CRRAB-2: PBL, TB and HIV (Individual - 5 hrs)

What is the mechanism of Arnold's fever/night sweats? Why is sweating more likely to occur at night? Are there diurnal fluctuations in our temperatures? If so, how do they relate to "nightsweats"?

Fever A) Infection → activates immune response mediators → activates leukocytes → activates pyrogenic cytokines (IL-1, TNF-ɑ, IFN) → hypothalamic endothelium → increase COX --> production of PGE2 (rise in cAMP) → elevated set-point → activation of vasomotor center neurons → peripheral vasoconstriction & heat production → FEVER Night sweats A) Again, in response to circulating chemical signals esp. TNF-ɑ → hypothalamus resets body temp to a higher level for a while → body temp is later returned to normal during daytime or lower than normal during night → extra heat is lost by sweating → night sweats

What is the mechanism for the elevation of C-reactive protein?

Likely due to inflammation as a result of Tb infection and pyroptosis of CD4+ T cells from HIV infection

Rifampin/Rifabutin: MOA, Clinical Use, AE, and Static/Cidal? What are the 4 R's of Rifampin?

MOA: *Binds to beta-subunit and inhibits DNA-dependent RNA polymerase. * 4R's of Rifampin: *R*NA polymerase inhibitor, *R*amps up microsomal cytochrome P-450, *R*ed/orange body fluids, *R*apid resistance if used alone. Adverse Effects: Rifabutin favored over rifampin in patients with HIV infection due to less cytochrome P-450 stimulation. Orange body fluids. Minor hepatotoxicity. Resistance: mutations reduce drug binding to RNA-polymerase. Monotherapy rapidly leads to resistance. Bactericidal or bacteriostatic depending on concentration given.

Ethambutol: MOA, Clinical Use, AE, and Static/Cidal?

MOA: *Decreases carbohydrate polymerization of mycobacterium cell wall by blocking arabinosyltransferase.* Adverse effects: *Optic neuropathy* (red-green color blindness) Primarily bacteriostatic; high doses exhibit bactericidal properties

Streptomycin/aminoglycosides: MOA, Clinical Use, AE, and Static/Cidal?

MOA: *Interferes with 30S component of ribosome* Second line therapy Adverse Effects: tinnitus, vertigo, ataxia, nephrotoxicity. Bactericidal

Isoniazid: MOA, Clinical Use, AE, and Static/Cidal?

MOA: *inhibits synthesis of mycolic acid*, an essential component of mycobacterial cell wall. Clinical Use: only agent used as solo prophylaxis against TB. Monotherapy for latent TB. Adverse Effects: hepatotoxicity, p-450 inhibition. Drug-induced SLE, AGMA, ***vitamin B6 deficiency which causes peripheral neuropathy (this is why we give pyridoxine with Isoniazid treatment!)*** Bactericidal or bacteriostatic; depending on drug concentration. INH is bactericidal against rapidly dividing intracellular and extracellular organisms.

Pyrazinamide: MOA, Clinical Use, AE, and Static/Cidal?

MOA: uncertain. Prodrug that is converted to active compound pyrazinoic acid. Works best at acidic pH (in host phagolysosomes.) Could possibly inhibit mycobacterial fatty acid synthase-1 enzyme and this could disrupt mycolic acid synthesis. Adverse Effects: Hyperuricemia, hepatotoxicity Bactericidal or bacteriostatic action depending on concentrations.

What are the other Mycobacteria that cause pulmonary infections and describe how they differ from TB?

Mycobacterium avium-intracellulare infection: A) complex of 3 mycobactrium→ M. avium, M. intracellulare, M. chimaera (MAC complex) B) Most often presents in immunocompromised people, especially in later stage AIDs C) Almost always persistent cough; also fever, diarrhea, malabsorption leading the weight loss D) Tx=clarithromycin or azithromycin, plus rifampicin and ethambutol; resistant to many of the typical TB drugs Mycobacterium kansasii: A) Chronic pulmonary disease similar to TB except not infectious B) Can get disseminated disease in immunocompromised, especially in late stage AIDs Mycobacterium abscessus complex (MABSC): A) Group of rapid growing, multi-drug resistant non-TB mycobacteria B) Cause chronic lung infections and skin/soft tissue infections mostly, but can infect the entire body C) Usually seen in people with suppressed immune systems or see skin infections in people who have recently had tattoos, surgery or acupuncture D) Chronic cough, purulent sputum, fatigue, weight loss

What agent causes TB?

