---

Tuberculosis - Complete Study Guide

---

1. Causative Agent and Transmission

Causative Agent

• Weakly Gram-positive, strongly acid-fast (Ziehl-Neelsen stain: red bacilli on blue background) rod-shaped bacterium
• Obligate aerobe, slow-growing (doubling time 15-20 hours; visible colonies in 3-8 weeks on solid media)
• Lipid-rich cell wall (mycolic acids, arabinogalactan, peptidoglycan) - responsible for acid-fastness, resistance to desiccation, disinfectants, and host immune responses
• Intracellular pathogen - survives and replicates within alveolar macrophages by preventing phagosome-lysosome fusion
• Humans are the only natural reservoir

Transmission

• Exclusively person-to-person via respiratory aerosols (droplet nuclei, 1-5 μm diameter)
• Generated by coughing, sneezing, speaking, or singing by a person with active pulmonary TB
• Droplet nuclei remain suspended in air for hours; very small inoculum required (1-10 bacilli)
• Risk factors for transmission: prolonged close contact, poorly ventilated enclosed spaces, high bacillary load in source patient (sputum smear-positive cases are most infectious)
• M. bovis can also be transmitted via unpasteurized milk (bovine TB) - causes extrapulmonary disease
• NOT transmitted by fomites, handshakes, or casual contact

1. Bacilli reach alveoli, phagocytized by alveolar macrophages
2. Primary complex (Ghon focus) forms in mid-lung + hilar lymphadenopathy
3. In 90-95% of immunocompetent people: infection is contained (latent TB infection, LTBI)
4. In 5-10%: primary progressive disease develops
5. Reactivation TB occurs in ~5% lifetime risk (much higher in HIV+, immunosuppressed, diabetes, malnutrition)

---

2. Global Epidemiology of Tuberculosis

Current Burden (WHO Global TB Report 2024)

Geographic Distribution

• 87% of new cases in 30 high-burden countries
• 8 countries account for >67% of global cases: India (25%), Indonesia (10%), Philippines (6.8%), China (6.5%), Pakistan (6.3%), Nigeria (4.8%), DRC (3.9%), Bangladesh (3.6%)
• By WHO region: South-East Asia (34%), Western Pacific (27%), Africa (25%)
• WHO End TB Strategy targets: 50% reduction in incidence and 75% reduction in deaths by 2025 vs. 2015 baseline - currently far off track (only 8.3% reduction in incidence achieved)

Key Epidemiological Indicators

---

3. Laboratory Diagnostics of Tuberculosis

A. Bacterioscopy (Microscopy)

• Smear of sputum stained with carbol-fuchsin + acid-alcohol decolorization + methylene blue counterstain
• AFB appear red on blue background
• Rapid, inexpensive, widely available
• Sensitivity: 40-60% for smear-positive pulmonary TB; requires ~5,000-10,000 bacilli/mL

• More sensitive than ZN (bacilli fluoresce yellow-orange on dark background)
• Preferred in high-volume labs; requires fluorescence microscope
• Sensitivity: ~10% higher than ZN

• 0: No AFB per 100 fields
• Scanty: 1-9 AFB per 100 fields (record exact number)
• 1+: 10-99 AFB per 100 fields
• 2+: 1-10 AFB per field in >50% of fields
• 3+: >10 AFB per field

B. Bacteriological (Culture)

• Culture allows drug susceptibility testing (DST) - mandatory for all confirmed TB cases
• Phenotypic DST: MIC determination, proportion method (Lowenstein-Jensen)
• Liquid culture systems (MGIT, BacT/ALERT): significantly faster, preferred

C. Molecular-Genetic Methods

• WHO-recommended first-line test for TB diagnosis
• Real-time PCR detecting M. tuberculosis DNA and rifampicin resistance (rpoB gene mutations)
• Results in 2 hours
• Sensitivity: 88% for smear-positive, 67% for smear-negative pulmonary TB
• Specificity: >98%
• Also detects resistance in extrapulmonary specimens

• Improved sensitivity over original Xpert (detects lower bacillary loads)
• Preferred for smear-negative, HIV+ patients, and extrapulmonary TB

• Detects resistance to isoniazid (katG, inhA), rifampicin (rpoB), fluoroquinolones, and injectable agents
• Used for rapid DST directly on smear-positive specimens or cultures
• Results in 5-6 hours

