Tuberculosis

Tuberculosis – High‑Yield Study Guide for Medical Students

Definition

Tuberculosis (TB) is a chronic granulomatous infectious disease caused by Mycobacterium tuberculosis complex, characterized by airborne transmission, primary lung involvement, and potential hematogenous or lymphatic dissemination to virtually any organ (extrapulmonary TB). Active disease reflects failure of host immunity to fully contain the bacilli, whereas latent TB infection (LTBI) denotes immunologic containment without clinical disease.

Epidemiology

TB remains one of the leading infectious causes of morbidity and mortality worldwide, particularly in low- and middle-income countries and in settings of high HIV prevalence. Delays in seeking medical care substantially increase transmission, especially in congregate environments such as schools and dormitories, and are a key barrier to TB elimination targets.^[1] Cluster outbreaks are well-documented in boarding schools and similar high-density settings, emphasizing the need for early detection and contact investigation.^[2]

• Global burden: Millions of incident cases annually; substantial underdiagnosis and underreporting in some regions.
• High-risk regions: Sub-Saharan Africa, South and Southeast Asia, parts of Eastern Europe.
• Risk groups: People with HIV, close contacts of active TB cases, healthcare workers, prisoners, homeless populations, people with diabetes, silicosis, CKD, malnutrition, and those receiving TNF-α inhibitors or other immunosuppressants.
• Post-TB lung disease: Survivors are at risk for chronic structural damage such as post-TB bronchiectasis, which carries ongoing morbidity and risk of exacerbations.^[3]

Pathophysiology

TB pathogenesis reflects a dynamic interaction between inhaled mycobacteria and the host immune response.

• Transmission: Inhalation of droplet nuclei (<5 μm) containing M. tuberculosis, expelled by individuals with pulmonary or laryngeal TB during coughing, sneezing, or speaking.
• Initial infection: Bacilli reach terminal bronchioles and alveoli (often mid–lower lung zones), are phagocytosed by alveolar macrophages, and may replicate intracellularly.
• Granuloma formation: Cell-mediated immunity develops over 2–8 weeks. Th1 CD4+ T cells secrete IFN-γ, activating macrophages, which aggregate with lymphocytes to form granulomas, often with central caseous necrosis. This containment leads to latent TB infection.
• Primary TB: The initial parenchymal focus (Ghon focus) plus involved hilar lymph nodes constitute the Ghon complex. In immunocompetent hosts, primary infection often heals with fibrosis and calcification.
• Reactivation TB: With waning immunity (e.g., HIV, diabetes, malnutrition, steroids), bacilli may reactivate, classically in apical/posterior segments of upper lobes, due to higher oxygen tension.
• Dissemination: Bacillemia can seed multiple organs (miliary TB) including CNS (tuberculous meningitis), bone (Pott disease), lymph nodes, kidneys, and reproductive organs.
• Immune evasion: M. tuberculosis uses specialized secretion systems (e.g., ESX-1 and related effectors) to manipulate host cells. Recent work demonstrates TB proteins can induce host DNA release and activate cGAS–STING signaling, paradoxically supporting bacterial survival by dysregulating innate immunity.^[4]

Clinical Presentation

Clinical manifestations differ between latent infection, pulmonary TB, and extrapulmonary TB.

Latent TB Infection (LTBI)

• Asymptomatic.
• Normal chest imaging.
• Detected by positive tuberculin skin test (TST) or interferon-γ release assay (IGRA).

Pulmonary TB (Active Disease)

• Constitutional symptoms: Low-grade fever, night sweats, anorexia, weight loss, fatigue.
• Respiratory symptoms: Chronic cough (>2–3 weeks), initially dry then productive, hemoptysis, pleuritic chest pain, dyspnea in advanced disease.
• Physical exam: Often nonspecific; may show crackles, bronchial breath sounds, or signs of pleural effusion; may be normal in early disease.
• Special populations: Children, older adults, and patients with HIV may have atypical or subtle presentations.

Extrapulmonary TB

• Lymph node TB: Painless lymphadenopathy, commonly cervical; may become matted, fluctuant, or sinus-forming.
• Pleural TB: Pleuritic chest pain, dyspnea, unilateral exudative effusion.
• TB meningitis: Subacute headache, fever, cranial nerve deficits, altered mental status.
• Skeletal TB (e.g., Pott disease): Back pain, gibbus deformity, neurological deficits if cord compression.
• Genitourinary TB: Dysuria, frequency, sterile pyuria, infertility.
• Miliary TB: Fever, weight loss, night sweats, multi-organ involvement; may be subtle with non-specific systemic illness.

