Tuberculosis & Mycobacterial Disease

Pathogenesis and natural history

Primary infection. Mycobacterium tuberculosis travels in inhaled droplet nuclei to the alveoli and is ingested by macrophages. Once cell-mediated immunity develops (Th1 cells, interferon-γ, TNF-α), the bacilli are walled off in caseating granulomas. A subpleural Ghon focus in the lower or middle lung zones plus the draining hilar nodes forms the Ghon complex. Most primary infections are contained silently and become latent.

Latent TB infection. The patient is asymptomatic and noninfectious, with a positive PPD or IGRA and a normal chest x-ray. About 5–10% of untreated immunocompetent people reactivate in their lifetime, roughly half within 2 years; HIV, TNF-α inhibitors, transplant immunosuppression, diabetes and silicosis raise the risk.

Reactivation. Reactivation favors the upper-lobe apices, where oxygen tension is highest, producing cavitary disease with weeks of cough, sometimes hemoptysis, fever, night sweats and weight loss.

TNF-α maintains granulomas: screen for latent TB before starting a TNF-α inhibitor such as infliximab.

Testing for latent infection

PPD versus IGRA. Latent infection is detected with the tuberculin skin test (PPD) or an interferon-γ release assay (IGRA, e.g., QuantiFERON). The PPD is read at 48–72 hours by measuring induration, so it needs a return visit. The IGRA is a single blood draw using TB-specific antigens, so it is not confounded by prior BCG vaccination and is preferred in BCG recipients. Neither test distinguishes latent from active disease.

Pitfalls. False-negative PPDs occur with anergy (advanced HIV, steroids, malnutrition, sarcoidosis) and in the 2–8 weeks after infection before conversion, so a negative contact is retested 8–10 weeks after exposure. Serially tested healthcare workers get two-step baseline testing so a boosted response is not mistaken for new infection.

After a positive test. Review symptoms and obtain a chest x-ray. A normal film in an asymptomatic patient means latent infection; symptoms or an abnormal film mean an active-TB workup.

Diagnosing active TB

Suspicion. Consider pulmonary TB when a cough of 2–3 weeks or more comes with fever, night sweats, weight loss or hemoptysis, especially with exposure or immunosuppression.

Isolation and public health. Isolation continues until three smears are negative or TB is excluded; when suspicion is high, start therapy without waiting for culture. TB is reportable, the health department traces contacts, and every patient with TB is tested for HIV.

Treatment

Latent TB. Treat only after active disease is excluded, because monotherapy of active TB breeds resistance. Rifamycin-based short courses are now preferred for adherence: rifampin for 4 months, isoniazid plus rifapentine weekly for 12 weeks (3HP), or isoniazid plus rifampin for 3 months. Isoniazid for 9 months, with pyridoxine, is the alternative.

Always confirm a normal chest x-ray and no symptoms before latent-TB therapy, or you risk creating resistance.

Active TB. The intensive phase is rifampin, isoniazid, pyrazinamide and ethambutol (RIPE) for 2 months, then rifampin plus isoniazid for 4 months (6 months total), given as directly observed therapy (DOT) to ensure adherence and limit resistance. Ethambutol can stop once isoniazid and rifampin susceptibility is confirmed. Extend therapy to 9 months for cavitary disease with a positive 2-month culture and to 9–12 months, with adjunctive dexamethasone, for CNS TB.

Drug resistance. Multidrug-resistant TB (MDR-TB) resists at least isoniazid and rifampin, the two most important drugs; extensively drug-resistant TB (XDR-TB) adds resistance to fluoroquinolones and other second-line agents. Suspect it with treatment failure or exposure to a resistant case; it needs prolonged, specialist-directed multidrug regimens.

Extrapulmonary TB and TB with HIV

Extrapulmonary disease. TB can strike almost any organ:

• Lymph nodes: cervical lymphadenitis (scrofula).
• Spine: Pott disease (TB spondylitis), often lower thoracic, with gibbus deformity, psoas abscess and cord compression.
• Meninges: basilar meningitis with cranial nerve palsies; CSF lymphocytes, high protein, low glucose.
• Miliary TB: hematogenous dissemination with innumerable tiny nodules.
• Kidney: sterile pyuria.
• Adrenals: destruction causing Addison disease.
• Pericardium: pericarditis that can become constrictive.

TB with HIV. TB is a leading killer in HIV worldwide. At low CD4 it may be smear-negative or atypical (lower-lobe, miliary or extrapulmonary), sometimes with a normal chest x-ray. Start anti-TB therapy first, then add ART, within 2 weeks if CD4 is below 50 and within 8 weeks otherwise. Rifampin lowers protease inhibitor levels, so rifabutin is often substituted. Immune reconstitution inflammatory syndrome (IRIS) can flare TB after ART begins; both therapies continue, with corticosteroids for severe reactions.

Nontuberculous mycobacteria

Environmental organisms. Nontuberculous mycobacteria (NTM) come from water and soil, not from other people, so no isolation is needed. Because one isolate may be a contaminant, pulmonary disease requires symptoms and imaging plus repeated positive cultures.

Lady Windermere syndrome. Pulmonary MAC in older, otherwise healthy women is classically attributed to habitual cough suppression, which favors the poorly drained right middle lobe and lingula.

MAC prophylaxis. Azithromycin has traditionally been given once CD4 falls below 50; current US guidelines reserve it for patients not starting fully suppressive ART promptly. Treatment of established disease is a macrolide-based multidrug regimen.