Amboss Pulmonology

Beta-2 adrenergic agonists β2 adrenergic agonists are used in pulmonology as bronchodilators, in obstetrics as tocolytic agents, and to manage patients with hyperkalemia. There are both short-acting and long-acting β2 agonists, and their duration of action determines their clinical application. Their effects are achieved through β2 receptor stimulation. Side effects are partially mediated by the β1 receptor and include anxiety and tremor, as well as life-threatening conditions such as ventricular arrhythmias.

All β2 adrenergic agonists selectively stimulate β2 adrenergic receptors. Relaxes bronchial smooth muscle Short-acting beta agonists (SABA)AlbuterolTerbutalinePirbuterolLevalbuterol1-5 min4-6 hLong-acting beta agonists (LABA)Formoterol1-5 min≥ 12 hSalmeterol30-45 min Side effects Cardiac: arrhythmias; tachycardia Central nervous system/muscular: tremor ElectrolytesHyperglycemiaHypokalemia Paradoxical bronchospasm may occur! ndications Bronchial asthma: used to achieve spasmolysis of the bronchi. COPD Preterm/undesired contractions in obstetrics: used for tocolysis Hyperkalemia: Beta-2 adrenergic agonists drive K+ intracellularly.

Chlamydia infections Chlamydiaceae is a family of gram-negative, obligate intracellular bacteria that includes 3 organisms pathogenic to humans: Chlamydia trachomatis, Chlamydophila pneumoniae, and Chlamydophila psittaci. C. trachomatis can be differentiated into serotypes A-C, D-K (the most common STI), and L1-L3. Serotypes A-C mainly affect the eyes and cause trachoma. An infection with serotypes D-K can result in genitourinary infections (e.g., vaginitis, PID, urethritis), conjunctivitis, and infant pneumonia. Serotypes L1-L3, in turn, lead to sexually transmitted lymphogranuloma venereum. While both C. pneumoniae and C. psittaci primarily affect the respiratory system, C. psittaci also causes psittacosis. Chlamydial infections are mostly diagnosed based on clinical presentation and are treated with doxycycline or macrolides. In all cases of sexually transmitted chlamydial infection, expedited partner therapy should also be initiated as soon as possible. All ocular manifestations are discussed in more detail in the conjunctivitis learning card.

Bacteria characteristics Gram-negative bacterium, but does not Gram stain well because: Obligate intracellular Lack of peptidoglycan (muramic acid) in the cell wall Visible as cytoplasmic inclusion bodies on Giemsa stain Characteristic life cycle consisting of two phases First phase: elementary bodies (characterize the infectious stage of Chlamydiaceae; metabolically almost inactive and environmentally stable)Attachment of extracellular elementary bodies to target cells (mostly on the respiratory or urogenital epithelium)EndocytosisTransformation into reticulate bodies in the endosome Second phase: reticulate bodies (represent the obligate intracellular, replicative, and metabolically active form of chlamydia)Multiplication and aggregation of various reticulate bodies in the endosome, which take over most of the infected cell, at which point they are called inclusion bodies. Inclusion bodies are visible under light microscopy.Transformation of reticulate bodies to elementary bodiesLysis of endosomesRelease of newly formed elementary bodies and exit from cellNew start of cycle Cultivation very difficult Chlamydia trachomatis A-CEyesSmear infection via discharge from the eyes or nose of infected personsCan be transmitted by direct contact, clothes, or insects. TrachomaD-KEyesGenitourinary tractLungsSexual intercourseVaginal birth (in which the mother is infected)Neonatal conjunctivitisInclusion conjunctivitisChlamydial genitourinary infectionsInfant pneumonia [1]Reactive arthritis [2]Proctitis (especially in MSMs) L1-L3Urinary tractAnorectal areaGenitourinary tractSexual intercourseLymphogranuloma venereum (LGV)Chlamydophila pneumoniaeLungsPerson-to-person transmission of respiratory secretionsInfection of the respiratory system → atypical pneumonia, especially in the elderly [3]Chlamydophila psittaciLungsAirborne transmission (pathogens in the feces and dander of birds)Respiratory disorder = psittacosis Chlamydial pneumonia Infant pneumonia due to Chlamydia trachomatis (serotypes D-K) [4][1]Transmission: perinatal transmission during delivery through contact with an infected mother's genital flora [5] Incubation period: 4-12 weeks after deliveryClinical features: pneumoniaStacatto cough, tachypnea, nasal congestion [6]Typically afebrile, although a mild fever is possibleAccompanied by neonatal conjunctivitis in up to 50% of all cases Prevention: maternal screening and treatment before birthComplications: respiratory failureTreatment: oral erythromycin (best choice), azithromycin[6] Chlamydophila pneumoniae Transmission: respiratory droplets [7]Incubation period: 3-4 weeksClinical features Sometimes asymptomaticGeneral symptoms of atypical pneumonia: fever, non-productive cough, headache, myalgias [8] Sometimes associated with pharyngitis and hoarseness [9] TreatmentFirst-line treatment: oral azithromycin, clarithromycinSecond-line treatment: oral doxycycline Chlamydophila psittaci → psittacosis ("parrot fever") (or ornithosis ) Transmission: airborne → pathogens from feces and dander of infected birds Mainly affects individuals in contact with free-ranging birds or pets, or occurs as an occupational diseaseIncubation period: 1-3 weeksClinical features: Symptoms can vary greatly. Acute onset of flu-like symptoms, especially fever[10]Atypical pneumonia with non-productive coughNotifiable disease: There is an obligation to report the condition in most states.[11]TreatmentFirst-line treatment: doxycyclineSecond-line treatment: macrolides (e.g., azithromycin, erythromycin) Drug of choice for children and pregnant womenAlternative: fluoroquinolones Sexually transmitted infections Chlamydial genitourinary infections Pathogen: Chlamydia trachomatis serotypes D-K (also see the learning card on sexually transmitted infections) Epidemiology: One of the most common STIs in the US (∼ 1.5 million reported infections per year)[12]One of the most common causes of pelvic inflammatory disease (PID) InfectionsMen: epididymitis, prostatitisWomen: vaginal infections, salpingitis, cervicitisBoth men and women: urethritis, proctitis [13] Clinical featuresThe majority of infected individuals are asymptomatic, which leads to a delay in seeking treatment, and thus increases the risk of disease transmission.(Muco)purulent vaginal discharge and/or intermenstrual or postcoital bleedingMay present with dysuria, polyuria, dyspareuniaSee "Clinical features" of pelvic inflammatory disease DiagnosticsNucleic acid amplification tests (NAAT): the gold standardPolymerase chain reaction (PCR) detects Chlamydia trachomatis RNA or DNA from vaginal swabs (women) or first-catch urine (men)Helps differentiate between C. trachomatis and N. gonorrheaAntigen detection Uses an enzyme immunoassayThe specimen is collected with a swab from the cervix or urethra.The sensitivity is 80-95%. [13] TreatmentAzithromycin or doxycycline [14][15]If gonococcal infection is suspected, combine azithromycin with ceftriaxone.[16]Pregnant women: azithromycinExpedited partner therapy is recommended in most cases of STIs, particularly chlamydia and gonorrhea.Asymptomatic patients should also be treated to prevent serious complications (i.e., PID and infertility) and further spreading [17]Children Erythromycin for children weighing < 45 kgAzithromycin for children weighing > 45 kgFluoroquinolones are contraindicated. ComplicationsPIDEctopic pregnancyInfertilityReactive arthritisPerinatal transmission of infection to the newborn is possible → risk of conjunctivitis, otitis media, and/or pneumonia Screening for chlamydia (CDC recommendations) Annual NAAT screening of chlamydia (typically also gonorrhea) for:[18]Sexually active women < 25 yearsWomen > 25 years with risk factors (e.g., new or multiple sex partners, sex partner with an STI)If positive for chlamydia, screen for HIV and other STIs.[15] Lymphogranuloma venereum [19] Lymphogranuloma venereum (LGV) causes painless genital ulcers, which heal spontaneously within a few days. After a few weeks, swelling of the lymph nodes occurs, with possible abscess formation and discharge of pus. Without antibiotictreatment, this can lead to chronic lymphedema. (Also see the learning card on sexually transmitted infections) Pathogen: Chlamydia trachomatis serotypes L1-L3 EpidemiologyFound mostly in tropical and subtropical countriesIncreasing incidence among MSMs Clinical featuresPrimary infection after about a week: painless, herpetiform ulcersSecondary infection after about three weeks: painful lymph nodes in the inguinal region (buboes) with formation of abscesses (pus), systemic symptoms Treatment: doxycycline; alternatively, erythromycin ComplicationsFibrotic changes; strictures in the anogenital tractGenital elephantiasisInfertility Lymphogranuloma venereum (pathogen: Chlamydia trachomatis serotypes L1-L3) should not be mistaken for granuloma inguinale or donovanosis (pathogen: Klebsiella granulomatis)!

Chronic obstructive pulmonary disease Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by airway obstruction due to inflammationof the small airways. It is caused predominantly by inhaled toxins, especially via smoking (90% of cases), but air pollution and recurrent respiratory infections can also cause COPD. Some individuals are genetically predisposed to COPD, particularly those with α1-antitrypsin deficiency (AATD). COPD begins with chronic airway inflammation that usually progresses to emphysema, a condition that is characterized by irreversible bronchial narrowing and alveolar hyperinflation. These changes cause a loss of diffusion area, which can lead to inadequate oxygen absorption and CO2release, resulting in hypoxia and hypercapnia. Most affected individuals present with a combination of dyspnea and chronic cough with expectoration. In later stages, COPD may manifest with more severe symptoms such as tachypnea, tachycardia, and cyanosis. Diagnosis is primarily based on clinical presentation and lung function tests, which typically show a decreased ratio of forced expiratory volume (FEV) to forced vital capacity (FVC). Imaging studies, such as chest x-ray, are helpful in assessing disease severity and the extent of possible complications, but they are not required to confirm the diagnosis. ABG and pulse oximetry are useful for quickly assessing the patient's O2 status. All COPD patients should be staged according to the staging system of the Global Initiative for Chronic Obstructive Lung Disease (GOLD), which considers a variety of factors (e.g., exacerbations, symptom severity, FEV1). Treatment options depend on the GOLD stage and mainly consist of short- and long-acting bronchodilators (beta-agonists and parasympatholytics) and glucocorticoids. Individuals with advanced disease typically require oxygen supplementation, which is the only treatment that decreases mortality. COPD may cause complications such as pulmonary hypertension or respiratory failure; the most significant complication is acute exacerbation of COPD (AECOPD).

Definition A chronic pulmonary disease characterized by persistent respiratory symptoms and airflow limitation (postbronchodilator FEV1/FVC < 0.70), which is caused by a mixture of small airway obstruction and parenchymaldestruction. COPD was formerly subdivided into chronic bronchitis and emphysema. These terms are still widely used to describe patient findings and found as subclasses of COPD in outdated literature. Chronic bronchitis: productive cough (cough with expectoration) for at least 3 months each year for 2 consecutive yearsEmphysema: permanent dilatation of pulmonary air spaces distal to the terminal bronchioles, caused by the destruction of the alveolar walls and the pulmonary capillaries required for gas exchange. Epidemiology Sex: 3:2 male/female ratio [1][2] The third most common cause of death worldwide [3] Prevalence: 6% [4] Etiology Exogenous factorsTobacco use (90% of cases) Smoking is the major risk factor for COPD, but those who have quit ≥ 10 years ago are not at increased risk. [6]Passive smoking Exposure to air pollution or fine dusts Nonorganic dust: such as industrial bronchitis in coal minersOrganic dust: ↑ incidence of COPD in areas where biomass fuel (e.g., wood, animal dung) is regularly burned indoorsRecurrent pulmonary infections and tuberculosisPremature birth Endogenous factorsα1-Antitrypsin deficiencyAntibody deficiency syndrome (e.g., IgA deficiency)Primary ciliary dyskinesia (e.g., Kartagener syndrome) For GOLD categories according to the FEV1 %, remember that 30 + 50 = 80. GOLD 1 (Class I)Mild≥ 80%GOLD 2 (Class II) Moderate50% ≤ FEV1 < 80%GOLD 3 (Class III) Severe30% ≤ FEV1 < 50%GOLD 4 (Class IV) Very severe< 30% CAT score = COPD assessment test score mMRC Dyspnea Scale = Modified Medical Research Council Dyspnea Scale Low risk = FEV1/FVC ratio ≤ 0.7, FEV1≥ 50% predicted, and 0-1 exacerbation in the last year High risk = FEV1/FVC ratio ≤ 0.7, FEV1 ≤ 50% predicted, and ≥ 2 exacerbations in the last year Emphysema is divided into the following subtypes: Centrilobular emphysema (centriacinar emphysema) Most common type of emphysemaClassically seen in smokersCharacterized by the destruction of the respiratory bronchiole (central portion of the acinus)Usually affects the upper lobe Panlobular emphysema (panacinar emphysema) Rare type of emphysemaAssociated with α1-antitrypsin deficiencyCharacterized by the destruction of the entire acinusUsually affects the lower lobe Other classifications or typesCicatricial emphysemaMainly caused by exposure to quartz dustResults in chronic inflammation and nodular scar formationGiant bullous emphysemaCharacterized by large bullae (congenital or acquired) that extrude into the surrounding tissueBullae may rupture, leading to pneumothorax.Depending on the shape of the bullae, resection should be considered.Senile emphysemaLoss of pulmonary elasticity with age may lead to an emphysematous lung.Not considered pathological but a normal consequence of aging COPD is characterized by chronic airway inflammation and tissue destruction. Chronic inflammation: results from significant exposure to noxious stimuli Caused by increased oxidative stress (most commonly due to cigarette smoke) as well as by increased release of reactive oxygen species by inflammatory cellsIncreased number of neutrophils, macrophages, and CD8+ T lymphocytes → release of cytokines →amplification of inflammation and structural changes of lung parenchyma (e.g., growth factor release)Promotes goblet cell proliferation, mucus hypersecretion, and impaired ciliary function → chronic productive coughReid index: The ratio of the width of the mucus-secreting glands to the combined width of the epithelium and cartilage in the bronchial tree. > 0.5 is characteristic of chronic bronchitis.Overproduction of growth factor → peribronchiolar fibrosis → narrowing of airway → obliteration →emphysema (airflow limitation)Smooth muscle hyperplasia of the small airways and pulmonary vasculature (mainly due to hypoxicvasoconstriction) → pulmonary hypertension → cor pulmonale Tissue destructionBronchopulmonary inflammation ↑ proteases, and nicotine use (or other noxious stimuli) inactivates protease inhibitors (especially α1-antitrypsin) → imbalance of protease and antiprotease → ↑ elastase activity → loss of elastic tissue and lung parenchyma (via destruction of the alveolar walls), which causes:Enlargement of airspaces → ↓ elastic recoil and ↑ compliance of the lung → ↓ tethering of small airways →expiratory airway collapse and obstruction → air trapping and hyperinflation → ↓ ventilation (due to air-trapping) and ↑ dead space → ↓ DLCO and ↑ ventilation-perfusion mismatch (Va/Q) → hypoxemia and hypercapnia↓ Blood volume in pulmonary capillaries → ↑ dead space → ↓ DLCO and ↑ Va/Q → hypoxemia and hypercapniaImbalance of oxidants and anti-oxidants and an overabundance of free radicals → contributes to chronic inflammation and inactivation of anti-elastase → exacerbates breakdown of elastic tissue Clinical features Symptoms are minimal or nonspecific until the disease reaches an advanced stage. Common presenting findings: Chronic cough with expectoration (expectoration typically occurs in the morning)Dyspnea and tachypneaInitial stages: only on exertionAdvanced stages: continuouslyPursed-lip breathing End-expiratory wheezing, crackles, muffled breath sounds, and/or coarse rhonchi on auscultationTachycardiaCyanosisOften weight loss and cachexia In cases of advanced COPD and/or cor pulmonale: Congested neck veins Barrel chest Asynchronous movement of the chest and abdomen during respirationUse of accessory respiratory muscles due to diaphragmatic dysfunction Hyperresonant lungs, reduced diaphragmatic excursion, and relative cardiac dullness on percussionDecreased breath sounds on auscultation: "silent lung" (silent chest on auscultation)Prolonged expiratory phasePeripheral edema (most often ankle edema) Right ventricular hypertrophy with signs of right heart failureHepatomegalySecondary polycythemiaConfusion Nail clubbing in the case of certain comorbidities (e.g., bronchiectasis, pulmonary fibrosis, lung cancer) According to their clinical appearance, patients with COPD are often categorized as either "Pink Puffer" or "Blue Bloater". Pink PufferEmphysemaNoncyanotic Cachectic Pursed-lip breathing Mild cough Blue Bloater Chronic bronchitisProductive cough Overweight Peripheral edemaMarked low O2 Increased (early hypercapnia) Patients with COPD in association with AATDAge of onset is generally younger (< 60 years)Also often have hepatic signs and symptoms (jaundice) related to hepatitis or cirrhosis Nail clubbing is not a finding specific to COPD; its presence usually suggests comorbidities such as bronchiectasis, pulmonary fibrosis, or lung cancer. Diagnostics Pulmonary function tests Spirometry and/or body plethysmography FEV1/FVC < 70% (Tiffeneau-Pinelli index) Normal or decreased FVCDecreased FEV1: used to classify COPD according to GOLD (see classification above)Increased FRC and RVTLCChronic bronchitis: normalEmphysema: increasedIncreased intrathoracic gas volumeDLCOChronic bronchitis: normalEmphysema: decreased Post-bronchodilator testAssesses reversibility of bronchoconstriction Procedure Spirometry to establish a baselineInhalation (e.g., salbutamol)Perform spirometry again after ∼10-15 min.Results: FEV1/FVC < 0.7 is diagnostic of COPD (in patients with typical clinical features and exposure to noxious stimuli). FEV1 > 12% (reversible bronchoconstriction): Asthma is more likely than COPD.If spirometry is normal, COPD can be excluded.FEV1 < 12% (irreversible bronchoconstriction): COPD is more likely than asthma. Blood gas analysis (BGA) and pulse oximetry Pulse oximetry: assess O2 saturation BGA: only indicated when O2 is < 92% or if the patient is severely ill (e.g., altered mental status, acute exacerbation) Hypoxemia and hypercapnia with acute or chronic respiratory acidosisDecreased pO2: partial respiratory failureDecreased pO2 and increased pCO2: global respiratory failure Possibly increased hemoglobin (polycythemia) Imaging Indications: not required for routine diagnosis but often used as an initial modality, mainly to rule out alternative conditions (e.g., pulmonary fibrosis, bronchiectasis) Chest x-rayNot sensitive, especially during the early stages of COPDCan be used to determine the etiology for an acute COPD exacerbation (e.g., pneumonia, congestive heart failure)Signs of hyperinflated lungs (barrel chest) Hyperlucency of lung tissue (decreased lung markings)Increased anteroposterior diameterDiaphragm pushed down and flattenedHorizontal ribs and widened intercostal spacesLong narrow heart shadowParenchymal bullae or subpleural blebs (pathognomonic of emphysema) The retrosternal space is increased on lateral view due to emphysematous changes in the lung tissue. Chest CTEvaluate possible complications (e.g., pneumothorax, ARDS).Plan surgery (e.g., lung volume reduction, lung transplantation).Rule out differential diagnoses (e.g., bronchiectasis, lung cancer). In most patients with COPD: centriacinar emphysema In patients with AATD: panacinar emphysema , bronchiectasis, bullae Other tests Laboratory studiesIncreased serum hematocrit In patients suspected of AATD (≤ 50 years of age, hepatic symptoms): α1-Antitrypsin levelsElectrophoresis: decreased alpha-1 peak Gram stain and sputum culture: in the case of suspected pulmonary bacterial infection (e.g., fever, productive cough, new infiltrate on chest x-ray) Bronchoscopy: to identify the pathogen in severe and acute exacerbation of COPD with infective etiology, especially if antibiotic treatment fails Liver biopsy in patients with AATD: PAS-positive, spherical inclusion bodies in periportal hepatocytes Treatment General treatment Cessation of tobacco use (single most effective step to slow the decline in lung function) VaccinationsPneumococcal: reduces the incidence of community-acquired pneumonia and invasive pneumococcal diseasesAge 19-64 years: Administer PPSV23.Age ≥ 65 yearsVaccinated: Administer PPSV23 (should be at least 5 years after the previous PPSV23 dose and at least 1 year after PCV13).Not vaccinated or unknown vaccination history: Administer PCV13 followed by PPSV23Immunocompetent patients: Administer PPSV23 after 1 year.Individuals with immunocompromising conditions, cerebrospinal leaks, or cochlear implants: Administer PPSV23 after 8 weeks.Influenza (annual): reduces serious illness and death in COPD patients Pulmonary rehabilitation (indicated in patients with GOLD B, C, and D): physiotherapy with breathing exercises Pursed lip breathing: A breathing technique in which the patient breathes in through the nose and breathes out slowly through pursed lips. This technique increases airway pressure and prevents bronchial collapse during the last phase of expiration.Physical activity helps maintain endurance and alleviate dyspnea. Supportive treatment (e.g., postural drainage) Vitamin D3 and calcium in cases of deficiency Medical treatment according to GOLD Medical treatment in COPD reduces the severity of symptoms, improves overall health status, and lowers the frequency and severity of exacerbation. The first-line treatment of COPD consists of bronchodilators, inhaled corticosteroids, and phosphodiesterase (PDE) type 4 inhibitors. Bronchodilators: either parasympatholytics (see muscarinic antagonists) or β2-agonists Long-acting parasympatholytics (long-acting muscarinic antagonists, LAMAs): tiotropium bromideLong-acting β2-agonists (LABAs): salmeterol, formoterolShort-acting parasympatholytics (short-acting muscarinic antagonists, SAMAs): ipratropium bromideShort-acting β2-agonists (SABAs): salbutamol, fenoterol Inhaled corticosteroids (ICS): budesonide, fluticasone, beclomethasone PDE type 4 inhibitors: roflumilast ≤ 1 exacerbation(Gold A)Any bronchodilator (SABA or LABA)(Gold B)Any long-acting bronchodilator (LABA or LAMA)If severe dyspnea: LABA and LAMA≥ 2 exacerbation or ≥ 1 exacerbation requiring hospitalization(Gold C)LAMA(Gold D)LAMA orIf highly symptomatic (CAT > 20): LAMA and LABAorIf eosinophil count is ≥ 300/μl: LABA and ICSFor all groups: a SABA and/or SAMA can be added as needed Follow-up treatment If dyspnea persistsMonotherapy with LABAIf severe symptoms: add LAMAIf eosinophil count is > 300/μl or if eosinophil count > 100/μl and ≥ 2 exacerbations or 1 hospitalization have occurred: add ICS If exacerbations still occurLABA and LAMA orLABA and ICS If exacerbations still occur, escalate to triple therapy:If eosinophil count is ≥ 100/μl: LABA, LAMA, and ICSIf eosinophil count is < 100/μl: LABA, LAMA, and either: PDE-4 inhibitor (roflumilast) orIf non-/ex-smoker: azithromycinIf exacerbations still occur with LABA, LAMA, and ICS triple therapy: If FEV1 < 50 % and chronic bronchitis: add roflumilastIf non-/ex-smoker: add a macrolide (e.g., azithromycin)Stop ICS (due to possible adverse effects such as pneumonia)If increasing purulent sputum and/or mechanical ventilation is involved: add empiric treatment with aminopenicillin with clavulanic acid, macrolide, or tetracycline Other treatment options TheophyllineMechanism of action: adenosine receptor blockade and nonspecific PDE inhibitionIndication: usually only severe and refractory COPDMetabolism by the liver cytochrome P450 oxidase systemSignificant risk for drug interactions (e.g., ciprofloxacin, cimetidine) and variable serum concentrationsSide effects: Drug monitoring is necessary because theophylline has a very low therapeutic index and elimination time varies among individuals. Severe, refractory nausea and vomiting with abdominal painCardiotoxicity: tachycardia that may degenerate into arrhythmias and hypotension in severe casesNeurotoxicity: CNS involvement (e.g., tremor, agitation, insomnia, psychotic symptoms), seizures in severe casesContraindications: damaged cardiac muscle Long-term oxygen therapy (LTOT) indicated in the case of: PaO2 ≤ 55 mm Hg or SaO2 ≤ 88 % at rest Increases the chance of survival in patients with COPDSupplemental O2 can worsen hypercapniaThe target oxygen saturations is 90-93%.PaO2 between 55 and 60 mmHg or SaO2 of 88 mmHg if there is evidence of pulmonary hypertension, congestive cardiac failure, or polycythemia Mucolytics (e.g., N-acetylcysteine) liquefy mucus by reducing the disulfide bonds of mucoproteins. Other indications include: Cystic fibrosisAcetaminophen overdose (antidote): acetylcysteine restores depleted hepatic glutathioneProphylaxis of contrast agent nephropathy Surgery may be beneficial in severe cases Lung resection for giant bullae in emphysemaLung transplantation for nonrepairable damage Complications Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) Definition: an acute worsening of respiratory symptoms (e.g., increased dyspnea, changes in sputum consistency) Etiology 80% of cases are caused by infection (especially in winter and fall). Most commonly Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae and viruses such as influenzaPseudomonas aeruginosa infection is possible in case of: Advanced COPDHistory of multiple hospitalizationsBronchiectasisFrequent antibiotic treatmentSystemic glucocorticoid use Congestive heart failure and pulmonary embolism Can be triggered by drugs (e.g., beta blockers), allergens, air pollution, stress Associated with former antibiotic use, advanced age, advanced COPD stage, and peripheral eosinophilia Clinical features Worsening of respiratory symptoms (cough, expectoration, dyspnea)Worsening of dyspneaIncreased frequency and severity of coughChange in quantity and quality of sputum Wheezing, tachypnea Fever accompanied by chills Previous treatment has not relieved symptoms. Patients with severe AECOPD present with: Respiratory failureRetractions Thoracoabdominal asynchrony Severe hypoxemia/respiratory acidosisAltered mental status Central cyanosis Diagnostics CXR to determine etiology of COPD exacerbation (e.g., features of pneumonia, congestive heart failure)Arterial blood gas findings/pulse oximetry: hypercarbia, hypoxemia, and acidosis Treatment Oxygen supplementation: if O2 < 92%, but be mindful that inappropriate O2 therapy poses a risk of life-threatening hypercapnia (CO2 narcosis)Although the causes are not entirely understood, oxygen-induced hypercapnia is theorized to occur via a combination of two mechanisms if too much O2 is given (inappropriate O2 therapy): [30]↓ Hypoxic pulmonary vasoconstriction: ↑ FiO2 → ↑ alveolar O2 tension → ↓ hypoxic pulmonary vasoconstriction → ↑ V/Q mismatch and hypercapniaHaldane effect: ↑ FiO2 → ↑ oxygenated Hb, which has less affinity to bind CO2 (right shift in the CO2dissociation curve) → CO2 is released from Hb and RBCs → ↑ PaCO2Another commonly taught mechanism for O2-induced hypercapnia is that giving O2 causes hypercapnia by inactivating the hypoxic respiratory drive, but studies have disproven this theory. [30] Medical treatmentBeta agonists: inhaled SABA (e.g., albuterol, levalbuterol) PLUSAnticholinergics: SAMA (e.g., ipratropium bromide)Possibly add: Systemic glucocorticoids: prednisolone (oral) or methylprednisolone (IV) in severe treatment-refractoryexacerbationsAntibiotic treatment is indicated for patients with ≥ 2 of the following cardinal symptoms:Increased dyspneaIncreased coughIncreased sputum productionAntibiotic treatment protocol in exacerbated COPD is the same as that for bacterial pneumonia and involves aminopenicillin in combination with clavulanic acid, macrolides, or tetracycline. It should cover Haemophilusinfluenza, Streptococcus pneumonia, and Moraxella catarrhalis.In the case of suspected of Pseudomonas aeruginosa infection: piperacillin-tazobactam, cefepime, ceftazidime, or levofloxacin Mechanical ventilation: indicated for patients with severe AECOPDNoninvasive ventilation (NIV): most commonly NIV with bilevel positive airway pressure (BiPAP)Invasive ventilation (i.e., intubation): only if NIV is contraindicated or not tolerated Supportive care Smoking cessation Bedrest in a recumbent position Avoid tobacco use Thromboprophylaxis Chronic respiratory failure Description: Chronic respiratory failure occurs in the advanced stages of COPD due to progressive emphysematous changes and loss of diffusion surface area.Depending on the severity and etiology, treatment includes: Long-term oxygen therapyUse of a portable respiratorLung volume reduction surgeryLung transplantation (only if absolutely necessary) Criteria: Long-standing partial respiratory failure (pO2 at rest < 60 mm Hg)Global respiratory insufficiency failure (pO2 changes at rest < 60 mm Hg and pCO2 > 45 mm Hg) Long-term oxygen therapy (LTOT): 16 hours oxygen administration per day (minimum dosage) is associated with lower mortality rates. Indication: patients with COPD GOLD D and severe respiratory insufficiency failure that exhibit long-standingpO2 < 55 mm Hg, despite administration of optimal medication Oxygen administration is regulated in a way that the pO2 value rises and pCO2 drops to a level of 60-70 mm Hg. Hypercapnia would lead to respiratory acidosis and disorientation and should be prevented. Portable respirationPrinciple: A type of non-invasive respiration done overnight when the patient is asleep. This allows recovery of the respiratory muscles and in turn permits better respiratory function during the day. Lung volume reduction surgeryPrinciple: Surgical or endoscopic removal of severely affected emphysematous areas of the lung. This procedure reduces lung hyperinflation, which improves dyspnea and lung function. Lung transplantation: It is considered the last resort in patients with emphysema associated with advanced COPD and severe diffusion dysfunction. Other complications Alveolar hypoventilation → hypoxic pulmonary vasoconstriction → pulmonary hypertension → cor pulmonale (right heart failure) Pulmonary cachexia Secondary spontaneous pneumothorax due to rupture of bullae (especially in bullous emphysema) Prognosis 40-70% of all COPD patients survive the first 5 years after diagnosis Survival rates vary significantly depending on the severity of the disease. [33] Measures the improve survival Cessation of tobacco useLong-term supplemental O2 therapy is the only treatment that improves mortality.

