Tuberculosis

Organism

M. tuberculosis. Slow-growing, obligate aerobic, non-motile, non-spore-forming. ACID-FAST — mycolic-acid-rich wall resists Gram stain, but retains carbol fuchsin (ZN stain) against acid-alcohol decolorization = “AFB” name origin. SLOW generation (10-15hr vs E.coli’s ~20min) → slow culture, months-long treatment.

Transmission/Pathogenesis

DROPLET NUCLEI inhalation (airborne, small aerosolized particles, reach alveoli directly — contrast larger Droplet Precaution particles, see Standard Precautions topic).

Phagocytosed by alveolar macrophages → SURVIVES/REPLICATES INTRACELLULARLY (blocks phagolysosome fusion). KEY: CMI, NOT humoral immunity, controls TB (see Immune Response topic) — explains TB severity link to CD4/CMI status, TB occurs at ANY CD4 count (unlike most HIV opportunists needing advanced immunosuppression).

Primary complex (Ghon complex): Ghon focus (parenchymal lesion) + hilar LN, mid/lower lung zones. Immunocompetent: CMI response contains within weeks → GRANULOMA (Type IV/DTH mechanism, see Hypersensitivity topic) → organism DORMANT/LATENT, not eliminated.

LTBI (Latent TB Infection): infected, asymptomatic, non-infectious, no radiographic disease. Lifetime reactivation risk ~5-10% (immunocompetent), concentrated first 2 years. HIV: reactivation risk ~5-10% PER YEAR (not lifetime) — dramatic difference, remember precisely.

Primary progressive TB: active disease directly from initial infection, no latent period. More common: young children, severely immunocompromised (failed containment).

Clinical Manifestations

Pulmonary TB (commonest): chronic cough (>2-3wk), hemoptysis, low fever+night sweats, weight loss. INSIDIOUS onset over weeks-months (contrast acute bacterial pneumonias).

Extrapulmonary TB: any organ via hematogenous/lymphatic spread. Dedicated topics: TB meningitis (CNS topic), Pott’s disease/spinal TB (Osteomyelitis topic), genitourinary TB.

Miliary TB: widespread hematogenous dissemination, numerous small (millet-seed) granulomas multi-organ. Failure of containment severe enough for blood spread. EMERGENCY, substantial mortality untreated. More common: very young, elderly, immunocompromised.

Laboratory Diagnosis

Sputum smear (ZN stain, or fluorescent auramine-rhodamine): rapid, cheap. LIMITED — needs relatively HIGH bacillary load (sensitivity ceiling, esp. paucibacillary disease, HIV-coinfected, children).

Culture: LJ solid medium (SLOW, 3-8wk) or automated liquid (BACTEC MGIT, faster ~1-3wk). GOLD STANDARD, ONLY method for phenotypic drug susceptibility testing.

NAAT — GeneXpert MTB/RIF: cartridge PCR, results ~2hr, DETECTS RIFAMPICIN RESISTANCE simultaneously (proxy for likely MDR-TB, since rifampicin resistance strongly correlates with broader MDR, faster than full culture susceptibility).

TST (Mantoux) + IGRA: detect IMMUNE SENSITIZATION (infection evidence, past or present), NOT active disease directly. CANNOT distinguish latent vs active alone — needs clinical/radiographic correlation.

Treatment

Standard drug-susceptible TB: 4-drug INTENSIVE phase (isoniazid, rifampicin, pyrazinamide, ethambutol) × 2 months → CONTINUATION phase (isoniazid, rifampicin) × 4 months = 6-MONTH TOTAL course. Multidrug rationale (same as leprosy, H. pylori Rx): prevents mutational resistance selection (single drug → resistant mutants selected; combo → mutant resistant to one still killed by others).

DOT (Directly Observed Therapy): supervised dosing, standard TB program component — completion (not just initiation) drives cure + prevents resistance.

MDR-TB (resistant ≥isoniazid+rifampicin) and XDR-TB (MDR + key 2nd-line resistance): longer, more toxic, less effective 2nd-line regimens. Growing global challenge.