• Comprehensive resistance profiling and strain typing
• Used in reference labs; increasingly available
• Identifies all resistance mutations and epidemiological clusters

• Important where culture unavailable and microscopy inaccurate
• Confirms TB in smear-negative patients
• Does NOT replace culture for complete DST

• Tuberculin skin test (TST/Mantoux): intradermal PPD injection, read at 48-72h; induration ≥10mm (≥5mm in HIV+/immunosuppressed) = positive; indicates TB infection (latent or active)
• IGRA (Interferon-Gamma Release Assay - QuantiFERON-TB Gold, T-SPOT.TB): measures IFN-γ release from sensitized T-cells; more specific than TST (no cross-reaction with BCG); preferred in BCG-vaccinated populations and for LTBI diagnosis

---

4. Methods for Timely Detection of Tuberculosis

Passive Case-Finding

• Patient presents with symptoms (cough >2-3 weeks, hemoptysis, weight loss, night sweats, fever)
• Basic workup: sputum smear microscopy + chest X-ray + Xpert MTB/RIF
• Most common but results in delayed diagnosis

Active Case-Finding (ACF)

• Systematic screening of high-risk groups (HIV+, contacts of TB cases, prisoners, healthcare workers, homeless)
• Door-to-door surveys in high-prevalence communities
• Mass radiological screening (fluorography/miniature chest X-ray) - used historically and still in some countries
• Digital chest X-ray with AI interpretation - increasingly used for community screening
• Symptom screening (cough, fever, weight loss, night sweats - any one = refer for testing)

Contact Investigation

• All household and close contacts of smear-positive TB cases must be investigated
• Chest X-ray + TST/IGRA + symptom assessment
• If active TB excluded but LTBI confirmed → preventive therapy

Child TB Detection

• Children rarely sputum smear-positive; use gastric aspirate, nasopharyngeal aspirate, stool Xpert MTB/RIF
• Tuberculin test, clinical score (Stegen-Toledo criteria)
• History of contact with index case is critical

Screening Tools Summary

---

5. Prevention of Tuberculosis

Vaccination

• Live attenuated M. bovis; given at birth or in early infancy
• Highly effective against severe childhood TB (miliary TB, TB meningitis): 70-80% protection
• Less effective against adult pulmonary TB (variable: 0-80% in different studies)
• Part of EPI (Expanded Programme on Immunization) in all high-burden countries
• Does NOT prevent TB infection; prevents dissemination in children
• Contraindicated in HIV+ infants with symptoms, immunosuppressed patients

Treatment of Latent TB Infection (LTBI)

• Indicated for: HIV+, close contacts of smear-positive TB, TST/IGRA converters, before anti-TNF therapy, dialysis patients, solid organ transplant recipients
• Regimens:
  • Isoniazid (INH) 6 months (6H) - standard
  • INH 9 months (9H) - preferred in HIV+
  • INH + Rifapentine weekly x 3 months (3HP) - highly effective, shorter
  • Rifampicin 4 months (4R) - alternative, good tolerability
• Must rule out active TB before starting (clinical + CXR + sputum if needed)

Infection Control (IPC)

• Administrative controls: rapid identification and isolation of infectious TB patients; reduce time to diagnosis
• Environmental controls: natural ventilation (keep windows open), negative-pressure isolation rooms, upper-room UVGI (ultraviolet germicidal irradiation)
• Respiratory protection: N95 respirators for healthcare workers entering isolation rooms

Social and Public Health Measures

• Directly Observed Therapy Short-course (DOTS) strategy
• Contact tracing and treatment of LTBI in contacts
• Social support programs (nutritional supplements, economic support) - address risk factors
• HIV treatment with antiretrovirals reduces TB incidence
• Improved housing, reduction of overcrowding
• Diabetes control reduces risk
• Smoking cessation

---

6. Miliary and Disseminated Pulmonary Tuberculosis

Pathogenesis

Clinical Features

• Acute: high fever, night sweats, weight loss, progressive dyspnea
• Can be subacute or chronic - insidious onset, often missed
• Multi-organ involvement: lung (primary), liver, spleen, bone marrow, meninges, adrenals, kidneys
• Choroidal tubercles on fundoscopy (pathognomonic when present - ~13%)
• Pancytopenia, elevated LFTs, hyponatremia (SIADH or adrenal insufficiency)
• Can present with TB meningitis concurrently (most serious complication)
• High-risk groups: HIV+, infants, malnourished, immunosuppressed

