptomatic for yearsPraziquantel, niclosamide

Sterilization and pasteurization

Sterilization Refers to a technique that completely destroys or removes all microbial life, including spores on a surface of an object or in a fluid. Medical devices that come in contact with sterile body parts or fluids must be sterilized. Heat-stable equipment is primarily sterilized by steam sterilization (autoclave). Heat- and moisture-sensitive equipment (plastics, electrical devices, and corrosion-susceptible metal alloys) require a low-temperaturesterilization technology such as ethylene oxide, hydrogen peroxide gas plasma, and peracetic acid. Sterilization techniques for heat stable equipment Steam sterilization (autoclave):Exposing equipment to direct steam at a certain temperature and pressure for a specified period of timeMechanism of action: irreversible coagulation and denaturation of enzymes and structural proteinsActive against bacteria, fungi, viruses, and sporesTreated at > 121°C: Typically uses 134°C for three minutes or 121°C for 15 minPrions are not destroyed by standard autoclaving. They must be sterilized at 121°C-132°C for 60 min (not a standardized method). Dry air sterilization:Exposing equipment to dry heat, which gets absorbed by the external layer and transferred inward to the interior layer by a process called conductionDenatures and oxidizes proteins and other cell componentsCommonly uses 170°C (340°F) for 60 min, 160°C (320°F) for 120 min, and 150°C (300°F) for 150 min Sterilization techniques for heat- and moisture-sensitive equipment Ethylene oxide gas sterilizationEthylene oxide: flammable and explosive gasThe sterilization process includes preconditioning and humidification, gas introduction, exposure, evacuation, and air washes.Mechanism of action: alkylation of protein, DNA, and RNAMicrobicidal against all microorganisms, but spores are somewhat resistantDisadvantages: lengthy cycle time, costly, and hazardous Hydrogen peroxide gas plasma sterilizationHydrogen peroxide diffusion and gas plasma generation → forms free radicalsFree radicals damage enzymes, nucleic acid, and disrupt cellular metabolismActive against bacteria (including mycobacteria), yeasts, fungi, viruses, and bacterial spores Pasteurization Aim: pathogen destruction through brief heating, especially of milk and other protein-containing products Procedure: treated with mild heat (< 100°C) Efficacy spectrum: destruction of a broad spectrum of bacteria but not heat-resistant spores

General mycology Mycoses are infections caused by fungi. They may be caused by dermatophytes (e.g., Trichophyton), yeast (e.g., Candida), or molds (e.g., Aspergillus). In immunocompetent individuals, mycoses usually result in local infection, which can be treated with local antifungals. Fungal infections may cause systemic infection in immunocompromised individuals (e.g., HIV-positive individuals, bone marrow transplant recipients), potentially leading to meningitis or severe sepsis.

Structure and characteristics of fungi Eukaryotes Possess a cell wall and a cell membrane (contains ergosterol; analogous to cholesterol in humans) Four basic morphological elements: Particularly in dermatophytes and molds:Hyphae → multicellular compartments, which are connected by porous septa Mycelium → network of hyphae, which are formed by asexual reproduction Particularly in yeasts:Budding cells (blastospores) → in unicellular fungi, formed by budding of daughter cells Pseudomycelium → chains of budding cells, which are stretched in a hyphen-like manner, but are divided by septa Fungi are not considered plants and are nonphotosynthetic. They extract energy (e.g., sugar and proteins) from living or dead organic matter. Azoles target the synthesis of ergosterol, the principal sterol in fungal cell membranes. They inhibit the synthesis of ergosterol from lanosterol by interfering with 14α-demethylase (cytochrome P-450 enzyme Substances synthesized by fungi Penicillin by Penicillium chrysogenum Toxins: Aflatoxins by molds (e.g., Aspergillus flavus) on nuts, seeds, and grains: poisonous carcinogenassociated with hepatocellular carcinomaAmanitin (see Amanita phalloides poisoning)Ergot alkaloids such as ergotamine produced by the ergot fungus Claviceps purpurea, which grows on rye: causes vasoconstriction by binding to 5-HT1D serotonin receptors and alpha-adrenergic receptors Detection of fungal infections Clinical features and microscopy → evaluation of fungal morphology Additional characterization via: Culture, (e.g., Sabouraud agar) Staining (e.g., silver stain)Antigen detection (e.g., capsule components in serum)Antibody detection plays a minor role. Wood lamp examination: used to evaluate superficial fungal infections of the skin (e.g., erythrasma), which appear characteristically fluorescent under ultraviolet light Latex agglutination test Candida, Aspergillus, and Cryptococcus are opportunistic fungal pathogens with low inherent virulence. They commonly cause systemic mycoses in immunocompromisedhosts but do not normally affect healthy hosts. Fungi overview Dermatophytes: filamentous fungi → dermatophytes (mainly affect skin and nails) TrichophytonMicrosporumEpidermophyton species Yeasts: budding fungi (may affect skin, mucous membranes, and internal organs) Candida species (particularly Candida albicans) → candidiasisCryptococcus neoformans → cryptococcosisMalassezia furfur → tinea versicolor Molds: Aspergillus fumigatus → aspergillosis (may affect internal organs)