Prevention

BCG vaccine (live attenuated M. bovis, birth dose high-burden countries incl. India, see Vaccines topic): protects severe CHILDHOOD forms (miliary, TB meningitis) well, only PARTIAL/variable protection adult pulmonary TB — vaccination status doesn’t rule out TB in symptomatic adult.

Isoniazid preventive therapy: identified LTBI (esp. HIV+, close contacts) → ↓reactivation.

Infection control (airborne precautions, negative pressure isolation, see Standard Precautions topic) + active case-finding/contact tracing.

The Organism

Mycobacterium tuberculosis is a slow-growing, obligate aerobic, non-motile, non-spore-forming bacillus, defined above all by its acid-fastness — a waxy, lipid-rich cell wall (rich in mycolic acids) that resists standard Gram staining (it stains poorly and inconsistently, effectively neither reliably Gram-positive nor Gram-negative) but, once stained by heat or detergent-assisted carbol fuchsin (Ziehl-Neelsen method), stubbornly retains that stain even against strong acid-alcohol decolorization — the defining property that gives “acid-fast bacillus” (AFB) its name and underlies the organism’s entire diagnostic and staining approach. The same mycolic-acid-rich wall explains the organism’s notoriously slow generation time (10–15 hours, versus roughly 20 minutes for E. coli), which is exactly why TB culture takes weeks and why TB treatment courses run for months rather than days.

Transmission and Pathogenesis

Transmission is by inhaling droplet nuclei — small, aerosolized respiratory particles from an infectious pulmonary/laryngeal TB case’s cough, capable of remaining airborne for extended periods and reaching the alveoli directly (unlike larger droplets, which settle quickly and are covered under Droplet Precautions rather than Airborne Precautions, as detailed under Needle Stick Injury and Standard Precautions). Once inhaled, bacilli are phagocytosed by alveolar macrophages, and the organism’s defining pathogenic feature is its capacity to survive and replicate within macrophages by blocking phagolysosome fusion — a genuinely central fact, since it is exactly why cell-mediated immunity, not humoral immunity, is what actually controls TB (see Immune Response for why CMI specifically governs intracellular organisms), and why TB disease and control are so tightly linked to a host’s CD4/CMI status (explaining TB’s dramatically increased frequency and severity in HIV/AIDS, and why TB can occur at essentially any CD4 count, unlike most other HIV-associated opportunists that require more advanced immunosuppression).

The primary complex (Ghon complex) — a small parenchymal lesion (Ghon focus) plus draining hilar lymph node involvement — forms at the initial infection site, usually in the well-aerated mid-to-lower lung zones. In most immunocompetent individuals, the developing cell-mediated immune response contains this primary infection within weeks, walling it off as a granuloma (the same mechanism covered under Hypersensitivity Reactions’ Type IV/DTH section, and the underlying reason a positive tuberculin skin test reflects this containment response rather than active disease) — the organism is not eliminated but rendered dormant/latent, capable of persisting for a lifetime without ever causing clinical disease. Latent TB infection (LTBI) — infected but asymptomatic, non-infectious, with no radiographic disease — carries a lifetime reactivation risk of roughly 5–10% in an immunocompetent host, concentrated disproportionately in the first two years after infection, but risk rises dramatically with any cause of impaired CMI (HIV specifically raises annual reactivation risk to roughly 5-10% per year rather than over a lifetime — a genuinely dramatic, clinically crucial difference worth remembering precisely). Primary progressive TB (active disease developing directly from the initial infection, without an intervening latent period) is more common in young children and the severely immunocompromised, whose immune response fails to contain the primary infection at all.

Clinical Manifestations

Pulmonary TB (the commonest form) presents with a constellation of constitutional and respiratory symptoms — chronic cough (classically >2–3 weeks), haemoptysis, low-grade fever (often with night sweats), and weight loss — that develop insidiously over weeks to months, in genuine contrast to the acute-onset pattern of most bacterial pneumonias covered elsewhere in this section.