Mycobacterium tuberculosis

Associate the organisms responsible for pulmonary infections in HIV+ patients with CD counts at *1500-500*

Mycobacterium tuberculosis [bacteria] -Nonmotile, acid-fast, bacilli, obligate aerobe -Enters through respiratory droplets or fomites → m0's engulf → cord factor (virulence factor) prevents phagosome-lysosome fusion → granuloma formation → necrosis (immunocompromised pt's) → fluid leakage → spread to other areas

Describe causes of pulmonary nodules and their prevalence

Prevalence: A) 1 in every 500 chest X-rays B) 1 in every 100 chest CT C) ~50% of smokers >50 years old will have lung nodules D) 150,000 new nodules found in U.S. each year Causes: A) Infections=bacterial(TB), fungal(coccidioidomycosis), parasitic (ascariasis) B) Inflammation=Rheumatoid arthritis, sarcoidosis, granulomatosis C) Benign tumors=hamartomas, bronchial adenomas, fibromas, blastomas, neurofibromas D) Malignant tumors E) Metastases=from other cancers like breast, colon, bladder cancer F) Pulmonary infarctions & blood vessel abnormalities

Describe the general epidemiology of TB

TB affects approx more than 1 billion ppl worldwide w/ 8.7 mil new cases and 1.4 million deaths each yr. HIV makes ppl more susceptible to TB. 13% of ppl who developed TB in 2011 were HIV+. In 2011 there were 10,528 new cases of TB in the US, 62% were foregin born.

What is pyridoxine? What drug is it usually given with?

Vitamin B6; after absorption from the GI tract it is converted in the liver to a coenzyme, pyridoxal phosphate, that is involved in many metabolic processes. Isoniazid interferes competitively with pyridoxine metabolism by inhibiting the formation of the active form of the vitamin and hence results in peripheral neuropathy. *We give this to the patient to prevent peripheral neuropathy in patients who are on ****isoniazid. ***

Fluconazole and Itraconazole MOA

Works like other Imidazole and Triazole antifungals: inhibiting fungal cyp P450 enzyme 14alpha demethylase. Mammalian demethylase activity is less sensitive to fluconazole than fungal. The inhibition inhibits conversion of lanosterol to ergosterol, an essential component of fungal cytoplasmic membrane, and subsequent accumulation of 14alpha methyl sterols. Fluconazole is primarily fungistatic; but may be fungicidal against certain organisms in a dose dependent manner, specifically Cryptococcus. Ergosterol is an essential component to fungal cell membrane, inhibition of its synthesis results in increased cellular permeability causing leakage of cellular contents.

Latent vs Active TB

asymptomatic/cant spread vs symptomatic and can spread Latent TB: -Do not feel sick and no symptoms. Infected w/ M. tuberculosis but do NOT have TB disease. -Only sign of TB infection is a positive tuberculin skin test or TB blood test. -*Persons w/ latent TB infections are NOT infectious and CANNOT spread TB to others.* Active TB: -When TB overcome immune defenses and multiply progressing from latent to active TB disease. -General symptoms: Unexplained weight loss, loss of appetite, night sweats, fever, fatigue, chills. -Symptoms of TB of the lungs include: Coughing for 3wks or longer, coughing up blood (hemoptysis), and chest pain. -Persons are considered infectious and may spread TB to others.

What is the significance of calcification of a nodule? What does it indicate?