Nosocomial infections Common causative pathogens

Surgical site infections S. aureus S. epidermidis, Enterococcus, E. coli, P. aeruginosa Nosocomial pneumonia S. aureus and P. aeruginosa Enterobacteriaceae , H. influenzae, S. pneumoniaeMRSAExtended spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae, A. baumannii Nosocomial urinary tract infections E. coli Klebsiella, Enterococcus, P. mirabilis, P. aeruginosa Bloodstream infectionsCoagulase negative staphylococci (e.g., S. epidermidis) Enterococcus spp., Klebsiella pneumoniae, E. coli

T cells

T cells (T lymphocytes) are a major component of the adaptive immune response and play an important role in cell-mediated immunity. SubtypesT-helper cells (Th cells, CD4+)Cytotoxic T cells (CD8+)Th17 cellsRegulatory T cells (Treg)Memory T cells T-cell receptors (TCRs) Binding of a T-cell receptor to its specific antigen triggers activation of the T cell.This antigen fragment has to bind to the major histocompatibility complex molecule on the surface of another cell in order to be recognized by the TCR.The adaptive immune response is initiated in secondary lymphoid organs, where antigens are presented on the surface of antigen-presenting cells(i.e., macrophages, dendritic cells, B cells).

T cell development

T cells originate from lymphoid progenitor cells in the bone marrow and mature in the thymus (hence "T cells").The thymus is a primary lymphatic organ that arises from the ventral wings of the third branchial pouches.The thymus grows during childhood after which it begins to atrophy (thymic involution).In young children, thoracic x-ray normally shows a prominent thymic shadow.Positive selection of T cells ensures that the thymus produces functional T cells.Takes place in the thymic cortexDense, peripheral region of the thymusPredominantly contains immature T cellsThymic cortical cells express MHC class I and MHC class II antigens.Tests if T-cell receptors can bind MHC appropriately (not too strongly or too weakly)T cells (CD4+ / CD8+) receive survival signal.Dysfunctional T cells then undergo apoptosis.Negative selection of T cells ensures that the thymus does not produce self-reacting T cells.Takes place in the thymic medullaCentral, pale region of the thymusPredominantly contains mature T cellsTests if T cells bind to tissue-restricted self-antigens presented on MHC by thymic medullary cellsT cells that do not bind receive survival signal.Dysfunctional T cells undergo apoptosis. Mediated by the autoimmune regulator protein (AIRE)Additionally, T cells bind with their cluster of differentiation (CD).The type of CD that the T cell has a higher affinity for is kept while the other is downregulated to either (CD4+ / CD8-) or (CD4- / CD8+). CD4 binds to MHC IICD8 binds to MHC I Immunocompetent (but still naive) T cells leave the thymus and migrate within and between peripheral tissues, blood vessels, and secondary lymphoid organs (e.g., lymph nodes, spleen, MALT).