Chest X-Ray / CT Findings

• Classic CXR: diffuse bilateral micronodular pattern (1-3 mm nodules), "snowstorm" appearance, evenly distributed through both lungs
• CT: better detection of nodules; "tree-in-bud" pattern may coexist
• Can be normal initially in immunocompromised
• Nodules may coalesce over time

Diagnosis

• Sputum smear/culture: often negative (hematogenous spread, not airway disease)
• Bronchoalveolar lavage with culture - more sensitive
• Bone marrow biopsy: granulomas in ~50%
• Liver biopsy: granulomas
• Blood cultures (BACTEC): positive in ~30-40% of HIV+ patients
• Xpert MTB/RIF on BAL or bone marrow
• TST may be falsely negative (anergy in severe disease)
• IGRA: can be negative in immunocompromised

Differential Diagnosis

---

7. Infiltrative Pulmonary Tuberculosis

Definition and Pathogenesis

Clinical Features

• Onset: insidious (weeks to months) - subacute presentation is typical
• Symptoms: low-grade fever (afternoon peaks), night sweats, fatigue, anorexia, weight loss, productive cough, hemoptysis
• Physical exam: dullness to percussion, decreased breath sounds, moist rales over affected area (most common: upper lobes, S1, S2, S6 - posterior segments)
• Can be asymptomatic (detected on routine X-ray / fluorography)

Radiological Forms (Classification by X-ray appearance)

1. Cloudy (cloud-like) - ill-defined opacity, poorly circumscribed
2. Rounded (round) - round or oval shadow up to 3 cm (pre-tuberculoma stage)
3. Lobular - irregular lobular consolidation
4. Segmental/lobar - involves an entire segment or lobe (caseous pneumonia)
5. Periscissurite - along the interlobar fissure
6. Caseous pneumonia - extensive consolidation with multiple cavities; severe, rapid course (historically "galloping consumption")

CXR/CT Features

• Upper lobe predominance (apical-posterior segments of upper lobes, superior segment of lower lobes)
• Heterogeneous opacity with ill-defined margins
• Satellite lesions (bronchogenic spread)
• Cavitation - indicates active disease and high infectiousness
• "Confluent bronchopneumonic foci"

Differential Diagnosis

---

8. Pulmonary Tuberculoma

Definition

Pathological Features

• Concentrically layered fibrous capsule
• Central caseous (cheese-like) necrosis
• Lymphocytic infiltration at periphery
• Mycobacteria may remain viable for decades (reservoir for reactivation)
• "Daughter lesions" (satellite nodules around main lesion) are characteristic

Clinical Features

• Usually asymptomatic - incidental finding on CXR
• Occasionally: mild cough, low-grade fever
• Sputum: often AFB-negative (intact capsule; no airway communication)
• IGRA/TST: typically positive

Radiological Features (CXR/CT)

• Round or oval, well-defined, smooth margins
• Upper lobe predominance (S1, S2)
• Calcification (central, stippled, or concentric/"target" pattern) - highly characteristic
• Satellite lesions (small nodules nearby) - strongly suggest TB
• Size stable or slowly changing over years
• CT shows: dense calcification, fibrous cap, satellite lesions, absence of spiculation (vs. carcinoma)

Differential Diagnosis

---

9. Fibro-Cavernous Pulmonary Tuberculosis

Definition and Pathogenesis

Pathological Changes

• Thick-walled fibrous cavities (cavity wall >3 mm; often 5-10+ mm)
• Surrounding extensive lung fibrosis, pleuritis, emphysema
• Bronchial deformation and bronchiectasis
• Contralateral bronchogenic spread (aspiration of cavity contents during cough)
• Lung volume loss with compensatory hyperinflation
• Frequent bacillary discharge - these patients are highly infectious