Clinical significance of calcification of a nodule is that on CXR and CT it decreases the possibility of a malignant neoplasm. Diffuse, central, laminated or popcorn calcifications are benign patterns of calcification. These types of calcification are seen in granulomatous disease and hamartomas. All other patterns of calcification should not be regarded as a sign of benignity. The exception to the rule above is when patients are known to have a primary tumor. For instance the diffuse calcification pattern can be seen in patients with osteosarcoma or chondrosarcoma. Similarly the central and popcorn pattern can be seen in patients with GI-tumors and patients who previously had chemotherapy.

MN reporting requirements for latent vs active Tb

Confirmed or suspected cases of TB must be reported to the Minnesota Department of Health w/in 1 working day of identification. Both pulmonary and extrapulmonary TB forms are reportable. The physician, infection preventionist, laboratory or other reporting agent should report to MDH all TB cases that meet either laboratory or clinical case definitions Latent TB infections are *NOT* a reportable condition in MN.

What is the mechanism of the nonproductive cough? Include receptor and neural pathway.

Cough is comprised of three phases (inspiratory, compressive and expiratory) and serves as a vital defensive mechanism for lung health. It prevents pulmonary aspiration, promotes ciliary activity and clears airway debris.

What part of the flow equation (deltaP = flow x resistance ) is altered by pulmonary infections. Precisely specify what is changed. Which key respiratory processes are affected by infections (ventilation; diffusion; perfusion; or gas transport)?

Could also note the anemia caused (potentially) by the disease(s) could lead to decreases in *Perfusion* and *Gas Transport* as well

Associate the organisms responsible for pulmonary infections in HIV+ patients with CD counts *less than 50*

*Aspergillus fumigatus* [fungus] -Only exist in mold form; have septate hyphae that branch at 45 degrees; may also have condial heads / fruiting bodies -Spores penetrate the lungs and germinate forming a fungal ball Mycobacterium avium-intracellulare complex (MAC) infection [bacteria] -Nonmotile, acid-fast, bacilli, obligate aerobe -Enters intestine and adheres to lamina propria → m0 endocytosis → replicates intracellularly → host cell apoptosis → spread of infection *CMV bronchiolitis* [virus] -Class I dsDNA, linear, icosahedral nucleocapsid, enveloped, Herpes simplex virus 5 -Uses glycoprotein B (gB) for host-cell entry, cell-to-cell transmission, and fusion of infected cells

Associate the organisms responsible for pulmonary infections in HIV+ patients with CD counts *less than 200*

*Pneumocystis jirovecii* pneumonia [fungus] -Saucer/cup shaped yeast -Trophozoite inhaled and attaches to type I pneumocytes in the lung via fibronectin, vitronectin, laminin, and mannose receptors -Coats itself in surfactant protein-A, which delays recognition and destruction by host immune system Histoplasmosis capsulatum infection [fungus] -Two forms: ++Mold in the cold ++Yeast in the heat -Found within macrophages -Heat shock protein 60 (HSP60) is a surface molecule that allows it to survive and replicate intracellularly Coccidioidomycosis [fungus] -Two forms: ++Mold in the cold ++Spherules in the heat -Spherules containing endospores within a thick refractive wall -Spherules rupture and endospores throughout the body, most commonly in the lungs

Amphotericin B MOA

-Binds ergosterol (unique to fungi); forms membrane pores that allow leakage of electrolytes. -Amphotericin "tears" holes in the fungal membrane by forming pores