Antibiotic Guidelines & therapy recommendations

Targeted antibiotic therapy Antibiotic therapy is initiated after a culture and sensitivity report is available. Empiric antibiotic therapy Empiric antibiotic therapy refers to starting antibiotic therapy that covers the most probable causative organism(s) before the resistance pattern and/or causative organism are known. Indications An infection that is potentially life-threatening (e.g., meningitis, encephalitis) and/or may result in severe morbidity (e.g., septic arthritis) if treatment is delayed to definitively identify the organism Infections that are commonly treated empirically Brain: meningitis, encephalitisLung: pneumonia, lung abscessSkin: cellulitis, necrotizing fasciitis, surgical site infectionsBone and/or joints: osteomyelitis, septic arthritisRespiratory tract: bacterial rhinosinusitis, tonsillitis, pharyngitisHeart: infective endocarditisGastrointestinal tract: dysentery, spontaneous bacterial peritonitisKidney and genital region: urinary tract infections including pyelonephritis, prostatitis, genital dischargeAny cause of sepsis Choosing empirical antibiotic therapy Attempt to target the most probable causative organism(s) Host factorsWhere was the infection acquired? Community-acquired vs. nosocomial infection If nosocomial: general ward vs. intensive care unit Geographical locationDifferences among individual hospitals Site of infectionInfections above the diaphragm are generally caused by gram-positive organisms (usually cocci), and infections below the diaphragm by gram-negative organisms (usually bacilli).For anaerobic infections Involving the bowel, genital region and/or CNS: metronidazoleElsewhere: clindamycinCertain sites are difficult to reach by antibiotics and require the use of higher/more frequent doses, longer duration of therapy, combinations of antibiotics, and/or the use of antibiotics that cross the blood-brain barrier. Age, pregnancy, lactation (also see "Contraindications" above)Pre-existing illness and/or comorbidities (also see "Contraindications" above) Hepatic and/or renal failureAllergiesImmunosuppression Previous antibiotic therapy Drug factorsRoute of administration Antibiotic toxicityCost of the antibioticDrug interactions Other guiding principles Escalation of antibiotic therapyIncreasing the spectrum of coverage of antibiotic therapy when clinical symptoms do not improve and/or if the infection persistsBroad-spectrum antibiotics have activity against both gram-positive and gram-negative bacteria. Aminopenicillins with beta-lactamase inhibitorsUreidopenicillinsCarbapenems3rd, 4th, and 5th generation cephalosporins3rd and 4th generation fluoroquinolonesTetracyclinesMacrolidesChloramphenicol De-escalation of antibiotic therapy: A more specific narrow-spectrum antibiotic regimen is initiated after the causative organism as well as its resistance and sensitivity patterns are known.

Antivirals against hepatitis B

Tenofovir Adefovir Nucleotide analog (adenosine analog): phosphorylated to triphosphate in hepatic cells (activation) → binds to viral DNA polymerase → causes premature termination of DNA transcription Nephrotoxicity(e.g., Fanconi syndrome) Headache and abdominal pain Disease exacerbation is possible. Chronic active hepatitis B, HIV Entecavir Lamivudine Telbivudine Nucleoside analog: inhibition of reverse transcriptase Occasional Gastrointestinal symptomsFeverHeadache Rare VasculitidesNeuropathiesNeutropeniaLactic acidosis Chronic active hepatitis B HIV

Allylamine derivatives

Terbinafine(oral, topical) Inhibit fungal squalene epoxidase, which decreases ergosterolsynthesis Dermatophytosis (especially onychomycosis) Tinea infections (e.g., tinea pedis) Important contraindications: impaired liver function, systemic lupus erythematosus Only use in children > 4 years Avoid during breastfeeding Headache Hepatotoxicity Dysgeusia Gastrointestinal upset Exacerbation of autoimmune diseases (e.g., systemic lupus erythematosus)

B cell activation

Th cell‑independent activation of B cells (1° response)Immediate response to an antigen → leads to production of IgM antibodies Polysaccharide, lipid, and lipopolysaccharide (LPS) antigens activate B cells and induce antibody production without any further stimulation by T-helper cells. B cell activation via Th cells (2° response)Requires activation of CD4+T-helper cells (see above)B lymphocytes recognize protein/peptide antigens via their B-cell receptors (membrane‑bound immunoglobulins, IgD or IgM) → B cell receptor-mediatedendocytosis of the BCR/antigen complex → breakdown of antigen into small fragments by lysosomal proteases → presentation of antigen fragment via MHC class II receptors on B cell surface to Th cells → interaction between Th2 cells and B lymphocytes → T cell‑dependent activation of B cells(plasma cells) → immunoglobulin production