Clinical Features

• Long history of TB (years to decades)
• Chronic productive cough with mucopurulent sputum
• Recurrent hemoptysis (can be massive from Rasmussen aneurysm - erosion of pulmonary artery into cavity)
• Progressive dyspnea (restrictive + obstructive pattern)
• Cor pulmonale (right heart failure from chronic hypoxia and pulmonary hypertension)
• Severe weight loss, cachexia
• Signs: barrel chest deformity, tracheal deviation, absent breath sounds, amphoric breathing over large cavities
• Drug resistance common (prolonged inadequate treatment)

Radiological Features

• Upper lobe fibrous-cavitary lesions with dense fibrous walls
• Lung destruction, volume loss, tracheal/mediastinal shift toward affected side
• Contralateral nodular (endobronchial) spread
• Pleural thickening, calcified pleura
• Emphysematous changes in lower lobes
• CXR: "destroyed lung" appearance in severe cases

Differential Diagnosis

---

10. Tuberculous Pleurisy

Pathogenesis

1. Rupture of a subpleural focus into the pleural space (most common - type IV hypersensitivity reaction to mycobacterial antigens)
2. Hematogenous seeding of the pleura
3. Lymphatic spread from mediastinal nodes
4. Direct extension from parenchymal TB

Clinical Features

• Acute presentation: pleuritic chest pain, dry cough, fever
• Dyspnea proportional to effusion size
• Constitutional symptoms (fever, night sweats, weight loss) - especially if associated parenchymal TB
• On exam: dullness to percussion, absent breath sounds, egophony at upper effusion border
• Effusion usually unilateral (bilateral in HIV+ or miliary TB)
• Can resolve spontaneously but often leaves residual pleural thickening

Pleural Fluid Characteristics (Exudate - Light's criteria)

Diagnosis

• ADA level is the most useful initial test; >40 U/L in lymphocyte-predominant exudate = TB until proven otherwise
• Pleural biopsy (Abrams needle or VATS): granulomas in 60-90%, culture positive in up to 80%
• Xpert MTB/RIF on pleural fluid: low sensitivity (~20%) but high specificity
• TST/IGRA: usually positive
• IFN-γ in pleural fluid: highly sensitive and specific

Differential Diagnosis

---

11. Pulmonary Hemoptysis and Bleeding in TB

Causes of Hemoptysis in TB

1. Cavitary TB - erosion of vessel in cavity wall; most common cause
2. Rasmussen aneurysm - aneurysmal dilation of pulmonary artery branch within/adjacent to cavity wall; can cause massive hemoptysis (life-threatening)
3. Bronchiectasis - associated with destroyed lung in FCTB
4. Aspergilloma (mycetoma) in old TB cavity - fungal ball erodes vessels; responsible for ~50% of massive hemoptysis in high-TB regions
5. Endobronchial TB - mucosal ulceration
6. Caseous granulation tissue eroding vessels
7. Concurrent lung cancer arising in areas of scar TB
8. Coagulopathy in advanced disease

Classification

• Mild/minor hemoptysis: <100 mL/24h; blood-streaked sputum; not immediately life-threatening
• Moderate: 100-300 mL/24h
• Massive/life-threatening: >300 mL/24h (or >150 mL in single episode); risk of asphyxiation

Diagnosis

• Careful history (distinguish from hematemesis and nasopharyngeal bleeding)
• CXR/CT: identify source (cavity, aspergilloma, bronchiectasis)
• CT angiography: gold standard for identifying bleeding vessel (bronchial artery anatomy)
• Flexible bronchoscopy: localizes bleeding to segment; allows direct visualization
• Coagulation studies, CBC, blood group/crossmatch

Treatment

• Bed rest, supine or affected-side-down position (prevents contralateral flooding)
• Antitussive agents (codeine) to reduce cough
• Hemostatic agents (tranexamic acid, etamsylate)
• Continue anti-TB treatment

• Maintain airway, oxygen supplementation
• IV access, blood transfusion if needed
• Position: affected side down (aspiration protection)
• Tranexamic acid (1g IV)
• Vasopressin (terlipressin) - reduces pulmonary circulation pressure

• Immediate ICU/bronchoscopy suite
• Intubation with large-bore ETT (consider selective intubation of unaffected lung)
• Bronchial artery embolization (BAE) - first-line interventional procedure; high success rate (~80-90%)
• Rigid bronchoscopy for direct tamponade, coagulation, balloon occlusion
• Surgical resection (lobectomy/pneumonectomy) - when BAE fails or unavailable; higher mortality
• Treat underlying cause (anti-TB drugs, antifungals for aspergilloma)