PBL Wrap Up Notes

5th generation- HIV 1 vs HIV 2 (HIV-1 is more prevalent) HIV-2 (West Africa) Drugs to control coughing: guanifensen, acts on mucin to reduce its secretion and reduce stress on mucociliary elevator so it can perform its physiologic function. Dextromethorphan NMDA antagonist raises coughing threshold (slight mu receptor affinity), also a serotonin reuptake inhibitor so do not prescribe on patients who are already on serotonin reuptake inhibitors to reduce instance of serotonin syndrome (evidence is lacking for being more beneficial than placebo). Quad therapy: RIPE: Rifamycin (Rifabutin in our case), Isoniazid, Pyrazinamide , Ethambutol (only use Ethambutol until sensitivity is back) (he was also on vitamin B6 to help with isoniazid- aka INH) -6 months is the regimen -But he does the quad for 2 months and then 4 months of just INH and rifabutin TB treatment is based on host (underlying disease-- HIV/TB) XDR vs MDR (second or third line drugs-- need to be on longer) Cavitation- higher burden of disease; longer to die (need to be on drugs longer) HIV and TB treatment -Dx at same time: always start TB immediately (priority) -Antiretrovirals: based on host, pregnancy, child -CD4 count-- 600 (high)- start HIV treatment within 8-12 weeks -CD4 count is below 50- start HIV treatment more urgently (within 2 weeks) CNS involvement of TB or not? Wait longer to start HIV treatment if CNS involvement -Tuberculoma (similar to granuloma in lung): serious problems if IRIS occurs -Tuberculous meningitis -With HIV- IRIS (immune reconstitution inflammatory syndrome) -- exaggerated immune response (highest in first 3 months of treatment)-- makes TB worse -PX or HX (don't do neuroimaging in absence of symptoms) -Cryptococcus/and TB think IRIS (systemic inflammation due to all out immune response, this is especially concerning in enclosed spaces like the brain, this systemic is the immediate concern and a paradoxical worsening of the initial TB infection) Measles and HIV may both cause reactivation of TB, due to being immunocompromised. AIDS: if AIDS defining illness (TB) or CD4+ count less than 200. -DDX?? -not every nodule is infectious -Candida test (positive if can build an immune response because everyone is exposed to it) (negative if CD4+ count is extremely low) Major drug interactions (drug/drug w/ rifampin) also serial liver function tests (AST/ALT) to check for liver toxicity For months 1-2, the patient will receive the four drug therapy For months 3-6, (4 additional months, not four months total) the patient will continue the rifabutin (not rifampin) and INH.

Which regions of the lungs are most likely to be infected by tuberculosis?

Apex of lung (Active) Ghon complex: Ghon focus + hilar lymph node (latent) -Ghon focus: granuloma or walled-off bacteria that leads to caseous necrosis within the granuloma from dying bacteria -Hilar lymph node: can become infected and caseate there as well -Usually subpleural and in lower lobes of lungs -Calcified/fibrosis ghon complex = Ranke complex Latent infection: walled off, but still viable -Immunocompromised => Ghon focus becomes reactivated -Infection spreads to upper lobes of lungs -Oxygenation is greatest in these areas AND M. tb are aerobes => want lots of oxygen

What is the morphology of granulomas, caseating and non-caseating and the common diseases associated with each

Caseating granuloma: A) Granulomas associated w/ certain infections (classically M. tuberculosis), a combination of hypoxia and free radical-mediated injury leads to a central zone of necrosis. Grossly it has a granular, cheesy appearance and is thus called caseous necrosis. Microscopically the necrotic material appears as amorphous, structureless, eosinophilic, granular debris w/ complete loss of cellular details. Non-caseating granulomas: A) Granulomas in Crohn disease, sarcoidosis, and foregin body reactions tend to NOT have necrotic centers and be noncaseating. Healing of granulomas is accompanied by fibrosis.

What are potential explanations for why Arnold feels tired all the time?

Anemia Decreased oxygenation of lungs due to granuloma formation

What is the most reasonable explanation for Arnold's anemia?

Anemia of chronic disease occurs in later stages of HIV infection and in cases of Tb Infection → inflammation → IL-6 release → hepcidin release → blocks ferroportin transporter on duodenum cells (decreased iron absorption) and prevents RBC degradation in the liver (decreased iron recycling) → decreased serum iron → decreased Hb production → anemia Functions to decrease serum iron which bacteria thrive off of

Dextromethorphan MOA

Antagonizes NMDA glutamate receptors

Describe gross morphologic and imaging features of a solitary pulmonary nodule that may favor a benign versus a malignant etiology.