Diagnosis

Diagnosis combines clinical assessment, radiology, microbiology, and immunologic testing.

Initial Evaluation

• History focusing on TB exposure, travel, residence in high-prevalence settings, comorbidities (HIV, diabetes, immunosuppression), prior TB treatment.
• Physical examination for pulmonary and extrapulmonary signs.
• Baseline labs: CBC, LFTs, HIV testing, glucose, and others as indicated.

Immunologic Tests for Infection

• Tuberculin Skin Test (TST): Intradermal purified protein derivative (PPD) with induration measured at 48–72 hours; interpretation depends on risk category (e.g., ≥5 mm, ≥10 mm, ≥15 mm thresholds).
• Interferon-γ Release Assays (IGRAs): Measure T-cell IFN-γ release in response to TB-specific antigens; not affected by most BCG vaccination, useful in high-risk adults, healthcare workers, and BCG-vaccinated individuals.
• Positive TST/IGRA indicates infection (latent or active), not disease. Active TB requires further evaluation.

Microbiologic Diagnosis

• Sputum examination:
  • Collect at least 2–3 sputum specimens (including early-morning) for acid-fast bacilli (AFB) smear and culture.
  • AFB smear: Rapid but less sensitive; positive smears correlate with infectiousness.
  • Mycobacterial culture: Gold standard; allows species identification and phenotypic drug susceptibility testing. Time to positivity typically 1–6 weeks depending on media.
• Nucleic acid amplification tests (NAATs):
  • Detect M. tuberculosis DNA and common resistance mutations (e.g., rifampicin) directly from sputum within hours.
  • Recommended for rapid confirmation of TB and early detection of drug resistance.
• Extrapulmonary samples: Pleural fluid, CSF, lymph node aspirates/biopsies, bone marrow, urine, etc., for AFB smear, culture, and NAAT as appropriate.

Imaging

• Chest radiograph:
  • Primary TB: Hilar/mediastinal lymphadenopathy, middle/lower lobe consolidation, pleural effusion.
  • Reactivation TB: Apical/posterior upper lobe infiltrates, cavitation, fibrosis; cavitary lesions are classically associated with high bacillary burden.
  • Miliary TB: Diffuse, tiny (1–3 mm) nodules throughout both lungs.
• CT chest: More sensitive for cavitation, bronchiectasis, small nodules, and pleural disease; helpful in complex or atypical cases, and in post-TB structural lung disease, such as post-TB bronchiectasis.^[3]

Histopathology

• Biopsy of lymph node, lung, pleura, or other sites may show caseating granulomas with epithelioid histiocytes and Langhans giant cells.
• AFB staining demonstrates mycobacteria but may be negative even in TB; culture and NAAT complement histology.

Advanced and Research Diagnostics (for context)

• Whole-genome sequencing: Emerging methods allow direct sequencing of M. tuberculosis from clinical specimens without culture, improving speed of drug resistance detection and epidemiologic tracking.^[5]
• Biomarkers: Plasma proteomic signatures related to coagulation and actin pathways show promise in predicting progression from latent infection to active TB, though currently mainly research tools.^[6]

Management

TB management aims to cure the individual, prevent transmission, and minimize drug resistance. Regimens and durations are often guided by national and WHO recommendations.

General Principles

• Use multiple drugs to prevent resistance.
• Ensure adequate duration of therapy.
• Promote adherence, often using directly observed therapy (DOT) or similar adherence-support strategies.
• Screen for and manage comorbidities (HIV, diabetes, malnutrition, substance use).

Treatment of Drug-Susceptible Pulmonary TB (Adults)

The classic “RIPE” regimen is used for drug-susceptible TB:

• Intensive phase (2 months):
  • Rifampicin (R)
  • Isoniazid (H) + pyridoxine (vitamin B6)
  • Pyrazinamide (Z)
  • Ethambutol (E)
• Continuation phase (usually 4 months):
  • Rifampicin + isoniazid

Total standard duration is typically 6 months for uncomplicated, smear-positive pulmonary TB, though longer durations may be required for extensive disease, slow response, or certain extrapulmonary sites (e.g., bone, CNS).