Myocarditis Myocarditis is an inflammatory disease of the myocardium that most often affects young patients, causing approx. 10% of sudden deaths in young adults. The disease is commonly caused by viral infections (e.g., parvovirus B19, coxsackie virus) or acute rheumatic fever, but may also manifest in patients with systemic conditions such as systemic lupus erythematosus or vasculitic syndromes. Adult patients are commonly asymptomatic or present with nonspecific symptoms, including fever, fatigue, and weakness. Some patients also experience cardiac signs that vary in severity from chest pain and arrhythmias to heart failure or sudden cardiac death. Infants and children typically have a more severe presentation. Inflammation may also spread and lead to concurrent pericarditis. Myocarditis should be suspected in patients with a history of flulike symptoms and new evidence of ECG abnormalities, such as sinus tachycardia or concave ST-segmentelevations. Further diagnostic tests may show elevated cardiac enzymes and cardiac enlargement in chest x-rays. If diagnosis is uncertain, an additional myocardial biopsy may also be indicated. Initial management of myocarditis involves supportive measures and treatment of any underlying diseases (e.g., antibiotic therapy). Cardiac symptoms usually require additional medication, including amiodarone for arrhythmias or beta blockers for congestive heart failure. Whereas most adults with viral myocarditis make a full recovery, there is a small risk of the condition progressing to dilated cardiomyopathy. The prognosis is especially poor for infants and small children.

The exact incidence is unknown. ∼ 1-5% of viral infections are estimated to have cardiac involvement. Often occurs in young patients (average age: ∼ 40 years) In ∼ 10% of sudden deaths in young adults, myocarditis is diagnosed in the post-mortem examination. Infectious Viral Most commonly implicated: Coxsackie B1-B5 (picornavirus), parvovirus B19, human herpesvirus 6 (HHV-6), adenovirus, HCV, HIV, EBV, CMV, Echovirus, H1N1 influenza A Bacterialβ-hemolytic Streptococcus group A (acute rheumatic fever)Corynebacterium diphtheriae (diphtheria, diphtheria toxin)Borrelia burgdorferi (borreliosis)Mycobacterium (tuberculosis)Mycoplasma Fungal (candidiasis, aspergillosis) Protozoan (Chagas disease, caused by Trypanosoma cruzi, is a common pathogen in South America) Parasitic (trichinella, echinococcus) Noninfectious Connective tissue diseases (e.g., systemic lupus erythematosus) Vasculitis syndromes (e.g., Kawasaki disease) Toxic myocarditisRadiation therapyMedication (e.g., sulfonamides), chemotherapy (e.g., anthracycline)Alcohol, cocaine Clinical features Often asymptomatic, but may range from acute, fulminant cases to chronically active or persistent myocarditis Preceding (1-2 weeks) flulike symptoms (fever, arthralgia, myalgia, upper respiratory tract infections) → indicates possible viral cause In infants and young children: poor feeding, irritability, respiratory distress, and failure to thrive Fatigue, weakness, dyspnea, nausea, vomiting Cardiac arrhythmias: often sinus tachycardia, ventricular extrasystoles with palpitations or syncope, heart block with bradyarrhythmia Chest pain: indicates pericardial involvement (perimyocarditis) Acute decompensated congestive heart failure with dilated cardiomyopathy: See symptoms of left heart failure and symptoms of right heart failure. Cardiogenic shock in fulminant cases Auscultation