Benign: A) May be called a "spot on the lung" or a "coin lesion." Most nodules are noncancerous, and may be found on up to .2% of all CXRs, and up to 50% of all lung CT scans. B) Less than 30mm in size, look to see if lung nodules have changed since past films, if it hasn't changed size or shape in 2 yrs, most likely benign. Patient is younger than 40, non smoker, there is calcium in the nodule. C) Wheezing, coughing that lasts or coughing up blood, SOB, and fever, especially if pneumonia is present are signs of benign lung nodules and tumors. Thus imaging may be indicated here. Malignant: A) If greater than 30mm or changed in size/shape w/in last 2 yrs doctor will likely order a PET scan to look for glucose uptake, indicating malignancy.

Define the cell layers involved in oxygen diffusion from the alveoli to the blood.

Blood-Gas Barrier A) Diffusion across surfactant, Type I pneumocyte, basement membrane and endothelial cell -Surfactant: produced by lamellar bodies of Type II pneumocytes; decreases surface tension; phagocytosed by alveolar macrophages -Type I pneumocyte: extremely thin squamous cells, do not divide; gas exchange Fusion of basal lamina of Type I pneumocytes and endothelial cells of capillaries

If Mr. Morland's tuberculosis infection advanced to an active stage, he will most likely suffer from reduced diffusion of oxygen. What part of the flow equation ( deltaP = flow x resistance ) is altered to account for the reduced flow of gas? If pressures are altered, specify which pressures are reduced or increased. If resistance is altered, specify which component of resistance is altered.

Both factors may be at play here: change in resistance and/or change in pressure Diffusion across blood-gas barrier is determined by: A) *Pressure difference* (driving force) B) Surface area of barrier C) *1/thickness of barrier* D) 1/(molecular weight of gas) E) Solubility of gas in barrier During initial infection TB, blood-gas barrier is infiltrated by mycobacteria and immune cells; immune response is effectively increasing thickness of the blood-gas barrier (resistance). ? There is an inverse relationship btwn diffusion of gas and thickness of barrier. So, as thickness increases, less gas is diffused. Later, formation of granuloma would also affect diffusion due to pressure changes (seems more likely...). Inside granuloma is hypoxic area. Lower alveolar pO2 means that the pressure gradient decreases btwn alveoli and pulm capillaries = less diffusion O2 across barrier.

Describe the pathogenesis of TB including the steps during infection leading to the initial granuloma

Brief summary: First the TB infects macrophages where it multiplies unchecked, which then mounts a Th1 cell response to stimulate more macrophages into the tissue which wall off the infected macrophages (granuloma) which kills the enclosed tissue (caseating granuloma). M. tuberculosis enters macrophages via phagosome-> inhibits fusion of phagosome w/ lysosome and grows/divides w/in phagosome of pulmonary alveolar macrophages -> bacteremia/seeding of multiple sites (despite this most ppl are asymptomatic/mild flu like sypmtoms)-> PAMPs of TB lead to innate immune response through Toll like receptors-> Th1 response secretes activates macrophages, mature APC cells secrete IL-12-> Th1 cell differentiation and IFN gamma production-> allows macrophages to contain TB infection, and expose bacteria to phagolysosome. In addition Th1 response-> IFNgamma-> Macrophage differentiation into epithelioid histiocytes-> they aggregate to form granuloma and may fuse together to form giant cells. (in many ppl this haults the infection, but in others, often immunosuppressed/advanced age, the ongoing immune response results in caseous necrosis.

Which cells mediate a positive Mantoux test?

CD8+ Th1 cells

How do you interpret a Mantoux Skin Test?