Pulmonary hypertension and cor pulmonale Pulmonary hypertension (PH) is elevated pressure in the pulmonary arteries ≥ 20 mm Hg at rest. It can be idiopathic or due to chronic pulmonary (e.g., COPD, chronic sleep apnea) and/or cardiac disease (e.g., mitral valve disease). Over time, the rise in pressure may result in structural changes (e.g., dilation or hypertrophy) or impaired function of the right ventricle. If these changes are secondary to diseases of the lungs or the pulmonary artery system, the condition is referred to as cor pulmonale. While PH and cor pulmonale are often asymptomatic in early stages, symptoms like dyspnea on exertion, fatigue, cyanosis, and syncope appear in later stages. In decompensated cor pulmonale, the risk of arrhythmias and death is high. Echocardiograms are used as an initial non-invasive test to estimate the pulmonary arterypressure and to demonstrate an altered structure of the right ventricle. Right heart catheterization provides the definite diagnosis and the exact mean pulmonary arterial pressure (mPAP). Treatment mainly consists of management of the underlying causes of PH and cor pulmonale. Supplemental oxygen, pulmonary vasodilators, and diuretics may be given to reduce pulmonary artery hypertension and improve blood oxygenation. Lung transplantation is the treatment of last resort in refractory cases.

Definition Pulmonary hypertensionChronically elevated mean pulmonary arterial pressure (mPAP) at rest ≥ 20 mm Hg (normal: 10-14 mm Hg) due to chronic pulmonary and/or cardiac disease or unknown reasonsPlus elevated pulmonary vascular resistance of ≥ 3 Wood units for patients with pre-capillary pulmonary hypertension (e.g., pulmonary arterial hypertension) [1] Cor pulmonale: altered structure (hypertrophy, dilation) or impaired function of the right ventricle caused by pulmonary hypertension resulting from a primary disorder of the respiratory or pulmonary artery system Chronic cor pulmonale: most common form; slow progressionAcute cor pulmonale: sudden overload of the right ventricle, usually due to acute pulmonary embolism; represents a life-threatening condition. Classification of pulmonary hypertension (WHO) by cause Group 1: Pulmonary arterial hypertension (PAH)IdiopathicHereditary (e.g., BMPR2 mutation)Drug-induced: sympathomimetic appetite suppressants (e.g., diethylpropion), amphetamines, cocaineAssociated conditions: HIV, connective tissue diseases, portopulmonary hypertension, congenital heart disease, schistosomiasis Group 2: Left heart disease (e.g. valvular heart diseases, left-to-right shunt) Group 3: Chronic lung diseases and/or hypoxemiaCOPD, emphysemaObstructive sleep apneaInterstitial lung disease Group 4: Chronic thromboembolic occlusion of the pulmonary vessels Group 5: Unclear multifactorial mechanisms Pulmonary hypertension can also be classified as pre-capillary or post-capillary. Chronic pulmonary and cardiac diseases can lead to pulmonary hypertension! Cor pulmonale Chronic form: diseases of the airway, pulmonary vasculature, and chest wallCOPD Chronic sleep apneaBronchiectasis [6]Idiopathic pulmonary arterial hypertensionKyphoscoliosis Life-threatening acute form is almost always due to acute massive pulmonary embolism. Pathophysiology Increased pulmonary vascular resistanceOcclusive vasculopathy (idiopathic pulmonary arterial hypertension (IPAH) , connective tissue diseases)Perivascular parenchymal changes (e.g., pulmonary embolism, interstitial lung disease)Hypoxic pulmonary vasoconstriction (e.g., COPD, obstructive sleep apnea) Chronic hypoxic pulmonary vasoconstriction → airway smooth muscle hypertrophy and pulmonary vascular bed destruction → increased pulmonary vascular resistanceInflammation (e.g., COPD) → increased inflammatory cell infiltration of intima → thickened endothelial wallPAH associated with endothelial dysfunction: ↑ endothelin → vasoconstriction [12] Increased pulmonary venous pressureVolume or pressure overload from left-sided heart disease (e.g. mitral valve regurgitation) Increased pulmonary blood flowLeft-to-right shunt (e.g., ASD, VSD, PDA)Sickle cell anemiaIncreased pressure in pulmonary circuit → elevated right ventricular afterload → dilatation and/or hypertrophy of the right heart→ right heart failure and arrhythmias → death. Clinical features Often asymptomatic in early stages Fatigue Dyspnea and/or syncope on exertion (due to an inadequate increase in cardiac output during exercise because of increased pulmonary vascular resistance) Cyanosis Chest pain Clinical features of underlying etiology Less common Hoarseness Cough, hemoptysis Physical examination Loud and palpable second heart sound (often split)Parasternal heave Nail clubbingJugular vein distention Symptoms of right heart failure Diagnostics The diagnostic evaluation of cor pulmonale is inseparable from the evaluation of PH. Testing aims at confirming PH with or without cor pulmonale and determining its severity and underlying pathology. Doppler echocardiography (best initial test)Hypertrophy and/or dilation of the right heart ventricleDilation of the coronary sinusEstimation of pulmonary arterial pressure Right heart catheterization (confirmatory test)mPAP ≥ 20 mmHg at restPulmonary capillary wedge pressure: ≥ 15 mmHg in PH due to left heart diseaseIn pre-capillary PH: pulmonary vascular resistance ≥ 3 Wood units [1] Electrocardiography: right axis deviation due to right ventricular hypertrophy Chest x-rayPronounced central pulmonary arteriesRight heart hypertrophy (prominent right heart border)Signs of underlying cause (e.g., nodular opacities in interstitial lung disease, barrel chest in COPD) Treatment Initial therapy should be directed at the underlying cause of PH or cor pulmonale. Patients with persistent pulmonary hypertension and cor pulmonale despite treatment of the underlying cause should be evaluated for pulmonary vasodilator therapy in a specialized center. Treatment of the underlying cause Additional treatmentDiuretics Physical exercise Oxygen therapy Pulmonary vasodilator therapy Calcium channel blockersLong-acting synthetic prostacyclin (epoprostenol) or prostacyclin analogs (e.g., iloprost, treprostinil): bind to prostacyclin receptors Endothelin receptor antagonists (e.g., bosentan, macitentan, and ambrisentan): inhibit endothelin-1 receptors Phosphodiesterase 5 inhibitors (e.g., sildenafil; see PDE-inhibitors) Patients who are refractory to medical treatmentAtrial septostomy (right-to-left shunt) orHeart-lung/bilateral lung transplantation In acute cor pulmonale: see treatment of "Pulmonary embolism"Maintain adequate blood pressure (e.g., IV fluids, vasoconstrictors)Correct primary problem (e.g., anticoagulation, thrombolytic or surgical embolectomy in pulmonary embolism)Over-diuresis may result in under-filling of the right ventricle and a decrease in cardiac output, leading to further complications such as prerenal failure! Therapy should be initiated early before irreversible changes in the pulmonary vessels occur!

Pulmonary embolism Pulmonary embolism (PE) is the obstruction of one or more pulmonary arteries by solid, liquid, or gaseous masses. In most cases, the embolism is caused by blood thrombi, which arise from the deep vein system in the legs or pelvis (deep vein thrombosis) and embolize to the lungs via the inferior vena cava. Risk factors include immobility, inherited hypercoagulability disorders, pregnancy, and recent surgery. The clinical presentation is variable and, depending on the extent of vessel obstruction, can range from asymptomatic to cardiogenic shock. Symptoms are often nonspecific, including chest pain, coughing, dyspnea, and tachycardia. The diagnosis of PE is based primarily on the clinical findings and is confirmed by detection of an embolism in contrast CT pulmonary angiography (CTA). Arterial blood gas analysistypically shows evidence of respiratory alkalosis with low partial oxygen pressure, low partial carbon dioxide pressure, and elevated pH. Another commonly performed test is the measurement of D-dimer levels, which can rule out PE if negative. Empiric anticoagulation with heparin is initiated to prevent further thromboembolisms as well as to promote the gradual dissolution of the embolism and the underlying thrombosis. Blood-thinning therapy must be continued for at least three months with oral anticoagulants such as warfarin. In fulminant PE with shock, resolution of the thrombus with thrombolytic agents or removal in an emergency surgery is attempted.

Epidemiology Accounts for ∼ 100,000 deaths in the US per year. Incidence rises with age. Sex: ♂ > ♀ Etiology Deep vein thrombosis (most common cause)Risk factors: obesity, hypomobility or immobility, malignancy, pregnancy, dehydration , hypercoagulability, use of contraceptives, previous DVT (see risk factors for deep vein thrombosis) Fat embolism during major surgical interventions (e.g., endoprosthesis replacement, osteosynthesis) Others: air embolism, amniotic fluid embolism, tissue embolism, cement embolism, bacterial embolism, tumorembolism Pathophysiology Mechanism: thrombus formation (see Virchow's triad) → deep vein thrombosis in the legs or pelvis (most commonly iliac vein) → embolization to pulmonary arteries via inferior vena cava → partial or complete obstruction of pulmonary arteries Pathophysiologic response of the lung to arterial obstructionInfarction and inflammation of the lungs and pleuraCauses pleuritic chest pain and hemoptysisLeads to surfactant dysfunction → atelectasis → ↓ PaO2Triggers respiratory drive → hyperventilation and tachypnea → respiratory alkalosis with hypocapnia(↓ PaCO2)Impaired gas exchangeMechanical vessel obstruction → ventilation-perfusion mismatch → arterial hypoxemia (↓ PaO2) and elevated A-a gradient (see "Diagnostics" below)Cardiac compromiseElevated pulmonary artery pressure (PAP) due to blockage → right ventricular pressure overload → forwardfailure with decreased cardiac output → hypotension and tachycardiaClinical features Acute onset of symptoms, often triggered by a specific event (e.g., on rising in the morning, sudden physical strain/exercise) Dyspnea and tachypnea (> 50% of cases) Sudden chest pain (∼ 50% of cases), worse with inspiration Cough and hemoptysis Possibly decreased breath sounds, dullness on percussion, split-second heart sound audible in some cases Tachycardia (∼ 25% of cases), hypotension Jugular venous distension Low-grade fever Syncope and shock with circulatory collapse in massive PE (e.g., due to a saddle thrombus) Symptoms of DVT: unilaterally painful leg swelling Initial management according to modified Wells criteria Hemodynamically stable patients (systolic BP > 90 mmHg) with high probability of PE (Wells score > 4) → CTA for definitive diagnosisUnless strongly contraindicated (e.g., high risk of bleeding, recent surgery), start empiric anticoagulation before conducting a CTA If too unstable for CTA → perform bedside echocardiography obtain a presumptive diagnosis of PE (right ventricleenlargement/hypokinesis or visualization of clot) prior to empiric thrombolysis. In patients with a low or medium probability of PE (Wells score ≤ 4) → measure D-dimer levels (+ ABG evaluation + CXR)If positive (D-dimers ≥ 500 ng/mL) → CTA → evidence/exclusion of PEIf negative → PE unlikely → consider other causes of symptoms (see "Differential diagnosis" below) Wells scorePointsClinical symptoms of DVT 3PE more likely than other diagnoses3Previous PE/DVT1.5Tachycardia (heart rate > 100/min)1.5Surgery or immobilization in the past four weeks1.5Hemoptysis1Malignancy (being treated, in palliative care or diagnosis less than 6 months ago)1Wells criteria (clinical probability)Total score of 0-1: low probability of PE (∼ 10%)Total score of 2-6: moderate probability of PE (∼ 30%)Total score of > 6: high probability of PE (∼ 65%)Modified/simplified Wells criteria (clinical probability)Total score of > 4: PE likelyTotal score of ≤ 4: PE unlikely Blood analysis Initial test: measure D-dimer levels (if suspicion for PE low) D-dimers: fibrin degradation products detected in the blood after thrombus resolution via fibrinolysis; normal levels < 500 ng/mLIf elevated in patients with low clinical probability of PE → further testing (see below)High sensitivity and negative predictive value: a negative D-dimer test most likely rules out PE Low specificity: positive results in all forms of fibrinolysis ↑ troponin T and B-type natriuretic peptide (BNP): possible elevation from right ventricular pressure overload → poor prognosis Arterial blood gas (ABG) testRespiratory alkalosis : ↓ paO2 < 80 mmHg, ↓ paCO2, ↑ pH↑ Alveolar-arterial (A-a) gradient : compares the oxygenation status of alveoli to arterial blood ↓ O2 saturation Imaging Helical spiral CT/CT pulmonary angiography (CTPA): best definitive diagnostic test Contrast-enhanced imaging of the pulmonary arteriesHigh sensitivity, specificity and immediate evidence of pulmonary arterial obstructionVisible intraluminal filling defects of pulmonary arteriesWedge-shaped infarction with pleural effusion is almost pathognomonic for PE Chest radiograph Initially often performed to rule out other causes (e.g., pneumonia, pneumothorax, pericarditis, aortic dissection)Findings that may indicate PE Atelectasis (visible collapse or incomplete expansion of the lung)Pleural effusions Signs of pulmonary embolus (rare) Hampton's hump: wedge-shaped opacity in the peripheral lung with its base at the thoracic wall; caused by pulmonary infarction and not specific for PE Westermark sign: embolus leads to diminished perfusion of downstream lung tissue, which appears hyperlucent on radiograph.Fleischner sign: prominent pulmonary artery caused by vessel distension due to a large pulmonary embolus(common in massive PE)Cardiomegaly Echocardiography: to detect right atrium pressure (RAP) signs Venous reflux with dilation of inferior vena cava (also liver congestion in ultrasound of the abdomen)Tricuspid regurgitation (tricuspid valve insufficiency) ↑ Pulmonary artery systolic pressure Dilatation and hypokinesis of the right ventricle Ventilation/perfusion scintigraphy Indication: alternative to CT angiography in patients with severe renal insufficiency or contrast allergyMethod: detects areas of ventilation/perfusion (V/Q) mismatch via perfusion and ventilation scintigraphy Assessment Perfusion failure in normally ventilated affected pulmonary area (mismatch) suggests PEEvidence of normal lung perfusion rules out PE → ventilation scintigraphy superfluous Pulmonary angiography Indications: only conducted if CT angiography unavailable Procedure: right heart catheterization → insertion of a catheter into a pulmonary artery → radiograph after administration of contrast agent Other diagnostic measures Electrocardiography (ECG)Sinus tachycardia most commonly seenSigns of right ventricular pressure overload SIQIIITIII -pattern New right bundle branch blockBradycardia < 50 or tachycardia > 100 bpmRight or extreme right axis deviation (30% of cases)T negativity in leads V2and V3 (∼ 30%) Compression Doppler ultrasound: diagnosis of potential underlying deep vein thrombosis Diagnostics for underlying causeThrombophilia workupMalignancies Treatment Acute management General measures 45° reclining sitting posture Oxygen supplementation and intubation if respiratory failure IV fluids and/or vasopressors in patients with hypotension Analgesics and sedatives Specific measures Non-life-threatening pulmonary embolism: therapeutic anticoagulation Empiric anticoagulation in patients with no absolute contraindication until definitive diagnosis has been made An absolute contraindication for empiric anticoagulation is a high risk of bleeding (e.g., recent surgery, hemorrhagic stroke, active bleeding)! Initial anticoagulation (0-10 days) Low molecular weight heparin (LMWH) or fondaparinux in stable patients without renal insufficiency, especially in cancer patients Unfractionated heparin (UFH) in patients with renal failure and those who may still require thrombolysis Long-term anticoagulation and prophylaxis (3-6 months) Anticoagulation treatment is indicated for a minimum of three months after PE (see "Therapy" in deep vein thrombosis). The following agents may be used: Warfarin (target INR 2-3)LMWHDirect oral anticoagulants (rivaroxaban, apixaban, edoxaban, dabigatran) Patients with a hypercoagulable state with DVT or PE: heparin followed by 3-6 months of warfarin for the first event, 6-12 months for the second, and lifelong anticoagulation for further events Massive, life-threatening pulmonary embolism: recanalization Thrombolytic therapyIndicationsIn cases of massive PE causing right heart failureIn hemodynamically unstable patients requiring resuscitationAlternative to PTCA for patients with STEMI if PTCA cannot be performed within 90-120 minutes (see "Treatment algorithm based on ECG findings" in the acute coronary syndrome learning card)Procedure: fibrinolysis, preferably with recombinant tissue-type plasminogen activator (tPA), e.g., alteplaseMost commonly systemic infusion via IV catheterAlternatively, direct infusion of tPA into pulmonary artery via pulmonary arterial catheter Administration of anticoagulants discontinued during thrombolysisComplicationsRisk of hemorrhage during thrombolytic treatment Observe contraindications for thrombolytic therapy EmbolectomyTreatment of last resort when thrombolysis is contraindicated or unsuccessfulSurgical or catheter-based thrombus removal There is no contraindication for systemic thrombolysis if the patient requires resuscitation! Further measures Inferior vena cava filter Indications In recurrent DVTs despite anticoagulationIf anticoagulation is contraindicated (e.g., high-risk of bleeding) in patients with a documented lower leg DVT DVT prophylaxis: (subcutaneous heparin or LMWH for all immobile patients, early ambulation, and compression stockings)Complications High risk of recurrence: without anticoagulant treatment ∼ 10% in the first year, ∼ 5% per year after Right ventricular failure Sudden cardiac death due to pulseless electrical activity Atelectasis (∼ 20% of cases) Pulmonary effusion Pulmonary infarction (∼ 10% of cases) Embolisms of smaller segmental arteries can lead to wedge-shaped hemorrhagic pulmonary infarctions Right ventricular failure, increased bronchial venous pressure, and preexisting pulmonary diseases increase the risk. Pneumonia from pulmonary infarction: peripheral infiltration on chest X-ray (typically wedge-shaped= Hampton's hump)Differential diagnoses See differential diagnosis of acute chest pain and differential diagnosis of acute dyspnea Post-surgery atelectasis Anxiety disorders

Sarcoidosis Sarcoidosis is a multisystem disorder characterized by noncaseating granulomatous inflammation. It is classified as either acute or chronic; chronic sarcoidosis is not necessarily preceded by acute sarcoidosis. Acute sarcoidosis has an abrupt onset with constitutional symptoms (e.g., fever, malaise) as well as cough, dyspnea, anterior uveitis, erythema nodosum, and arthralgia, and it is self-limiting after a few years. Chronic sarcoidosis has an insidious onset and is often asymptomatic in its early stages. It primarily affects the lungs, although other systemic manifestations are also possible. The first symptoms of chronic sarcoidosis usually include exertional dyspnea and a dry cough with mild rales on pulmonary examination. A chest x-ray is the most appropriate initial test in a patient with suspected sarcoidosis. An x-raymay show parenchymal disease with bilateral hilar lymphadenopathy, but these features are not always evident. A biopsyis the gold standard for diagnosis. The most common histopathological finding is noncaseating granulomas with giant cells. Glucocorticoid therapy is indicated with disease progression or if certain organs, such as the eyes or heart, are affected. While spontaneous remission rates are high during the early stages of sarcoidosis, irreversible lung fibrosis may develop as the disease recurs or progresses.

Epidemiology Bimodal distribution: 25-35 years old with a second peak for females 45-65 years old Sex: ♀ > ♂ (2:1) Prevalence: 10 times higher among African Americans than whites in the US. African Americans are also more likely to have chronic and more severe disease courses. Sarcoidosis most frequently affects young African American women in the US! Etiology The cause of sarcoidosis is still unknown. Current hypotheses suggest that the etiology is multifactorial. Genetic Environmental agent exposure Infectious agentsPathophysiology Sarcoidosis is a systemic disorder characterized by widespread, immune-mediated formation of noncaseating granulomas. T-cell dysfunction and increased B-cell activity result in local immune hyperactivity and inflammation. Formation of non-caseating granulomas within the lungs and the lymphatic system (see granulomatous inflammationfor details) Macrophages activate Th1 cells. Th1 cells stimulate the formation of epithelioid cells and multinucleated giant cells by releasing IFN-γ.Epithelioid cells produce angiotensin-converting enzyme (ACE) and release cytokines, which recruit more immune cells.A mature granuloma is composed of epithelioid cells and macrophages in the center, which are surrounded by lymphocytes and fibroblasts. Fibrosis and subsequent damage of organs and tissue: Epithelioid cells secrete cytokines to recruit fibroblasts, which cause fibrosis. Calcium dysregulation: activated macrophages produce 1-α hydroxylase → ↑ 1,25 hydroxyvitamin D(hypervitaminosis D) → hyperphosphatemia, hypercalcemia, and possibly renal failureClinical features Acute sarcoidosis and chronic sarcoidosis are two distinct manifestations of the disease, where acute sarcoidosis does not necessarily precede chronic sarcoidosis. Acute sarcoidosis (approx. ⅓ of cases) Typically has a sudden onset and remits spontaneously within approx. 2 years Progression to chronic sarcoidosis is rare. General: fever, malaise, lack of appetite, weight loss Pulmonary: dyspnea, cough, chest pain Extrapulmonary: arthritis, anterior uveitis, erythema nodosum Chronic sarcoidosis (approx. ⅔ of cases) In rare cases, preceded by acute sarcoidosis Gradual disease course; may be recurrent or progressive Pulmonary (most common) Often asymptomatic in the early stages Dry cough, exertional dyspnea Mild rales on pulmonary auscultation Extrapulmonary CommonPeripheral lymph nodes are the most frequent site of extrapulmonary manifestation (40%). Eyes (25%): granulomatous uveitis; blurred vision (ocular sarcoidosis) Skin (25%) Lupus pernio: pathognomonic, extensive, purple skin lesions (violaceous skin plaques) on the nose, cheeks, chin, and/or ears; also referred to as epithelioid granulomas of the dermis Scar sarcoidosis: inflamed, purple skin infiltration and elevation of old scars or tattoos Other manifestationsMusculoskeletal ; bone lesionsNervous system (neurosarcoidosis): cranial nerve palsy (7th cranial nerve palsy is the most common), diabetes insipidus, meningitis, hypopituitarismHeart Liver Kidneys Spleen Subtypes and variants Lofgren syndrome Highly acute clinical presentation with fever and the following triad of symptomsMigratory polyarthritis: symmetrical arthritis that primarily affects the anklesErythema nodosum: primarily affects the extensor surface of the lower legsBilateral hilar lymphadenopathy Heerfordt syndrome Chronic clinical presentation with fever and the following triad of symptoms ParotitisUveitis (iridocyclitis)Facial palsy Stage 0Normal findings Stage IBilateral hilar lymphadenopathy (reversible)*Stage IIBilateral reticular or ground-glass opacities with hilar lymphadenopathy → disseminated, reticulonodular infiltratesStage IIIBilateral reticular or ground-glass opacities without hilar lymphadenopathyStage IVLung fibrosis Diagnostics A chest x-ray (which may reveal parenchymal disease with hilar lymphadenopathy) is the most appropriate initial test for a patient with suspected sarcoidosis. Laboratory tests may support the diagnosis of sarcoidosis, but a biopsy is the gold standard. Additional tests can help determine the severity of the disease, possible complications, and prognosis. Chest x-ray Best initial test Sarcoidosis is frequently an incidental finding detected on chest x-ray Findings: hilar lymphadenopathy with or without bilateral reticular opacities Chronic sarcoidosis is categorized according to chest x-ray findings (see "Stages" above). Patients with chronic sarcoidosis often have moderate clinical manifestations but radiographic findings of extensive disease! Laboratory tests Acute sarcoidosis↑ Inflammatory markersFindings typical for sarcoidosis are absent (e.g., ↑ ACE, ↑ IgG, ↑ calcium) Chronic sarcoidosis↑ Calcium due to elevated levels of 1,25-(OH)2-vitamin D3↓ CD4+ T cells: T helper cells are consumed during granuloma formation → CD4+ levels are low in serum and high in bronchoalveolar lavage.↑ IgG (approx. 50% of patients)↑ Angiotensin-converting enzyme (ACE) blood levels; may be used to monitor disease activity and therapy ↑ Inflammatory markers, possible lymphopeniaUrine analysis: hypercalciuria Bronchoscopy Biopsy: the gold standard for diagnosis Origin of specimen: lung tissue and lymph nodesFindings: non-caseating granulomas with giant cellsAsteroid bodies, Schaumann bodies Bronchoalveolar lavage (BAL): increased CD4+/CD8+ ratio Pulmonary function tests Restrictive or obstructive pattern (see restrictive lung disease and obstructive lung disease) Differential diagnoses SarcoidosisAfrican American females in the USDry coughErythema nodosumLupus pernioAnterior (and possibly posterior) uveitisNon-caseatinggranulomasGiant cells↑ CD4+/CD8+ ratio in bronchoalveolar lavageTuberculosis (TB)ImmunocompromisedindividualsPrevious TB and/or recent TBexposureFever, weight loss, and night sweatsProductive cough that does not respond to conventional antibiotic therapyHemoptysisCaseating granulomasLanghans giant cells, epithelioid macrophages, and lymphocytesAcid-fastM. tuberculosisM. tuberculosis or its DNAHodgkin lymphomaHistory of infectious mononucleosisPel-Ebstein feverAlcohol-induced painPruritusNon-caseatinggranulomasReed-Sternberg cellsInflammatory cell infiltrate (e.g., eosinophils, fibroblasts, plasma cells)Single or combined cytopenias (i.e., anemia, leukopenia, and/or thrombocytopenia)Non-Hodgkin lymphomaInfections (e.g., EBV infectionor Helicobacter pylori)Cell damage (caused by toxic substances, immunosuppressive drugs, cytostatic therapy, radiation)Indolent lymph nodeenlargementSplenomegalyEvidence of bone marrow suppression (i.e., pallor, infections)Possible large abdominal mass (in Burkitt lymphoma)Non-caseatinggranulomas without Reed-Sternberg cellsB-lymphocytes or T-lymphocytesInflammatory cell infiltrateSingle or combined cytopeniasPneumoconiosisExposure to mineral dust (e.g., silica)Often, patients are asymptomatic and the physical examination is unremarkable.In symptomatic patients Progressive exertional dyspneaChronic cough (possibly with sputum)Auscultatory findings (e.g., rales, crackles)Signs of respiratory failure (e.g., digital clubbing)Non-caseatinggranulomasSilica/asbestos bodiesPositive berylliumlymphocyte proliferationtest (BeLPT)Granulomatosis with polyangiitisCaucasian individuals aged 65-74 yearsChronic rhinitis/sinusitis with thick purulent/bloody dischargeTreatment-resistantpneumoniaGlomerulonephritisNon-caseatinggranulomasPositive cytoplasmic ANCAHistoplasmosisAIDSExposure to bird or bat excrementPulmonary (e.g., dry cough, oral ulcers) or extrapulmonary (e.g., splenomegaly) manifestationsCaseating granulomasIdentification of H. capsulatum yeastwith silver stainPositive polysaccharideurine and serum antigen testTreatment Isolated pulmonary sarcoidosis: In most cases, no treatment is required. The disease is often asymptomatic, non‑progressive, and has a high rate of spontaneous remission. Symptomatic or extrapulmonary sarcoidosisFirst line: glucocorticoidsSecond line: alternative immunosuppressive therapy (e.g., methotrexate or azathioprine), possibly in combination with glucocorticoidsAntimalarial drugs (e.g., chloroquine, hydroxychloroquine) Last resort in severe pulmonary disease: lung transplantationNSAIDs are always indicated for symptom relief. Complications Patients with sarcoidosis have an increased risk of malignant changes (esp. within the lungs and lymph nodes). Pulmonary complications BronchiectasisLung fibrosis: Irreversible fibrotic remodeling together with compression of large pulmonary arteries due to bilateral hilar lymphadenopathy may increase pulmonary vascular resistance, resulting in pulmonary hypertension(PH). Chronic renal failure (see "Clinical features" above) Prognosis Increased calcium is associated with a poorer prognosis Acute sarcoidosis: spontaneous remission > 95% Chronic sarcoidosis (% remission rate) Type IV: Life expectancy is limited because of severely impaired lung function.Type III: approx. 20%Type II: approx. 50%Type I: approx. 70%The spontaneous remission rates in acute sarcoidosis are extremely high. In chronic sarcoidosis, the remission rates vary depending on the type!

Anthrax Anthrax is a rare, infectious disease caused by Bacillus anthracis, a gram-positive spore-forming bacterium that is found in soil. Human infection usually results from contact with infected livestock or infected animal products (e.g., wool or meat). B. anthracis spores have also been weaponized for biological warfare/terrorism. Depending on the route of entry, three distinct clinical syndromes can occur: inhalation anthrax, cutaneous anthrax, and gastrointestinal anthrax. Cutaneous anthrax (the most common form) presents initially as a papular lesion, which later becomes vesicular, and eventually forms a necrotic eschar. Inhalation anthrax results in hemorrhagic mediastinitis and presents with fever, acute, nonproductive cough, retrosternal chest pain, and/or pleural effusion. Gastrointestinal anthrax, which is very rare, causes gastrointestinal ulceration, which results in hematemesis and/or bloody diarrhea. The diagnosis of anthrax is confirmed by the microscopic evidence of B. anthracis. Mortality is high but swift treatment with antibiotics (e.g., fluoroquinolones, linezolid, meropenem) can increase survival. Prognosis of cutaneous anthrax is usually better than that of inhalation and gastrointestinal anthrax.