---

12. Spontaneous Pneumothorax as a Complication of TB

Mechanism

• Rupture of a subpleural cavity or emphysematous bulla into the pleural space
• Rupture of caseous focus with bronchopleural fistula formation
• Can complicate any active TB form but most common in fibro-cavernous TB
• Pyopneumothorax: simultaneous pus + air in pleural space (ruptured TB cavity into pleural space)
• Risk: young patients with primary progressive TB, FCTB, miliary TB

Clinical Features

• Sudden onset pleuritic chest pain
• Dyspnea (degree depends on lung reserve and pneumothorax size)
• Tachycardia
• Tension pneumothorax: tracheal deviation away from affected side, JVD, hypotension, absent breath sounds - life-threatening emergency
• In TB patients: often presents on background of chronic respiratory symptoms

Diagnosis

• CXR (upright expiratory film): visceral pleural line, lung collapse, mediastinal shift (tension)
• CT chest: more accurate for small pneumothorax; identifies underlying TB pathology
• Point-of-care ultrasound (POCUS): absence of lung sliding = pneumothorax

Treatment

• Observation + supplemental O₂ (accelerates reabsorption 4x)
• Serial CXR every 4-6 hours

• Needle aspiration (2nd intercostal space, midclavicular line) - first step for simple pneumothorax
• Intercostal chest drain (tube thoracostomy) - 4th-5th ICS, midaxillary line; underwater seal drainage
• Continue anti-TB treatment

• Immediate needle decompression (2nd ICS, MCL, 14-16G needle) - before CXR
• Followed by chest tube insertion

• Pleurodesis (chemical - talc, tetracycline; or surgical)
• VATS/thoracoscopy for persistent air leak (bronchopleural fistula)
• Surgical management: resection of bullae/cavity

• Chest drain + IV antibiotics + anti-TB treatment
• Often requires decortication (surgical)

---

13. Tuberculosis in Combination with HIV Infection

Epidemiology

• People with HIV are 12 times more likely to develop active TB than HIV-negative individuals
• TB is the leading cause of death in people with HIV worldwide
• In 2024: ~150,000 HIV-associated TB deaths
• Risk proportional to degree of immunosuppression (CD4 count)
• HIV + TB form a "lethal combination": TB accelerates HIV progression; HIV accelerates TB progression

Clinical Features and Course Differences

Diagnosis

• Sputum Xpert MTB/RIF (preferred over smear alone)
• BAL if sputum negative
• Blood cultures (mycobacterial) - valuable in low CD4 (<100)
• LPA for rapid DST
• TST/IGRA may be falsely negative - do NOT rule out TB if negative in HIV+
• Rule out other OIs (PCP, cryptococcosis, histoplasmosis)

Treatment

1. When to start ART:
   • CD4 <50 cells/μL: start ART within 2 weeks of TB treatment
   • CD4 50-200: start ART within 2-4 weeks
   • CD4 >200: start ART within 8 weeks (or earlier for severe disease)
2. Drug interactions:
   • Rifampicin is a potent inducer of CYP450 enzymes - reduces levels of most PIs and NNRTIs
   • Efavirenz (NNRTI) is the preferred ARV in TB/HIV (with dose adjustment if needed)
   • Avoid rifampicin with most PI-based regimens; use rifabutin as substitute if PI-based ART required
3. Immune Reconstitution Inflammatory Syndrome (IRIS):
   • Paradoxical worsening after ART initiation (especially if CD4 very low)
   • "Unmasking IRIS" or "paradoxical IRIS"
   • Managed with continued ART + TB treatment + corticosteroids if severe
   • Must distinguish from TB treatment failure or new OI
4. TB-IRIS prophylaxis: Consider early corticosteroids in patients at high risk for IRIS (CD4 <100, started ART within 30 days of TB treatment)
5. Preventive therapy: All HIV+ individuals with LTBI (or unknown exposure in high-burden settings) should receive TB preventive therapy (TPT) after active TB excluded

