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Microbiology
Mycobacteria: Tuberculosis Pathogenesis, Atypical Mycobacteria, Mycobacterium leprae
Core Principle of Mycobacterial Pathogenesis
Mycobacteria are acid-fast bacilli with unique cell walls containing mycolic acids — long-chain fatty acids that resist decolorization by acid-alcohol after carbolfuchsin staining.
This waxy cell wall provides resistance to desiccation, chemical damage, and many antibiotics, while also preventing phagolysosomal fusion — the key virulence mechanism.
Mycobacteria are obligate aerobes that grow slowly (doubling time 12–24 hours for M. tuberculosis), explaining why TB favors the oxygen-rich lung apices and why culture takes weeks.
Board pearl: The acid-fast property is due to mycolic acids, not peptidoglycan — this explains why mycobacteria resist gram staining and require Ziehl-Neelsen or auramine-rhodamine stains.
Primary TB Infection and the Ghon Complex
Initial M. tuberculosis infection occurs via inhalation of droplet nuclei (1–5 μm) that reach the lower lung zones where ventilation exceeds perfusion.
Alveolar macrophages phagocytose the bacilli but cannot kill them — instead, bacteria multiply within macrophages, eventually causing cell lysis and spread.
The primary lesion (Ghon focus) forms in the middle or lower lung zones, accompanied by hilar lymphadenopathy — together forming the Ghon complex.
In 90% of immunocompetent hosts, cell-mediated immunity contains the infection, forming granulomas that may calcify (Ranke complex on chest X-ray).
Board clue: Calcified hilar nodes with a peripheral lung nodule in an asymptomatic patient → healed primary TB.
Cell-Mediated Immunity and Granuloma Formation
Infected macrophages present mycobacterial antigens via MHC class II to CD4⁺ T cells, which differentiate into Th1 cells secreting IFN-γ.
IFN-γ activates macrophages to form epithelioid cells that fuse into multinucleated giant cells, while surrounding lymphocytes form the granuloma periphery.
Central caseous necrosis occurs due to cytotoxic T cell-mediated killing of infected macrophages — the cheese-like appearance results from coagulative necrosis.
This immune response takes 2–8 weeks to develop, corresponding to tuberculin skin test conversion.
Board pearl: Patients with impaired cell-mediated immunity (HIV, anti-TNF therapy, organ transplant) cannot form proper granulomas → disseminated disease.
Secondary (Reactivation) Tuberculosis
Reactivation occurs when dormant bacilli in granulomas escape immune control — typically years to decades after primary infection.
Risk factors include HIV, malnutrition, diabetes, chronic kidney disease, silicosis, anti-TNF therapy, and other immunosuppressive states.
Reactivation favors the lung apices (high oxygen tension, impaired lymphatic drainage) — look for cavitary lesions in upper lobes on imaging.
Cavitation occurs when caseous material liquefies and erodes into bronchi, creating highly infectious patients who spread TB via cough.
Board distinction: Primary TB affects middle/lower lobes with hilar adenopathy; reactivation TB affects upper lobes with cavitation.
Extrapulmonary TB Manifestations
Miliary TB: hematogenous spread creating millet seed-sized granulomas throughout lungs and organs — seen in severe immunosuppression.
TB meningitis: rupture of subependymal tubercle into CSF → basilar exudates, cranial nerve palsies, communicating hydrocephalus.
Pott disease: vertebral osteomyelitis with anterior wedging, gibbus deformity, and potential psoas abscess formation.
Scrofula: cervical lymphadenitis with painless, matted nodes that may form draining sinuses.
Renal TB: "sterile pyuria" — WBCs in urine but negative routine culture.
Board pearl: TB can affect any organ except nails and hair — always consider TB in the differential of chronic inflammation.
TB Diagnostics: Tuberculin Skin Test and IGRAs
TST measures delayed-type hypersensitivity to purified protein derivative (PPD) — induration ≥5mm (HIV, recent contact), ≥10mm (high risk), or ≥15mm (low risk) is positive.
False positives occur with BCG vaccination and nontuberculous mycobacteria; false negatives with anergy, recent infection (<8 weeks), or overwhelming TB.
Interferon-gamma release assays (IGRAs) measure IFN-γ production by T cells exposed to TB-specific antigens — more specific than TST, unaffected by BCG.