Epidemiology Global distribution: Anthrax is endemic in agricultural regions of the USA, Canada, Central and South America, southern and eastern Europe, central and southwest Asia, and sub-Saharan Africa. Incidence: 0-2 cases per year Sex: ♂ > ♀ Etiology Pathogen: Bacillus anthracisGram-positive, spore-forming, nonmotile rod Edge of colony shows irregular comma-shaped outgrowths on blood agar (also referred to as "Medusa head").Spores of B. anthracis can remain viable for decades. Anthrax is a zoonotic infection that primarily infects cows, goats, and sheep TransmissionHuman infection occurs following exposure to B. anthracis or its spores, usually as a result of contact with infected animals or infected animal products (e.g., wool, hide, meat)Weaponized anthrax: infection resulting from exposure to weaponized anthrax spores (from an act of bioterrorism or biological warfare) Person-to-person transmission typically does not occur. The clinical manifestations of anthrax depend on the site of entry of B. anthracis. (see "Clinical features" below) Pathophysiology Virulence factorsAntiphagocytic capsule (containing poly-D-glutamate) Anthrax toxin: responsible for the local and systemic manifestations of anthraxAnthrax toxin is made up of A and B subunits. B subunit binds to endothelial receptors → the B subunit facilitates entry of the A subunit into the host cell.The A subunit has 2 components: EF (edema factor): EF binds to calcium and calmodulin and gains adenylate cyclase activity → ↑ cAMP→ cell edemaLF (lethal factor): LF is a metalloprotease which destroys MAPKK (mitogen-activated protein kinase) → cell death InfectionLocal germination of B. anthracis spores and multiplication of bacteriaSpread to local/regional lymph nodesBacteremia → systemic spread Cutaneous anthrax ∼ 95% Skin contact Typically 5-7 days Skin lesion: painless, pruritic papule → vesicle → ulcer with a surrounding edema → necrotic, black eschar → healing by granulation → hyperpigmented skin and/or scar Swab of fluid from the vesicle and/or eschar Full-thickness punch biopsy Blood CSF Oral monotherapy with either a fluoroquinolone (e.g., ciprofloxacin, levofloxacin, or moxifloxacin) or doxycycline Inhalation anthrax ∼ 5% Inhalation Typically 1-3 days Prodromal phase (1-6 days): nonspecific symptoms Fulminant phase: substernal chest pain, high-gradefever, progressive dyspnea, hypoxia, shock, mediastinal widening due to hemorrhagic mediastinitis Pleural fluid Swab of respiratory secretions Blood CSF Large pleural effusions: chest tubeinsertion or thoracocentesis Gastrointestinal anthrax < 1% Ingestion 2-5 days Nausea, vomiting Abdominal pain Severe, bloody diarrhea Hematemesis Hemorrhagic lymphadenitis Ascites Local/regional lymphadenopathy In case of bacteremia: meningitis, septic shock Oral and rectal swabs Ascitic fluid Splenic and/or mesenteric lymph node biopsy Blood CSF In case of ascites: ascitic tap Pathogen detectionDiagnosis of anthrax infection can be made if either the confirmatory test or at least two of the supportive microbiologic tests indicate an infection.Confirmatory test: microscopic examination and culture Supportive tests PCR Immunohistochemistry ELISA in acute-phase serum and convalescent-phase serum Additional findingsLeukocytosis↑ AST, ALTIn inhalational anthrax: chest x-ray and/or chest CT reveals mediastinal widening, perihilar interstitial pneumonia, and/or hemorrhagic pleural effusion Antitoxin therapy: raxibacumab, obiltoxaximab, or anthrax immunoglobulin Combination of IV antibioticsPatients without meningitis: ciprofloxacin and linezolidPatients with (confirmed or suspected) meningitis: ciprofloxacin, linezolid, and meropenemFluid resuscitation in case of shock Systemic glucocorticoids are indicated in the following situations: MeningitisShock that does not respond to fluid resuscitation and vasopressorsSevere edema of the head and neck While gastrointestinal anthrax and inhalational anthrax are rare, they have a particularly poor prognosis, even with antibiotictreatment! Prevention AVA (anthrax vaccine adsorbed) is the only FDA-approved vaccine that is available for active immunization against anthrax in the US. Pre-exposure prophylaxis : AVA Post-exposure prophylaxis : AVA along with antibiotics (ciprofloxacin or doxycycline) AVA is contraindicated among children < 18 years, adults > 65 years, and pregnant/lactating women. In these groups, antitoxin therapy with raxibacumab, obiltoxaximab, or anthrax immunoglobulin is indicated instead of AVA.Anthrax is a notifiable disease! It is also categorized as a category A bioweapon hazard by the CDC.

Neonatal respiratory distress syndrome Neonatal respiratory distress syndrome (NRDS), or surfactant deficiency disorder, is a lung disorder in infants that is caused by a deficiency of pulmonary surfactant. It is most common in preterm infants, with the incidence and severity decreasing with gestational age. Surfactant deficiency causes the alveoli to collapse, resulting in impaired blood gas exchange. Symptoms manifest shortly after birth and include tachypnea, tachycardia, increased breathing effort, and/or cyanosis. The suspected diagnosis is based on clinical features and confirmed by evaluating the extent of atelectasis via chest x-ray. Blood gases show respiratory and metabolic acidosis in addition to hypoxia. Treatment primarily involves emergent resuscitative measures, including nasal continuous positive airway pressure (CPAP) and stabilizing blood sugar levels and electrolytes. In addition, intratracheal surfactant is administered if ventilation alone is unsuccessful. Most cases resolve within 3-5 days of treatment. However, complications such as hypoxemia, tension pneumothorax, bronchopulmonary dysplasia, sepsis, and neonatal death may still occur. NRDS can be prevented by administering antenatal glucocorticoids to the mother if premature delivery is expected.

Epidemiology Incidence1% of all newborns10% of all preterm babies The risk of developing NRDS depends on gestational age. < 28 weeks of pregnancy: > 50%> 37 weeks of pregnancy: < 5% Etiology Impaired synthesis and secretion of surfactant Risk factorsPremature birthGenetic predispositionCesarean section (c-section): results in lower levels of fetal glucocorticoids than vaginal delivery (uterine contractions during vaginal delivery increase fetal stress levels, which cause glucocorticoids to be released as a physiologic response to stress) Maternal diabetes mellitus: leads to ↑ fetal insulin, which inhibits surfactant synthesisHydrops fetalisMultifetal pregnancies In rare cases, hereditary Pathophysiology SurfactantPulmonary surfactant is a mixture of phospholipids and proteins produced by lamellar bodies of type II alveolar cells. These phospholipids reduce alveolar surface tension, preventing the alveoli from collapsing.Any infant born preterm is vulnerable to surfactant deficiency for the following reasons:Surfactant production occurs at around 20 weeks' gestation.Distribution throughout the lungs begins around weeks 28-32 and does not reach sufficient concentration until week 35. Surfactant deficiency → little or no reduction of alveolar surface tension → increased alveolar collapse → atelectasis → decreased lung compliance and functional residual capacity → hypoxemia and hypercapniaHypoxemia and hypercapnia → vasoconstriction of the pulmonary vessels (hypoxic vasoconstriction) and metabolic acidosis → intrapulmonary right-to-left shunt → increased permeability due to alveolar epithelialdamage → fibrinous exudation within the alveoli → development of hyaline membranes in the lungs (hyaline membrane disease) Clinical features History of premature birth Onset of symptoms: usually immediately after birth but can occur within 48-72 hours postpartum Signs of increased breathing effortTachypneaNasal flaring and moderate to severe subcostal/intercostal and jugular retractions Typical expiratory "grunting" Auscultation: decreased breath sounds Cyanosis due to peripheral hypoxic vasoconstriction Diagnostics Chest x-ray: diffuse, fine, reticulogranular (ground-glass) densities with low lung volumes and air bronchograms Blood gas analysisHypoxia with respiratory acidosis; can lead to increased lactate levelsEvaluate for partial respiratory failure or global respiratory failure Amniocentesis for prenatal testing of NRDS: screening for markers of fetal lung immaturityLecithin-sphingomyelin ratio < 1.5 (≥ 2 is considered mature)The amount of sphingomyelin in the amniotic fluid remains relatively consistent during pregnancy.The amount of lecithin, which is the major component of surfactant, starts increasing after week 26 of gestation.The lower the lecithin-sphingomyelin ratio, the more likely it is that the lungs are immature.Foam stability index < 0.48Low surfactant-albumin ratio Pathological findings [6]Hyaline membranes lining the alveoli Composed of fibrin, cellular debris, and red blood cellsAppear as eosinophilic, amorphous material lining the alveolar surfaceEngorged and congested capillary vessels in the interstitium Differential diagnoses Pulmonary hypoplasiaUnderdevelopment of the lungs characterized by a decreased number of alveoli and small airways and reduced lung volumes in one or both lobesResult in impaired gas exchangeAssociated with congenital diaphragmatic hernia (usually left-sided), oligohydramnios, and the Potter sequenceAfter birth, the neonate presents with severe respiratory distress and requires intubation, as in respiratory distress due to surfactant deficiency. Congenital diaphragmatic hernia Pneumothorax Neonatal pneumonia Treatment VentilationNasal CPAP with a PEEP of 3-8 cm H2O If respiratory insufficiency persists, start intubation with mechanical ventilation and O2 inhalation. Endotracheal administration of artificial surfactant within 2 hours postpartum Supportive measures: IV fluid replacement; stabilization of blood sugar levels and electrolytes Physiologic O2 saturation in neonates is around 90% instead of 100%. A saturation of 100% is considered toxic for neonates! Complications Bronchopulmonary dysplasia (BPD) Definition: chronic lung disease primarily found in premature infants exposed to prolonged mechanical ventilation andoxygen therapy for neonatal RDS Etiology: An immature lung with exposure to ventilation leads to barotrauma, oxygen toxicity, and inflammation.Ventilation for more than 28 days Clinical featuresSeen in infants < 32 weeksPersistence of symptoms similar to NRDS (e.g., tachypnea, grunting, nasal flaring); episodes of desaturation DiagnosticsChest x-ray: diffuse, fine, granular densities, areas of atelectasis interspersed with areas of hyperinflationHistology: atelectasis, fibrosis, emphysematous alveolar changes Therapy: controlled oxygenation, diuretics, possibly glucocorticoids Further complications Pneumothorax Hypoxia Patent ductus arteriosus (due to a persistently low partial pressure of oxygen in the blood) Cardiovascular arrest Neonatal sepsis Complications of O2 inhalation: retinopathy of prematurity, bronchopulmonary dysplasia, intraventricular hemorrhage Prognosis If left untreated, NRDS has a case fatality rate of 30%. Most cases that are promptly treated resolve within 3-5 days. Prevention Prevent premature birth if possible. See tocolysis. Antenatal corticosteroid therapy administered to the mother (stimulates infant lung maturation)Given 48 hours before delivery2 doses of IM betamethasone 24 hours apart or 4 doses of IM dexamethasone 12 hours apart Neonatal respiratory distress syndrome Preterm Deficiency of pulmonary surfactant Preterm delivery Male sex Maternal diabetes Within the first minutes/hours after birth Tachypnea Increased breathing effort Cyanosis Hypoxia Decreased breathing sounds Diffuse, fine, reticulogranular (ground-glass) densities Low lung volumes and air bronchogramsSupportive care Administration of artificial surfactant Transient tachypnea of the newborn(wet lung disease) Usually full term Delayed resorption of fetal lung fluid C-section Male sex Macrosomia Maternal asthma Maternal diabetes Immediately after birth and within the next 2 hours Tachypnea Increased breathing effort Diffuse crackles, diminished, or normal breathing sounds on auscultation Symptoms are reversible Fluid in the lung fissures and increased lung volumes Supportive care (e.g., supplemental oxygen, neutral thermal environment, adequate nutrition) Persistent pulmonary hypertension of the newborn (PPHN) Full term or late preterm Elevated pulmonary vascular resistance Perinatal asphyxia Prolonged premature rupture of the membranes Infection Within 24 hours after birth Low APGAR scores Cyanosis and signs of respiratory distress Heart examination: prominent precordial impulse and a narrowly split and accentuated S2 Pulmonary hypertension on echocardiography Supportive care Severe cases: inhaled nitric oxide Last resort: ECMO Meconium aspiration syndrome Usually postterm Intrauterine passage of meconium and aspirationleading to airway obstruction Postterm delivery Nonreassuring fetal heart rate tracing Perinatal asphyxia Placental insufficiency Oligohydramnios C-section Maternal hypertension and diabetes Maternal infection/chorioamnionitis Immediately after birth Green amniotic fluid Low APGAR scores Tachypnea Increased breathing effort Hypoxia Lung rales and rhonchi Increased lung volumes Asymmetric, patchy opacities Pleural effusion Emergency intubation and endotracheal drainage

Lung cancer Lung cancer is the leading cause of cancer death worldwide with around 70% of cases attributable to smoking. Lungcancer is classified into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). SCLC is characterized by its central location, rapid tumor growth, early metastases, and association with numerous paraneoplastic syndromes. NSCLCcomprises a number of cancer types, including peripheral adenocarcinoma and central squamous cell carcinoma. Symptoms such as dyspnea, cough, hemoptysis, and chest pain typically develop in advanced stages of disease. New onset cough or pneumonia constitute warning signs, particularly in smokers. Over 50% of patients have metastases at the time of diagnosis, most commonly in the brain, liver, adrenal glands, or bones. Solitary pulmonary nodules detected on chest x-ray should be compared to previous chest x-rays, if available, or evaluated in a chest CT scan. Bronchoscopy or CT-guided biopsy confirm the diagnosis. Chemotherapy is the mainstay of treatment. Surgical resection of one or more pulmonary lobes is only possible in early stages of lung cancer. Approx. 65% of patients are inoperable at the time of diagnosis because of tumor metastases or poor pulmonary function. Radiation therapy is indicated in nonsurgical candidates, as an adjunct to chemotherapy, or for palliative management of metastastic disease. Even with a multimodal approach, the 5-year survival rate is 17%.

Epidemiology Incidence: second most common carcinoma ; leading cause of cancer death (worldwide) Peak incidence: 50-70 years Sex: ♂ > ♀ (∼ 3:1)Adenocarcinoma is an exception: ♂ < ♀ (∼ 1:6)Etiology Risk factors Nicotine: smoking causes approx. 90% of lung cancers Occupational and environmental exposure to carcinogens: passive smoking, asbestos, arsenic, radon, uranium Family history (genetic predisposition) Scar tissue in the lungs (e.g., pulmonary fibrosis, history of tuberculosis) Idiopathic: particularly adenocarcinoma Etiology Risk factors Nicotine: smoking causes approx. 90% of lung cancers Occupational and environmental exposure to carcinogens: passive smoking, asbestos, arsenic, radon, uranium Family history (genetic predisposition) Scar tissue in the lungs (e.g., pulmonary fibrosis, history of tuberculosis) Idiopathic: particularly adenocarcinoma Small cell lung cancer (SCLC) ∼ 15%CentralStrong correlation with cigarette smoking Pulmonary neuroendocrine tumor; associated with several paraneoplastic syndromes Very aggressive ; early metastasesAssociated mutations: l-myc Non-small cell lung cancer (NSCLC) approx. 85% Adenocarcinoma∼ 40%PeripheralMost common type of lung cancer overall and in womenMost common lung cancer in non-smokers Associated mutations: EGFR , ALK , and KRASDistant metastases are commonNoninvasive subtype: bronchioloalveolar carcinoma Squamous cell carcinoma (SCC)20-25% CentralairwaysStrong association with smoking! Cavitary lesions are commonDirect spread to hilar lymph nodes↑ Parathyroid hormone-related protein (PTHrP) leads to hypercalcemia (See Hypercalcemia of malignancy) [6] Large cell carcinoma5-10%PeripheralLate metastasesPoor prognosis Clinical features Symptoms commonly only develop in advanced stages of the disease. Pulmonary symptoms Cough (chronic or recently developed) Hemoptysis Progressive dyspnea Chest pain Recurring common colds in patients ≥ 40 years should always raise the suspicion of lung cancer! Extrapulmonary symptoms Constitutional symptoms (weight loss, fever, weakness) Clubbing of the fingers and toes Signs or symptoms of tumor infiltration or compression of neighboring structuresSuperior vena cava syndrome (SVC syndrome): Compression of the superior vena cava impairs the venous backflow to the right atrium, resulting in venous congestion in the head, neck, and upper extremities. Feeling of fullness in the headDyspneaEdema of the upper extremities and faceProminent venous pattern on the chest, face, and upper extremitiesParalysis of the recurrent laryngeal nerve: hoarseness Paralysis of the phrenic nerve: results in diaphragmatic elevation and dyspneaMalignant pleural effusion: dullness on percussion, reduced breath sounds on the affected side Dysphagia Postobstructive pneumonia (See secondary pneumonia) Paraneoplastic syndromes NSCLC/SCLCGeneral paraneoplastic manifestations: cachexia, increased risk of thrombosis (and lung embolism!)DermatomyositisAcanthosis nigricansSee also paraneoplastic syndromes. NSCLC Endocrine Hypercalcemia of malignancy (squamous cell carcinoma)Gynecomastia (large cell carcinoma) Other Hypertrophic osteoarthropathy (also known as Pierre-Marie-Bamberger disease) Clubbing of the fingers and toes (Hippocratic fingers)Swelling and pain in joints and long bones Hypercoagulability and thrombophlebitis migrans (adenocarcinoma) Nonbacterial verrucous endocarditis (adenocarcinoma) SCLCEndocrine Cushing syndromeSyndrome of inappropriate antidiuretic hormone secretion (SIADH) Neurologic Lambert-Eaton syndrome (similar clinical features as myasthenia gravis) Paraneoplastic cerebellar degenerationPeripheral neuropathy Symptoms of metastatic disease Early lymphogenic and hematogenic metastasis (particularly in SCLC) Brain: headaches, behavioral changes, seizures, focal motoric deficits (see also brain metastases)Liver: nausea, jaundice, ascites (see also metastatic liver disease)Adrenal gland: usually asymptomatic Bones: bone pain Approx. 50% of patients with NSCLC and 60-70% of patients with SCLC have metastatic disease at the time of presentation! Pancoast tumor A peripheral lung carcinoma (predominantly NSCLC) that is located in the superior sulcus of the lung; often involves the cervical sympathetic nerves and brachial plexus. Symptoms of Pancoast syndromeSevere, localized pain in the axilla and shoulder Horner syndromeAtrophy of arm and hand muscles Edema of the arm, facial swelling, morning headaches Bronchioloalveolar carcinoma Noninvasive subtype of adenocarcinoma (also known as adenocarcinoma in situ) Chest x-ray findingsEarly disease: solitary peripheral noduleAdvanced disease: diffuse consolidation that can resemble pneumonia Stage IAT1Tumor size ≤ 7 cmNo lymph node involvement beyond the ipsilateral hilar nodesNo mediastinal invasionNo metastasesStage IBT2aStage IIAT2b, N0 or T1, N1Stage IIBT3, N0 or T2b, N1Stage IIIAUp to T4, N1 or T3, N2Tumor size > 7 cmMediastinal lymph node involvement and/or regional spreadNo mediastinal invasion or metastasesStage IIIBT4, N2 or N3Mediastinal invasionDistant nodes and/or distant metastasesStage IVM1 As soon as distant metastases are detected, the cancer is classified as UICC stage IV! Staging of SCLC The SCLC staging mostly depends on whether the tumor is limited to one hemithorax or has spread beyond the hemithorax. Alternatively, the TNM classification may be used. Very limited diseaseConfined to one hemithoraxT1-2, N0-1approx. 5%Limited diseaseT3-4, N0-1 or T1-4, N2-3approx. 20%Extensive diseaseBeyond one hemithoraxContralateral supraclavicular or hilar lymph node involvementMalignant pericardial or pleural effusionDistant metastasisM1approx. 75% Chest x-ray and comparison to previous images if available CT imaging for further evaluation indicated ifNew lesion detected on chest x-rayChanges (e.g., enlargement) compared to previous chest x-ray are inconclusiveNo previous CXR/CT is available Assessment of lesion size and probability of malignancy (based on CT findings and patient characteristics) Increased probability of malignancyHistory of smokingPatient age > 40 years Other known risk factors (e.g., positive family history, asbestos exposure) < 4 mmLowNo follow-up neededHighFollow-up CT at 12 months4-6 mmLowFollow-up CT at 12 monthsHighFollow-up CT at 6-12 months6-8 mmLowFollow-up CT at 6-12 monthsHighFollow-up CT at 3-6 months≥ 8 mmLow or highPET and/or biopsy In patients aged > 40 years, any pulmonary nodule detected on CXR is considered lung cancer unless proven otherwise! Chest x-ray Findings Solitary nodule Indirect signs: atelectasis, postobstructive pneumonia, pleural effusion (particularly unilateral), mediastinalwidening, cavitary lesions CT imaging Signs of malignancy Solid lesion ≥ 8 mm Irregular marginsSpiculesNo or irregular calcifications Positron emission tomography (PET) More accurate than CT at differentiating between benign and malignant nodules Performed prior to biopsy if the CT imaging is inconclusive, particularly for patients with a high probability of malignancy Bronchoscopy and biopsy Confirmatory test Procedures Bronchoscopy with transbronchial biopsy: central nodules CT-guided transthoracic biopsy: peripheral nodulesThoracoscopy: if bronchoschopy or CT-guided biopsy are inconclusive, or in small peripheral nodules Mediastinoscopy: to biopsy mediastinal nodes or masses Staging of diagnosed lung cancer CT scan (chest, liver, adrenal glands) to evaluate Nodules: localization, size, margins, calcificationsRegional spread (hilar lymph nodes, mediastinal invasion, pleural effusions)Distant metastasis (hepatic lesions, adrenal gland mass) Blood tests: CBC, serum chemistry (calcium, alkaline phosphatase, liver function test, kidney function test) Further radiographic imaging Abdominal ultrasound and CT: assesses lymph node involvement and extent of metastatic diseaseSkeletal scintigraphy: detects bone metastasesCranial MRI: detects CNS metastasesWhole body PET-CT: best method for detection of occult disease Preoperative evaluation for thoracic surgery Pathology Small cell lung cancer Kulchitsky cells: Small, dark blue neuroendocrine cells with hyperchromatic nuclei and scarce cytoplasm.Hyperchromatic nuclei (salt and pepper appearance) is a marker for rapid growth and high metabolic activity Rapid growth pattern Immunohistochemistry: expression of chromogranin A, neuron-specific enolase, synaptophysin, CK18, and CK7 Non-small cell lung cancer Squamous cell carcinomaSolid, epithelial tumorSubtypes: keratinizing, nonkeratinizing, basaloid Histology: intercellular bridges (desmosomes), keratin pearlsImmunohistochemistry: expression of cytokeratin subtypes CK5 and CK6 AdenocarcinomaGlandular tumorMucin-producing cells (positive mucin staining)Subtypes of adenocarcinomas are classified according to the growth pattern (e.g., lepidic , papillary, acinar, solid) Preinvasive lesions Atypical adenomatous hyperplasiaAdenocarcinoma in situ (≤ 3 cm): tumor cells with a lepidic growth pattern showing no evidence of invasion of the stroma, lymphatic, vascular or pleural tissueInvasive adenocarcinomaMinimally invasive adenocarcinoma (≤ 3 cm lepidic predominant adenocarcinoma, invasion ≤ 5 mm)Invasive lepidic predominant (formerly: mucinous bronchioloalveolar carcinoma)Acinar adenocarcinomaPapillary adenocarcinomaAdditional subtypesDetection of EGFR mutations and ALK translocations (immunohistochemistry or FISH) Immunohistochemistry: expression of napsin A and TTF-1 Large cell carcinomaPoorly differentiated, pleomorphic giant cellsCan secrete β-hCG Primary lung cancerSCLC/NSCLCCentral or peripheral noduleIrregular margins and/or spiculesTumor size typically > 2 cmNo calcifications or irregular calcificationsLung metastasesBreast cancerColorectal cancerRenal cell carcinomaProstate cancerBladder cancerMelanomaMore commonly multiple pulmonary nodules Nodule size typically > 1 cmPulmonary neuroendocrine tumorCarcinoid bronchial carcinoma Round or oval opacitiesSize typically 2-5 cmHilar or perihilar mass Benign tumorsHamartomas"Popcorn" calcificationsRound, well-circumscribed nodules, lobulated by respiratory epitheliumHistology findings Disorganized connective and epithelial tissue: predominantly cartilage that may undergo calcification or osseous changesFat, fibromyxoid tissue, sometimes smooth muscleSize typically 1-3 cm90% are peripheral, 10% are endobronchialInfectious granulomas TuberculosisNontuberculous mycobacteriaHistoplasmosisRound, well-defined, calcified noduleInflammatory conditionsSarcoidosisGranulomatosis with polyangiitis(Wegener granulomatosis)Multiple bilateral cavitating nodular lesions Pulmonary nodules are more commonly metastases of other cancers rather than primary lung cancer! Treatment While early stages of lung cancer are treated with a curative approach, the majority of cases are diagnosed in advanced stages and can therefore only be treated palliatively. Surgery is often not possible due to distant metastases or because the patient has poor pulmonary reserve. In such cases, chemotherapy is the mainstay of treatment; radiation therapy is also frequently necessary. An individual treatment approach is usually determined by an interdisciplinary tumor board and discussed with the patient. SCLCs initially respond very well to chemotherapy, but remission only lasts for a short period! Only in very rare cases can patients be healed by surgery! Therapeutic options Medical therapyPolychemotherapy (mainstay of treatment), e.g., SCC: cisplatin and vinorelbineSCLC: cisplatin and etoposideTargeted therapyEGFR inhibitors (e.g., gefitinib) in advanced-stage NSCLC that is EGFR-positiveALK tyrosine kinase inhibitors (e.g., crizotinib) in advanced-stage NSCLC that is ALK-positiveManagement of concurrent symptoms/conditions (e.g., pain, electrolyte imbalances due to paraneoplastic syndromes, dysphagia, cachexia, COPD) Radiation therapy includes prophylactic cranial irradiation Surgical management: see preoperative pulmonary assessmentProcedures: open surgery or video-assisted thoracoscopic surgery Lobectomy (standard approach): resection of one lobe If FEV1 > 1.5 L and DLCO > 60%: lobectomy can be toleratedSublobar resection: wedge resection or segmentectomy for patients who cannot tolerate lobectomyAdvantages: lower perioperative mortality than lobectomy; preserved lung functionDisadvantages: only possible for small, localized tumors Pneumonectomy: complete lung resection in the case of a central tumorSystematic lymph node dissectionComplicationsDisplacement of the heart towards the operated side Bronchial stump insufficiency Severe complication of lung resectionInvariably leads to effusions; risk of pleural empyemaPneumothorax (possibly tension pneumothorax)Postoperative hemorrhage → hemothoraxChylothorax (damage to the thoracic duct)AtelectasisPneumoniaAcute cor pulmonalePrognosis Overall 5‑year survival rate: approx. 17% SCLCLimited disease 5-year survival: 12-15%Extended disease 5-year survival: 2% (median survival 8-13 months) NSCLC: better prognosis, depends primarily on extent of disease and lymph node status Locally confined stages (no lymph node involvement, no metastasis) have a survival rate of up to 60-70%. Prevention Cessation of smokingAfter cessation, the risk of lung cancer reduces by half within 5-10 years. After approx. 15-20 years, the risk decreases to the corresponding level in nonsmokers. Screening with low-dose CT imaging in patients aged 55-74 years (USPSTF recommends 55-80 years) with either: A history of smoking (≥ 30 pack years) and continue smoking or stopped within 15 yearsOr a history of smoking (≥ 20 pack years) and another risk factor for lung cancer (see "Etiology" above)

Pneumothorax A pneumothorax develops when air as the result of disease or injury enters the pleural space, resulting in the loss of negative pressure between the two pleural membranes. This loss of negative pressure leads to the partial or complete collapse of the lung. Pneumothorax is classified as spontaneous (e.g., by rupture of a subpleural bleb or diseased lung), traumatic, or iatrogenic. Each type can lead to a tension pneumothorax, which is a life-threatening variant of pneumothorax. Patients with pneumothorax present with sudden-onset dyspnea, ipsilateral chest pain, diminished breath sounds, and hyperresonant percussion on the affected side. A tension pneumothorax additionally presents with distended neck veins, tracheal deviation, and hemodynamic instability. Both should be suspected on clinical evaluation. While a tension pneumothorax requires immediate chest decompression, a chest x-ray may be considered to confirm the diagnosis in a stable patient. Small pneumothoraces may resorb spontaneously, but treatment of larger defects usually requires placement of a chest tube to re-establish the negative pressure within the pleural space.