---

14. Tuberculosis, Pregnancy, and Motherhood

Effect of TB on Pregnancy

• Active TB in pregnancy is associated with: preterm birth, low birth weight, intrauterine growth restriction, increased perinatal mortality
• Risk of congenital TB (placental/hematogenous transmission): rare but reported
• Vertical transmission risk increases with disseminated/miliary TB or TB bacteremia

Effect of Pregnancy on TB

• Immunity in pregnancy is T-cell suppressed (Th2 shift) - may facilitate TB reactivation
• TB diagnosis is often delayed (symptoms attributed to pregnancy)
• CXR is avoided (concerns about radiation); delays diagnosis
• Postpartum period: increased risk of reactivation

Diagnosis in Pregnancy

• TST (Mantoux): safe in pregnancy - no teratogenic risk
• IGRA: safe; increasingly preferred
• CXR with abdominal shielding: safe when clinically necessary (fetal dose minimal at standard CXR)
• Xpert MTB/RIF on sputum: safe

Treatment in Pregnancy

Breastfeeding

• Anti-TB drugs are safe during breastfeeding (small amounts in breast milk, not harmful to infant)
• Mother on treatment should breastfeed (benefits outweigh risks)
• Infant should be screened for TB and given INH preventive therapy if mother is sputum-positive (then BCG after preventive therapy course)
• Mother with active sputum-positive TB: physical separation from newborn only if smear-positive; wear mask when handling infant

BCG for Newborn of TB Mother

• If mother is on treatment and infant is healthy: give BCG at birth (standard EPI)
• If mother has MDR-TB: consult specialist; INH preventive therapy less effective

---

15. General Principles of Treatment of Tuberculosis

Goals of Treatment

1. Cure the patient (achieve bacteriological cure)
2. Prevent death from active TB or its late effects
3. Prevent relapse
4. Prevent development of drug resistance
5. Reduce transmission to others

First-Line Anti-TB Drugs

Standard Regimen for Drug-Sensitive TB (DS-TB)

• Total: 2HRZE / 4HR
• Drug doses: INH 5 mg/kg, RIF 10 mg/kg, PZA 25 mg/kg, EMB 15-20 mg/kg (all once daily)
• Directly Observed Therapy (DOT): recommended to ensure adherence; cornerstone of DOTS strategy
• Fixed-dose combinations (FDC): simplify regimens, prevent selective non-adherence

Monitoring During Treatment

• Sputum smear/culture at 2 months (end of intensive phase): should be negative
• If positive at 2 months: extend intensive phase or suspect resistance (order DST)
• LFTs at baseline and as needed (hepatotoxicity monitoring)
• Visual acuity/color vision: baseline, monthly if on ethambutol
• CXR at baseline and end of treatment

Drug-Resistant TB (DR-TB)

• Mono-resistance: resistance to one drug
• Poly-resistance: resistance to >1 drug (not MDR)
• MDR-TB (Multi-Drug Resistant): resistance to at least INH + Rifampicin
• Pre-XDR-TB: MDR-TB + resistance to any fluoroquinolone
• XDR-TB (Extensively Drug Resistant): MDR-TB + resistance to fluoroquinolones + at least one of bedaquiline or linezolid

• Bedaquiline + Pretomanid + Linezolid (BPaL) - 6 months (6 BPaL)
• Bedaquiline + Pretomanid + Linezolid + Moxifloxacin (BPaLM) - 6 months if moxifloxacin-susceptible
• Older regimens (18-20 months) largely replaced by these shorter effective regimens
• Clofazimine, cycloserine, delamanid used in specific situations

Response to Treatment

• Clinical improvement expected within 2-4 weeks (fever resolution, weight gain)
• Sputum conversion to negative by 2 months in ~80% of DS-TB
• Residual radiological changes may persist even after cure (scarring, calcification)
• Relapse (<5% with standard regimen in drug-sensitive TB)
• Treatment failure defined as positive cultures at 5 months or later

Adjunctive Therapies

• Corticosteroids (prednisolone/dexamethasone): indicated for TB meningitis (grade A evidence - reduces mortality and neurological sequelae), TB pericarditis (reduces constrictive pericarditis risk), severe IRIS
• Pyridoxine (B6) 25-50 mg/day: with INH to prevent peripheral neuropathy (mandatory in pregnancy, diabetes, malnutrition, HIV)
• Nutritional support

---

Summary Table: Differential Diagnosis Quick Reference

---