Neither TST nor IGRA distinguish active from latent TB — they only indicate prior exposure and immune response.
Board pearl: In BCG-vaccinated individuals, IGRA is preferred over TST to avoid false positives.
Direct TB Detection Methods
Acid-fast bacilli (AFB) smear: rapid but insensitive — requires 5,000–10,000 organisms/mL for positivity. Three morning sputum samples increase yield.
Culture on Löwenstein-Jensen medium: gold standard but takes 4–8 weeks. Liquid media (MGIT) reduce time to 1–3 weeks.
Nucleic acid amplification tests (NAAT): detect M. tuberculosis DNA/RNA within hours — high specificity but variable sensitivity.
Xpert MTB/RIF: automated NAAT that simultaneously detects M. tuberculosis and rifampin resistance in <2 hours.
Board clue: AFB-positive sputum with negative NAAT → likely nontuberculous mycobacteria.
Nontuberculous (Atypical) Mycobacteria Overview
NTM are environmental organisms found in soil and water — not transmitted person-to-person like TB.
They cause disease in patients with structural lung disease (COPD, cystic fibrosis, bronchiectasis) or immunosuppression.
Common species include M. avium complex (MAC), M. kansasii, M. abscessus, and rapidly growing mycobacteria (M. fortuitum, M. chelonae).
NTM grow at various temperatures and speeds — some visible in days (rapid growers) vs weeks (slow growers).
Board pearl: NTM are inherently resistant to standard TB drugs — treatment requires prolonged multidrug regimens based on species identification.
MAC Disease Presentations
In HIV/AIDS with CD4⁺ <50: disseminated MAC causes fever, night sweats, weight loss, diarrhea, hepatosplenomegaly, and pancytopenia.
Blood cultures grow MAC; treat with clarithromycin + ethambutol ± rifabutin. Prophylaxis with azithromycin when CD4⁺ <50.
In immunocompetent hosts: pulmonary MAC causes chronic cough, bronchiectasis, and nodular infiltrates — "Lady Windermere syndrome" in elderly women who suppress cough.
Hot tub lung: hypersensitivity pneumonitis from inhaling MAC aerosols — distinct from MAC infection.
Board distinction: Disseminated MAC requires profound immunosuppression; pulmonary MAC occurs with normal immunity but abnormal lungs.
Other Clinically Important NTM
M. kansasii: causes TB-like pulmonary disease with cavitation — most similar to M. tuberculosis clinically and radiographically.
M. marinum: fish tank granuloma — nodular skin lesions along lymphatics after aquarium exposure, resembles sporotrichosis.
M. abscessus: rapid grower causing skin/soft tissue infections after surgery or trauma, extremely drug-resistant.
M. fortuitum/chelonae: rapid growers causing catheter infections, surgical site infections, and cosmetic procedure complications.
Board pearl: Rapid-growing NTM (visible in <7 days) are often resistant to TB drugs but may respond to conventional antibiotics like macrolides or fluoroquinolones.
Mycobacterium leprae Basic Biology
M. leprae cannot be cultured on artificial media — grows only in armadillos and mouse footpads (cool body sites).
Optimal growth at 30°C explains predilection for cooler body parts: skin, peripheral nerves, nasal mucosa, testes.
Transmitted via nasal secretions with prolonged close contact — despite myths, leprosy is not highly contagious.
Extremely slow growth (doubling time 14 days) means incubation period of 2–20 years.
Board pearl: The inability to culture M. leprae distinguishes it from all other pathogenic mycobacteria — diagnosis relies on clinical findings and tissue demonstration.
Leprosy Immunologic Spectrum
Tuberculoid leprosy: strong Th1 response → few organisms, well-formed granulomas, localized disease with <5 hypopigmented, anesthetic skin patches.
Lepromatous leprosy: weak cell-mediated immunity with Th2 predominance → numerous organisms, foamy macrophages (Virchow cells), diffuse disease.
Borderline forms exist between these poles, with intermediate bacterial loads and immune responses.
Board pearl: The lepromin skin test is positive in tuberculoid (good CMI) and negative in lepromatous (poor CMI) — it indicates immune status, not infection.
Clinical Features of Tuberculoid Leprosy
Well-demarcated hypopigmented or erythematous patches with raised borders and central clearing.