First-Line Drug Mechanisms and Key Adverse Effects

• Isoniazid (H): Inhibits mycolic acid synthesis.
  • Adverse effects: Hepatotoxicity, peripheral neuropathy (prevent with pyridoxine), rare lupus-like syndrome.
• Rifampicin (R): Inhibits DNA-dependent RNA polymerase.
  • Adverse effects: Hepatotoxicity, orange discoloration of body fluids, numerous drug–drug interactions (CYP450 inducer).
• Pyrazinamide (Z): Disrupts mycobacterial membrane energetics and transport.
  • Adverse effects: Hepatotoxicity, hyperuricemia, arthralgias.
• Ethambutol (E): Inhibits arabinosyl transferase, impairing cell wall synthesis.
  • Adverse effects: Optic neuritis (red–green color blindness), require visual acuity/color vision monitoring.

Drug-Resistant TB

• Multidrug-resistant TB (MDR-TB): Resistance to at least isoniazid and rifampicin.
• Extensively drug-resistant TB (XDR-TB): MDR plus additional resistance to fluoroquinolones and key second-line agents.
• Management requires individualized regimens using second-line agents (e.g., fluoroquinolones, bedaquiline, linezolid, clofazimine, others), often for 9–18 months or longer, guided by drug susceptibility testing and specialized protocols.
• New compounds and combinations are under investigation to optimize pharmacokinetics and drug–drug interactions in TB therapy, including agents evaluated alongside clofazimine and clarithromycin for synergistic activity.^[7]

Extrapulmonary TB

• Most forms use similar regimens as pulmonary TB, often with extended durations.
• TB meningitis and CNS TB: Longer treatment (9–12 months), early initiation, and adjunctive corticosteroids to reduce inflammation and neurologic complications.
• Bone and joint TB: Prolonged therapy (often 9–12 months); surgical intervention may be necessary in cases of spinal instability or neurologic compromise.

Latent TB Infection (LTBI) Treatment

• Goal is to prevent progression from infection to active disease, particularly in high-risk individuals.
• Common regimens (examples; exact choice may vary by guidelines):
  • Isoniazid daily for 6–9 months; or
  • Rifampicin daily for 4 months; or
  • Once weekly isoniazid plus rifapentine for 3 months (3HP), where available.
• Screen for active disease before initiating LTBI therapy to avoid monotherapy in active TB.

Supportive and Public Health Measures

• Education on adherence, potential side effects, and infection control measures (respiratory hygiene, ventilation).
• Contact tracing and evaluation of household and close contacts, particularly in outbreaks such as those seen in boarding schools.^[2]
• Addressing delays in care-seeking through student and community education, especially in high-risk environments like universities and boarding schools.^[1]
• Vaccination with BCG in high-burden countries to reduce severe childhood TB manifestations (e.g., miliary TB, TB meningitis).

Key Clinical Pearls for Exams and Practice

• Airborne disease: TB is transmitted via airborne droplet nuclei; prolonged close contact is usually required. Always think of TB in chronic cough with systemic symptoms.
• Latent vs active: Positive TST/IGRA indicates infection, not necessarily active disease. Always rule out active TB before treating LTBI.
• Upper lobe predilection: Reactivation TB most commonly involves apical/posterior segments of upper lobes due to higher oxygen tension.
• Caseating granulomas: Histologic hallmark of TB but not entirely specific; correlate with microbiology.
• Drug toxicity monitoring: Monitor liver function for isoniazid, rifampicin, and pyrazinamide; monitor visual acuity for ethambutol.
• Post-TB lung disease: Even after microbiologic cure, patients may develop or retain structural lung damage such as post-TB bronchiectasis, which increases risk of recurrent infections and exacerbations.^[3]
• Outbreak settings: TB clusters occur in high-density institutions (boarding schools, prisons, dormitories); early detection, rapid isolation, and thorough contact investigation are critical.^[2]
• Advanced diagnostics: NAATs and, increasingly, culture-free whole-genome sequencing can accelerate diagnosis and resistance profiling, especially valuable in high-burden and resource-limited settings.^[5]
• Preventive strategy: Reducing diagnostic and treatment delays, combined with LTBI treatment in high-risk groups, is essential to curb TB incidence and transmission.^[1]

Quick Exam-Oriented Summary

• Bug: Mycobacterium tuberculosis, acid-fast, obligate aerobe.
• Classic triad (pulmonary TB): Prolonged cough, night sweats, weight loss.
• Radiology: Reactivation TB = upper lobe cavitary lesions; primary TB = Ghon focus + hilar nodes.
• Gold standard: Culture; NAATs for rapid confirmation and rifampicin resistance.
• Standard regimen: 2 months RIPE + 4 months RI (6 months total) for drug-susceptible pulmonary TB (unless otherwise indicated).
• Public health: Contact tracing, LTBI treatment, and reducing delays in diagnosis are central to TB control.