Example of delayed (cellular) hypersensitivity reaction A) T cells sensitized by prior infection (of TB) are recruited to the skin site where they release lymphokines. These lymphokines induce duration through local vasodilation, edema, fibrin deposition, and recruitment of other inflammatory cells to the area. The reaction is: -Delayed, reaching peak more than 24 hrs after injection -Indurated -Occasionally vesiculated and necrotic Not able to be positive until about 8 days after TB infection (because it is a measure of T cell hypersensitivity response) *Five mm or more* is positive in: A) *HIV-positive person*--our patient B) Recent contacts of active TB cases C) *People with nodular or fibrotic changes on CXR consistent with old healed TB * D) Organ transplant recipients and other immunosuppressed patients who are on cytotoxic immune-suppressive agents such as cyclophosphamide or methotrexate. E) Patients on long term systemic corticosteroid therapy (> than six weeks) and those on a dose of prednisone ≥ 15 mg/day or equivalent. F) End stage renal disease *Ten mm or more* is positive in: A) Recent arrivals (less than five years) from high-prevalence countries B) *Injectable drug users* C) Residents and employees of high-risk congregate settings (e.g., prisons, nursing homes, hospitals, homeless shelters, etc.) D) Mycobacteriology lab personnel E) Persons with clinical conditions that place them at high risk (e.g., diabetes, prolonged corticosteroid therapy, leukemia, end-stage renal disease, chronic malabsorption syndromes, low body weight, etc.) F) Children less than four years of age, or children and adolescents exposed to adults in high-risk categories G) Infants, children, and adolescents exposed to adults in high-risk categories *Fifteen mm or more* is positive in: A) *Persons with no known risk factors for TB. Reactions larger than 15 mm are likely to be due to previous BCG vaccination (TB vaccine) or exposure to environmental mycobacteria* False positive A) Some people may react to TST even though they aren't infected with M. tuberculosis.

Describe the common microbiological stains used in tissue sections (Gram, Warthin Starry, Gemori Methenamine Silver, and Zihel Nielsen) with the types of organisms identified by each.

Gram stain A) for bacteria, Warthin Starry A) for spirochetes Gomori Methenamine Silver A) for fungus Acid Fast staining: Zihel nielsen A) for mycobacterium Gomori Methenamine Silver stain: A) Abbreviated GMS. Used widely for staining fungal infections, particularly useful in staining carbohydrates. It can be used to identify yeast-like fungus Pneumocystitis jiroveci. Cell walls of these organisms are outlined by the brown to black stain Warthin Starry: A) Silver nitrate based stain method used for detection of spirochetes. Stains H. pylori, Lawsonia intercellulairs, Microsporidia and particulates. Also important for confirmation of Bartonella henselae, a causative organism of cat scratch disease. It stains organisms dark brown to black, and background light golden brown/golden yellow. Acid Fast staining: Zihel nielsen, used for mycobacterium A) Mycobacterium have lots of mycolic acid in their cell wall, which prevents the normal stain from "sticking" 1. Heat fix bacteria to slide. Add carbol fuchsin (dye) to slide, then heat slide. Heating the slide allows the carbol fuchsin to penetrate cell wall. 2. At this point, all bacteria on the slide will be red. Next we use methanol to "decolorize" cells. Non mycobacterium cells will lose their color, while mycobacterium will remain red. 3. Counter stain with methylene blue to turn all non mycobacterium blue. Mycobacterium TB will appear 2-4 um in length and .2-.5 um wide (bacilli)

Compare and contrast primary, secondary, and miliary TB with regards to clinical presentation, gross pathologic findings, and microscopic pathologic findings.

Primary: A) Form of disease that develops in a previously unexposed/unsensitized person. Most often resembles an acute bacterial pneumonia w/ consolidation of the lobe, hilar adenopathy, and pleural effusion. B) Combination of parenchymal lung lesion and nodal involvement is known as the Gohn complex* Secondary: (cavitation is more likely in secondary, not primary) A) Disease pattern that arises in a previously sensitized host, may follow shortly after primary TB, but most commonly years after initial infection when host defenses are weakened and stems from reactivation of latent infection. Reactivation is more common in low prevalence areas whereas reinfection is more common in areas of high contagion. B) Classically involves the apex of the upper lobes of one or both lungs. Regional lymph nodes less prominently involved early in secondary disease than in primary TB, but cavitation occurs readily in the secondary form. Localized secondary infections may be asymptomatic. Systemic symptoms most likely related to cytokine release from macrophages often appear early in the course and include malaise, anorexia, wt. Loss fever and night sweats. Progressive pulmonary sputum mucoid first->purulent later. Hemoptysis in 50% of all TB cases, pleuritic pain may result from extension of infection to pleural surfaces. Miliary: A) Occurs when organisms draining through lymphatics enter the venous blood and circulate back to the lungs. Individual lesions are either microscopic or small, visible foci of yellow-white consolidation through the lung parenchyma (adjective miliary is derived from the resemblance of these foci to millet seeds). Miliary lesions may expand and coalesce, resulting in consolidation of large regions or even whole lobes of the lung.