findings Brief systolic murmursHeart failure → S3 (and S4) gallopsPericarditis → pericardial friction rub Diagnostics Patients suspected of myocarditis should have an ECG and laboratory tests conducted to support the diagnosis. Ultimately, if the diagnosis is unclear, a biopsy may be indicated to help determine treatment. ECG/24-hour Holter monitoring Although ECG abnormalities due to myocardial inflammation are very nonspecific and may only manifest temporarily, myocarditis should be suspected if the following findings are observed: Sinus tachycardia Arrhythmias: atrial or ventricular ectopic beats, complex ventricular arrhythmia, atrial tachycardia Repolarization abnormalities ST depression, negative T wavesPossible ST elevations with a concave ascending S wave → indicates perimyocarditis Heart block: right bundle branch block, complete heart block, AV block Rule out myocardial infarction: loss of R wave and pathological Q wave specific to myocardial infarction, not found in myocarditis Pericardial effusion: low voltage (low R-wave with poor progression) Laboratory findings ↑ Cardiac enzymes (CK, CK-MB, troponin T) ↑ ESR (and CRP) Leukocytosis ↑ BNP Virus serology Imaging Chest x-ray and CT: cardiac enlargement, pulmonary congestion, pleural effusions EchocardiographyFindings often unremarkable Ventricles: dilation, diffuse hypokinesia, reduced ejection fraction, impaired contractility, regional wall motion abnormalities Pericardial effusion: localized or circumferential fluid surrounding the ventricles Exclusion of other possible etiologies of heart failure (e.g., heart defects) Myocardial biopsy Via cardiac catheterization of the left heart and MRI-supported biopsyIndications New onset heart failure, severe arrhythmias, resistance to treatmentOnly performed if previous diagnostics are inconclusive and a definitive diagnosis of myocarditis might influence treatment Results Possible detection of viral DNA/RNAImmunohistochemical detection of inflammation (with lymphocytic infiltrates in a viral etiology) Differential diagnoses See differential diagnoses of acute chest/epigastric pain. Pericarditis Myocardial infarction Treatment Supportive therapyInpatient surveillance (cardiac monitoring, oxygen administration, management of fluid status) Rest; avoid physical activity Analgesic drugs if required Causative treatmentAntibiotic therapy for bacterial myocarditisAntimycotic therapy (fluconazole, amphotericin B) for fungal infections Treatment of complicationsCongestive heart failure: (e.g., management of fluid accumulation with diuretics, beta blockers , ACE inhibitors) Treatment of cardiac arrhythmias (e.g., amiodarone) Heart transplantation Complications Progression to dilated cardiomyopathy (∼ 15% of cases) Concurrent pericaridits (perimyocarditis) that may lead to cardiac tamponade (associated with large pericardial effusions) Heart failure or sudden cardiac death: probably due to ventricular tachycardia or fibrillation Acute and/or persistent arrhythmias Atrioventricular block Prognosis Viral myocarditis: Most adults make a full recovery; however, progression to dilated cardiomyopathy may occur. However, prognosis is very poor for infants (75% lethality rate!) Lethality rate for children is 25% and another 25% may develop chronic heart failure complications Markers of poor prognosisPoor ventricular function, left bundle-branch block, low ejection fractionPersistent viral genome (in the myocardium) Chronic inflammation