Epidemiology Primary spontaneous pneumothoraxSex: ♂ > ♀ (approx. 6:1)Peak incidence: 20-30 years Secondary spontaneous pneumothoraxSex: ♂ > ♀ (approx. 3:1)Peak incidence: 60-65 yearsDefinition A pneumothorax is a collection of air within the pleural space in between the lung (visceral pleura) and the chest wall(parietal pleura) that can lead to partial or complete pulmonary collapse. Spontaneous pneumothorax: spontaneously occurring pneumothorax Primary spontaneous pneumothorax: occurs in patients without clinically apparent underlying lung diseaseSecondary spontaneous pneumothorax: pneumothorax occurs as a complication of underlying lung disease Tension pneumothorax: life-threatening variant of pneumothorax characterized by progressively increasing pressures within the chest and cardiorespiratory compromise Etiology Spontaneous pneumothoraxPrimary (idiopathic or simple pneumothorax)Ruptured subpleural apical blebsRisk factorsFamily historyMale genderAsthenic body habitus (slim, tall stature) (e.g., in Marfan syndrome)Smoking: 90% of cases; up to 20-fold increase in risk (risk increases with cumulative number of cigarettes smoked)HomocystinuriaSecondary (pneumothorax as a complication of underlying lung disease) Catamenial pneumothorax (extremely rare; thoracic endometriosis)Pulmonary tuberculosisCystic fibrosis → bronchiectasis with obstructive emphysema and bleb or cyst rupturePneumocystis pneumonia → alveolitis, rupture of a cavityCOPD (smoking) → rupture of bullae in emphysema Traumatic pneumothorax: blunt (e.g., motor vehicle accident with impact of thorax onto the steering wheel or rib fracture) or penetrating (e.g., gunshot) injury Iatrogenic pneumothorax: Mechanical ventilation (Mechanical ventilation with high PEEP may result in barotrauma), thoracocentesis, central venous catheter placement, or bronchoscopy Pathophysiology Increased intrapleural pressure → alveolar collapse → decreased V/Q ratio and increased right-to-left shunting Spontaneous pneumothorax: rupture of blebs and bullae → air moves into pleural space with increasing positive pressure → ipsilateral lung is compressed and collapses Traumatic pneumothoraxClosed pneumothorax: air enters through a hole in the lung (e.g., following blunt trauma) Open pneumothorax: air enters through a lesion in the chest wall (e.g., following penetrating trauma)Air enters the pleural space on inspiration and leaks to the exterior on expirationAir shifts between the lungs Tension pneumothorax: disrupted visceral pleura, parietal pleura, or tracheobronchial tree → air enters the pleural space on inspiration but cannot exit → progressive accumulation of air in the pleural space and increasing positive pressure within the chest → collapse of ipsilateral lung and compression of contralateral lung, trachea, heart, and superior vena cava → impaired respiratory function, reduced venous return to the heart and reduced cardiac output → hypoxia and hemodynamic instability Clinical features Clinical features vary from asymptomatic to cardiopulmonary compromise Sudden, severe, and/or stabbing, ipsilateral pleuritic chest pain and dyspnea Reduced, or absent breath sounds, hyperresonant percussion, decreased fremitus on the ipsilateral side Subcutaneous emphysema Additionally in tension pneumothorax: Severe acute respiratory distress: cyanosis, restlessness, diaphoresisReduced chest expansion on the ipsilateral sideDistended neck veins and hemodynamic instability (tachycardia, hypotension, pulsus paradoxus) Secondary injuries (e.g., open or closed wounds) Diagnostics General Suspected pneumothorax is confirmed by chest x-ray. Immediate x-ray or an extended focused assessment with sonography for trauma (eFAST) in adults with severe respiratory compromise and children CT may provide detailed information about the underlying cause (e.g., bullae in spontaneous pneumothorax). Tension pneumothorax is primarily a clinical diagnosis and prolonged diagnostic studies should be avoided to initiate immediate treatment. Diagnostic tests Arterial blood gas analysis (ABG) To detect respiratory acidosis Chest x-ray (confirmatory test) Ideally in two projections (PA and lateral), in supine and upright position Ipsilateral pleural line with reduced/absent lung markings Sudden change in radiolucency Deep sulcus sign: dark and deep costophrenic angle on the affected side If pulmonary disease is present: airway or parenchymal lesions Additional features in tension pneumothorax: Ipsilateral diaphragmatic flattening/inversion and widened intercostal spacesTracheal deviation towards the contralateral sideChest CT In stable adults without severe respiratory compromise and responsive to resuscitation. Other indications : Presurgical workup Suspected underlying lung disease, to determine the likelihood of recurrent disease Uncertain diagnosis despite chest x-ray ECG For all patients with anterior chest trauma Reduced QRS amplitude in leads V2-V6 in left-sided pneumothoraxIncreased QRS amplitude in leads V5-V6 in right-sided pneumothoraxST elevation or depressionA negative eFAST does not exclude a pneumothorax! In cases of tension pneumothorax, immediate decompression is a priority and should not be delayed by imaging! Treatment Approach Simple pneumothoraxIf small (≤ 2 to 3 cm between the lung and chest wall on a chest x-ray) and asymptomaticUsually resolve spontaneously within a few days (∼ 10 days)Supplemental oxygen (4-6 L/min) via nasal cannula or mask with reservoirSerial follow-up with repeat CXRIf small and symptomatic (but hemodynamically stable) or large (> 3 cm between the lung and chest wall on chest x-ray) primary pneumothorax, iatrogenic, traumatic, or secondary pneumothorax Immediate supplemental oxygen (4-6 L/min) via nasal cannula or mask with reservoirUpright positioning Symptomatic treatmentTube thoracostomy Open pneumothoraxSimple partially occlusive dressings taped at 3 out of 4 sides of the lesionFollowed by thoracostomyObserve for development of tension pneumothorax Tension pneumothoraxEmergency chest decompression via chest tube placement if immediately available Otherwise perform emergency needle thoracostomy, followed by chest tube placementProcedures Chest tube placementBülau drain: 4th intercostal space (nipple line) in between anterior and median axillary line (safe triangle; midaxillary line) Needle thoracostomyImmediate insertion of a large-bore needle into the 2nd intercostal space along the midclavicular line (followed by insertion of a chest tube) Complications Complete pulmonary collapse → respiratory failure Tension pneumothorax → cardiac failure Mediastinal flutter in case of open pneumothorax → hemodynamic shock Hemothorax in cases of trauma Pneumomediastinum Pneumoperitoneum Recurrence Post-surgical/-procedural complications Persistent fistula with continuous air leakInjury to intercostal nerves and vesselsInfection

Cystic fibrosis Cystic fibrosis (CF) is an autosomal recessive disorder caused by a mutation in the CFTR gene, which encodes for the cystic fibrosis transmembrane conductance regulator protein. The mutation leads to the production of defective chloridechannels in cell membranes of the exocrine glands, and symptoms are caused by these glands producing abnormally hyperviscous secretions. Failure to pass meconium (meconium ileus) is often the first clinical sign of cystic fibrosis. Later, the lungs, digestive system, and sweat glands are commonly affected. Bronchial accumulation of hyperviscous mucus and impaired ciliary clearance predispose patients to chronic respiratory infection, pulmonary colonization with multiresistant bacteria, and long-term complications such as emphysema. Impaired secretion of pancreatic and biliary juices leads to digestive problems and chronic organ damage. The sweat test (pilocarpine iontophoresis) is considered the gold standard for detecting elevated levels of chloride in sweat, which is a characteristic sign of cystic fibrosis. The mainstay of treatment is symptomatic management. The median life expectancy is 39 years. Complications of chronic lung disease are the leading cause of death.

Epidemiology Second most common hereditary metabolic disorder in white populations Most common lethal genetic disorder in white populations IncidenceNon-Hispanic whites: ∼1/3300 Heterozygote frequency among non-Hispanic whites: 1/25 Children of heterozygous parents have a 25% chance of developing cystic fibrosis! Etiology Hereditary autosomal recessive disorderDefective CFTR (cystic fibrosis transmembrane conductance regulator) protein due to mutation in CFTR geneThe most common mutation is delta F508 on chromosome 7.Delta F508 (ΔF508 mutation) denotes the absence of the amino acid phenylalanine (F) in position 508 of the protein (present in 70% of non-Hispanic white patients with CF). Pathophysiology The CFTR gene, which is located on the long arm of chromosome 7, encodes the CFTR protein, which is an important component of the ATP-gated chloride channel in cell membranes. Mutated CFTR gene (ΔF508 mutation) → misfolded protein → defective protein is retained in the rough endoplasmic reticulum (rER) for degradation → ATP-gated chloride channel is absent on the cell surface of epithelial cells throughout the body (e.g., intestinal and respiratory epithelia, sweat glands, exocrine pancreas, exocrine glands of reproductive organs)In sweat glands: The chloride channel is responsible for transporting Cl- from the lumen into the cell(reabsorption).Defective ATP-gated chloride channel → inability to reabsorb Cl- from the lumen of the sweat glands → reduced reabsorption of Na+ and H2O → excessive loss of salt and elevated levels of NaCl in sweatIn all other exocrine glands: The chloride channel is responsible for transporting Cl- from the cell into the lumen (secretion).Defective ATP-gated chloride channel → inability to transport intracellular Cl- across the cell membrane → reduced secretion of Cl- → accumulation of intracellular Cl- → ↑ Na+ reabsorption (via ENaC) → ↑ H2O reabsorption → formation of hyperviscous mucus → accumulation of secretions and blockage of small passages of affected organs → chronic inflammation and remodeling → organ damage (see "Clinical features" below for details)↑ Na+ reabsorption → transepithelial potential difference between interstitial fluid and the epithelial surface increases (i.e., becomes more negative: e.g., from normal -13 mv to abnormal -25 mv In all exocrine glands, the Cl- channel is responsible for transporting intracellular Cl- across the cell membrane. However, in sweat glands, the Cl- channel is responsible for transporting Cl- from the lumen into the cell. The sweat test relies on the inability of the sweat glands to reabsorb salt, which results in elevated NaCl levels in sweat (see "Diagnostics" below). Clinical features Gastrointestinal Meconium ileus in newborns Failure to thrive due to malabsorption Gastrointestinal symptoms are common in infancy. Pancreatic diseasePancreatitisExocrine pancreatic insufficiencyFoul-smelling steatorrhea (fatty stools) may occur.MalabsorptionAbdominal distention DiarrheaDeficiency of fat-soluble vitamins (e.g., night blindness due to vitamin A deficiency, rickets due to vitamin D deficiency)CF-related diabetes mellitus (CFRD) Liver and bile duct abnormalitiesCholecystolithiasis, cholestasisFatty metamorphosis of the liver, eventually progressing to liver cirrhosis Biliary cirrhosis with portal hypertension Intestinal obstruction: abdominal distention, pain, and a palpable mass Rectal prolapse (rare) Respiratory Respiratory symptoms are common in adulthood. Obstructive lung disease with bronchiectasis Chronic sinusitis; nasal polyps may eventually develop Recurrent or chronic productive cough and pulmonary infections with characteristic microorganismsS. aureus is the most common cause of recurrent pulmonary infection in infancy and childhood.P. aeruginosa is the most common cause of recurrent pulmonary infections in adulthood. Dangerous bacteria (especially Pseudomonas aeruginosa) are easily transmitted to patients with CF → rapid decline in pulmonary function and increased risk of death (multiple antibiotic courses in their lifetime → high resistance to commonly used antibiotics!)Expiratory wheezing (obstruction), barrel chest , moist rales (indicate pneumonia), hyperresonance to percussionSigns of chronic respiratory insufficiency: digital clubbing associated with chronic hypoxia Airway hyperreactivity (e.g., wheezing) Sweat glands Especially salty-tasting sweat → electrolyte wasting Hyperhidrosis does not occur. Musculoskeletal Frequent fractures because of osteopenia Kyphoscoliosis Urogenital UrinaryNephrolithiasis, nephrocalcinosisFrequent urinary tract infections GenitalThe following factors may compromise the fertility of patients or cause them to be completely infertile: MenObstructive azoospermia is common. The vas deferens may also be absent. Undescended testicleWomenViscous cervical mucus can obstruct fertilization.Menstrual abnormalities (e.g., amenorrhea) Delayed secondary sexual development in both sexes Diagnostics General In most cases, CF is suspected based on clinical features, a positive newborn screen, or a sibling with CF. Best initial test is the sweat chloride test.If results are abnormal or borderline, DNA testing for the two CFTR mutations is indicated to confirm the diagnosis.If only one or no CFTR mutations are identified, an expanded DNA analysis or second sweat test should be performed; a positive result on either one of these confirms the diagnosis. Diagnostic criteria Typical clinical manifestations of CF: chronic sinopulmonary disease, gastrointestinal and nutritional irregularities, syndromes of salt loss, obstructive azoospermia AND evidence of CFTR dysfunction Sweat chloride ≥ 60 mmol/L on two occasionsOR CFTR gene mutationOR abnormal nasal potential difference test Neonatal screening ↑ Immunoreactive trypsinogen (IRT)Usually the first screening assay performed on neonatesDetects elevated levels of IRT in heel-prick blood DNA assayEither primary screening test or confirmation of CF after abnormal IRT resultIdentification of common CFTR mutations All neonates are screened for CF in the US! Laboratory tests Quantitative pilocarpine iontophoresis (sweat test) is the best initial test.Chloride levels > 60 mmol/L on two or more occasions are consistent with CF.The test should be conducted in patients > 2 weeks of age and > 2 kg in weight (more accurate). DNA analysisPrenatalIndication: if both parents are carriers of a CFTR mutationSpecimen collected via chorionic villus sampling or amniocentesisPostnatal/adult analysis: may be required if the sweat test is negative in a patient with suspected CF Nasal potential difference testIndication: unclear findings in sweat chloride and DNA tests despite CF-like disease in an organ systemVoltage measurements before and after the nose is perfused with different solutions show abnormal epithelialsecretion of chloride (e.g., more negative baseline potential difference and no difference in nasal potential difference after a chloride-free solution is administered). Supportive tests Other blood tests Contraction alkalosis and hypokalemia may occur (due to excessive loss of H2O and NaCl via the sweat glands and renal H+/K+ wasting) Stool: ↓ chymotrypsin and pancreatic elastase Chest x-ray/CT: hyperinflation Pulmonary function tests: ↓ FEV1:FVC ratio and ↑ residual volume (RV) and total lung capacity (TLC) ratio Findings are consistent with an obstructive ventilatory disorder; see spirometry. Ultrasound: increased liver echogenicity (fatty liver) Treatment Symptomatic management Ideally, management should be supervised by specialists in cystic fibrosis centers. RespiratoryHypertonic saline nebulization or aerosolized dornase alpha (recombinant DNAse that is a specific mucolytic agent that breaks down extracellular DNA in sputum) Bronchodilator therapy (e.g., albuterol)Chest physiotherapyIn chronic rhinosinusitis: intranasal glucocorticoids (see sinusitis)Mucolytics (e.g., N-acetylcysteine)High-dose ibuprofen has been shown to reduce respiratory disease progression. In chronic respiratory insufficiency Long-term oxygen inhalation therapyTreatment of last resort: lung transplantation Diet Additional sodium chloride intake High-energy diet to compensate for increased demand Pancreatic enzyme supplementsOral supplementation of lipophilic vitamins A, D, K, and E CFTR modulators [12] Indication: patients with CF who are homozygous for the delta F508 mutation in the CFTR gene Mechanism of action: These drugs modulate the expression of the defective CFTR protein by improving the production, intracellular processing, and function of the defective protein. Combination therapy: The drugs work synergistically to increase both the quantity and function of the CFTR protein on the cell surface, resulting in enhanced chloride transport. DrugsIvacaftor: improves Cl- transport by increasing the likelihood that the Cl- channel is open at the cell surface.Combination therapy with either tezacaftor or lumacaftorLumacaftor: improves the conformational stability of the defective CFTR protein, which leads to increased intracellular processing and trafficking of functional CFTR protein to the cell surfaceTezacaftor: increases the amount of mature CFTR protein on the cell surface by improving intracellular processing and trafficking of the CFTR protein Because CFTR modulators are only effective in patients with certain CFTR mutations, it is essential to perform CFTRgenotyping prior to initiating treatment. InfantsStaphylococcus aureusHaemophilus influenzaeIV vancomycinAdultsPseudomonas aeruginosaBurkholderia cepaciaFirst line: inhaled tobramycinAlternative: ciprofloxacin PO + inhaled colistinTreatment-resistant cases or if inhalation is not possible IV antibiotics: tobramycin, ceftazidime, or meropenemAspergillusItraconazole or voriconazole POStenotrophomonas maltophilia Trimethoprim/sulfamethoxazole (TMP/SMX) Preventive measures Annual influenza vaccine for all CF patients > 6 months with inactivated influenza vaccine (IIV) Pneumococcal vaccine (see the immunization schedule) Palivizumab: antibody against respiratory syncytial virus (RSV) for infants < 24 months Long-term treatment with azithromycin may be used to prevent recurrent pulmonary infections. Complications Gastrointestinal Meconium ileusDefinition: failure to pass the first stool in neonates (meconium usually passes in the first 24-48 hours after birth)Etiology: Cystic fibrosis is the leading cause in (> 90%) of cases.Clinical findings: signs of a distal small bowel obstructionBilious vomitingAbdominal distentionNo passing of meconium or stoolDiagnostics: abdominal x-ray (with contrast agent) Dilated small bowel loops, microcolon, Neuhauser sign ("soap bubbles" effect) Air-fluid levels are uncommon because of the viscous consistency of meconium.Differential diagnosis: See differential diagnosis of intestinal obstruction in neonates.TreatmentEnema with a contrast agent Surgery is required in complicated cases: intestinal perforation or volvulus Small bowel obstruction can also occur in older children and adults. Respiratory Hemoptysis Allergic bronchopulmonary aspergillosis (ABPA): ∼ 10% of patients develop this condition. Pulmonary emphysemaPneumothorax Cor pulmonale Prognosis Median life expectancy: ∼ 39 years The main determinant of life expectancy is the severity of pulmonary disease: chronic respiratory infections and mucus plugging → bronchiectasis (irreversible) → progressive respiratory failure → death Progress in the medical and psychological management of patients with CF has lead to: Significant improvement in survival in recent yearsSuccessful pregnancies

Granulomatosis with polyangiitis Granulomatosis with polyangiitis (GPA, previously known as Wegener's granulomatosis) is a systemic vasculitis that affects both small and medium-sized vessels. Patients typically initially suffer from a limited form that may consist of constitutional symptoms and localized manifestations such as chronic sinusitis, rhinitis, otitis media, ocular conditions, and/or skin lesions. In later stages, more serious manifestations may arise, including pulmonary complications and glomerulonephritis, although the skin, eyes, and heart may also be involved. Diagnosis is based on laboratory testing (positive for PR3-ANCA/c-ANCA), imaging, and biopsy of affected organs, which demonstrate necrotizing granulomatous inflammation. GPA is treated with immunosuppressive drugs, typically consisting of glucocorticoids combined with methotrexate, cyclophosphamide, or rituximab. Relapses are commo

Epidemiology Sex: ♂ = ♀ Peak incidence: 65-74 years Affects white patients disproportionately; African-American patients are rarely affected. Etiology IdiopathicGPA occurs more often after infections, especially those affecting the respiratory tract Pathophysiology GPA is a type of ANCA-associated vasculitis The following processes play a key role in the pathophysiology of GPA: Aberrant epigenetic expression of proteinase-3 on the cell membrane of neutrophilsFormation of antibodies against proteinase-3 (PR3-ANCA) Binding of PR3-ANCA to PR3 activates neutrophils → release of neutrophilic inflammatory mediators, formation of neutrophil extracellular traps, complement activation → damage to endothelial cells of small blood vessels Clinical features Constitutional symptoms: fever, night sweats, weight loss, arthralgias ENT involvement(∼ 90% of cases): often the first clinical manifestationChronic rhinitis/sinusitis: nasopharyngeal ulcerations → nasal septum perforation → saddle nose deformity(depression of the nasal dorsum)In some cases, thick, purulent discharge, sometimes containing bloodOral ulcersChronic otitisGingival hyperplasia (strawberry gingivitis) Lower respiratory tract (∼ 95% of cases): potentially life-threateningTreatment-resistant, pneumonia-like symptoms with cough, dyspnea, hemoptysis, wheezing, hoarseness, or pleuritic painClinical features of pulmonary fibrosis, pulmonary hypertension, or pulmonary hemorrhage may occur. Renal involvement (∼ 80% of cases): potentially life-threateningPauci-immune glomerulonephritis (Pauci‑immune indicates that there is little evidence of immune complex/antibody deposits.) → rapidly progressive (crescentic) glomerulonephritis (RPGN), with possible pulmonary-renal syndrome Skin lesions (∼ 45% of cases) Papules, vesicles, ulcersPurpura of the lower extremities Ocular involvement (∼ 45% of cases) Conjunctivitis, episcleritis, retinal vasculitisCorneal ulcerations Cardiac involvement (∼ 33% of cases): potentially life-threateningPericarditis, myocarditisVasculitis of the coronary arteries; may lead to myocardial infarction and deathUpper respiratory manifestations (i.e., purulent, sometimes bloody discharge; chronic nasopharyngeal infections; saddle nose deformity) are the most common chief complaints! GPA triad: necrotizing vasculitis of small arteries, upper/lower respiratory tract manifestations, and glomerulonephritis!Diagnostics Laboratory analysisBlood↑ Creatinine and ↑ BUN↑↑ ESR and ↑ CRPEvidence of PR3-ANCA/c-ANCA (anti-proteinase 3): highly sensitive and positive in ∼ 90% of patientsNormocytic normochromic anemia (in ∼ 50% of patients) UrineUrinalysis: microscopic hematuria, proteinuriaUrine sediment: dysmorphic RBC and RBC casts → nephritic sediment ImagingChest x-ray/CT: multiple bilateral cavitating nodular lesions PathologyDiagnosis should be confirmed by biopsy of affected tissueNecrotic, partially granulomatous vasculitis of small and medium-sized vesselsNecrotizing granulomas (intravascular and extravascular)Glomerulonephritis A biopsy is necessary to confirm the diagnosis! Granulomatosis with polyangiitis (GPA)Glomerulonephritis Localized necrotizing vasculitis Upper/lower respiratory tract manifestations with granulomas PR3-ANCA/c-ANCA (anti-proteinase 3) Microscopic polyangiitis Potentially palpable purpura Nasopharyngeal involvement less common No granulomatous inflammation MPO-ANCA/p-ANCA (anti-myeloperoxidase) Treatment Remission inductionIf mild disease → glucocorticoids + methotrexate (MTX) Patients who do not benefit from MTX may be switched to either cyclophosphamide or rituximab.If moderate to severe disease → glucocorticoids + either cyclophosphamide or rituximabPCP prophylaxis in patients receiving cyclophosphamide and corticosteroids: trimethoprim/sulfamethoxazole(TMP/SMX) Glucocorticoids should be tapered gradually as soon as the patient begins responding to the immunosuppressantagent. In the case of concurrent Goodpasture syndrome: plasmapheresis Remission maintenance : immunosuppressive drugs (e.g., azathioprine, rituximab or methotrexate). Prognosis Without adequate treatment, the mortality rate is approx. 90% within 2 years. 5-year survival with adequate treatment is approx. 80%.

TuberculosisTuberculosis (TB) is a common infectious cause of morbidity and mortality worldwide that is caused by Mycobacterium tuberculosis and typically affects the lungs. Primary infection, which is transmitted via airborne droplets, is often initially asymptomatic. Typically, M. tuberculosis remains dormant as the host's immune system keeps it in check (latent tuberculosis). However, if the immune system becomes compromised, reactivation disease may occur. Patients with active disease classically present with fever, weight loss, night sweats, and a productive cough (with or without hemoptysis) that does not respond to conventional antibiotic therapy. The infection may spread hematologically to any organ. However, disseminated disease is rare, unless the patient is severely immunocompromised. Patients with possible latent TB infection (LTBI) should be tested using the purified protein derivative (PPD) skin test or γ-interferon release assay (IGRAs) and be treated accordingly. Treatment of LTBI reduces the risk of active infection in up to 90% of cases, and therefore plays a crucial role in active TB prevention. Any suspicion of active TB infection should be followed by imaging and an attempt to identify M. tuberculosis using microscopy, cultures, and/or polymerase chain reaction (PCR). The treatment of tuberculosis is a lengthy process due to the slow growth of M. tuberculosis, its concealment in macrophages, and the fact that drugs cannot easily penetrate its cell wall. The standard empirical treatment includes combination therapy with rifampin, isoniazid, ethambutol, and pyrazinamide for 2 months, followed by rifampin and isoniazid for an additional 4 months. Despite combination therapy, the incidence of multidrug-resistant tuberculosis is steadily increasing.

Epidemiology Sex: ♂ > ♀ (2:1) United StatesThe incidence of TB infection in the US has been slowly declining.Foreign-born individuals (especially Asians and Hispanics) account for two-thirds of new TB cases. GloballyA leading infectious cause of death worldwide Despite ∼ 1 in 3 individuals being infected with TB worldwide, the overall incidence and prevalence have been declining.Countries with the highest incidence of TB: India, Indonesia, China, Nigeria, Pakistan, and South Africa The incidence of multidrug-resistant tuberculosis is steadily rising.Mycobacteria General featuresNonmotile, aerobic, gram-positive, acid-fast bacilli with a rich lipid cell wall Resistance: survives in aerosols, even over long distancesAcid-fast: able to survive in gastric secretionsComplex waxy, resistant cell walls increase the resistance to antimicrobial medication → Antibiotics only have an effect if used in combination over a long period of time. SpeciesMycobacterium tuberculosisMain pathogen causing tuberculosis: 95% of casesTransmission: mostly spread via droplet infectionPathogen host: predominantly humansMycobacterium bovis: Common pathogen causing gastrointestinal tuberculosisMechanism of infection: predominantly via ingestion of contaminated cow's milkPathogen reservoir: predominantly cattleEtiology Risk factors Immunosuppression (TB is considered to be the most common cause of mortality in patients with HIV globally) Drug abuse Alcoholism Malnutrition Diabetes mellitus Pre-existing damage to the lungs (e.g., silicosis, COPD) Poverty Residents and employees of congregate settings (e.g., prisons, hospitals, homeless shelters) Treatment with TNF-α inhibitors TB infection; no active diseasePositive tuberculin skin testNo clinical, bacteriological, or radiographic evidence of TBConsider chemoprophylaxis in certain patients in this groupTB infection; active disease, clinical evidencePositive tuberculin skin test OR positive M. tuberculosis culture (if done)Clinical and radiographic evidence of TBYesTB not clinically activeHistory of episodes of TB ORAbnormal but stable radiological changes; positive tuberculin skin test; negative M. tuberculosis cultureMay have completed chemoprophylaxis therapy; may never have received therapy before or may be completing chemoprophylaxis currently.TB suspectedDiagnosis is pendingTB treatment may or may not have commenced. Primary tuberculosis (primary infection) Latent tuberculosis infection (LTBI) Definition: primary infection without any pathological findings on radiological imaging; however, screening testsindicating previous infection with M. tuberculosis are positive. The lifetime risk of reactivation TB for a person with LTBI is about 5-10%. Active primary tuberculosis (only 1-5% of cases): primary infection with radiological-pathological findings of tuberculosis (see "Diagnostics" below) Reactivation tuberculosis (secondary infection) Definition: following a latent primary TB infection; 80% of secondary infections begin in the lungs (many months or years may pass between the onset of primary and secondary infection). Endogenous reactivation (very common) Exogenous reinfection (rare) M. tuberculosis remains dormant within the host and may be reactivated once the immune system becomes compromised (e.g., by high doses of glucocorticoids or chemotherapeutic agents, HIV infection)! Drug-resistant tuberculosis Causes: inadequate combination therapy or drug concentration Commonly affects multiple organs; relapse is common. Prognosis: Chances of recovery are about half that of non-resistant pathogens.Pathophysiology Alveolar macrophages (CD14+) phagocytose the TB bacteria but cannot eliminate them. Cord factor (trehalose-6,6'-dimycolate): a glycolipid in the cell wall of M. tuberculosis that inhibits fusion of phagosome and lysosome, thereby preventing lysis of phagocytosed mycobacteria By hiding inside the macrophages, TB bacteria do not provoke a humoral immune response (antibody production by B lymphocytes) in the host → therefore, antibody detection tests play no role in the diagnosis of TB.The mycobacteria replicate safely within the macrophagesPhagocytosed M. tuberculosis can only be destroyed by activated T lymphocytes. The infection is usually contained in the lung by formation of caseating granulomas (see "Pathology" below) that limit damage to the lungs and bacterial dissemination.Granuloma formation is caused by a delayed T cell-mediated reaction (i.e., type IV hypersensitivity reaction) that leads to the activation of alveolar macrophages (i.e., epithelioid cells) and their fusion into multinucleated giant cells.The bacteria may remain dormant in the granulomas for many years without any active clinical disease manifesting (latent TB).Immunosuppression (compromised T cell function) → dormant bacteria become active, replicate in the macrophages and spread into the lungs and other organs (active TB). IFN-γ deficiency: impaired phagocytosis and impaired granuloma formation → disseminated TBClinical features Latent infectionAsymptomaticThe patient is not contagious. Active infection (either primary or reactivated) Constitutional symptoms: fever, weight loss, night sweats, fatigue, lymphadenopathyPulmonary symptoms: dyspnea, productive cough (possibly hemoptysis) lasting > 3 weeksThe patient is contagious80% pulmonary tuberculosis 20% extrapulmonary tuberculosis Always consider TB as a differential diagnosis in a young patient with hemoptysis! Depending on the degree of immunosuppression, TB in HIV-positive patients may progress atypically or more rapidly! Subtypes and variants Extrapulmonary TB The most common sites of extrapulmonary TB include the bones, pleura, lymphatic system, and liver. TB may also affect the central nervous system (CNS), heart, urogenital and gastrointestinal tracts, and the skin. Urogenital tuberculosis Clinical featuresUrinary tract involvement: dysuria, flank pain, hematuria, low-grade fever♂: e.g., symptoms of prostatitis♀: e.g., secondary amenorrhea and lesions of the fallopian tube with infertility/sterility In cases of pyosalpinx: discharge containing pus, metrorrhagia, and hypermenorrhea DiagnosisUrinary tractSterile leukocytosis in the first urine cultureImaging: calcifications, strictures, and cavitiesAdnexal involvementDirect identification of M. tuberculosis in the menstrual blood Imaging: pyosalpinx ManagementNormal TB therapySurgical intervention to remove adhesions (♀) and urethral strictures Adrenal tuberculosis Clinical featuresAdrenal insufficiencyPossible symptoms of overt Addison disease DiagnosisCT/MRIAcute bilateral enlargement of the adrenal cortexMedullary destruction and chronically enlarged adrenal glands with calcificationsAbnormal labs (e.g., ↑ ACTH if Addison disease) Management: normal TB therapy Miliary tuberculosis Definition: massive lymphohematogenous spread of Mycobacterium tuberculosis bacilli from a pulmonary or extrapulmonary focus with multiple organ involvement and very small granuloma lesions (1-2 mm) Epidemiology: accounts for ∼ 20% of all extrapulmonary TB cases Etiology: may present 2-5 months after initial infection or years after Pulmonary involvement (most common)Chest x-ray: multiple, small, nodular densities of equal size, scattered throughout the lungs (often described as having a "millet seed" appearance) Other commonly affected organs: central nervous system, choroid, skin, liver/spleen (hepatosplenomegaly), kidneys, adrenal glands ManagementNormal TB therapy Surgical interventions depending on the affected sites and scope of disease Dermatological tuberculosis Lupus vulgaris: most common dermatological manifestation (especially prominent in countries with poor hygiene) Localization: primarily the faceEfflorescence: painless reddish-brown nodules ("apple jelly nodules"), which later develop into ulcers Other areas Heart (1-2 % of patients with pulmonary TB): most often pericarditis with pericardial effusion that may develop into constrictive pericarditis, often with calcifications BonesCommonly in the vertebral column (> 50%) → tuberculous spondylitis (Pott disease); see vertebral osteomyelitisImaging: osteolysis Meninges (tuberculous meningitis) Bowel EtiologyPreviously due to ingestion of unpasteurized milk infected with M. bovis (rare today)May occur as a severe complication of pulmonary TB Symptoms: chronic, possibly bloody diarrhea, fever, weight lossLocalization: Up to 90% of cases occur in the ileocecal region Tuberculous pleurisyEtiology: normally presents concurrently with pulmonary TB Clinical featuresNonproductive coughPleuritic chest painPossible constitutional symptoms (e.g., fever, weight loss)DiagnosisThoracentesis: exudative pleural effusion with elevated adenosine deaminase Thoracoscopic biopsy: may show acid-fast bacilli, granulomas, and/or positive culture results Diagnostics Active TB Assess risk of active TB through history and physical examination Moderate to high risk: chest x-ray → if suggestive of pulmonary TB, collect three sputum samples for culture, PCR , and microscopy → initiate treatment if tuberculous mycobacteria are confirmed (through culture) and also if PCR and microscopy are positive for tuberculous mycobacteria (while culture is pending)Low risk: consider testing for latent tuberculosis (see below) Chest x-ray findings in tuberculosis If reactivated disease: upper lobe cavitary lung lesions If primary TB infection Cavitation is uncommon in primary TBHilar lymphadenopathyPleural effusionsGhon complex: sequelae of primary TB infection Sputum microscopy with acid-fast stain (Ziehl-Neelsen stain)Rapid results but lacks sensitivityNo differentiation between M. tuberculosis or nontuberculous mycobacteria possible Culture (gold standard)Used for species identification, sensitivity testing, and to identify possibly resistancesCulturing can take up to six weeks (not useful for initial therapy planning)E.g., Löwenstein-Jensen agar Latent tuberculosis (LTBI) Test patients at risk for reactivation or new LTBI who would benefit from treatment of LTBI.Asymptomatic individuals in whom new infection is suspected (e.g., close contacts of patient with active TB, health care workers) People at risk for reactivation (e.g., immunocompromised patients) If patients would benefit from treatment → TST or IGRAPositive test → Evaluate for active TB (see "active TB" above) to decide whether treatment for active or latent TBis indicated.Negative test Repeat test after 8 weeks in patients who are close contacts of patients with active TB or annually in patients with ongoing exposure (e.g., healthcare workers).If none of the above applies, no repeat testing is necessary and the patient is considered negative for LTBI. Both TST and IGRA are adequate, with the following exceptions:IGRA is preferred in patients who received Bacillus Calmette-Guérin (BCG) vaccine. TST is preferred for children younger than 5 years of age. Interferon-γ release assay (IGRA)ELISA test that measures the level of interferon-γ expressed by T cells after coming into contact with synthetic TB-specific peptides Results available within 24 hours Tuberculin skin test (TST) or purified protein derivative (PPD) test5 units (= 0.1 mL) of purified protein derivative tuberculin is injected intradermally into the ventral surface of the lower arm. The diameter of the induration at the injection site is measured after 48-72 hours. The test only becomes positive 6-8 weeks after infectionLimited specificity and sensitivity (∼ 70%) False negative results due to an inadequate T-cell response in immunocompromised, malnourished, or elderly patients False positive results in patients who have received the BCG vaccination or have an infection with nontuberculous mycobacteria ≥ 5 mm, positive HIV-positive patients Recent contact with a TB-infected person Signs of TB on chest x-ray ≥ 10 mm Patients with high risk of reactivationIV drug useHomelessnessImmigration from endemic countryChronic illness (e.g., diabetes, kidney or lung disease, malignancy)Occupation (health care or prison workers) ≥ 15 mm, highly positive, may have partial blisteringAlways considered positive, even without risk factors Pathology Gross pathology Histopathology Tuberculous granuloma Activated macrophages and other immune cells surround the site of infection Caseous necrosis: multiple activated macrophages that form a conglomerate (polynuclear Langhans giant cells). Calcium deposits visible on x-ray Caseous tuberculous granulomas are a sign of a functioning immune system in TB infection. However, they do not necessarily demonstrate TB infection. Other mycobacteria (including tuberculoid leprosy) and tertiary syphilis may present similarly! Differential diagnoses See differential diagnosis of granulomatous disease See nontuberculous mycobacterial infections and mycobacterium avium complex infection Atypical pneumonia Lung cancer Treatment General Isolation: Every patient diagnosed with active TB must be isolated until sputum, gastric juices, and urine are negative! Therapy monitoringMonthly sputum samples for microscopy and cultureMonitor drug side effects: renal retention parameters, ophthalmological check-up , ENT, and liver function tests For treatment of extrapulmonary TB manifestations, see "Subtypes and variants" above. Active disease Initiation phase: 2 months of isoniazid + rifampin + pyrazinamide + ethambutol Continuation phase: 4 months of isoniazid + rifampin Isoniazid 6 months Hepatotoxicity (acute hepatitis, chronic liver failure) Peripheral polyneuropathy and other symptoms of pyridoxine deficiency (e.g., stomatitis, glossitis, convulsions, and anemia)Optic neuritis Reduce side effects through simultaneous pyridoxine (vitamin B6) administration Rifampin6 monthsHepatotoxicCYP-inducer (especially CYP3A4, CYP2C9)Red or orange body fluids (e.g., urine, tears) Pyrazinamide2 monthsHepatotoxicityHyperuricemia ArthralgiaMyopathy Ethambutol2 monthsOptic neuritis The efficacy of drugs metabolized by cytochrome P450 may be reduced because of hepatic enzyme induction by tuberculostatic drugs (especially oral diabetic treatments, calcium antagonists, statins, and oral contraceptives)! Latent tuberculosis infection Isoniazid monotherapy for 9 months in patients with positive interferon-γ and/or PPD test but without clinical signs of active TB Alternative regimens: 6 months of isoniazid, 4 months of rifampin, or 3 months of isoniazid and rifapentine Postexposure management Recent contact with a person who has active TBPerform PPD test or IGRAs and a chest x-rayPositive results and/or clinical symptoms of active TB → sputum stain and culture Sputum stain and/or culture positive: immediate initiation of treatment for active TB disease (see "Treatment of active disease" above)Sputum stain and/or culture negative but interferon-γ and/or PPD test positive: start treatment for LTBI (see "Treatment of LTBI" above)All tests negative: LTBI treatment for infants, children, and HIV-positive patients Prevention BCG-vaccinationChildren with a negative TST and continued high-risk exposure (e.g., drug-resistant TB)Health-care workers on an individual basis Notification: Any health care worker that knows of a case of suspected or confirmed tuberculosis in a patient should notify the TB program in their department within 24 hours Postexposure management: after recent contact with a person who has active TBPerform PPD test or IGRAs and a chest x-rayPositive results and/or clinical symptoms of active TB → sputum stain and culture Sputum stain and/or culture positive: start treatment for active TB (see "Treatment of active disease" above)Sputum stain and/or culture negative but interferon-γ and/or PPD test positive: start treatment for LTBI (see "Treatment of LTBI" above)If tests are negative in infants, children, and HIV-positive or other severely immunocompromised patients → LTBItreatment