Anesthesia within lesions due to destruction of dermal nerves — test with pinprick or temperature.
Enlarged peripheral nerves (greater auricular, ulnar, posterior tibial) that may be palpable as cords.
Asymmetric distribution with minimal skin lesions (<5) and no systemic symptoms.
Biopsy shows well-formed granulomas with epithelioid cells, few or no acid-fast bacilli (paucibacillary).
Clinical Features of Lepromatous Leprosy
Diffuse, symmetric skin involvement with numerous macules, papules, and nodules — "leonine facies" from facial infiltration.
Loss of eyebrows (madarosis), saddle-nose deformity from nasal cartilage destruction, testicular atrophy.
Glove-and-stocking peripheral neuropathy — symmetric but less pronounced than tuberculoid form.
Biopsy shows foamy macrophages (Virchow cells) packed with acid-fast bacilli (multibacillary).
Board clue: Numerous skin lesions with minimal anesthesia → lepromatous; few lesions with prominent anesthesia → tuberculoid.
Leprosy Complications and Reactions
Type 1 reaction (reversal reaction): delayed hypersensitivity in borderline patients — acute inflammation of existing lesions with neuritis.
Type 2 reaction (erythema nodosum leprosum): immune complex vasculitis in lepromatous patients — painful nodules, fever, arthralgias, iritis.
Peripheral nerve damage leads to trauma and secondary infections → auto-amputation of digits, Charcot joints, corneal ulceration from lagophthalmos.
Board distinction: Type 1 reactions involve existing lesions becoming inflamed; Type 2 reactions involve new painful nodules appearing.
Diagnosis and Treatment of Leprosy
Diagnosis: clinical findings plus demonstration of acid-fast bacilli in skin smears or biopsy (slit-skin smear from earlobes, elbows, knees).
Tuberculoid (paucibacillary): dapsone + rifampin for 6 months.
Lepromatous (multibacillary): dapsone + rifampin + clofazimine for 12 months.
Dapsone can cause hemolysis in G6PD deficiency and methemoglobinemia; clofazimine causes red-brown skin discoloration.
Board pearl: All forms require multidrug therapy to prevent dapsone resistance — monotherapy is never appropriate.
BCG Vaccine and TB Prevention
BCG (Bacillus Calmette-Guérin) is a live attenuated strain of M. bovis used in high-TB-burden countries.
Provides protection against severe childhood TB (miliary, meningitis) but variable protection against pulmonary TB in adults.
Contraindicated in immunocompromised patients — can cause disseminated BCG disease.
Causes false-positive TST for years but does not affect IGRA results.
Board pearl: BCG is also used as intravesical therapy for superficial bladder cancer — an immunotherapy application.
Drug Resistance in Mycobacteria
Multidrug-resistant TB (MDR-TB): resistant to at least isoniazid and rifampin — requires second-line drugs with more toxicity.
Extensively drug-resistant TB (XDR-TB): MDR plus resistance to fluoroquinolones and injectable aminoglycosides.
Resistance mechanisms: mutations in drug targets (katG for isoniazid, rpoB for rifampin) or decreased drug activation.
NTM have intrinsic resistance to many TB drugs due to different drug targets and efflux pumps.
Board pearl: Never add a single drug to a failing TB regimen — this promotes resistance. Always add at least two new drugs.
Board Question Stem Patterns
Apical cavitary lesion in a diabetic patient → reactivation TB.
Miliary pattern on CXR with CD4⁺ <200 → disseminated TB (or MAC if CD4⁺ <50).
Positive AFB smear but negative TB PCR → nontuberculous mycobacteria.
Hypopigmented anesthetic patch with thickened nerve → tuberculoid leprosy.
Leonine facies with numerous skin nodules → lepromatous leprosy.
Pulmonary disease in elderly woman who suppresses cough → MAC (Lady Windermere).
Fish tank exposure with ascending nodular lymphangitis → M. marinum.
Sterile pyuria with negative urine culture → genitourinary TB.
One-Line Recap
Mycobacteria resist killing through unique cell wall mycolic acids and phagolysosomal fusion inhibition, with TB forming caseating granulomas via Th1 immunity, NTM causing opportunistic infections based on host factors, and M. leprae producing a spectrum from localized tuberculoid to disseminated lepromatous disease determined by the strength of cell-mediated immunity.
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