Vertical transmission: an infection acquired directly from the mother that is transmitted to the embryo, fetus, or newborn through the placenta or birth canal. TORCH infections: vertically transmitted infections that are capable of significantly influencing fetal and neonatal morbidity and mortality ToxoplasmosisOthers (e.g., syphilis, varicella, parvovirus B19 infection, listeriosis, group B Streptococci, E. coli, gonococcal infections and chlamydial infections, West Nile virus, Zika virus, measles virus, enterovirus, and adenoviru)RubellaCytomegaly (CMV)Herpes simplex virus (HSV) infection/HIV/HepB

Toxoplasmosis Classic triadChorioretinitisHydrocephalusIntracranial calcifications (ring-enhancing lesions)Petechiae and purpura (blueberry muffin rash)T. gondii-specificIgM antibodiesPCR for T. gondiiDNARing-enhancinglesions on head MRIPyrimethamine, sulfadiazine, and folinic acidAvoidance of uncooked meatAvoidance of handling cat fecesSpiramycin: prevention of fetal toxoplasmosis in acute maternal toxoplasmosis infection Syphilis Early congenital syphilis (onset < 2 years) Jaundice and hepatosplenomegalyLymphadenopathyNasal discharge (sniffles)Maculopapular rash (with desquamation of the palms and soles)Skeletal abnormalities (e.g., osteodystrophy)Late congenital syphilis (onset > 2 years) Facial abnormalities: Frontal bossing, rhagades, Hutchinson triad (saddle nose, Hutchinson teeth, mulberry molars)Interstitial keratitisSensorineural deafnessSaber shinsVDRL or RPRDark-field microscopyPCRPenicillin Treatment (penicillin G) of mother in early pregnancy Listeriosis Spontaneous abortion and premature birthMeningitis, sepsisVesicular and pustular skin lesions (granulomatosis infantiseptica)Bacterial cultureAmpicillin and gentamicinAvoidance of unpasteurized dairy productsAvoidance of cold deli meats Varicella zoster virus(VZV) IUGR, premature birth Chorioretinitis, cataractEncephalitisPneumoniaCNS abnormalitiesHypoplastic limbsDirect fluorescent antigen test (DFA)PCR for VZVDNASerology (IgM antibodies)Varicella-zosterimmune globulin(VZIG) AcyclovirBreastfeedingActive immunization of mother before pregnancy Passive immunization with VZIG Parvovirus B19 Aplastic anemia Fetal hydrops PCR for parvovirus B19DNASerial ultrasounds to rule out fetal hydrops Intrauterine fetal blood transfusion if indicated Frequent hand washing Pregnant women with risk factors for TORCH infection should avoid potentially contaminated workplaces (e.g., schools, pediatric clinics) Rubella Petechiae and purpura (blueberry muffin rash)Congenital rubella syndrome (rare in developed countries) IUGRSensorineural deafness CataractsHeart defects (e.g., PDA, pulmonary artery stenosis)CNS abnormalities (e.g., intellectual disability, speech defect) HepatitisViral cultureSerology (IgM antibodies)PCR for rubellaRNASupportive careActive immunization of mother before pregnancy Second immunization of mother after delivery if serologic titers remain negative Cytomegaly virus (CMV) Jaundice, hepatosplenomegaly IUGR Chorioretinitis Sensorineural deafness Periventricular calcifications Petechiae and purpura (blueberry muffin rash) MicrocephalySeizures Viral culturePCR for CMVDNA Ganciclovir and valganciclovir Supportive careFrequent hand washingPregnant women with risk factors for TORCH infection should avoid potentially contaminated workplaces (e.g., schools, pediatric clinics) Herpes simplex virus (HSV) Premature birth, IUGR Skin, eyes, and mouth involvement: vesicular lesions, keratoconjunctivitis Localized CNS involvement: meningitis Disseminated disease: multiple organ involvement, sepsis Viral culture PCR for HSV DNA Acyclovir Supportive care Cesarean section if lesions are present at delivery Transplacental transmission occurs following primary infection of a seronegative mother during pregnancy. Maternal IgM antibodies, which are unable to cross the placenta, form first. Protective IgG antibodies, which are able to cross the placenta, have not yet been formed, so the infant is not protected from infection via the placenta. In general, the earlier the TORCH infection occurs during pregnancy, the more severe the complications! Attenuated live vaccines (measles, mumps, rubella, and varicella) are contraindicated in pregnancy! Conception should be avoided for at least 3 months after immunization with live vaccines!

Fever Treatment

Treatment Antipyretics Acetaminophen Acetaminophen is the preferred antipyretic during pregnancy but should be avoided in patients with severe hepatic dysfunction. NSAIDs IbuprofenAspirin NSAIDs are contraindicated in pregnancy and hemorrhagic fevers. They should be used with caution in breastfeeding patients and those with CAD.

Dermatophytes PathogenicityDermatophytes produce keratinase, which allows them to infect the skin, hair, and nails. Many dermatophytes are obligate pathogens. MorphologyForm hyphae and myceliumAfter penetration into the skin, concentric propagation may occur around the entry site.

Trichophytonspecies Occurs worldwide Partial yellow-greenfluorescence under Wood lamp Epidermophytonspecies Occurs worldwide No typical fluorescence under Wood lamp Microsporum species Occurs worldwide Partial blue-greenfluorescence under Wood lamp Dermatophyte infectionsTinea corporis(ringworm) and capitisTinea unguinum(onychomycosis) Tinea cruris(jock itch) Tinea pedis(athlete's foot) Tinea capitis Local: terbinafine and azoles Systemic .: terbinafine, itraconazole, fluconazole, and griseofulvin

Sexually transmitted infections The term "sexually transmitted infections" (STIs) refers to a group of infections that are mainly transmitted via sexual intercourse. The most common symptoms of STIs are pain in the suprapubic and genital area, urethral or vaginal discharge, and genital lesions, which may or may not be painful. Some STIs (e.g., HPV) may induce or predispose to malignant changes. The majority of STIs are asymptomatic, and therefore easily spread. If a patient is already infected with an STI, they are predisposed to coinfections with further STIs. There are various treatment options for each STI, with simultaneous treatment of the partner often necessary to prevent recurrent infections. In some cases, health care providers are required by law to report cases of STIs to county and health state departments (e.g., HIV, hepatitis B).