Silicosis Silicosis is a common occupational lung disease that is caused by the inhalation of crystalline silica dust. Silica is the most abundant mineral on earth. Workers that are involved for example in constructions, mining, or glass production are among the individuals with the highest risk of developing the condition. Acute silicosis causes severe symptoms (e.g., exertional dyspnea, cough with sputum) and has a very poor prognosis. Chronic silicosis has a very variable prognosis and affected individuals may remain asymptomatic for several decades. However, radiographic signs are usually seen early on. Typical radiographic findings are calcifications of perihilar lymph nodes, diffuse ground glass opacities, large numbers of rounded, solitary nodules or bigger, confluent opacities. Avoiding further exposure to silica is crucial, especially since the only treatment available is symptomatic (e.g., bronchodilators). Silicosis is associated with an increased risk of tuberculosis and lung cancer.

Epidemiology There are currently approx. 2.3 million workers exposed to silica dust Overall incidence and mortality have significantly decreased over the last decades Etiology Inhalation of crystalline silica, most commonly as dust High-risk occupations for the development of silicosis include sandblasting, mining (e.g., coal mining), construction(e.g., tunnel construction), hydraulic fracturing, ceramics production, quarrying, glass manufacturing, and working in foundries. Pathophysiology Inhalation of silica dust → deposition in the airways → interaction of crystalline silica surfaces with aqueous media produces oxygen radicals → inflammatory reaction and injury to pulmonary cells (e.g., alveolar macrophages) ) → pulmonary fibrosis and scarring Clinical features Acute silicosis Acute silicosis refers to a short-term exposure to a large amount of crystalline silica dust. Within days to weeks Dyspnea, coughPleuritic painFever Within months to years Weight lossFatigueCyanosisRespiratory failure Chronic silicosis Chronic silicosis refers to long-term exposure to crystalline silica dust. Patients may remain completely asymptomatic or develop symptoms only after several decades of exposure Chronic cough (often with sputum) and exertional dyspnea Fatigue and weight loss Signs of respiratory failure and cor pulmonale Special form: Caplan syndrome (pneumoconiosis in combination with rheumatoid arthritis) → rapid development of basilar nodules and mild obstruction of ventilation Diagnostics Occupational history Chest x-rayEggshell calcification = well-defined, sickle-shaped calcification of the rims of hilar lymph nodes Bilateral diffuse ground glass opacities Large number of rounded, solitary, small (≤ 1 cm in diameter) opacities particularly in the upper lobe of the lungsConfluence of solitary lesions to form opacities that gradually enlarge to ≥ 1 cm Lung function tests: ↓ FVC, ↓ TLC, ↓ FEV1, ↓ FEV1/FVC ratio → findings indicate a mix of restrictive and obstructive lung disease Pulse oximetry/ABG: reduced oxygen saturation Biopsy: silicotic nodules, characterized by weakly birefringent silica particles in a central hyalinized region surrounded by concentric "onion-skin" collagen fibers Treatment There is no causal treatment for either acute or chronic silicosis. Avoid further exposure to crystalline silica Lung transplantation (in patients with advanced respiratory failure) Symptomatic treatment Smoking cessationBronchodilatorsSupplemental oxygenVaccination against pathogens causing respiratory infections (e.g., pneumococci) Silicosis is a national notifiable disease Complications Tuberculosis (silicotuberculosis): advanced silicosis increases the risk of tuberculosis. Lung cancer: silicosis doubles the risk for developing lung cancer.

Pertussis ertussis, or whooping cough, is a highly infectious disease of the respiratory tract caused by the gram-negative bacteria Bordetella pertussis. The disease is mainly transmitted via airborne droplets and is most commonly occurs in children. Typically, pertussis manifests in three stages, with the second and third stage characterized by an intense paroxysmalcoughing that is followed by a distinctive whooping sound on inhalation and, in some cases, vomiting. Young infants may not develop the typical cough, and often present with apnea and cyanosis instead. The disease is most often diagnosed via laboratory tests, especially detection of B. pertussis in bacterial culture. However, as test results may take time to obtain, treatment should be initiated as soon as clinical suspicion of pertussis arises. Subsequent management includes hospitalization of high-risk patients (e.g., infants) and antibiotic therapy with macrolides. These may lessen the length and severity of the disease if administered early, while also reducing infectivity and further disease transmission. Macrolidesare also the drug of choice for post-exposure prophylaxis (PEP), which is recommended for all people with a recent history of exposure to pertussis. PEP is administered regardless of the individual immunization status, as both vaccinationand prior infection may shorten the disease course, but do not provide full immunity.

Epidemiology Typically a childhood disease (particularly children aged < 1 year); however, older patients are increasingly affected High rate of infections in newborns: no transfer of maternal immunity (passive immunity) Etiology Pathogen: Bordetella pertussis is a gram‑negative, obligate aerobic coccobacillus Transmission: airborne droplet (through coughing); direct contact with oral or nasal secretions InfectivityWithout antibiotic treatment: 4-6 weeksWith treatment: ∼ 5 daysHighly virulent Incubation period: on average 7-10 daysPathophysiology Bordetella pertussis proliferates on ciliated epithelial cells of the respiratory mucosa → produces virulence factors → paralyze cilia of respiratory epithelium and cause inflammation → inflammatory exudate secreted into respiratory tract → compromises small airways → cough, pneumonia, cyanosis Bordetella pertussis produces pertussis toxin → catalyzes the ADP-ribosylation of the α subunit of Gi protein , thereby impairing it → adenylate cyclase activity is no longer inhibited by Gi protein → leads to accumulation of cAMP → impairs cell signaling pathwaysPertussis toxin is responsible for most of the systemic manifestations associated with whooping cough (e.g. hypoglycemia, lymphocytosis, modulation of host immune response) Neither vaccination nor actual infection confer lifelong or complete immunity. Stages Catarrhal stage (∼ 1-2 weeks) Nonspecific symptoms similar to an upper respiratory infection (mild cough, watery nasal discharge, rarely low-gradefever) Possibly conjunctivitis Paroxysmal stage (∼ 2-6 weeks) Intense paroxysmal coughing (often occurring at night) Followed by a deep and loud inhalation or high-pitched "whooping" soundAccompanied by tongue protrusion , gagging, and struggling for breathPossibly accompanied by cyanosisIncreases in frequency and severity throughout the stage Followed by the expulsion of phlegm or posttussive vomiting (risk of dehydration) In infants (< 6 months): risk of apnea; infants may not develop the typical cough and only manifest with apnea → close monitoring necessary! Convalescent stage (weeks to months) Progressive reduction of symptoms Coughing attacks may persist over several weeks before resolving Diagnostics A presumptive diagnosis of pertussis may be made based on clinical history and findings. However, if possible, laboratory tests should be performed to confirm the diagnosis. History Clinical diagnosis possible in patients with a cough lasting ≥ 2 weeks and at least one of the following symptoms: Coughing paroxysmsWhoop on inspirationVomiting following coughing attackApnea (in infants) Inquire about immunization history and possible contact with infectious persons. Laboratory tests Blood count: lymphocyte-predominant leukocytosis (50,000-60,000/μL) that corresponds with disease severity Pathogen detection (to confirm the diagnosis) Culture (gold standard) or PCR: samples from deep nasopharyngeal aspiration or posterior nasopharyngeal swabAs B. pertussis only grows on respiratory epithelium, blood cultures are always negative! Differential diagnoses Bordetella parapertussis infection Respiratory syncytial virus bronchiolitis Pneumonia, particularly due to Chlamydia trachomatis or Mycoplasma pneumoniae Croup (laryngotracheobronchitis) Foreign body aspiration Treatment General approach Early initiation of treatment, especially in high-risk patients (e.g., infants), while confirmatory laboratory tests are pending Hospitalization and monitoring: infants < 4 months; severe cases (e.g., respiratory distress, cyanosis, apnea, inability to feed) Oxygen administration with humidification Increased fluid intake and nutritional support If necessary, sedation Medical therapy Macrolides (e.g., azithromycin, clarithromycin, erythromycin)In children > 1 month and adults: any macrolide Alternative if macrolides are not tolerated: trimethroprim-sulfamethoxazoleInfants < 1 month: azithromycin Early administration may lessen symptoms of the catarrhal stage and early paroxysmal stage. Late antibiotic administration has little influence on disease severity but reduces infectivity. Complications Infections: otitis media, pneumonia Pulmonary: atelectasis, pneumothorax Neurologic: seizures, encephalopathy wih possible permanent damage Prognosis In children > 3 months: very good; lengthy convalescence, but full recovery In children < 3 months: mortality 1-3%, particularly due to apnea Increased risk for complications: premature infants; children < 6 months; people with underlying cardiac, pulmonary, neurologic, or neuromuscular disease Prevention ImmunizationChildren Routine immunization: administer DTaP vaccine (diphtheria, tetanus, and pertussis) at 2, 4, 6, and 15-18 months, as well as 4-6 years (see immunization schedule) Booster vaccination: administer Tdap vaccine: Single dose at 7-10 years of age if immunization is incomplete; Single-dose boost at 11-18 years of age, at least 10 years following the last dose Contraindications: known anaphylactic reactions, encephalopathy following previous vaccination Adults One-time dose of TdapIn particular, pregnant women and people in contact with newborns should be vaccinated! → increases passive immunity Post-exposure prophylaxis: choice of antibiotics identical to treatment recommendations (see "Therapy" above) Household and close contacts of infected people; especially people at risk of developing complications or close contacts of high-risk individuals (see "Complications" above)Administered regardless of immunization status Isolation: for 5 days after initiation of antibiotic therapy Reporting: Pertussis is a notifiable disease

Bronchiectasis Bronchiectasis is an irreversible and abnormal dilation in the bronchial tree that is generally caused by cycles of bronchial inflammation in addition to mucous plugging and progressive airway destruction. Although the widespread use of antibiotics has made bronchiectasis rare, conditions such as cystic fibrosis (CF), severe or protracted pneumonia, immunodeficiency, and COPD continue to cause it. The most important clinical finding is a chronic cough with copious mucopurulent sputum. Other symptoms may include dyspnea, rhinosinusitis, and hemoptysis. Physical examination reveals crackles and rhonchi on auscultation, often accompanied by wheezing. High-resolution computer tomography is the best diagnostic test and shows thickened bronchial walls, a signet-ring appearance, and "tram track" lines. Treatment focuses on alleviating symptoms and preventing exacerbations, and includes pulmonary physiotherapy and antibiotics to treat underlying infections. In rare cases, massive hemoptysis may complicate bronchiectasis and necessitate surgery or pulmonary artery embolization.

Etiology Bronchiectasis requires the combination of two important processes taking place in the bronchi: local infection or inflammation and either inadequate clearance of secretions, airway obstruction, or impaired host defenses. Pulmonary infections (i.e., bacterial, viral, fungal), especially severe or chronic infections Disorders of secretion clearance or mucous pluggingCystic fibrosis (CF) Primary ciliary dyskinesia (PCD)Allergic bronchopulmonary aspergillosis (ABPA) Bronchial narrowing or other forms of obstructionCOPDAspirationTumors Immunodeficiency (e.g., common variable immunodeficiency, hypogammaglobulinemia, HIV) Chronic inflammatory diseases (e.g., rheumatoid arthritis, Sjögren syndrome, Crohn's disease) Clinical features Chronic productive cough (lasting months to years) with copious mucopurulent sputum ; the following may be heard on auscultation: Crackles and rhonchiWheezing (due to obstruction from secretions, airway collapsibility, or a concomitant condition) Bronchophony Rhinosinusitis Dyspnea Hemoptysis: usually mild/self-limiting but severe hemorrhage that requires embolization may occur. Nonspecific symptoms (i.e., fatigue, weight loss, pallor due to anemia) Clubbing of nails (uncommon) Exacerbations of bronchiectasis Increased production of mucous above baselineLow-grade fever Bronchiectasis should be suspected in a patient with chronic cough producing large amounts of sputum! Diagnostics ImagingChest x-ray (best initial test)Inflammation and fibrosis of bronchial walls lead to the appearance of parallel "tram track" lines Thin-walled cysts (i.e., dilated bronchi forming sacs), possibly with air-fluid levels Late-stage bronchiectasis: honeycombingHigh-resolution computer tomography (HRCT): confirmatory testDilated bronchi with thickened walls; possible signet-ring appearance and tram track linesCysts, especially at bronchial ends in lower lobes, and honeycombing Other testsSputum culture and smear: to determine infectious etiology (i.e. bacteria, mycobacteria, and fungi)Blood testsCBC with differential: may show anemia of chronic disease and ↑ WBCs, ↑ neutrophilsHIV testing, genetic testing for CF, immunoglobulin quantitation to determine other possible etiologiesPulmonary function tests: findings consistent with obstructive pulmonary disease (i.e. ↓ FEV1/FVC ratio)Bronchoscopy: to visualize tumors, foreign bodies, or other lesions; may also be used in combination with bronchoalveolar lavage (BAL) to obtain specimens for staining and culture Bronchiectasis cannot be ruled out with a chest x-ray! Treatment Bronchiectasis is a permanent anatomical malformation and therefore cannot be cured. However, symptoms and advancement of the disease can be controlled. The treatment of any underlying cause is also very important. ConservativeBronchopulmonary hygiene and chest physiotherapy: "cupping and clapping" and postural drainage, hydration, directed coughAntibiotic therapy of exacerbations Smoking cessation Vaccinations (i.e. seasonal influenza vaccine, pneumococcal vaccine)Bronchodilators, corticosteroids, and nebulized hypertonic saline are not routinely used but may be considered, especially in patients with notable obstructive symptoms. Invasive proceduresSurgical resection of bronchiectatic lung or lobectomy: indicated in pulmonary hemorrhage, inviability of bronchus, and substantial sputum production in unilateral bronchiectasisPulmonary artery embolization: indicated in pulmonary hemorrhage Lung transplantation should be considered in severe disease. Complications Recurrent bronchopulmonary infections → obstructive ventilation disorder → respiratory failure and cor pulmonale Pulmonary hemorrhage (massive hemoptysis) Pleural empyema Lung abscess Prevention Primary prevention: antibiotic control of bronchial and pulmonary infections in predisposed individuals Secondary prevention: long-term low-dose macrolide treatment (e.g., azithromycin) in patients with two or more bronchiectasis exacerbations within one year

Hypersensitivity pneumonitis Hypersensitivity pneumonitis (or extrinsic allergic alveolitis) is a hypersensitivity reaction following exposure to environmental allergens. It is associated with inflammatory interstitial lung disease. Occupational groups affected by hypersensitivity pneumonitis are most commonly exposed to birds, hay, or certain reactive chemical species. Hypersensitivity pneumonitis can be classified into acute, subacute, or chronic forms depending on the frequency, length, and intensity of exposure, severity of symptoms, and duration of subsequent illness. The acute form is characterized by fever, flu-like symptoms, and leukocytosis. The subacute form is characterized by the insidious onset of productive cough, dyspnea, and fatigue over weeks to months. Chronic hypersensitivity pneumonitis is characterized by long-termprogressive dyspnea, weight loss, cough, and fatigue. Diagnosis is usually based on occupational history and evidence of fibrosis on imaging, bronchoalveolar lavage with lymphocytosis, positive inhalation challenge testing, or histopathologyshowing poorly formed noncaseating granulomas or mononuclear cell infiltrate. The preferred treatment for the acute form includes allergen avoidance (e.g., change of occupation) and administration of glucocorticoids for symptomatic relief . The prognosis for the acute form is good. Once severe damage to lung structures has occurred, however, few treatment options remain. Chronic hypersensitivity pneumonitis may lead to pulmonary fibrosis, which may ultimately require transplantation.

Etiology Combined type III and type IV hypersensitivity reaction with genetic predisposition Inhalation of organic particles (< 5 microns), primarily through occupational exposure (notifiable occupational disease) Animal proteinsAvian proteins Pigeon breeder's lungMicroorganism (s)Actinomycete spores from air conditioners, humidifiers, and water reservoirsHumidifier lung (air-conditioner setting)Actinomycete spores from moldy hay Farmer's lungActinomycete spores from sugar caneBagassosisActinomycete spores from moldy compost Mushroom worker's lung (compost treatment)Aspergillus clavatus spores from moldy paintsMalt worker's lungGrain weevil dustGrain handler's lungVarious bacteria in saw dust (through logging)Woodworker's lungChemical substance(s)Isocyanates (used in the adhesive and foam industry)Chemical worker's lung Clinical features Acute (commencing 4-8 hours after exposure) Flu-like symptoms: Fever, chills, malaise, cough, headacheDyspnea without wheezingDiffuse fine crackles upon auscultationSymptoms subside after 12 hours to several days (in the absence of additional exposure) Chronic (months after continuous exposure)Insidious onset of fatigue, productive cough, progressive dyspnea, cyanosisBilateral ralesWeight loss A recurrent 'common cold' with an irritating cough and fever may indicate hypersensitivity pneumonitis! Diagnostics Primarily a clinical diagnosis based on history of exposure and typical clinical presentation, which is supported by the presence of any one of the following: Positive serology: IgG, IgA, or IgM antibodies Chest x-ray or CTAcute: Patchy reticulonodular or diffuse infiltrates may be found in the mid to upper zone. Chronic : ground-glass attenuation with honeycombing (fibrotic changes) +/- emphysema Pulmonary function test : restrictive pattern Bronchoalveolar lavage (BAL) : lymphocytic predominance In hypersensitivity pneumonitis, IgG antibodies are found during an allergic reaction! Pathology Granulomatous inflammation with lymphocytes and polynuclear giant cells Treatment Antigen avoidance Glucocorticoid therapy Complications Respiratory failure Pulmonary heart disease

Interstitial lung disease Interstitial lung diseases (ILDs) are a heterogeneous group of disorders marked by inflammatory changes in the alveoli. ILDs may be idiopathic or due to secondary causes such as autoimmune disease, pharmacotherapeutic changes, or exposure to toxic substances. These changes can cause irreversible fibrosis and impaired pulmonary function. The main symptoms are exertional dyspnea and a dry cough. Bibasilar inspiratory crackles or rales are usually heard on auscultation. Treatment is based on the underlying cause. Immune modulators and corticosteroids are used in cases of unknown etiology. In advanced stages of disease ILD can result in pulmonary insufficiency and respiratory heart failurewith right ventricular insufficiency.

Etiology Idiopathic pulmonary fibrosis (IPF): most commonRisk factors: cigarette smoking, environmental or occupational exposures, chronic aspiration, genetic predisposition Other idiopathic subtypesDesquamative interstitial pneumonia (DIP)Nonspecific interstitial pneumonia (NSIP)Cryptogenic organizing pneumonia (COP)Acute interstitial pneumonia (AIP) (an idiopathic, interstitial lung disease with an acute onset that can progress rapidly to respiratory failure) Occupational, environmental, and iatrogenic causesPneumoconiosesAsbestosisSilicosisRare pneumoconioses (e.g., berylliosis, anthracosis)Radiation pneumonitis PharmacologicChemotherapeutic agents: bleomycin , methotrexate, busulfanOther agents: amiodarone , nitrofurantoin, phenytoin, penicillamine, cocaine, and heroin Secondary to underlying diseaseGranulomatous ILD: Sarcoidosis: noncaseating granulomas in multiple organs, including the lungPulmonary Langerhans cell histiocytosisGranulomatosis with polyangiitis (formerly Wegener granulomatosis)Eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome)Infectious diseases (eg, tuberculosis, legionellosis)Alveolar filling disease Hypersensitivity reactions Connective tissue disorders Bronchoalveolar carcinoma Clinical features Main symptoms Exertional dyspnea that progresses to dyspnea at restPersistent nonproductive coughFatigueOther symptoms related to underlying primary disorder (eg, joint pain in connective tissue disorder) Later stages of disease: digital clubbing due to chronic hypoxia IPF: The majority of patients (> 70%) do not respond to therapy and experience progressive respiratory failure. Diagnostics Due to the wide variety of subtypes and symptoms, there is no generally recommended diagnostic algorithm. Physical examination, serology, pulmonary function tests, and imaging (chest x-ray , CT scan) is performed almost always, while lavage or biopsy depend on the individual case. AuscultationBibasilar, inspiratory crackles or ralesIn advanced pulmonary fibrosis: loud inspiratory squeaksSigns of restriction: diaphragmatic elevation; sudden cessation of breathing on deep inhalation Pulmonary function testsRestrictive lung disease (e.g., low lung volumes, high/normal FEV1/FVC ratio)Decreased diffusing capacity for CO (DLCO) → highly sensitive parameter Chest x-rayNormal in approximately 10% of patients.Increase in reticular opacities (sign of fibrosis)Ground-glass opacities and honeycombing CT or HR-CT: Irregular thickening of the interlobular septa, honeycombing, and bronchiectasis BiopsyIndications: atypical or rapidly progressive symptomsIn patients with minimal signs or symptoms and stable disease, close observation (e.g., PFTs, HR-CTs over several months) may be sufficient. LaboratoryArterial blood samples show: elevated alveolar-arterial partial pressure of oxygen gradient, decreased partial pressure of oxygen Screen for rheumatic and autoimmune diseases. Treatment In secondary disease, the first step is to limit exposure to the toxic substance, cease therapy with the drug causing symptoms, or treat the underlying disease. Antibiotics if bacterial interstitial pneumonia is suspected Corticosteroids and immune modulators Oxygen for symptomatic or end-stage ILD Lung transplantation in end-stage ILD Pirfenidone and nintedanib are commonly used medication for ILD.

Atelectasis Atelectasis is a loss of lung volume that may be caused by a variety of ventilation disorders, for instance, bronchial injury or an obstructive mass such as a tumor. It may be categorized as obstructive, nonobstructive, postoperative, or rounded. Clinical features depend on the severity and extent of atelectasis, ranging from no symptoms to respiratory distress. Physical examination reveals a dull note on percussion and diminished breathing sounds over the affected area. On x-ray, the atelectatic section of the lung appears condensed and, due to decreased lung volume, may extend to the surrounding tissue. This effect can lead to an elevated diaphragm and mediastinal shift to the affected side. Treatment depends on the underlying cause. Complications of atelectasis include pneumonia or, depending on the extent of disease, respiratory failure.

Etiology Obstructive atelectasis (most common): airway obstruction (e.g., by a foreign body, mucus plug, malignancy) → nonventilated alveoli → reabsorption of gas in the poststenotic space → lung collapse Nonobstructive atelectasisCompression atelectasis: external space-occupying lesion (e.g., pleural effusion) that compresses the lung → forcefully pushes air out of the alveoliAdhesive atelectasis: surfactant deficiency or dysfunction → increases surface tension of alveoli → instability and collapse (e.g., acute respiratory distress syndrome (ARDS) in adults, respiratory distress syndrome in premature infants)Cicatrization (contraction) atelectasis: parenchymal scarring that leads to contraction of the lung (due to chronic destructive lung processes such as tuberculosis, sarcoidosis, and fibrosispneumothorax, pleural effusion Postoperative atelectasis: one of the most common post-operative complications (especially after chest or abdominal surgery); often occurs within 72 hours of surgery Clinical features Symptoms depend on the acuity and extent of atelectasis. Large number of affected alveoli or rapid onset → acute dyspnea, chest pain, tachypnea, tachycardia, and cyanosis Dull percussion note, diminished breath sounds, and decreased fremitus over the affected lung Diagnostics Arterial blood gas analysis: hypoxemia, potentially low PaCO2, and respiratory alkalosisAlveoli that are unable to participate in gas exchange → increased alveolar dead space → increased physiologic dead space Chest x-ray and CT: evidence of lobar collapseDirect signs: displacement of fissures and homogeneous opacification of the collapsed lobeIndirect signs Elevation of ipsilateral diaphragmDisplacement of the hilum and mediastinal structures towards the affected sideLoss of volume in the affected side of the chest Treatment Early mobilization Deep breathing exercises, directed coughing, and incentive spirometry Treatment of underlying condition; see foreign body aspiration, pleural effusion, pneumothorax The risk of atelectasis after surgery can be avoided by prescribing opioids in doses that are sufficient for pain relief, as well as encouraging the use of incentive spirometry. At the same time, opioids should be used with caution due to their suppression on coughing. Smoking should be avoided 6-8 weeks prior to surgery. Complications Pneumonia Lung abscess Respiratory failure

Acute respiratory distress syndrome Acute respiratory distress syndrome (ARDS) is a severe inflammatory reaction of the lungs to pulmonary damage. Sepsisis the most common cause, but a variety of systemic and pulmonary factors (e.g., pneumonia, aspiration) can lead to ARDS. Affected individuals initially present with acute onset cyanosis, dyspnea, and tachypnea. Most patients will improve significantly in the weeks following the initial presentation, but some cases progress to pulmonary fibrosis, which prolongs hospital stay and delays the resolution of symptoms. The chief finding in ARDS is hypoxemic respiratory failurewith decreased arterial oxygen pressure, which usually progresses to hypercapnic respiratory failure. Chest x-ray typically shows diffuse bilateral infiltrates (butterfly pattern). Management of ARDS focuses on maintaining adequate oxygenation, which often requires intubation and (lung protective) mechanical ventilation because nasal prongs and/or mask ventilation are insufficient. Moreover, any treatable causes of ARDS should be addressed. Even if adequate treatment is initiated, ARDS remains an acutely life-threatening disease with a high mortality rate.