How is an HIV infection confirmed? What tests are used? What test do you use to Monitor the HIV infection?

Screening ELISA A) ELISA for detecting antigen (p24)--acute HIV infection -An antibody against p24 is linked to solid support plate or bead. Specimed added, and if antigen is present, they will bind to the antibody. Bound antigen detected by a second antibody linked to an enzyme. Add chromogenic molecule that will be converted by enzyme B) ELISA for detecting antibody--p24 antibody--looks for immune response to HIV protein -P24 is linked to solid support plate. Specimen is added, and if antibody is present, it will bind to the immobilized antigen. Bound antibodies are detected using a second antibody linked to an enzyme that binds to the first. Add chromogenic molecule that will be converted by the enzyme. Confirmed by HIV-1/HIV-2 ELISA A) Antigen/antibody assay that detects HIV-1, HIV-2, and HIV-1 p24 antigen B) Positive predictive value is the probability that subjects with a positive screening test truly have the disease C) Neg predictive value is probability that subjects with a negative screening test truly don't have the disease Western blot (but not used as much anymore) To monitor patients with HIV A) CD4+ T cell enumeration by flow cytometry B) PCR: measures viral DNA C) RT-PCR: measures viral RNA in serum

What is the mechanism for the elevation of monocytes in TB? HIV?

Seen both as a result of Tb and HIV infections Chronic inflammation → monocyte production → macrophage production → remove damaged cells

What is the significance of the smooth border of the nodule? What does it indicate?

Smooth borders of a Solitary Pulmonary Nodule are very significant in predicting whether a nodule is benign or malignant. Hamartomas and Adenomas make up the largest class of these benign smooth bordered nodules. Metastatic *pulmonary calcification* usually *occurs* in normal *pulmonary parenchyma* (alveolar walls, bronchi and blood vessel walls), the kidney and the stomach. Such *calcification is secondary to abnormal calcium metabolism* without any prior soft tissue damage. *Corona radiata sign* - highly associated with malignancy (image) *Lobulated or scalloped margins* - intermediate probability *Smooth margins* - more likely benign unless metastatic in origin

***Define PPD. Describe the parameters of a tuberculin test and how they are interpreted.***

purified protein derivative: a highly purified preparation of tuberculin used in skin tests (as the Mantoux test) to detect tubercle bacillus infection —abbreviation PPD. An intradermal skin test to detect tuberculosis infection (active or dormant - does not differentiate). Tuberculin, a protein fraction of tubercle bacilli, is injected intradermally in the human. Read 48-72 hours later. A localized thickening with redness indicates an accumulation of small, sensitized lymphocytes, which occurs as a result of active or dormant tuberculosis (type IV hypersensitivity rxn) Clients at high risk for tuberculosis (*HIV-infected persons*, the very young and the very old, the malnourished, alcoholics, drug abusers, and the chronically ill) *should be screened with the tuberculin skin test. Clients with human immunodeficiency virus infection are at increased risk for developing tuberculosis infection and should be screened with the tuberculin skin test. * Positive: -Depends on the population being tested -For adults and children with *HIV infection*, close contacts of infectious cases, and those with fibrotic lesions on chest radiograph, *a reaction of ≥5 mm is considered positive* -For other at-risk adults and children, including infants and children younger than 4 years of age, a reaction of ≥10 mm is positive -Persons who are unlikely to be infected with Mycobacterium tuberculosis should generally not be skin tested. If a skin test is performed on a person without a defined risk factor for tuberculosis infection, ≥15 mm is positive Negative: lack of redness or induration of skin at site of skin test; zone of redness and induration <5 mm