Viral Human papillomavirus (HPV)Condylomata acuminataBowenoid papulosis (condylomata plana)Local cytotoxic therapy (e.g., with 5-fluorouracil)CryotherapyOperative management: curettage (surgical excision), laser surgery, or electrosurgery Herpes simplex virus type 2 (HSV-2)Genital herpesAcyclovir PO for episodic or suppressive treatment HIVNoneSystemic antiretroviral therapy: HAART/cART Hepatitis BNoneSystemic antiviral therapy PO (e.g., entecavir)Interferon (immune modulating, antiviral, and antiproliferative agent) injected SC or IM Bacterial Chlamydia trachomatis D-KUrogenital chlamydia infections♀: Urethritis, vulvovaginitis, cervicitis, salpingitis, tubo-ovarian abscess, pelvic inflammatory disease (PID)♂: Urethritis, epididymitis, prostatitis Chlamydia trachomatis L1-L3Lymphogranuloma venereum Drug of choice: doxycycline or azithromycin POAlternative: fluoroquinolone (e.g., ciprofloxacin, moxifloxacin) Klebsiella granulomatisGranuloma inguinale Drug of choice: doxycycline or azithromycin POAlternative: fluoroquinolone (e.g., ciprofloxacin, moxifloxacin) Haemophilus ducreyiChancroidCeftriaxone IM single dose Plus azithromycin PO single dose Neisseria gonorrheaGonorrhea♀: Urethritis, Bartholin gland cyst, salpingitis, tubo-ovarian abscess, pelvic inflammatory disease, cervicitis♂: Urethritis, epididymitis Ceftriaxone IM single dose Plus azithromycin PO single dose Treponema pallidumSyphilisChancreCondylomata lataPenicillin G IMAlternatives if allergic to penicillin: tetracycline, macrolides or cephalosporin FungalCandida albicansVulvovaginal candidiasis (yeast infection)Local antimycotic agent (e.g., clotrimazole, nystatin)Alternative: fluconazole PO single dose ParasiticTrichomonas vaginalisTrichomoniasis (cervicitis)Metronidazole PO Phthirus pubisPediculosis pubis (pubic lice, crab louse) Irritated skin in the pubic hair region; tiny brown lice droppings detectablePermethrin 1% lotion (insecticide) Genital lesions PainlesslesionsHuman papillomavirusCondylomata acuminata Single or multiple skin-colored papular eruptions (1-5mm) ; smooth or verrucousUsually painlessLocated on internal and external genitaliaBowenoid papulosisSingle or multiple small papules (may coalesce into larger plaques)Pigmented, with a flat-to-verrucous surfaceMost commonly on the penis shaft or external female genitals Clinical exam and biopsy Klebsiella granulomatisGranuloma inguinale Large (5-10 mm), beefy-red, expanding suppurative ulcers ;Painless; bleed easilyOften malodorous because of bacterial coinfection Commonly located in skin foldsClinical exam and biopsy (Donovan bodies) Chlamydia trachomatis L1-L3Lymphogranuloma venereumTransient painless, small papule, or shallow ulcerRapid spontaneous healing without scarring♂: foreskin, glans, and scrotum♀: posterior vaginal wall, cervix, and vulvaPossibly concurrent discharge, cervical/adnexal/testicular tenderness, and painful inguinal lymphadenopathyPCR detects Chlamydia trachomatisRNA or DNA Treponema pallidumChancre Singular red, round, and raised painless ulcer with elevated edges Heals spontaneously within 4-8 weeksManifests mainly on the glans penis, or vulva and cervix Possibly concurrent regional adenopathyCondylomata lata Painless, warty erosions on the genitals in the secondary phase of syphilisthat are velvety, moist, and broad-basedResolve spontaneously after weeks to monthsDark field microscopy (spirochetes)Serum antibody test Painful lesionsHerpes simplex virus type 1 and 2 (mostly HSV-2)Genital herpesMultiple grouped, painful vesicles (1-3 mm) on an erythematous ground Possibly concurrent malaise, myalgias, and feverReactive painful inguinal lymphadenopathy commonExternal female genitalia and cervix , or glans and penis shaft Clinical examBest initial test: Tzanck smear(multinucleated giant cells) Haemophilus ducreyiChancroid Single or multiple painful papules or pustules (10-20 mm); yellowish-greyish exudate in the centerAffects the glans, penis shaft, and scrotum, or vulva and perineal areaPossibly concurrent painful inguinal lymphadenopathy and abscessformation Clinical exam and culture