Etiology Systemic causes Sepsis (most common cause)E.g., secondary to trauma, infection or peritonitis Trauma Shock Massive transfusion (See "TRALI" for details) Acute pancreatitis Hematopoietic stem cell transplantation Medication (e.g., salicylic acid, tricyclic antidepressants, bleomycin) Recreational drug overdose (e.g., cocaine) Primary damage to the lungs Pneumonia Aspiration Inhaled toxins Pulmonary contusion Inhalation injury (e.g., inhalation of hyperbaric oxygen) Near drowning Fat embolism (e.g., through blunt trauma) Amniotic fluid embolism (e.g., during labor) Lung transplantation Sepsis is the most common cause of ARDS! Pathophysiology Tissue damage (pulmonary or extrapulmonary) → release of inflammatory mediators (e.g., interleukin-1) → inflammatory reaction → injury to alveolar capillaries and endothelial cells leading to:Excess fluid in interstitium and on alveolar surface → pulmonary edemaExudation of neutrophils and protein-rich fluid (hyaline membrane) into the alveolar space → diffuse alveolar damage (DAD) to type I and type II pneumocytes → decrease in surfactant → intrapulmonary shunting → late stage: proliferation of type II pneumocytes and infiltration of fibroblasts → progressive interstitial fibrosisImpaired gas exchange, reduced compliance, hypertension and a right-to-left pulmonary shunt (increased shunt fraction) → hypoxemia → compensation through hyperventilation → respiratory alkalosisClinical features Acute onset Tachypnea and tachycardiaCyanosis, dyspnea, and diffuse cracklesFever, cough, and chest pain may also be present. Disease course Most patients begin to improve after the first 1-3 weeks and symptoms usually resolve fully.Some develop pulmonary fibrosis with prolonged resolution of symptoms and extended ventilator dependence. Diagnostics Laboratory studiesArterial blood gasInitially, hypoxemic respiratory failure with ↓ PaO2 and respiratory alkalosis → PaO2/FiO2 ≤ 300 mm HgHypercapnic respiratory failure develops with disease progression.Additional findings depend on the underlying cause (e.g., abnormal white blood count in sepsis) or associated complications (e.g., increased creatinine levels in acute tubular necrosis). Imaging: chest x-ray Diffuse bilateral infiltrates (perihilar bat wing or butterfly distribution of infiltrates)Air bronchogram AtelectasisPleural effusions ARDS is a likely diagnosis in the presence of both typical causes and therapy-resistant hypoxemia. The diagnosis is further supported by characteristic findings on chest x-ray that are not explained by underlying cardiac disease.Differential diagnoses Cardiogenic pulmonary edema: presents with signs of cardiac dysfunction (e.g., murmurs, jugular venous congestion) Acute exacerbations of interstitial lung diseases: examine patient history and past chest x-rays Transfusion-related acute lung injury (TRALI) Transfusion-associated circulatory overload (TACO): a rapid, high-volume infusion, which causes symptoms similar to ARDS See differential diagnoses for dyspnea Treatment Approach The primary objective is achieving sufficient oxygen saturation (while avoiding oxygen toxicity). Treat the underlying cause (e.g., sepsis). Sedation (benzodiazepines, opioids) If oxygenation is insufficient: Noninvasive oxygenation (e.g., via masks and nasal tubes) can usually deliver a FiO2 of ∼ 70%.Endotracheal intubation and lung protective ventilation can usually provide a FiO2 of 100% and should be administered early on in most patients. Lung protective ventilation Description: Pressure-controlled ventilation with a low tidal volume and low peak inspiratory pressure to avoid further pulmonary damage. However, increasing the positive end-expiratory pressure (PEEP) is often necessary during treatment. With this type of ventilation, higher levels of CO2 can be tolerated (permissive hypercapnia). SettingsStandard tidal volume ≅ 6 mL/kg body weightFiO2 < 0.5 (< 50% in the gas mixture) to avoid oxygen toxicityPEEP and FiO2 can be adjusted to recruit collapsed alveoli and guarantee sufficient oxygen saturation. Goal: SaO2 > 90% (or PaO2 > 55 mm Hg)A high respiratory rate and a low tidal volume are the principles of lung protective ventilation! Extracorporeal life support (ECMO) Definition: ECMO is a method of artificially supporting the circulatory system. In patients with severely reduced or no pulmonary function, the O2/CO2 exchange is achieved through the use of artificial lung membranes. Depending on the exact technique/machinery used, several other terms are employed as well (e.g., extracorporeal membrane oxygenation). IndicationsIn adults: severe, treatment-refractory respiratory or cardiorespiratory failure (e.g., in cases of ARDS, severe pulmonary edema, or acute heart failure) In children: e.g., patients with meconium aspiration syndrome, infant respiratory distress syndrome, or neonatal sepsis Prognosis In cases with simultaneous multi-organ failure, the mortality rate can rise to over 50%. Can progress to interstitial fibrosis and restrictive lung disease.

Asbestosis Asbestosis is a type of pneumoconiosis caused by the inhalation of asbestos fibers and occurs primarily as a result of occupational exposure. After a long latency period, this condition manifests with nonspecific symptoms, e.g., coughingand dyspnea, which are caused by fibrotic changes in the lungs. The diagnosis is established based on a history of occupational exposure (such as working with textiles, cement, ship-building, insulation) and characteristic changes on chest x-ray (reticular opacities and pleural plaques). Currently, there is no curative treatment for asbestosis. Management consists of measures that provide symptomatic relief like oxygen therapy, prompt antimicrobial treatment of respiratory infections, cessation of exposure, and immunization against influenza and pneumococcal pneumonia. Long-termexposure to asbestos can lead to complications like fibrosis, respiratory failure, and malignancy (especially bronchogenic carcinoma, and mesothelioma). Pleural effusion may be the first sign of a malignant mesothelioma. A combination of chemotherapy, surgery, and/or radiation therapy is used to manage malignant mesothelioma. However, the prognosis of patients with malignant mesothelioma is poor, with the mean survival time being ∼ 1 year.

Etiology Type of pneumoconiosis caused by inhalation of asbestos fibers Risk factorsOccupations involving the manufacture or demolition of ships, plumbing, roofing, insulation, heat-resistantclothing, and brake lining Smoking Pathophysiology Inhalation of airborne asbestos fibers into alveoli → inflammation and fibrosis of pleural parenchyma → risk of carcinogenic effects A high cumulative dose of asbestos is associated with a higher incidence of asbestosis. In smokers, the disease progresses more rapidly because mucociliary clearance is impaired. Clinical features Long latent period Nonspecific findings Exertional dyspnea Dry cough → productive cough Digital clubbing Bilateral fine, basal end-inspiratory rales Diagnostics Imaging Chest x-ray (classification according to the International Labor Office): diffuse bilateral infiltrates predominantly in the lower lobesInterstitial fibrosis Supradiaphragmatic and pleural reticulonodular opacities/plaques Rounded atelectasis In some cases, pleural effusionHR-CT: Parenchymal fibrosis (especially basilar, peribronchiolar, and septal)Pleural plaques and subpleural linear opacities Pulmonary function testRestrictive ventilatory defects (decreased pulmonary compliance)Early: decreased DLCOLater: reduced vital capacity and total lung capacityNormal to increased ratio of FEV1 to FVC Bronchoalveolar lavage : microscopic asbestos bodiesStain positive with Prussian blueAppear as ferruginous bodies: dumbbell-shaped and golden-brown fusiform rods, surrounded by an iron protein coat Biopsy Microscopic asbestos bodiesFibrosisTreatment No curative treatment exists. Cessation of exposureOxygen therapy Immunization against influenza and pneumococcal pneumoniaAntimicrobial treatment of respiratory infections Palliative care in the case of advanced disease Complications Mesothelioma Definition: primarily malignant tumor that develops from mesothelial cells EpidemiologySex: ♂ > ♀ (3:1)Age range: ∼ 40-70 years Etiology: secondary to asbestos exposure LocalizationPleural mesothelioma (most common)Peritoneal mesothelioma (rarely)Pericardial mesothelioma (very rarely) Clinical findingsDyspnea and nonpleuritic chest pain (most common)Fever, sweats, weight loss, fatigueFeatures of pleural effusion: dull percussion; absent or reduced breath sounds on affected side DiagnosisPleurocentesis : bloody (exudative) pleural effusionImaging (chest x-ray and CT) : Multiple nodular, pleural lesions (pleural thickening)Ipsilateral hemothoraxReduced size of ipsilateral lung fieldsObliteration of the diaphragmLaparoscopy, thoracoscopy, and pleuroscopy with stained biopsy : mesothelioma cells and psammoma bodies It is important to differentiate mesothelioma from adenocarcinoma. Immunohistochemistry: Mesothelioma often stains positive for mesothelin, serum mesothelin-related protein (SMRP), calretinin, cytokeratin 5/6, and vimentin. Microvilli in mesothelioma are long and slender; they are short and stubby in adenocarcinoma. Treatment: radiation, with or without chemotherapy (cisplatin and pemetrexed); surgery (pleurectomy or pneumonectomy) may be indicated in cases with severely impaired pulmonary function Prognosis: poor, with a mean survival time of ∼ 1 year Other MalignancyBronchogenic carcinoma (most common malignant complication of asbestosis)Laryngeal cancerAlso of the esophagus, biliary system, kidneys, and ovaries Pulmonary hypertension Cor pulmonale Right-sided heart failure Progressive respiratory failure Caplan syndrome The most common malignancy associated with asbestosis is bronchogenic carcinoma, not mesothelioma!

Nonthrombotic embolism Embolisms of fat, air, and amniotic fluid are uncommon but potentially life-threatening events caused when these substances enter the circulatory system. Fat emboli mostly originate from the bone marrow in patients with long bone fractures. Air can enter the circulatory system during surgical procedures (mostly neurosurgery), while amniotic fluidemboli occur during delivery. The emboli usually lodge within the pulmonary arteries and cause right ventricular outflow obstruction and circulatory collapse. Clinical features of special embolisms typically include acute onset of hypoxia, hypotension, and neurological symptoms (altered consciousness, seizures, coma). The diagnostic sign of fat embolism is a petechial rash on the upper body (if present), while that of venous air embolism is a mill wheel cardiac murmur. Diagnosis of any type of special embolism is primarily clinical, with arterial blood gas evaluation, ECG, and chest x-ray providing additional evidence. Treatment is mainly supportive and includes oxygenation, mechanical ventilation, and administration of vasopressors, if necessary. Mortality rates of all types of special embolisms are high

Fat embolism Definition: potentially life-threatening condition caused by the entry of fat cells, usually from bone marrow, into the circulatory system EtiologyTraumatic fat embolism (95% of cases) Most commonly long bone fractures (e.g., femoral fracture)Orthopedic surgeriesBone marrow transplantNon-traumatic fat embolismSickle cell crisis Others: pancreatitis, osteomyelitis, parenteral lipid infusion Clinical featuresSymptoms develop within 12 hours to 2 weeks of the inciting insultClassic triad of Hypoxia (most common symptom): tachypnea, dyspnea, cyanosis, diffuse crackles in the chest Neurological symptoms: confusion, lethargy, seizures, focal neurological deficits, comaPetechial rash (seen in up to 50% patients) : mainly seen in the axilla, chest wall, head, neck, conjunctiva, and buccal mucosa Diagnosis: mainly clinical Complete blood count: anemia, thrombocytopeniaChest x-ray: mostly normal; bilateral infiltrates may be seenMicroscopic examination of urine and sputum: fat droplets may be seen Treatment: supportive care in an intensive care unit Prognosis: mortality rate ∼ 15% Air embolism Definition: potentially life-threatening condition caused by the entry of air into circulation, often during a surgical procedure EtiologySurgery : neurosurgical procedures (highest risk) ; laparoscopic surgery Trauma Barotrauma: mechanical ventilation ; decompression sicknessAccidental injection of air (infusion-related errors); intentional injection of air (suicidal/homicidal intent) Venous air embolism Sudden hypotension, tachycardia, hypoxia Distended jugular veins Mill wheel murmur Cardiac arrhythmia/arrest Chest x-ray: air shadows (hyperlucency) in the pulmonary arteriesand cardiac chambers Echocardiography: evidence of air in the (right) cardiac chambers Arterial air embolism Focal neurological deficits, impaired consciousness, coma Acute heart failure, myocardial infarction, cardiac arrhythmias Acute kidney failure Ophthalmoscopy: air bubbles within the retinal vessels CT scan of the brain, abdomen, or pelvis may show ischemic changes in the affected organs. TreatmentGeneral measures Compression of the suspected site of entry (airtight sealing) Correction of hypoxia and hypotensionInitiate CPR, if necessaryPosition change (venous air embolism): Trendelenburg (head down position) and left lateral decubitus (Durant's maneuver) Central venous line insertion and direct aspiration of air bubbles from the cardiac chambers Prognosis: high mortality rate (≥ 30%) Amniotic fluid embolism Definition: rare, but life-threatening condition caused by the entry of fetal cells and debris (from the amniotic fluid) into maternal circulation Risk factorsMaternal age > 30 yearsMultiparityComplicated labor (e.g., placenta previa/abruption, forceps delivery, eclampsia) Clinical featuresAFE mostly occurs during labor. Acute onset ofRespiratory collapse: hypoxia, dyspnea, tachypnea, cough, cyanosis, basal crepitations, acute respiratory distress syndromeCardiovascular collapse: hypotension, arrhythmias, cardiac arrestAltered consciousness (drowsiness, seizures) Features of disseminated intravascular coagulation Multi-organ dysfunctionFetal bradycardia (decelerations on cardiotocography) Diagnosis: mainly clinical Arterial blood gas evaluation: features of respiratory acidosis Complete blood count: anemia, thrombocytopeniaCoagulation studies: prolonged prothrombin time (PT) TreatmentCorrection of hypoxia: high flow oxygen or intubation and mechanical ventilationCorrection of hypotension/shock: vasopressors (noradrenaline or dopamine) Correction of anemia and coagulopathy: transfusion of platelet/fresh frozen plasma (FFP) and packed red blood cells Emergency cesarean section PrognosisHigh maternal mortality rate Neurological deficits in surviving infants

Pulmonary examination The examination of the pulmonary system is a fundamental part of the physical examination that consists of inspection, palpation, percussion, and auscultation (in that order). Recognition of surface landmarks and their relationship to underlying structures is essential. The physical examination of the pulmonary system begins with the patient seated comfortably on the examination table and his/her upper body completely exposed. The chest and the patient's breathing pattern are then inspected, followed by palpation of the chest wall, percussion of the thorax, and auscultation of the lung fields. A carefully recorded medical history and thorough physical examination allow for differential diagnosis and prompt initiation of therapy.

Inspection The following should be assessed: Breathing patternNormal respiratory rate is 12-20/min in adults, and up to 44/min in infantsBradypnea: respiratory rate < 12/min Tachypnea: respiratory rate > 20/min, shallow breathing Hyperpnea: respiratory rate > 20/min, deep breathing Inspiratory:expiratory ratio: The ratio of the inspiratory time to expiratory time during spontaneous breathing, which is normally 1:2.Common abnormal patterns of breathing include: Cheyne-Stokes breathing: alternating periods of deep breathing followed by apnea Results from a delay in detecting changes in ventilation and arterial carbon dioxide pressure.Common causes include: advanced heart failure, damage to respiratory centers (e.g., stroke, traumatic brain injuries, metabolic encephalopathies), and central sleep apneaAtaxic breathing: irregular breathing in rhythm and depth Obstructive breathing: prolonged exhalation Increased effort of breathingTachypneaUse of accessory muscles of respiration during inspiration Sternomastoid musclesScalene musclesPectoralis majorTrachea off midline Tripod position: patients with emphysema and respiratory distress will lean forward while sitting, resting with their hands on their knees. Peripheral signs of respiratory dysfunctionCyanosis: bluish discoloration of the skin and mucosa (due to deoxygenated hemoglobin)Nail clubbing EtiologyCommonly chronic hypoxemia (including congenital heart disease, cardiac shunts, interstitial lung disease, cystic fibrosis and lung cancer)COPD does not cause nail clubbing and a COPD patient with nail clubbing is concerning for underlying malignancy.Can also be seen in hypertrophic osteoarthropathy: a syndrome (either hereditary or paraneoplastic) that manifests with painful nail clubbing, synovial effusions, and periostitisClinical featuresPainless swelling of connective tissue in the distal phalangesLovibond angle ≥ 180°: angle between the base of the nail and its surrounding skinNail bed feels spongy when pressed and springs back when released.Schamroth testPlace distal phalanges against each other so that both fingernails touchWhen there is nail clubbing, the normal diamond-shaped "window" between the nail beds will not be seen. Abnormalities in the shape of the thoraxThe anteroposterior diameter of the thorax may increase in COPD, leading to a "barrel chest" appearance.Retraction of the intercostal spaces Asymmetric movement may be associated with pleural disease, phrenic nerve damage, or pleural effusion.Kyphosis or scoliosis may lead to decreased forced vital capacity, forced expiratory volume and overall respiratory function Sputum production or secretions, if anyWhite and translucent: viral infection (for example, bronchitis that presents with a typical early-morning cough)White and foamy: pulmonary edemaYellow-green: bacterial infectionGreen: an indication of a pseudomonal infectionGrayish: pneumoconiosis, a waning bacterial infectionBlackish-brown: possibly old blood; should be further investigated (can also be a harmless incidental finding)Friable: tuberculosis, actinomycosisHemoptysis: see section below In newborn and infantsJugular, sternal, and intercostal retraction Nasal flaring or flaring of the nostrils Neck extension Hemoptysis DefinitionExpectoration of bloodMassive hemoptysis: 100-600 mL of coughed up blood in 24 hours EtiologyBronchogenic carcinoma (symptoms include SOB, cough, blood-tinged sputum)Severe lung inflammation: bronchiectasis, tuberculosis, aspergilloma, bronchitisPulmonary vascular disorders: pulmonary embolism, raised pulmonary capillary pressure (e.g., mitral stenosis)Airway trauma: incessant coughing, foreign body, iatrogenicCoagulopathy Approach for massive hemoptysisDependent positioning if side of bleeding can be identified (e.g., position the patient in right-side down decubitus position if the right lung is bleeding)Secure airway (intubation)Stabilize cardiovascular function (IV fluids/transfusion)Stop bleeding (correct coagulopathy, flexible bronchoscopy with balloon tamponade, arteriography with embolization if other measures fail) A chest x-ray, to determine the underlying pathology, is mandatory in all patients with hemoptysis. Patients with massive hemoptysis require stabilization before imaging! Palpation Evaluate areas of tenderness or bruising Symmetry of chest expansionPlace both hands on the patient's back at the level of the 10th ribs with thumbs pointing medially and parallel to the rib cage.As the patient inhales, evaluate for asymmetric movement of your thumbs. Tactile fremitusAsk the patient to say "toy boat" and feel for vibrations transmitted throughout the chest wall.Can be asymmetrically decreased in effusion, obstruction, or pneumothorax, among othersCan be asymmetrically increased in pneumonia Percussion Pathological findingsHyper-resonant percussion noteSign of increased air inside the thoracic cavity: emphysema, bronchial asthma, pneumothoraxDull percussion noteSign of fluid inside the thoracic cavity: pneumonia, pleural effusion Auscultation Physiological breath sounds Vesicular breathing Pathological breath sounds Types of pathological breath sounds Crackles or rales: discontinuous, intermittentFine: soft, high-pitched (e.g., normal, asbestosis, sarcoidosis)Coarse: loud, low-pitched (e.g., COPD, pulmonary edema) Wheezes (sibilant wheezing): musical, prolonged Rhonchi (sonor wheezing): low-pitched, snoring Stridor: high-pitched, over trachea which may occur on: Inspiration (inspiratory stridor): narrowing of the extrathoracic airway; characteristic of epiglottitis, pseudocroup, foreign body aspiration, bilateral vocal cord palsyExpiration (expiratory stridor): obstruction of the intrathoracic airways; characteristic of bronchial asthma, COPDInspiration and expiration (biphasic stridor): obstruction at the level of the glottis Muffled or absent breath sounds Transmitted sounds EgophonyIf it sounds like "A" rather than "E", this is called egophony and suggests lobar pneumonia. Whispered pectoriloquyClearly audible in the presence of pulmonary consolidation Main symptomTactile fremitusPercussionAuscultation (breath sounds)Tracheal deviation Physiological-NormalResonantVesicularNonePleural effusionDyspnea may be presentDecreasedDullDecreasedTo the opposite side of the lesion (no deviation in small effusions)Pulmonary edemaSevere dyspneaPossibly increasedDullFine or coarse crackles, depending on severityNoneSimple pneumothoraxAcute dyspneaDecreased or absentHyperresonantDecreased or absentNoneTension pneumothoraxSevere dyspneaDecreased or absentHyperresonantDecreased or absentTo the opposite side of the lesionBronchial asthma1Paroxysmal attacks of dyspnea, wheezingDecreasedHyperresonantWheeze, a prolonged expiratory phase, possibly decreased breath soundsNoneChronic bronchitis1Chronic coughDecreasedHyperresonantWheezing, rhonchiNoneEmphysemaChronic dyspneaDecreasedHyperresonantDecreasedNonePneumonia2Fever, dyspneaIncreasedDullCoarse cracklesNoneLung fibrosisCachexia and weakness, dyspneaNormal or slightly increasedDullBasal inspiratory cracklesTo the side of the lesionAtelectasisPain may be presentDecreasedDullDecreasedTo the side of the lesionPulmonary embolism1Acute dyspnea, pleuritic chest pain, tachypneaNormalNormalNormalNoneTumor1,2,3Hemoptysis, constitutional symptoms (weight loss, fever, night sweats)Possibly decreasedPossibly dullPossibly decreasedTo the opposite side of the lesion

Infectious diseases Legionellosis Chlamydia infections Anthrax Pneumocystis pneumonia Aspergillosis Nosocomial infections Acute Bronchitis Pneumonia Tuberculosis Pertussis Influenza General mycology

Legionellosis Legionellosis is an infection caused by Legionella pneumophila, a gram-negative rod that thrives in warm aqueous environments such as drinking-water systems, hot tubs, and air-conditioning units. Transmission occurs by inhaling contaminated, aerosolized water droplets. Legionellosis is a common nosocomial infection and outbreaks are typical. Notable risk factors include smoking, chronic lung disease, advanced age, and immunosuppressive conditions. There are two forms of legionellosis: Legionnaires' disease and Pontiac fever. Patients with Legionnaires' disease present with atypical pneumonia (shortness of breath, cough), commonly in combination with various other symptoms, including gastrointestinal (e.g., diarrhea) and neurological (e.g., confusion). Laboratory abnormalities are common, especially hyponatremia. Pontiac fever is a milder, self-limiting, flu-like illness. A urine antigen test is used to confirm infection with L. pneumophila. Fluoroquinolones are the treatment of choice for Legionnaires' disease. In the U.S., legionellosis is a notifiable disease and steps should be taken to eliminate contaminated sources and to prevent future outbreaks. Epidemiology Frequency: occurs rarely in infants, almost solely in adults (of any age) and typically in outbreaks High-risk patientsElderlyPatients with chronic diseasesImmunocompromised individualsSmokers Etiology Causative organism Legionella pneumophila (gram-negative, obligate aerobic, facultative intracellular rod) causes over 90% of Legionnaires' disease outbreaks Pontiac fever is generally due to lesser known types of Legionella Path of infection Inhalation of contaminated aerosolsCold and hot water systems: e.g., those found in hotels, hospitals, and retirement homesWhirlpools/hot tubs, swimming pools, showersAir-conditioning systems with contaminated condensed water Common associations Nursing homes Hospitals Confined travel accommodations (e.g., cruise ships, hotels, resorts) Legionnaires' disease Incubation period: 2-10 days Clinical featuresFever, chills, headachePneumoniaUnilateral lobar pneumoniaORSymptoms of atypical pneumonia: dry cough which can become productive , chills, shortness of breathAuscultation: crackles bilaterallyRelative bradycardia (uncommon) DiarrheaNeurological abnormalities, especially confusion, agitation and stuporFailure to respond to beta-lactam monotherapy Pontiac fever Incubation period: 1-3 days Mild, self-limiting course of legionellosis without pneumonia Symptoms are difficult to distinguish from the flu and include fever, headache, and muscle aches Laboratory findings BloodHyponatremia (serum sodium < 130 mEq/L) and hypophosphatemia are common.Aminotransferases and creatinine may be elevated.Possible thrombocytopenia and leukocytosis UrineLegionella urinary antigen test: the most important diagnostic tool Rapid test, but only detects serogroup 1 Hematuria and proteinuria are common Respiratory secretionsGram stain of respiratory secretions shows many neutrophils; usually no organisms identifiedRequires silver stainLegionella culture: slow; requires buffered (iron and cysteine) charcoal yeast extract agarResults after 3-5 days PCR: high sensitivity, high specificity Serology: A four-fold rise in antibody titer confirms legionellosis. However, the antibody titers have low specificityand sensitivity, and seroconversion can take up to 12 weeks. Therefore, more rapid tests like the urinary antigen test or PCR are used more often. Imaging Chest x-ray: usually abnormal, diffuse, interstitial infiltrates Treatment Legionnaires' disease should be treated early with antibiotics, especially because of its high mortality rate of 10%. If atypical pneumonia is suspected but not yet verified → see medical treatment of pneumonia If legionellosis is verified Drug of choice: fluoroquinolones (preferably levofloxacin, alternatively moxifloxacin) for 7-10 days Initial parenteral treatment is recommended for all patients to avoid possibly poor gastrointestinal absorption Second-line treatment: macrolides (e.g., erythromycin or azithromycin) for 3 weeks If patients are unresponsive to monotherapy, consider addition of rifampin or tigecycline In any case of atypical pneumonia, antibiotic treatment needs to cover Legionella! Prevention Legionellosis is a notifiable disease Course of action when contaminated water sources are detected in medical facilities Contaminated water systems should be disinfected Use terminal tap water filters, especially for high-risk patients (e.g., immunocompromised or the elderly)

Obstructive sleep apnea Obstructive sleep apnea (OSA) is the most common breathing-related sleep disorder and is typically associated with obesity. It is characterized by obstruction of the upper airways due to the collapse of the pharyngeal muscles. OSA results in multiple episodes of interrupted breathing (apnea and hypopnea) during sleep, which leads to alveolar hypoventilation. Affected individuals generally suffer from severe daytime sleepiness and impaired cognitive function (e.g., deficits in attention and/or memory) as a result of sleep disruption. Their partners commonly describe observing restless sleep associated with irregular snoring, gasping, or choking episodes. Diagnosis is based on the assessment of risk factors and polysomnography. Many patients with OSA (> 50%) are affected by secondary hypertension. The cardiovascular consequences of secondary hypertension reduce life expectancy. However, these effects can be counteracted with weight loss and nightly continuous positive airway pressure (CPAP). Other important aspects of management include avoidance of precipitating factors (e.g., alcohol) and improvement of sleep hygiene.