Extrapulmonary TB can affect essentially any organ via haematogenous or lymphatic spread from the primary site, and several forms are covered as their own dedicated topics elsewhere given their clinical importance: TB meningitis (see Infections of the Central Nervous System), Pott’s disease/spinal TB (mentioned under Osteomyelitis), and genitourinary TB. Miliary TB — widespread haematogenous dissemination producing numerous small (millet-seed-sized, hence the name) granulomas across multiple organs simultaneously — represents a failure of containment severe enough to allow blood-borne spread, and is a genuine medical emergency with substantial mortality if untreated, more common in the very young, the elderly, and the immunocompromised.

Laboratory Diagnosis

Sputum smear microscopy (Ziehl-Neelsen staining, or the more sensitive fluorescent auramine-rhodamine stain read by fluorescence microscopy) remains a rapid, cheap, widely deployable method, though genuinely limited by the need for a relatively high bacillary load to be reliably positive (a real sensitivity ceiling, particularly in paucibacillary disease, HIV-co-infected patients, and children, who characteristically have lower bacillary burdens). Culture — on Löwenstein-Jensen solid medium (slow, taking 3–8 weeks given the organism’s generation time) or in automated liquid culture systems (BACTEC MGIT and similar, faster at roughly 1–3 weeks) — remains the diagnostic gold standard and, critically, is the only method that also enables phenotypic drug susceptibility testing. Nucleic acid amplification tests, most importantly GeneXpert MTB/RIF (a cartridge-based, automated PCR assay), have transformed practical TB diagnosis by delivering results within about 2 hours while simultaneously detecting rifampicin resistance directly — genuinely important given rifampicin resistance’s strong correlation with broader multidrug resistance (making it a practical, fast proxy for flagging likely MDR-TB long before full culture-based susceptibility results would otherwise be available). The tuberculin skin test (Mantoux) and interferon-gamma release assays (IGRA) both detect immune sensitization (evidence of infection, past or present) rather than active disease directly, and cannot distinguish latent from active TB on their own — a genuinely important limitation, since a positive result in either test requires correlation with clinical/radiographic findings to determine whether it represents latent infection or active disease.

Treatment

Standard first-line treatment for drug-susceptible TB uses a four-drug intensive phase — isoniazid, rifampicin, pyrazinamide, ethambutol — for 2 months, followed by a continuation phase — isoniazid and rifampicin — for a further 4 months, giving a standard 6-month total course. This multidrug approach exists for the same reason multidrug therapy is used in leprosy and H. pylori eradication (see those topics): TB’s naturally occurring mutational resistance (see Antimicrobial Agents and Antimicrobial Resistance) means single-drug therapy would rapidly select out resistant mutants, whereas combining agents with independent resistance mechanisms defeats this since a mutant resistant to one drug is still killed by the others. Directly observed therapy (DOT) — supervised medication-taking — is a standard component of TB control programmes, reflecting how directly treatment completion (not just initiation) drives both individual cure and population-level resistance prevention. Multidrug-resistant (MDR-TB) — resistant to at least isoniazid and rifampicin — and extensively drug-resistant (XDR-TB) — MDR-TB with additional resistance to key second-line agents — require longer, more toxic, less effective second-line regimens, representing a genuine and growing global public health challenge.

Prevention

BCG vaccination (live attenuated M. bovis, given at birth in high-burden countries including India, see Vaccines and Immunoprophylaxis) provides meaningful protection against severe childhood TB forms (miliary TB, TB meningitis) but only partial, variable protection against adult pulmonary TB — a genuinely important limitation worth remembering, since BCG vaccination status does not reliably rule out TB in a symptomatic adult. Isoniazid preventive therapy for identified latent TB infection (particularly in HIV-positive individuals and close contacts of active cases) reduces reactivation risk. Infection control (airborne precautions, negative-pressure isolation for infectious cases, covered under Needle Stick Injury and Standard Precautions) and active case-finding/contact tracing round out standard TB control strategy.

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