Viral replication cycle and targets of antiviral drugs

Viruses are obligate pathogens, which depend on host-cell machinery for replication. Most antiviral agents target key enzymes required for viral replication (see viral life cycle for details). Fusion with host cellAttachment: CCR5-antagonist (e.g., maraviroc) Penetration: Fusion inhibitor (e.g., enfuvirtide)* Uncoating Release of nucleic acid Amantadine Replication of viral genomeReverse transcriptionNRTI (e.g., lamivudine)*NNRTI (e.g., nevirapine, efavirenz)* DNA integration (integrase) Integrase inhibitors (e.g., dolutegravir, elvitegravir, raltegravir)* Nucleic acid synthesis (DNA polymerase) Guanosine analogs (e.g., acyclovir, ganciclovir) Viral DNA polymerase inhibitors (cidofovir, foscarnet) Guanine nucleotide synthesis inhibitor: ribavirin Protein synthesis and assembly of viral components Protein synthesis (transcription and translation)Interferon alpha Proteolytic processing (protease) Protease inhibitors (e.g., boceprevir for HCV; atazanavir, darunavir, indinavirfor HIV)*Release of new viruses from host cellViral buddingNeuraminidase inhibitors (e.g., oseltamivir, zanamivir)

Inactivated vaccines

Whole inactivated or dead virus/bacteria Cannot replicate Subunit products of pathogen Toxoids Bacterial cell wall polysaccharide Conjugate polysaccharide vaccine is linked to a protein Polio (Salk; inactivated vaccine) Hepatitis A Rabies Pertussis (cellular vaccine) Cholera Japanese encephalitis Subunit: Hepatitis BInfluenzaPertussis(acellular vaccine)HPVAnthrax Toxoid vaccineDiphtheriaTetanus Hib Pneumococcal Meningococcal Salmonella typhi Mostly humoral immune response Number of circulating antibodies decreases over time Polysaccharides induce a relative T cell-independent B-cell response and therefore achieve sufficient immunization only in adults and older children. In conjugate vaccines, the carrier protein activates T-cells, which stimulate a more rapid and long-lasting immune response, especially in infants and toddlers. Less affected by circulating antibodies than live vaccines Not consistently immunogenic in infants Usually injected into the deltoid muscle (alternatively, e.g., in infants, injected into the vastus lateralis muscle) First dose does not provide protective immunity Multiple doses required Periodic "boosts" necessary to ensure sufficiently high antibody titers Inactivated vaccines may generally be combined with other vaccines without any time interval in between

Isotype switching (class switching)

Within the germinal centers of lymph nodes, activated B cells change the antibody isotype in response to specific cytokines that are released by Th cells. IgM, the primary antibody on B cells before getting activated, is switched to IgA, IgE, or IgG. IgM is also secreted by plasma cells (stimulated by IL-6). B cell class switching occurs via two signaling mechanisms1. signal = activation: Antigen bound to MHC II molecule binds to T-cell receptor on the surface of T-helper cells. 2. signal = CD40 membrane receptor on the B cell binds to CD40 ligand (CD40L) on the surface of CD4+ T cell (CD40L/CD40) → Released cytokinesdetermine immunoglobulin class switching.IL-4, IL-13 stimulate class switching to IgE.IL-5, TGF-β stimulate class switching to IgA.IFN-β stimulates class switching to IgG. The resulting antibody has the same affinity for the antigen but a different function. Isotype switching is irreversible.

Invasive diarrhea Food Poisoning Pathogens penetrate the mucosa and invade the reticuloendothelial system of the distal small intestine → enteric fever WBC positive (fecal mononoculear leukocytes) Blood may be present

Yersinia Milk/porkMay present as pseudoappendicitis Salmonella typhi or paratyphiPoultry/eggs