Obstructive sleep apnea (OSA): breathing-related sleep disorder in which airflow significantly decreases or ceases because of upper airway obstruction (typically the oropharynx) Apnea: respiratory arrests of ≥ 10 seconds Hypopnea: reduction of airflow by ≥ 30% of pre-event baseline for ≥ 10 seconds in combination with reduction of blood oxygenation by ≥ 3% or EEG arousal Epidemiology Sex: ♂ > ♀ (2:1) Prevalence: ∼ 20-30% in men and 10-15% in women Etiology Obstruction of the upper airways due to the collapse of the pharyngeal muscles during sleep Risk factorsObesity, especially around the neck (short, wide "bull neck")Structural abnormalities that impair respiratory flow: adenotonsillar hyperplasia (especially in children), nasal septum deviation, previous upper airway surgery, enlarged uvula, tongue, or soft palate (especially in adults), overbite with a small chin, hypertrophied pharyngeal muscles, nasal polypsAlcohol consumption before sleepIntake of sedatives and/or beta-blockers before sleepSmokingFamily historyAcromegalyHypothyroidismPathophysiology Obstruction of the upper airways → apnea → ↓ partial pressure of oxygen in arterial blood (PaO2), ↑ partial pressureof carbon dioxide in arterial blood (PaCO2, also known as hypercapnia)→ ↑ Hypoxic pulmonary vasoconstriction → ↑ pulmonary hypertension → cor pulmonale→ ↑ Sympathetic activity → secondary hypertension→ Respiratory acidosis → renal compensation → increased HCO3 retention and decreased chloridereabsorptionClinical features Restless sleep with waking, gasping, or choking Loud, irregular snoring with apneic episodes (third-party reports) Excessive daytime sleepiness (e.g., patient falls asleep, microsleep during meetings or while watching TV) Impaired cognitive function (e.g., impaired concentration, memory loss) Depression, decreased libido Diagnostics General considerations Initial assessment: standardized questionnaires and third-party reports (interview sleeping partner regarding snoringand respiratory interruptions) Laboratory tests are not usually considered useful in the diagnosis of OSA, but may help identify underlying conditions or physiological consequences of OSA. Polycythemia (↑ Hct, ↑ Hb): This occurs because hypoxia induces erythropoietin secretion by the kidneys, which stimulate the blood marrow, leading to increased RBC production.TSH (thyroid-stimulating hormone) may be considered in patients with possible hypothyroidism.PaO2 is usually normal during the day. Sleep studies Polysomnography: first-line method; a test that records physiologic variables during sleep (including sleep stages, respiratory flow, respiratory pauses, and oxygen saturation); it may also help to identify the type of sleep disorder and associated conditions (e.g., seizures) Classic findingsApnea and hypopnea events; cease on arousalOxygen desaturationArousal events on EEG↑ Pulse pressure BradycardiaFragmentation of sleep with pathological reduction of REM-sleep phases and slow-wave sleep Home sleep apnea testing (less sensitive): ambulatory screening method based on the use of a device for monitoring cardiorespiratory parameters during the night. Indicated in patients with a high pretest probability of moderate to severe OSA or when in-laboratorypolysomnography is not feasible Differential diagnoses Central sleep apnea (CSA) Definition: Breathing-related sleep disorder characterized by repetitive cessation or decrease of respiratory effort during sleep due to impaired function of the respiratory center. Airway obstruction is absent. Etiology: idiopathic or caused by an underlying disorder Risk factorsAge > 65 yearsMale sexHeart failure Central nervous system disease (e.g., trauma, brainstem tumor, stroke) Certain drugs (e.g., chronic opioid use) Pathophysiology: lack of stimulation to the respiratory center with patent upper airways → periodic lack of respiratory muscle innervation → interruption of thoracic and/or abdominal respiratory movements Clinical featuresMorning headachesRepeated waking at nightDaytime sleepinessSnoring Association with OSA is very commonPossibly Cheyne-Stokes breathing (especially in patients with heart failure) DiagnosisBased on clinical history (e.g., underlying conditions such as heart failure or stroke)Polysomnography TreatmentTreat underlying disorder (if present)CPAPPolysomnography in central sleep apnea shows an absence of respiratory effort, which distinguishes the condition from OSA.The 3 C's of Central sleep apnea are Congestive heart failure, CNS trauma or toxicity, and Cheyne-Stokes breathing. Obesity hypoventilation syndrome (Pickwickian syndrome) Definition: a breathing disorder that only affects morbidly obese individuals; frequently accompanied by OSA, it is characterized by diurnal hypercapnia Etiology: obesity (BMI ≥ 30 kg/m2) Risk factors: identical to those of obesity Pathophysiology: obesity reduces inspiratory muscle strength and restricts respiratory excursions → alveolar hypoventilation, sleep-disordered breathing (e.g., OSA), and failure of ventilatory compensatory mechanisms → decreased PaO2 and increased PaCO2 during sleep (PaCO2 retention extends to the waking hours) Clinical featuresSame symptoms as those of OSAHeadaches and severe sleepiness Diagnostic criteriaBMI ≥ 30 kg/m2Arterial blood gasses showing diurnal hypercapnia (PaCO2 > 45 mm Hg) that cannot not be explained by another condition Polysomnography shows hypoventilation during sleep with or without obstructive apnea events. TreatmentWeight lossNasal intermittent positive pressure ventilationTreatment Mild to moderate OSA (mild symptoms and < 20 apneic episodes) Weight loss Reduce and/or avoid risk factors: alcohol, nicotine, sedatives (e.g., benzodiazepines) Sleep hygiene: regular and sufficient sleep Lateral as opposed to supine sleeping position Blood pressure control Oral appliances Severe OSA (> 20 apneic episodes and alterations in arterial oxygen saturation) Surgery (uvulopalatopharyngoplasty) Resection of the uvula and redundant retrolingual, soft palate, and tonsillar tissue This procedure should only be considered as a supplementary treatment.Bilevel positive airway pressure (BPAP) Continuous positive airway pressure (CPAP) Nocturnal positive pressure therapy via CPAP is the therapy of choice in symptomatic OSA. The success of therapy is highly dependent on patient adherence and regular monitoring with sleep studies! Complications Systemic hypertension Hypoxia-induced cardiac arrhythmia (e.g., (atrial fibrillation, atrial flutter) Pulmonary hypertension and cor pulmonale Global respiratory insufficiency Cardiac infarction, stroke, and sudden cardiac death (the risk of sudden death is high in infants and the elderly) Polycythemia Risk of accidents (e.g., car crashes, occupational accidents) due to microsleep Increased risk of developing vascular dementia Poor sleep leads to increased appetite and obesity. Prognosis The mortality rate is higher in patients with severe OSA who do not receive adequate treatment. CPAP ventilation can significantly lower the risk of mortality in OSA.

Rare pneumoconiosesPneumoconioses are a group of restrictive interstitial lung diseases caused by the inhalation of certain dusts, which are often associated with mining and agriculture. Inhalation of inorganic dust - especially chronic, occupational exposure - causes an inflammatory reaction in the lung parenchyma, which may lead to symptoms such as cough and breathlessness. Typically, disease manifestation occurs after many years of exposure. An occupational history of patients with findings indicative of interstitial disease suffice to diagnose the condition. Chest x-ray serves as an adjunct diagnostic tool and allows the scarring associated with the disease to be visualized. There is no effective targeted therapy for pneumoconioses; management involves avoidance of triggers, supplemental oxygen, and supportive therapy. Prevention through screening programs, use of masks and adequate ventilation, and/or change of jobs can help lower the impact of the condition.

Overview Etiology: mostly occupational exposure Pathophysiology: Inhalation of dust particles → phagocytosis by alveolar macrophages → destruction of dust cells, inflammatory reaction → scarring, granuloma formation Common clinical featuresCough and progressive exertional dyspnea are the most common symptoms.Pulmonary fibrosis, cor pulmonale, lung cancer, and Caplan syndrome are possible complications of all types of pneumoconioses. See clinical features of interstitial lung diseases AluminosisAluminum dustWelders (e.g., automobile industry)Symptoms occur after many months of exposure.Complication: bullous emphysema → spontaneous pneumothoraxNodular or diffuse infiltrates (predominantly affects the upper lungfields)Small cystic radiolucencies ("honeycombing") AnthracosisCarbon dust and sooty airCity dwellersCoal minersMilder than other types of pneumoconiosisPulmonary fibrosis rarely occurs.Coal workers' pneumoconiosis (also known as black lung disease or black lung): A more severe form of anthracosisOccurs only with prolonged exposure to large amounts of coalCarbon-laden macrophages induce inflammationCharacterized by chronic bronchitis that progresses to progressive massive pulmonary fibrosisAnthracosis: heterogenous pulmonary infiltrates, with/without mass lesionCoal workers' pneumoconiosis: fine nodular opacifications (< 1 cm) in upper lung zoneBerylliosisBerylliumWorkers in high-techfields , where alloys are often utilizedNoncaseating granulomatous diseaseaffecting the lungs and skinChronic beryllium disease: Progressive dyspnea may occur within a few days of high-grade exposure.Reticular interstitial pattern (similar to sarcoidosis), affecting the upper lobesIn some cases, hilar lymphadenopathyPulmonary siderosisIron dustWelders, iron miners, foundry workersUsually asymptomatic; occasionally, presents with features similar to COPDPulmonary fibrosis rarely occurs.Small, round, patchy shadows on x-ray

Cough A cough is a forceful expulsion of air from the lungs that helps to clear secretions, foreign bodies, and irritants from the airway. It may be classified as acute (< 3 weeks), subacute (3-8 weeks), or chronic (> 8 weeks), as well as productive (with sputum/mucus expectoration) or dry. Upper respiratory tract infections (URI) and acute bronchitis are the most common causes of acute cough. Subacute cough is often a sequela of a URI (postinfectious cough) but can also be due to chronic bronchitis or pneumonia. Chronic cough is often caused by rhinitis/sinusitis (upper airway cough syndrome), asthma, GERD, and ACE inhibitors. A thorough medical history and physical examination often suffice to diagnose the etiology of cough. Chronic cough or the presence of associated red flag symptoms (dyspnea, fever, hemoptysis, weight loss) are indications for further investigation. Sputum culture, chest x-ray/CT scan, and pulmonary function tests are useful diagnostic tests in the evaluation of cough, but are not routinely indicated. Treatment of cough depends on the underlying etiology.

Pathophysiology Definition: a forceful expulsion of air from the lungs that helps to clear secretions, foreign bodies, and irritants from the airway May be voluntary or a reflex to airway irritants/triggers Mechanical Inhaled/aspirated solid or particulate matter (e.g., smoke, dust)MucusChemicalGastric acid (GERD)Inflammatory mediators: bradykinin, prostaglandin E2Thermal: cold air Cough reflex arcIrritation of cough receptors in the nose, sinuses, and upper and lower respiratory tracts (see the triggers above) Transmission along the afferent pathway via the vagus nerve (CN X) to the cough center in the medullaGeneration of efferent signal in the medulla and initiation of cough via the vagus, phrenic, and spinal motor nerves Mechanism of cough reflexIrritation of cough receptors → initiation of the cough reflex arc, which leads to: Rapid inspiration, closure of the epiglottis and vocal cords (which traps inhaled air in the lungs), and contraction of the diaphragm, expiratory, and abdominal muscles → rapid increase of intrathoracic pressureA sudden opening of the vocal cords and forceful expulsion of air from the lungs Differential diagnosis of acute cough (< 3 weeks) Non-life-threateningcausesUpper respiratory infections (URIs)Acute bronchitisAcute hypersensitivity pneumonitisLife-threateningcausesCongestive heart failureAcute pulmonary embolismPneumoniaAcute exacerbation of asthma/COPDAcute pericarditis (rare cause)Acute inhalation injury In childrenURIs (most common)Croup (barking cough)Bronchiolitis (children < 2 years).Subacute cough(3-8 weeks)Postinfectious cough (most common) PneumoniaAcute exacerbation of chronic bronchitisDifferential diagnosis of chronic coughIn adults(> 8 weeks)Common causesUpper airway cough syndrome (UACS): Abnormally increased nasal mucus secretion that drips down the back of the throat and can lead to coughing, a feeling of obstruction in the throat, and throat clearing Chronic rhinitis Chronic sinusitis Vasomotor rhinitisAsthmaGastroesophageal reflux disease (GERD)Chronic bronchitis ACE-inhibitor-induced cough Less common causesEmphysemaBronchiectasisChronic hypersensitivity pneumonitisLung cancer/pulmonary metastasisPulmonary tuberculosisInterstitial lung disease (e.g., sarcoidosis. silicosis)Cystic fibrosisIn children(> 4 weeks)InfantsCongenital defects (e.g., esophageal atresia with/without tracheoesophageal fistula, vascular rings)Foreign body aspirationOlder childrenAsthmaURIsGERDPertussis Viral bronchitisCystic fibrosisImmune deficiency disorders QualityProductive (cough with production of phlegm/mucus): pneumonia , bronchitis , bronchiectasis , pulmonary edema , tuberculosis Nonproductive (dry cough): asthma, interstitial lung disease, viral pneumonia (e.g., adenovirus. RSV, influenza virus) TimingNocturnal cough: asthma ; upper airway cough syndrome (UACS) ; GERD Seasonal/geographical variation: allergy/irritant-induced cough (e.g., asthma, hypersensitivity pneumonitis, UACS due to allergic rhinitis/sinusitis, acute bronchitis) Risk factorsHistory of smoking (pack years)Occupational history (e.g., pneumoconiosis, hypersensitivity pneumonitis) Medication history (E.g., ACE inhibitors, β blockers, aspirin can induce dry cough and/or bronchoconstriction.) History of allergies History of contact with an individual who has TB Associated symptomsURI: rhinorrhea, odynophagia, myalgia, fever: suggestive of URIAllergic origin: itching and watering of eyes, rhinorrhea, pruritusCough-variant asthma: exacerbation of cough with activityGERD (3rd most common cause of chronic cough) : heartburn or reflux Red flag symptoms: Systemic symptoms: persistent fever (pneumonia, TB); night sweats, weight loss (TB, lung cancer) Dyspnea (asthma, congestive heart failure, COPD, interstitial lung disease)Hemoptysis (TB, lung cancer); copious sputum production (bronchiectasis)Severe thoracic pain/pleurisy (pneumonia, TB, pulmonary embolism)Change in character of a chronic cough (esp. in a smoker's cough) History of contact with TB and/or HIVDiagnostics An acute cough is often a clinical diagnosis (diagnostic tests are not routinely indicated in this case). Patients with chronic cough and/or red flag symptoms (see "Approach" above) require further assessment. Laboratory tests Complete blood count: indicated in patients with chronic cough/red flag symptoms if an infective etiology (e.g., neutrophilic leukocytosis in pneumonia, lymphocytosis in TB) or allergic etiology (e.g., eosinophilia in asthma) is suspected Tuberculin skin test: patients with suspected TB Sputum examinationSputum culture: suspected bacterial pneumonia, TBSputum examination for acid-fast bacilli: suspected TB Nasopharyngeal swab/deep nasopharyngeal aspirate culture and PCR for pertussis: indicated in patients with subacute/chronic cough, esp. if associated with an inspiratory whoop and/or post-tussive vomiting Blood culture: suspected pneumonia Arterial blood gas analysis: patients with dyspnea and those with suspected life-threatening causes of acute cough Bronchoalveolar lavageInconclusive non-invasive diagnostic tests (e.g., in bronchiectasis, asbestosis, bronchioloalveolar carcinoma)Suspected infectious etiology in patients who are unable to expectorate sputum for examination (e.g., tuberculosis, PCP, histoplasmosis, aspergillosis) Imaging Chest x-ray Suspected pneumonia or TBChronic cough with abnormal physical examination findings or prolonged history of nicotine abuseRed flag symptoms X-ray of paranasal sinuses: patients with UACS secondary to suspected sinusitis Chest CT scanSuspected bronchiectasis (diagnostic test)Recurrent pneumoniaChest x-ray findings suggestive of lung cancer (e.g., mass, hilar lymphadenopathy)Inconclusive chest x-ray findings in patients with foreign body aspiration BronchoscopyForeign body aspiration Lung cancer Suspected tracheoesophageal fistula Pulmonary function tests Spirometry: indicated to differentiate between obstructive lung disease (e.g., asthma, COPD) and restrictive lung disease (e.g., interstitial lung disease) Bronchial challenge test (metacholine challenge test; bronchodilator reversibility test): to differentiate asthma from other obstructive lung disease Single-breath diffusing capacity: to differentiate between intrapulmonary (e.g., interstitial lung disease) and extrapulmonary causes (e.g., pleural effusion) of restrictive lung disease Miscellaneous BNP levels, ECG, and ECHO: patients with cough due to suspected heart failure Endoscopy, 24-hour esophageal pH monitoring, and/or barium swallow: patients with chronic cough suspected to be due to GERD/achalasia that is not responsive to a trial of PPIs Acute cough Non-life-threatening acute cough (URI, acute bronchitis): Nonpharmacological treatment Honey Menthol (vapors) Hydration, lozenges, and humidifiersNSAIDs: for myalgia, headaches, feverAntibiotics: usually not recommended Hypersensitivity pneumonitis: antigen avoidance with/without glucocorticoid therapy Life-threatening acute coughInhalation injury: secure airway (endotracheal intubation/tracheostomy) ; administer high-flow oxygen; administer aerosolized bronchodilators and N-acetylcysteine with/without heparin; chest physiotherapy Treat the underlying cause: See congestive heart failure, pulmonary embolism, asthma, COPD, and acute pericarditis. In children: See "treatment" of croup and bronchiolitis. Subacute cough Post-infectious coughOften resolves spontaneously (no treatment needed)Cough interfering with sleep/daily activities: antitussives (see below), inhaled bronchodilators, oral/inhaled corticosteroids Suspected pertussis: early administration of macrolide antibiotics See "treatment" of pneumonia and COPD. Chronic cough Stop inciting or aggravating factor(s)Cessation of smokingStop/substitute ACE-inhibitors Chronic cough with no abnormal physical examination findings and no history of ACE-inhibitor use: Empirical trial of treatment with first-generation antihistamines (e.g., dimetindene, diphenhydramine) → improvement of symptoms within 2 weeks → diagnostic of UACS; treat the underlying cause (see "treatment" of allergic rhinitis and sinusitis)No/partial improvement with antihistamines→ Empirical trial of inhaled bronchodilators or corticosteroids → symptomatic improvement → diagnostic of cough-variant asthma → See "treatment" of asthma (bronchodilators, corticosteroids, leukotriene receptor antagonists). → Empirical trial of proton pump inhibitors and anti-reflux lifestyle modification (see "treatment" of GERD) → symptomatic improvement → continue PPIs for 8-12 weeks Treat the underlying cause Symptomatic treatment of a cough Productive coughDrugs to decrease the viscosity of mucus and enhance mucociliary clearance (no cough suppression) Expectorants (e.g., guaifenesin)Loosen mucus by increasing the fluid content of bronchial secretions via an unknown mechanismShould be taken with sufficient amount of water for the best effectMucolytics (e.g., N-acetylcysteine)Decrease the viscosity of mucus by disrupting disulfide bonds of mucus glycoproteins Used in patients with viscous mucus in chronic bronchopulmonary diseases (e.g., cystic fibrosis, COPD)Also used as an antidote in acetaminophen poisoningChest physiotherapyChest percussion/vibration may be used with postural drainage to mobilize and enhance the clearance of mucus from the airway.Indicated in patients with thick mucus and/or ineffective cough (e.g., cystic fibrosis, bronchiectasis, pneumonia) Non-productive cough: cough suppressants (antitussive medications)Centrally acting cough suppressants Examples: dextromethorphan, codeineSee opioids for more informationPeripherally acting cough suppressants (e.g., benzonatate) Antitussive medications decrease coughing, which is important for the expectoration of mucus! They are not usually indicated if an infection is the cause of cough.

Foreign body aspiration Foreign body aspiration (FBA) is a potentially life-threatening emergency that most commonly occurs in children aged 1-3 years. FBA typically manifests with sudden onset of coughing and choking, followed by stridor and dyspnea. Obstruction of the larynx or trachea is a potentially life-threatening situation that causes severe respiratory distress, cyanosis, and suffocation. Most commonly, the foreign body (FB) becomes lodged in the main and intermediate bronchi; approx. 60% of FB are located in the right main bronchus due to the more vertical orientation compared to the left main bronchus. Partially obstructed airways result in the formation of a ball-valve obstruction, in which air trapping occurs in the lung segments distal to the obstruction. This focal hyperinflation of the lung segments are detectable on x-ray as hyperlucency and reduced pulmonary marking. Complete obstruction results in atelectasis distal to the FB. The FB should be removed via bronchoscopy as soon as possible. If an FBA remains undetected, it may result in chronic cough and recurrent pulmonary infections.

Pathophysiology LocalizationBronchi: the right main bronchus is more often affected than the left main bronchusAspirated particles are most likely to become lodged at the junction of the right inferior and right middle bronchiUpper right lobe affected in bedridden patients Clinical features Immediate symptomsChoking and coughingDyspneaHoarseness and inability to speakRespiratory distress, cyanosis, altered mental state Physical examDiminished breath soundsStridor, wheezingHyper-resonance on the affected side in partial obstruction Late symptoms: days or weeks later if the initial aspiration and choking episode is not witnessed Persistent or recurrent coughFever Life-threatening FBA (respiratory distress)Immediate intervention (no imaging required!)Stable patients with suspected FBAPhysical examChest x-ray or CT (if x-ray is inconclusive)Bronchoscopy Chest x-rayFocal hyperlucency and reduced pulmonary markings of the affected lung60% of FB are located in the right main bronchus due to the more vertical CT (nearly 100% sensitivity): if x-ray is inconclusive Bronchoscopy: if imaging is inconclusive but there is a high clinical suspicion of FBA If there is a high suspicion of FB aspiration, bronchoscopy or CT should be performed even if the chest x-ray is inconclusive! Treatment Life-threatening FBA In alert patients, encourage coughing Heimlich maneuver: if the patient is unable to speak or cry Intubation: Attempt to mobilize FB via endotracheal tube Emergency tracheotomy may be required Removing the foreign body Bronchoscopy (gold standard) omplications Atelectasis pneumonia, lung abscess In complete obstruction: Suffocation, asystole, and deathHypoxia: brain damage

Pulmonary function testing Pulmonary function tests (PFTs) measure different lung volumes and other functional metrics of pulmonary function. They can be used to diagnose ventilatory disorders and differentiate between obstructive and restrictive lung diseases. The most common PFT is spirometry, which involves a cooperative patient breathing actively through his or her mouth into an external device. This simple and cost-effective test measures both dynamic and static lung volumes (with the exception of residual volume and total lung capacity), as well as airflow rates. Full-body plethysmography is an additional PFT that is able to estimate both residual volume and total lung capacity and is performed with the patient in a closed space. Lastly, single-breath diffusing capacity helps determine if the alveolar membrane is thickened (e.g., pulmonary fibrosis) or destroyed (e.g., emphysema), or if the pulmonary vasculature is affected (e.g., pulmonary hypertension).

Peak expiratory flow (PEF)The maximum airflow rate attained during forced expiration (in L/s)≥ 80% of the predicted average value based on race, height, gender, and age Forced expiratory volume in 1 second(FEV1)The maximum volume of air that can be forcefully expired within 1 second after maximal inspiration≥ 80% of the predicted average value based on height, gender, and age (or >75%of vital capacity)Vital capacityThe difference between the volume of air in the lungs after maximal inspiration and after maximal expirationVC can be measured through: Slow respiratory maneuvers Inspiratory vital capacity (IVC): The maximum volume of air that can be inspired after maximal expiration.Expiratory vital capacity (EVC): The maximum volume of air that can be expired after maximal inspiration.Forced respiratory maneuvers Forced vital capacity (FVC): The maximum volume of air that can be forcefully expired after maximal inspiration.Among young individuals IVC, EVC, and FVC have nearly the same value. However among patients with obstructive lung disease: IVC > EVC > FVC. Depends on race, height, age, and gender; approximately 4.5-5 L in healthy young adults FEV1/FVC (Tiffeneau-Pinelli index, relative FEV1)Ratio of FEV1 to forced vital capacity expressed as a percentage≥ 70%Forced expiratory flow rate at 75%, 50%,and 25% of vital capacity (FEF75%, FEF50%, FEF25%)Average airflow rates observed during forced expiration when 75%, 50%, and 25% of the vital capacity remains in the lungs. ≥ 65% of the predicted average value based on race, height, gender, and age Obstructive and restrictive lung diseases Obstructive lung disease Increased resistance to air flow caused by narrowing of airways COPD (chronic bronchitis, emphysema) Bronchial asthma Bronchiectasis, cystic fibrosis FEV1↓FEV1/FVC↓ Vital capacity↓ Residual volume↑ Total lung capacityNormal or ↑ Resistance to air flow↑ Lung complianceNormal Spirometer tracingAir trapping: a "scalloping" of the expiratory limb in conditions such as emphysema or in patients who have undergone a pneumectomy. Restrictive lung diseaseImpaired ability of the lungs to expand (as a result of reduced lung compliance) Intrinsic causes (parenchymal diseases)Interstitial lung disease (e.g., sarcoidosis, pneumoconioses, idiopathic pulmonary fibrosis) Alveolar (e.g., pneumonia, pulmonary edema or hemorrhage) Extrinsic causes (extrapulmonary causes) Diseases of the pleura and pleural cavity (e.g., chronic pleural effusion, pleural adhesions, pneumothorax)Deformities of the thorax/mechanical limitation (e.g., kyphoscoliosis, ankylosing spondylitis, obesity, ascites, pregnancy)Respiratory muscle weakness (e.g., phrenic nerve palsy, myasthenia gravis, ALS, myopathies): See respiratory muscle function for more details. FEV1 Normal or ↓ FEV1/FVC Normal or ↑ Vital capacity ↓ Residual volume Normal or ↓ Total lung capacity↓ Resistance to air flow Normal Lung compliance Normal (extrinsic causes) or ↓ (intrinsic causes)In restrictive lung disease, alterations in blood gas analysis are seen much later in the course of the disease! Bronchial challenge tests help distinguish bronchial asthma from other causes of obstructive lung disease Methacholine challenge test (bronchoprovocation test)Indication: to determine if airway hyperresponsiveness is presentDescription: Lung function tests are performed before and after the administration of methacholineInterpretation: a reduction of FEV1 of at least 20% points to a diagnosis of airway hyperresponsiveness (e.g., bronchial asthma). Because the methacholine challenge test can trigger a life-threatening asthma attack, medications that reverse bronchospasm(e.g., epinephrine, atropine) should be kept at hand during the test! Bronchodilator reversibilty test (post-bronchodilator test) Indication: allows reversible airway obstruction to be differentiated from irreversible obstructionDescription:FEV1 and airway resistance are measured before and 10 minutes after the inhalation of a fast-actingbronchodilator (e.g., albuterol, ipratropium bromide)Interpretation: An increase in FEV1 by 200 mL or 12% of the initial value indicates reversible airway obstruction Single-breath diffusing capacity Description: measures the ability of the alveoli to exchange gases with pulmonary capillaries IndicationsTo differentiate between intrapulmonary (e.g., interstitial lung disease) and extrapulmonary causes (e.g., pleural effusion, respiratory muscle weakness)Hypoxemia that remains unexplained even after spirometry Measured parameters KCO (carbon monoxide transfer coefficient)DLCO (diffusing capacity of the lung for carbon monoxide) Restrictive lung disease (normal or ↑ FEV1/FVC) ↓ DLCO Late interstitial lung disease Post-pneumonectomy Pulmonary edema (e.g., as a result of severe congestive heart failure) Emphysema Pulmonary vascular diseases (pulmonary hypertension, pulmonary embolism, hepatopulmonary syndrome) Early interstitial lung disease Pre-existing carboxyhemoglobinemia (e.g., due to smoking) Anemia Normal DLCORespiratory muscle weaknessPleural disordersThoracic cage deformitiesObesityAlpha-1-antitrypsindeficiency BronchiectasisCystic fibrosisChronic bronchitisBronchial asthmaHealthy findings ↑ DLCOObesityBronchial asthmaPolycythemiaMild heart failure and left-to-right cardiac shunts Respiratory muscle function used to diagnose and monitor patients with respiratory muscle weakness: Test of inspiratory muscle function (e.g., diaphragm): maximal inspiratory pressure (MIP); sniff nasal inspiratory pressure (SNIP) Test of expiratory muscle function: maximal expiratory pressure (MEP)Patients with respiratory muscle weakness show spirometric findings of restrictive lung disease! Causes of respiratory muscle weaknessDepression of the respiratory centerencephalopathyOpiate poisoningBrainstem strokeTraumatic brain injuryPhrenic nerve palsy due to: amyotrophic lateral sclerosisGuillain-Barre syndromeMyasthenia gravisMyopathies; muscular dystrophyClinical features of respiratory muscle weakness do not manifest until diaphragmatic strength is reduced to a quarter of its normal strength! (Unilateral diaphragmatic paralysis decreases ventilatory capacity by only 20%.) Total lung capacity (TC,TLC)Volume of air in the lungs after maximal inhalation 6-6.5 LVital capacity (VC)Difference in lung volume between maximal exhalation and maximal inhalation4.5-5 LResidual volume (RV)Volume of air that remains in the lungs after maximal exhalation1-1.5 LTidal volume (TV)Volume of air that is inhaled and exhaled in a normal breath at rest∼ 500 mL or 7 mL/kgInspiratory reserve volume (IRV)Maximum volume of air that can still be forcibly inhaled following the inhalation of a normal TV3-3.5 LInspiratory capacity (IC)Maximum volume of air that can be inhaled after the exhalation of a normal TV3.5-4 LExpiratory reserve volume (ERV)Maximum volume of air that can still be forcibly exhaled after the exhalation of a normal TV1.5 LExpiratory capacityFunctional residual capacity (FRC)Volume of air that remains in the lungs after the exhalation of a normal TV2.5-3 L

Arterial blood gas analysis and pulse oximetry Arterial blood gas (ABG) analysis is a test regularly performed to measure oxygen saturation, carbon dioxide, and bicarbonate blood levels. It provides quick assessment of gas exchange processes and acid-base balance. Pulse oximetryis a non-invasive and quick way of measuring the oxygen saturation of peripheral arterial hemoglobin. The test relies on the fact that oxygenated and deoxygenated hemoglobin absorb different wavelengths of light. Physiological levels of oxygen saturation are generally above 95%.These tests provide vital information about a patient that is especially important in emergency and intensive care settings.

Pulse oximetry Reference range: Resting > 95% A PaO2 of 100 mm Hg is necessary to reach a SpO2 level of ∼ 98%. Arterial blood gas analysis Reference rangesPaCO2: 35-45 mm HgpH: 7.35-7.45HCO3-: 21 to 27 mEq/LResting PaO2 > 80 mm Hg is considered normal. Procedure: A modified Allen test must be performed before the radial artery is punctured to assess collateral circulation in the hand.Arterial blood can be drawn from radial arteries or an indwelling arterial catheter Interpretation Hypoxemic respiratory failure (type 1 respiratory failure): ↓ PaO2Hypercapnic respiratory failure (type 2 respiratory failure): ↑ PaCO2 and ↓ PaO2

Chest painNontraumatic chest pain is one of the most common causes of emergency department visits and is common in both inpatients and outpatients. The differential diagnosis is broad and includes cardiac (e.g., acute coronary syndrome, pericarditis), gastrointestinal (e.g., GERD, gastritis, PUD), musculoskeletal (e.g., costochondritis), and psychiatric (e.g., generalized anxiety disorder, panic attack) etiologies. Any life-threatening causes of chest pain, such as acute coronary syndrome and pulmonary embolism, should be immediately evaluated and assessed. Once life-threatening causes have been ruled out (either by patient history, examination, or rapid diagnostics), a more thorough history and examination should be performed to narrow the differential diagnosis and guide further diagnostic workup and therapy. Traumatic causes of chest pain are not addressed here.

