Tuberculosis: Complete Review

Overview and Epidemiology

1. Lymphatic
2. Pleural
3. Skeletal
4. Genitourinary
5. Gastrointestinal (next most common)
6. CNS (~5% of EPTB in the US)

I. PULMONARY TUBERCULOSIS

Pathogenesis and Disease Spectrum

• Bacterial elimination (no disease)
• Latent TB infection (TST/IGRA positive, asymptomatic, culture negative)
• Subclinical disease
• Progressive primary disease (within 1 year of infection)
• Reactivation (post-primary disease, distant from initial infection)

Clinical Features

• Most common symptom: Persistent cough (productive or nonproductive) - up to 25% of culture-confirmed cases do not report cough
• Constitutional symptoms: Fever, chills, night sweats, weight loss
• Hemoptysis - occurs in advanced disease
• Physical exam: Post-tussive rales in upper lung zones; amphoric breath sounds indicate a cavity; lymphadenopathy uncommon in immunocompetent adults

Chest Radiology

• Primary TB: Parenchymal consolidation, hilar/paratracheal lymphadenopathy, pleural effusion
• Post-primary/Reactivation: Upper lobe predominance, cavitation, fibrosis, volume loss
• Miliary TB: Diffuse 1-2 mm nodules throughout both lung fields

TB Pleuritis

• Pleural fluid is exudative, predominantly lymphocytic
• Fulminant TB empyema is much rarer
• 10% of patients develop restrictive spirometric defects after a median of 23 months
• Cochrane evidence shows oral corticosteroids may improve radiographic appearances of residual pleural changes but do not improve long-term respiratory function and are associated with more adverse events

II. ABDOMINAL TUBERCULOSIS

A. Gastrointestinal (Intestinal) Tuberculosis

• 3.5% of extrapulmonary cases in the US
• Ileocecal region: most common site (64% of GI TB cases), followed by jejunum and colon
• Only 15-25% of GI TB cases have concomitant pulmonary TB
• M. bovis from unpasteurized dairy products is an additional cause in developing countries

1. Swallowing of infected sputum (direct seeding)
2. Hematogenous spread
3. Lymphatic spread
4. Direct spread from adjacent structures (lymph nodes, fallopian tubes)

• Abdominal pain and GI obstruction (most common presentation)
• Fever, nausea, diarrhea, weight loss
• Gastrointestinal bleeding
• Palpable mass in ileocecal region
• Can mimic Crohn disease, acute appendicitis, or carcinoma

• Crohn's disease (key mimic - granulomas are noncaseating, <400 μm, poorly organized)
• Appendicitis, malignancies (lymphoma, carcinoma)
• Sarcoidosis, amyloidosis
• NSAIDs-related enteropathy
• Infectious: Salmonellosis, Yersiniosis, Cytomegalovirus, Histoplasmosis, MAC enteritis
• Actinomycosis, Anisakiasis, Typhlitis, Eosinophilic enteritis, Vasculitides, Ischemia

• AFB smear/culture of tissue (gold standard but positive in <40% of cases with ZN staining positive in only ~3%)
• Endoscopic biopsy showing caseating granulomas
• PCR/Xpert MTB-RIF assay (sensitivity 50-100%, specificity 62-97% - further validation needed)
• CD4+ T-cell activation markers (CD38, HLA-DR, Ki67+) are being studied as differentiating tools

B. Peritoneal Tuberculosis

• Subacute abdominal pain, anorexia, abdominal swelling
• Systemic symptoms: fever, night sweats, weight loss
• Can mimic acute abdomen
• Often underlies liver disease (cirrhosis) - may obscure TB symptoms
• Intra-abdominal lymphadenopathy on CT
• Active pulmonary TB is uncommon in patients with TB peritonitis
• Fever + abdominal tenderness in a person with ascites should always prompt paracentesis

• Laparoscopy with biopsy = best diagnostic test (characteristic findings + histology + culture)
• ADA in ascitic fluid: sensitivity 100%, specificity 97% at cut-off 39 IU/L (meta-analysis of 12 studies)
• In cirrhotic patients, ADA may be less sensitive (but not confirmed by systematic reviews)
• Paracentesis mandatory whenever TB peritonitis is suspected

III. TUBERCULOUS MENINGITIS (TBM)

Pathogenesis

1. Hematogenous seeding of meninges and subpial regions → formation of tubercles
2. Rupture of one or more tubercles → discharge of bacteria into the subarachnoid space

Pathological Findings

• Small, discrete white tubercles scattered over the base of the cerebral hemispheres (and lesser degree on convexities)
• Thick, gelatinous exudate accumulates in basal meninges - obliterating the pontine and interpeduncular cisterns, extending to the floor of the 3rd ventricle, optic chiasm, and undersurfaces of temporal lobes
• Microscopically: central zone of caseation surrounded by epithelioid cells, giant cells, lymphocytes, plasma cells
• Cranial nerves frequently involved as they traverse the subarachnoid space
• Arteries become inflamed and occluded → brain infarction
• Blockage of basal cisterns → obstructive hydrocephalus
• Process is a true meningoencephalitis (penetrates pia and ependymia into brain parenchyma)