STEMI [4]Heavy, dull, pressure/squeezing sensationSubsternal pain with radiation to left shoulderNausea, vomitingDiaphoresis, anxietyDizziness, lightheadedness, syncopePain may improve with nitroglycerin.ECG: ST-segment elevation/depression, T-waveinversions, Q waves↑ TroponinTTE: hypokinesis, regional wall motion abnormalitiesSee the acute management checklist for STEMI.NSTEMI/UA [5]ECG: nonspecific changes, including T-wave inversions, ST-segment depressions Increased or normal troponinTTE: Regional wall motion abnormalities may be present.See the acute management checklist for NSTEMI/UA.Aortic dissection [6][7][8]Sudden onset of severe, sharp tearing chest or abdominal pain that radiates to the back Hypotension, syncope, neurological symptoms Asymmetrical blood pressure, pulse deficitNew diastolic murmurSymptoms of myocardial ischemiaElevated D-dimerECG: nonspecific ST-segment changesCXR: widening of the aorta CT angiography of chest/abdomen/pelvis: intimal flap with false lumen TEE: proximal aortic dissection, tamponade, aortic regurgitationSee the acute management checklist for aortic dissection.Cardiac tamponade [9]Tachypnea, dyspneaTachycardiaPulsus paradoxusCardiogenic shockBeck triad: hypotension, elevated JVD, muffled heart soundsECG: low voltage, electrical alternansCXR: enlarged cardiac silhouetteTTE: circumferential fluid layer, collapsible chambers , high EF, dilated IVC Inspiration: Both ventricular and atrial septa move sharply to the left.Expiration: Both ventricular and atrial septa move sharply to the right.See the acute management checklist for cardiac tamponade.Pericarditis [10][11]Sharp, pleuritic, retrosternal chest painExacerbated by lying down; improved by leaning forwardNot relieved with nitratesHigh-pitched pericardial friction rub↑ ESR, ↑ CRP, leukocytosis↑ Troponin [10]ECG: diffuse, ST-segment elevations without reciprocal ST-segment depression, PR-segment depression, or T-wave inversionsCXR: normalTTE: Pericardial effusion may be present.See the acute management checklist for acute pericarditis. Heart failureexacerbation[12][13][14][15]Chest pressureCough, dyspneaHypoxemiaCrackles, JVD, peripheral edemaClinical diagnosisLabs: ↑ BNP, ↑ troponin, hyponatremiaCXR: diffuse opacities, Kerley B linesTTE: global or focal wall abnormalities, systolic and/or diastolic dysfunction, decreased LVEFSee the acute management checklist for heart failure exacerbation.Esophageal perforation [17][18]Retrosternal chest pain, neck pain, epigastric pain with radiation to the back Dyspnea, tachypnea, tachycardiaDysphagiaSigns of sepsisMackler triad (chest pain, vomiting, subcutaneous emphysema)Mediastinal crepitusHistory of recent endoscopy or severe emesis (Boerhaave syndrome)CXR, upright AXR: mediastinal air and/or subdiaphragmatic air, pleural effusion, pneumothoraxLateral neck x-ray: subcutaneous emphysemaContrast esophagography (gold standard): contrast leak [19]CT chest (with oral contrast) : extraluminal air, esophageal thickeningSee the acute management checklist for esophageal perforation.GERD and erosive esophagitis [20][21]Postprandial substernal chest pain, pressure, burning, reflux symptomsAggravated by lying in the supine position and certain foods (e.g., coffee, spices)Epigastric tendernessClinical diagnosisDefinitive diagnosis requires EGD and/or 24-hour esophageal pH monitoringSee the acute management checklist for GERD. Peptic ulcer disease [22][23][24]Epigastric painDuodenal ulcer: pain relieved with food; weight gain Gastric ulcer: pain exacerbated by food; weight loss Signs of GI bleedHistory of NSAID intakeAnemia, positive FOBT (in cases of bleeding ulcer)Urea breath test for H. pylori: positive in most cases of PUDEGD: mucosal erosions and/or ulcersSee the acute management checklist for PUD. Acute pancreatitis [25][26][27]Severe epigastric pain that radiates to the backNausea, vomitingEpigastric tenderness, guarding, rigidityUpper abdominal painHypoactive bowel sounds History of gallstones or alcohol use↑ Lipase, amylaseAbdominal ultrasound: pancreatic edema, peripancreatic fluid, gallstonesAbdominal CT with IV contrast : pancreaticedema, peripancreatic fat stranding, gallstonesSee the acute management checklist for acute pancreatitis. Mallory-Weiss syndrome [28][29]Epigastric pain that radiates to the backRepeated episodes of severe vomitingHematemesisMelena, dizziness, syncopeCBC: anemiaEGD: longitudinal mucosal tears, typically at the gastroesophageal junctionSee the acute management checklist for Mallory-Weiss syndrome.Pulmonary embolism [30]Pleuritic chest painAcute onset dyspnea, hypoxemiaCough, hemoptysisUnilateral leg swelling or history of DVTHypotension, shock (if massive PE)Elevated D-dimer↑ Troponin, BNPECG: normal sinus rhythm (most common), sinus tachycardia, signs of right ventricular strain CTA chest: pulmonary artery filling defect V/Q scan: perfusion-ventilation mismatch TTE: right ventricle hypokinesis with normal apical movement Wells criteria for pulmonary embolismSee the acute management checklist for pulmonary embolism.Tension pneumothorax [31][32]Severe, sharp chest painDyspnea, hypoxemiaHistory of traumaHyperresonance, decreased breath sounds, tracheal deviationTachycardia, hypotensionClinical diagnosisCXR: absent lung markings, tracheal deviation, pneumomediastinumSee the acute management checklist for tension pneumothorax.Pneumonia [33]Fever, chillsCough, dyspneaHypoxemiaCrackles, egophonyLabs: leukocytosis, ↑ ESR/CRP, ↑ procalcitoninPositive sputum cultureCXR: consolidation, pleural effusionCT chest with IV contrast: hyperdense consolidation See the acute management checklist for pneumonia. Spontaneous pneumothorax [34][31][35]Sudden, sharp unilateral chest painAcute dyspneaHypoxemiaHyperresonance, decreased breath sounds on affected sideCrepitusHistory of lung disease or trauma CXR (in inspiration): increased lucency, displaced lung markings, subcutaneous emphysemaUltrasound: absent lung slidingSee the acute management checklist for spontaneous pneumothorax. Asthmaexacerbation [36]Dyspnea, coughTachycardiaTachypnea, hypoxemiaDiffuse wheezing, decreased or absent breath soundsIncreased work of breathingABG: ↓ pH, ↑ PaCO2, ↓ PaO2 (respiratory acidosis) Peak expiratory flow: decreased from predicted or personal bestSee the acute management checklist for asthma exacerbation. Pleural effusion[37][38]Unilateral, pleuritic chest painDyspneaDry, nonproductive coughDullness to percussion, decreased breath sounds, decreased tactile fremitusPleural friction rubCXR: homogeneous opacity with blunting of the costophrenic angleUltrasound: hypoechoic space between the parietal and visceral pleuraSee the acute management checklist for pleural effusion.Other causes Costochondritis [39] Clinical features Sharp, well-localized pain that is reproducible on palpation of costal cartilage Acute herpes zoster [40][41] Clinical features Maculopapular rash that develops into a vesicular rash in a dermatomal distribution Panic disorder [42] Clinical features: Recent stressful exposure

Pleural effusion Pleural effusion is an accumulation of fluid in the pleural cavity between the lining of the lungs and the thoracic cavity(i.e., the visceral and parietal pleurae). The pleural fluid is called a transudate if it permeates (transudes) into the pleural cavity through the walls of intact pulmonary vessels. It is called an exudate if it escapes (exudes) into the pleural cavitythrough lesions in blood and lymph vessels, e.g., as caused by inflammation and tumors. The accumulation of transudateis typically due to increased hydrostatic pressure (e.g., in congestive heart failure) and/or decreased oncotic pressure (e.g., in cirrhosis or nephrotic syndrome). Since transudate is a filtrate, it is typically a clear fluid with a low protein and cell content. By contrast, the lesions responsible for the outflow of exudate allow larger molecules and even solid matter to pass into the pleural cavity. For this reason, exudate is a cloudy fluid with a high protein and cell content. The effusion follows gravity and, unless the patient is bedridden, collects in the lower margins of the pleural cavity. Percussion over the area of effusion generates a dull tone, and breath sounds are diminished or completely absent on auscultation. Chest x-ray and ultrasound are usually performed as first-line tests to diagnose pleural effusion, but chest CT is sometimes required (e.g., for very small effusions). Thoracentesis with pleural fluid analysis is required to establish the underlying diagnosis in most pleural effusions and can also serve a therapeutic role. Treatment should focus on correcting the underlying condition.

Transudative pleural effusion ↑ Capillary hydrostatic pressure (increased capillary wedge pressure) ↓ Capillary oncotic pressure Congestive heart failure Hepatic cirrhosis Nephrotic syndrome Protein-losing enteropathy Chronic kidney disease Exudative pleural effusion ↑ Capillary permeability (e.g., due to inflammation) InfectionPneumonia (parapneumonic effusion)TuberculosisPleural empyema Malignancies E.g., lung cancer, metastatic breast cancer, lymphoma, mesothelioma Pulmonary embolism Autoimmune diseaseVasculitisSLERheumatoid arthritisSarcoidosis Pancreatitis Hemothorax Chylothorax Pseudochylothorax Clinical features Symptoms [5] Characteristic symptoms DyspneaPleuritic chest painDry, nonproductive coughSymptoms of the underlying disease (e.g., fever in empyema, cachexia in cases of malignancy, symptoms of left-sided heart failure) Physical exam findings Inspection and palpation Asymmetric expansionReduced tactile fremitus Auscultation Faint or absent breath sounds over the area of effusionPleural friction rub Percussion: dullness over the area of effusion Subtypes and variants Parapneumonic effusion and pleural empyema [6][7][8][9] DescriptionPleural empyema: accumulation of pus in the pleural cavity Etiology [10]Most common: pneumonia → extension of bacterial infection into the pleural spaceLess common: infected hemothorax Clinical features [10][11]See "Clinical features" aboveFever, chills, cough DiagnosticsChest x-ray [12]See "Diagnostics" belowMeniscus at the proximal aspect of the x-ray opacificationChest CT [13]Split pleura sign: thickening of visceral and parietal pleura caused by fibrin that adheres to the surfaces, which results in vascular proliferationPleural fluid analysisExudative effusionLow glucose (< 60 mg/dL) and pH < 7.3 TreatmentAppropriate systemic antibiotic treatmentChest tube (thoracostomy) to remove empyema fluidThoracoscopic debridement (removal of pus and pleural fibrosis) if empyema does not resolve after chest tubedrainage Chylothorax [14] Clinical featuresSee "Clinical features" above. DiagnosticsChest x-ray: See "Diagnostics" below.Pleural fluid analysis [4]Exudative effusionTotal cholesterol usually < 200 mg/dLTriglyceride concentration > 110 mg/dL Pseudochylothorax [15][14] DiagnosticsSee "Diagnostics" belowPleural fluid analysisExudative effusionTotal cholesterol usually > 200 mg/dLTriglyceride concentration < 110 mg/dL In contrast to chylothorax, a pseudochylothorax is characterized by high cholesterol and low triglyceride levels in the pleural fluid. The presence of cholesterol crystals may also help differentiate a pseudochylothorax from a chylothorax. Hemothorax [16] Description: accumulation of blood in the pleural cavity EtiologyMost commonly due to penetrating or blunt trauma Clinical featuresSee "Clinical features" abovehypotension, tachycardiaIf due to trauma Chest wall deformityParadoxical chest wall movementCrepitus on palpation DiagnosticsSee "Diagnostics" belowChest ultrasoundCommonly used in the FAST protocol for trauma assessmentPleural fluid analysisRed blood cellsThe pleural hematocrit level is ≥ 50% of the patient's peripheral hematocrit level. TreatmentChest tube (thoracostomy) with blood evacuation A hemothorax, however small, must always be drained because blood in the pleural cavity will clot if not evacuated, resulting in a trapped lung or an empyema. Malignant pleural effusion [17] Etiology: caused by either direct invasion of the pleural space or distant metastasesMost common: lung cancer, breast cancer Pathophysiology: increased permeation of plasma protein, blood cells, and tumor cells into the pleural space caused by a cancer-related barrier dysfunction of the capillary walls DiagnosticsChest x-raySee "Diagnostics" belowPleural fluid analysisCell-rich exudative effusionpH usually low (< 7.3)LDH usually highCytology [14]identification of malignant cells ; pronounced nucleoli, cells with multiple nuclei, numerous figures of mitosis Treatment [18]SymptomaticLarge-volume thoracentesisIndwelling pleural catheterChemical pleurodesis Diagnostics Chest x-ray Findings [19]blunting of the costophrenic anglemeniscus-shaped marginLarge effusionComplete opacification of the lungMediastinal shiftTracheal deviation away from the effusion (space-occupying lesion) Ultrasound [14][19] Very sensitive: can detect fluid amounts as low as 20 mL Chest CT [14] Thoracentesis Aspiration of fluid from the pleural space for diagnostic (e.g., transudate vs. exudate) and/or therapeutic purposes Indications Any new unilateral effusion > 1 cm on x-ray in an undiagnosed patientdyspnea Transudative effusion Does not froth or form clots Specific gravity≤ 1.016 pH Normal pH ∼ 7.6 7.4-7.55 Glucose≥ 60 mg/dL Cholesterol< 60 mg/dL otal protein≤ 30 g/L Light's criteriaPleural fluidprotein:serum proteinratio≤ 0.5 Pleural fluid LDH:serum LDH ratio≤ 0.6 Pleural fluid LDH (lactate dehydrogenase)< ⅔ the upper limit of normal serum LDH Exudative effusion Cloudy or straw-colored fluid (may rarely be hemorrhagic) Froths when shook and forms clots when left standing SG > 1.016 7.3-7.45 A pH < 7.30 should raise concern for parapneumonic effusion/empyema or malignant effusion. Glucose < 60 mg/dL 30-59 mg/dL: suggests malignant effusion, tuberculous pleurisy, empyema, pneumonia, esophageal rupture, or lupus pleuritis< 30 mg/dL: suggests rheumatoid pleurisy or empyema Cholesterol ≥ 60 mg/dL Total protein > 30 g/L Light's criteriaPleural fluidprotein:serum proteinratio >.5 Pleural fluid LDH:serum LDH ratio >0.6 Pleural fluid LDH (lactate dehydrogenase) Pleural fluid LDH > ⅔ the upper limit of normal serum LDH Very high LDH levels (e.g., > 1000 IU/L) suggest empyema, malignancy, or rheumatoid effusion. Transudate is usually clear, has a decreased cell count, and has low levels of protein, albumin, and LDH. Exudate typically appears cloudy, has an increased cell count, and has high levels of protein, albumin, and LDH. Think MEAT to memorize causes of pulmonary effusion with decreased glucose content: M = Malignancy, E = Empyema, A = Arthritis (rheumatoid pleurisy), T = Tuberculosis! Pleural fluid with a bloody appearance suggests a malignant etiology or hemothorax! reatment Treat underlying condition (e.g., loop diuretics for acute congestive heart failure, antibiotics for pneumonia Surgical procedures Tube thoracostomy: for recurrent pleural effusion or urgent drainage of infected and/or loculated effusionsVideo-assisted thoracoscopic surgery (VATS)Pleurodesis: chemical or surgical obliteration of the pleural spaceIndication: recurrent malignant effusions A chest x-ray should be performed after each of these procedures in order to rule out iatrogenic pneumothorax!

Asthma Asthma is a chronic inflammatory disease of the respiratory system characterized by bronchial hyperresponsiveness, episodic exacerbations (asthma attacks), and reversible airflow obstruction. Allergic (extrinsic) asthma usually develops in childhood and is triggered by allergens such as pollen, dust mites, and certain foods. Nonallergic (environmental or intrinsic) asthma usually develops in patients over the age of forty and can have various triggers, such as cold air, medication (e.g., aspirin), exercise, and viral infection. The cardinal symptoms of asthma are intermittent dyspnea, coughing, and high-pitched expiratory wheezing. Symptoms remit in response to antiasthmatic medication or resolve spontaneously upon removal of the trigger. Confirmation of the diagnosis involves pulmonary function tests, allergy tests, and chest x-ray. First-line treatment consists of inhaled bronchodilators (e.g., short-acting beta-2 agonists) for acute exacerbations and inhaled corticosteroids (e.g., budesonide) for long-term asthma control. Patients should be taught the correct usage of inhalers for self-medication and measurement of peak expiratory flow (PEF) to self-monitor disease progression and severity. Severe asthma exacerbation can be life-threatening and may require emergency treatment and/or hospitalization.

pidemiology Prevalence5-10% of the US populationMore common in black than white patientsFor unknown reasons, the prevalence of asthma has been increasing over the past 20 years. [1] Sex: differs depending on age at onset ♂ > ♀ in patients < 18 years♀ > ♂ in patients > 18 years Age of onset Allergic asthma: typically in childhoodNonallergic asthma: typically > 40 years Etiology The exact etiology of asthma remains unknown. Known risk factors for asthma include the following: Family history of asthma Past history of allergies Atopic dermatitis Low socioeconomic status Childhood exposure to second-hand smoke increases the risk of developing asthma! The following factors can also act as initial triggers of asthma or exacerbate an existing condition: Allergic asthma (extrinsic asthma)Cardinal risk factor: atopyEnvironmental allergens: pollen (seasonal), dust mites, domestic animals , mold sporesAllergic occupational asthma: from exposure to allergens in the workplace (e.g., flour dust) Nonallergic asthma (intrinsic asthma)Viral respiratory tract infections (one of the most common stimuli, especially in children) [4]Cold airPhysical exertion (exercise-induced asthma)Gastroesophageal reflux disease (GERD): often exists concurrently with asthma Chronic sinusitis or rhinitisMedication: aspirin/NSAIDS (aspirin-induced asthma), beta-blockersStressIrritant-induced asthma (e.g., from exposure to solvents, ozone, tobacco or wood smoke, cleaning agents) Pathophysiology Asthma is generally characterized as an inflammatory disease driven by T-helper type 2 (Th2-cell) that manifests in individuals with a genetic predisposition. It consists of the following three pathophysiologic processes: Bronchial hyperresponsiveness Bronchial inflammation Symptoms are primarily caused by inflammation of the terminal bronchioles, which are lined with smooth musclebut lack the cartilage found in larger airways.Overexpression of Th2-cells → inhalation of antigen results in production of cytokines (IL-3, IL-4, IL-5, IL-13) → activation of eosinophils and induction of cellular response (B-cell IgE production) → bronchial submucosal edemaand smooth muscle contraction → bronchioles collapse [6][7] Endobronchial obstruction caused by: BronchospasmMucosal edemaHypertrophy of smooth muscle cellsIncreased mucus production Some forms of asthma have specific pathophysiologies: Allergic asthma: IgE-mediated type 1 hypersensitivity to a specific allergen; characterized by mast cell degranulationand release of histamine after a prior phase of sensitization Nonallergic asthmaIrritant asthma: irritant enters lung → ↑ release of neutrophils → submucosal edema → airway obstructionAspirin-induced asthma: NSAID inhibition of COX-1 → ↓ PGE2 → ↑ leukotrienes and inflammation → submucosal edema → airway obstruction Clinical features Chronic/persistent signs and symptoms Mild to moderate signs and symptomsPersistent, dry cough that worsens at night, with exercise, or on exposure to triggers/irritants (e.g., cold air, allergens, smoke)End-expiratory wheezesDyspneaChest tightnessChronic allergic rhinitis with nasal congestion Severe signs and symptomsSevere dyspneaPulsus paradoxusHypoxemiaAccessory muscle useIncreased risk of pulmonary infection (in chronic asthma) Cough variant asthmaA form of asthma in which the predominant symptom is chronic, dry coughOther characteristic symptoms of asthma (e.g., wheezes, congestion, dyspnea) are absent. Acute asthma attack Definition: acute, reversible episode of lower airway obstruction that may be life-threatening BreathlessnessWhile walkingWhile at restAt restPositionCan lie downPrefers sittingHunched overAbility to speakSentencesPhrasesIndividual wordsAlertnessMay be agitatedUsually agitatedAgitatedSignsRespiratory rateIncreasedIncreasedOften > 30/minuteWheezingModerate, often only end-expiratoryLoud; throughout exhalationThroughout inhalation and exhalation; can also be absentUse of accessory musclesRarelyCommonlyUsuallyPulse/minute< 100100-120> 120Pulsus paradoxusAbsentMay be presentOften presentPCO2 < 42 mm Hg> 42 mm Hg≥ 42 mm HgSaO2> 95%90-95%< 90% Clinical examination Auscultation (characteristic findings are usually only present during acute attacks) Prolonged expiratory phase with wheezing (dry crackles)Decreased breath sounds; possibly "silent chest"Tachypnea PercussionHyperresonant soundInferior displacement and poor movement of the diaphragm In severe attacksAltered level of consciousnessCyanosis Diagnostics A combination of clinical findings and objective measurement of pulmonary function (for adults and children ≥ 5 years of age) is needed to confirm the diagnosis and assess the severity of asthma. Evaluation of pulmonary function Pulmonary function testing (spirometry) First-line diagnostic test for confirmation of the diagnosis in patients ≥ 5 years of age. Shows signs of obstructive lung disease with increased airway resistance → ↓ FEV1, ↓ Tiffeneau index (FEV1/FVC ratio)Obstruction is reversible with bronchodilators → diagnostic confirmation via post-bronchodilator test Methacholine challenge test (bronchoprovocation test)Second-line diagnostic test if pulmonary function testing is nondiagnosticEvidence of bronchial hyperresponsiveness after inhalation of methacholinePositive if FEV1 reduced ≥ 20% Chest x-ray Usually only indicated in patients with severe asthma to exclude differential diagnoses (e.g., pneumonia, pneumothorax)Normal in mild casesSigns of pulmonary hyperinflation in cases of severe asthmaLow, flattened diaphragmWide intercostal spacesBarrel chest Laboratory studies and further workup Pulse oximetry and blood gas analysis (ABG)Blood gas analysis should be performed if oxygen saturation (SpO2) is < 94%.Findings on ABGInitially: ↓ pCO2, ↑ pH, ↓ pO2 leading to type 1 respiratory failureUltimately: severe respiratory distress: ↑ pCO2, ↓ pH, and ↓↓ pO2 leading to type 2 respiratory failure Patients with acute asthma exacerbations initially have ↓ PCO2 and respiratory alkalosis (↑ pH) due to tachypnea. Rising PCO2is a sign of respiratory fatigue and impending respiratory failure! ICU admission and intubation should be considered. In allergic asthma Antibody testing, total IgE (increased), allergen-specific IgE (increased)CBC: possibly eosinophilia Skin allergy tests: skin prick testing (SPT) or intradermal skin testing In asthma triggered by infection: elevated inflammatory markers Sputum sampleCurschmann spirals (whorled mucous plug in sputum that is formed by shed bronchial epithelium)Charcot-Leyden crystals (histopathologic finding in patients with eosinophilic inflammation and/or proliferation)and/or Creola bodies (aggregate of desquamated epithelial cells) [1] Classification of asthma severityMild intermittentasthmaMild persistentModerate persistentSevere persistentSymptoms (e.g., dyspnea, wheezing, cough)≤ 2 days/week> 2 days/weekDailyThroughout the dayNighttime symptoms (e.g., difficulty falling asleep because of symptoms, nighttime awakenings)Rare3-4 times/month1-2 times/weekOften (most nights)FEV1> 80%> 80%60-80%< 60% Treatment Causal Avoid triggers (see "Etiology" above). Allergen immunotherapy in allergic asthma Early treatment of infections in infection-triggered asthma If GERD is suspected: proton pump inhibitors Beta-2 agonistsShort-actingbeta-2 agonists (SABA)AlbuterolTerbutalineLong-actingbeta-2 agonists (LABA)SalmeterolFormoterolDilate bronchial smooth muscles (see beta-2 agonists).SABA: acute exacerbationsLABA: long-term maintenance treatmentInhaled corticosteroids(ICS)BeclomethasoneFluticasoneBudesonideCiclesonideMometasoneTriamcinoloneInhibit transcription factors (e.g., NF-κB) → ↓ expression of pro-inflammatory genesAlso see "Effects" in glucocorticoids.Long-term maintenance treatment (first-line)Leukotrienepathway modifiersMontelukastZafirlukastLeukotriene receptor antagonists(LTRAs): prevent leukotrienes from binding to their receptors↓ Bronchoconstrictionand inflammationLong-term maintenance treatment (particularly in children)Exercise-induced and aspirin-induced asthmaZileutonInhibits 5-lipoxygenase → ↓ productionof leukotrienesMuscarinic antagonistsShort-acting muscarinic antagonists(SAMA): ipratropium bromideLong-acting muscarinic antagonists (LAMA): tiotropium bromideCompetitively inhibit postganglionic muscarinic receptors in bronchial smooth muscle → bronchodilation See muscarinic antagonists.Option for long-term maintenance treatmentBiological agentsOmalizumabAnti-IgE antibody that binds to serum IgEReduced serum levels of IgE prevent binding of IgE to high affinityIgE receptor (FcεRI) on mast cells and basophils → The inflammatory cascade triggering asthma is inhibited.Long-term reduction in serum IgE levels will reduce surface expression of IgE receptor on mast cells and basophils.Allergic asthmaMepolizumab [12]Monoclonal antibody against IL-5: potent chemoattractant for eosinophilsAdditional medication for severe eosinophilic asthmathat is not sufficiently controlled with other measuresMethylxanthinesTheophyllineInhibits phosphodiesterase (PDE) → ↑ cAMP levels → anti-inflammatory and mild bronchodilatory effectSee "Treatment" in chronic obstructive pulmonary disease.Limited use (cardiotoxic, neurotoxic)Mast cell stabilizersCromolyn sodiumNedocromil sodiumPrevents release of inflammatory mediators from mast cells.Preventive treatment prior to exercise or unavoidable exposure to known allergensin patients ≥ 5 years oldOral corticosteroidsMethylprednisolonePrednisoneSimilar to inhaled corticosteroidsUsed in severe and refractory cases Acute management For mild symptoms: short-acting beta-2 agonist For exercise-induced asthma: short-acting beta-2 agonist prior to exercise For severe asthma exacerbations, see "Treatment" in status asthmaticus. The following drugs are not effective during an acute asthma attack: LABA, leukotriene pathway modifiers, theophylline, mast-cell stabilizers, biological agents! To remember the meds for asthma exacerbations, think ASTHMA: Albuterol, Steroids, Theophylline (rare), Humidified O2, Magnesium (severe exacerbations), Anticholinergics. Long-term management General principlesReduce number of asthma attacks → Medical therapy is escalated or de-escalated depending on the patient's individual needs.Self-monitoring for patients: peak flow meter to measure peak expiratory flow rate (PEFR) Patients can avoid exacerbations with frequent PEFR measurements: PEFR decreases before symptoms appear → indicates insufficient medication regimenInfluenza and pneumococcal vaccines are administered in all patients. Pharmaceutical managementReliever medications: provide relief of asthma symptoms and are taken as needed when symptoms are presentController medications: control underlying inflammation of asthmaShift in treatment paradigm as of 2019 [13]Previously: As-needed SABA reliever inhaler was the mainstay of intermittent asthma treatment.New recommendation: ICS-containing controller inhaler for every adult and adolescent with asthma (no more SABA-only treatment)Reasoning: ICS addresses the underlying problem of airway inflammation → reduces both frequency of symptoms and risk of severe asthma exacerbations (SABAs only address symptoms)Note that many resources still list as-needed SABA reliever treatment as the only therapy necessary in intermittent asthma. TreatmentMild intermittentMild persistentModerate persistentSevere persistentPreferred relieverAs-needed low-dose ICS-formoterol or SABAPreferred controllerAs-needed low-dose ICS-formoterolDaily low-dose ICSOR as-needed low dose ICS-formoterolDaily low-dose ICS-LABADaily medium/high-dose ICS-LABAAlternative and add-oncontrollersOR low-dose ICS whenever SABA is takenOR LTRA OR low-dose ICS whenever SABA is takenOR low-dose ICS + LTRAOR medium dose ICSOR high-dose ICS± LAMA± LTRA± Low-dose OCS± Omalizumab or mepolizumab in refractory cases MonitoringRoutine follow-up every 1-6 months, depending on severityPurpose of follow-up: assessment of asthma symptom control Complications Status asthmaticus Definition: extreme asthma exacerbation that does not respond to initial treatment with bronchodilators Clinical featuresInitially: orthopnea, tachypnea, tachycardia, and cyanosisSigns of imminent respiratory arrestDrowsiness/confusionParadoxical thoracoabdominal movementBradycardiaAbsent wheezingPulsus paradoxus DiagnosisThe following diagnostic workups should be done in patients with status asthmaticus attacks: ABG (i.e., to identify hypercapnia and hypoxemia) CBCBMPPeak expiratory flow measurement Chest x-ray ECG (in older patients) ManagementHospitalizationPEF or FEV1: 50-70% of the predicted valuePEF or FEV1 < 50% of the predicted value → admitted in the ICUMedicationsShort-acting beta-2 agonist (SABA)Short-acting muscarinic antagonists (SAMA) like ipratropium bromideOral corticosteroidIntravenous magnesium sulfateOxygenation and ventilationSupplemental oxygen and/or helium-oxygen mixture (heliox)Noninvasive ventilation (NIV) Bilevel positive airway pressure (BiPAP) provides greater support. Maintains airways open → decreases airways resistance → reduces auto-PEEP → reduces work of breathingUse for 1-2 hours in cooperative patients not responding to medical therapy.Do not delay intubation when it is indicated.Indications for intubationUse of accessory musclesDecreased oxygen saturationInability to speak in full sentencesInadequate response to initial therapyNormalizing PCO2 or pH (see "Laboratory Studies" under "Diagnostics" above) Special patient groups Pregnant womenAsthma symptoms can be worse, better, or unchanged during pregnancy.Same stepwise management as with other patientsInhalation treatments preferred Poorly managed asthma can increase the risk of pregnancy complications (e.g., preeclampsia, premature birth, congenital abnormalities).Monthly monitoring of asthma is recommended. ChildrenAsthma in patients under 5 years of age is challenging to diagnose and is often underdiagnosed, as children in this age group are not typically able to adequately perform the spirometric maneuvers.Treatment similar to that for adults, with inhaled corticosteroids as the initial drug of choiceYoung children (< 5 years) may require nebulizers because of difficulty using inhalers. [