MRI in Tuberculous Meningitis

Clinical Features

• Low-grade fever, malaise, headache (>50% of cases), lethargy, confusion
• Stiff neck (75% of cases), Kernig and Brudzinski signs
• Symptom evolution over 1-2 weeks - much slower than bacterial meningitis

• Cranial nerve palsies - ocular palsies (most common), facial palsy, deafness - in 20% at diagnosis
• Papilledema
• Diplopia (basilar exudate) - up to 70% of patients
• Focal neurologic deficit from hemorrhagic infarction
• Hypothermia and hyponatremia (SIADH is common)
• Lacunar infarcts / movement disorders (basal ganglia vessel involvement)
• Hemiparesis / hemiplegia (middle cerebral artery involvement)
• Ultimate evolution: coma, hydrocephalus, intracranial hypertension

CSF Findings

Neuroradiology (Classic Triad on CT/MRI)

1. Basal meningeal enhancement
2. Hydrocephalus
3. Cerebral or brainstem infarction

Tuberculoma

• Tumor-like masses of tuberculous granulation tissue, 2-12 mm
• Multiple or single, in brain parenchyma
• Can cause mass effect, periventricular obstructive hydrocephalus, seizures, focal signs
• CT/MRI: contrast-enhanced ring lesions
• In developing countries: 5-30% of all intracranial mass lesions
• CSF: small lymphocytosis, increased protein, glucose not reduced (serous meningitis pattern)
• Biopsy required for diagnosis; responds to anti-TB drugs

Tuberculous Serous Meningitis

IV. TREATMENT

Standard Anti-TB Regimen (All Forms)

Dosing (Adults)

TBM-Specific Treatment

• Same 4-drug regimen (HRZE) for first 2 months
• Total duration: 9-12 months
• Alternative: INH + PZA + high-dose rifampin + moxifloxacin
• Adjunctive dexamethasone (IV 0.4 mg/kg/day with tapering) reduces mortality from 41% to 32% (RCT, Thwaites et al, Vietnam) - WHO recommends dexamethasone or prednisolone tapered over 6-8 weeks
  • Note: A recent placebo-controlled study showed no benefit in PLWH (people living with HIV)
• For intracranial tuberculoma: same regimen; surgical excision if mass effect persists or if no radiological response
• For Pott disease with cord compression: surgical exploration + triple-drug therapy

GI TB Treatment

V. DIAGNOSIS SUMMARY

VI. OTHER EXTRAPULMONARY MANIFESTATIONS (Brief)

• Osteoarticular TB (Pott disease): Lower thoracic/upper lumbar vertebral involvement; starts in subchondral anterior vertebral body; involves two adjacent vertebrae + intervertebral disc; paravertebral abscesses; gibbus deformity; spinal cord compression
• Pericardial TB: Exudative pericardial effusion (serosanguineous); ADA sensitivity 87%, specificity 89%; chronic constrictive pericarditis in 30-60%
• Immunologic manifestations: Erythema nodosum, erythema induratum (tuberculids); Poncet disease (reactive arthritis + erythema nodosum); TB-IRIS (5-50% of patients starting ART)
• Genitourinary TB: Presents as sterile pyuria; dysuria, hematuria
• Lymphadenitis: Most common site of EPTB

• Goldman-Cecil Medicine, 26th ed. - Chapters 299 (Pulmonary TB, Intestinal TB, Peritoneal TB)
• Adams & Victor's Principles of Neurology, 12th ed. - Chapter 31 (Tuberculous Meningitis, Tuberculoma)
• Harrison's Principles of Internal Medicine, 22nd ed. (2025) - Extrapulmonary TB, TBM, CSF findings
• Murray & Nadel's Textbook of Respiratory Medicine - TB pleuritis, peritoneal TB, pericardial TB
• Yamada's Textbook of Gastroenterology, 7th ed. - GI TB epidemiology, differential diagnosis, treatment
• ROSEN's Emergency Medicine - CNS TB, GI disease clinical features

WHO TB Treatment Guidelines: 2025 Updates

PART 1: DRUG-SUSCEPTIBLE TB (DS-TB)

Standard Regimen (Still Valid)

NEW: 4-Month Regimen (2025 WHO + ATS/CDC/ERS/IDSA Update)

• Ethambutol replaced by Moxifloxacin (fluoroquinolone backbone)
• Rifampin replaced by Rifapentine (longer half-life, more potent rifamycin)
• Total duration: 4 months vs. 6 months

• Rifapentine: 1200 mg daily (7 days/week)
• Moxifloxacin: 400 mg daily

• Non-inferiority demonstrated vs. 2HRZE/4HR in adults and adolescents ≥12 years
• Cure rate 84.5%, retention 99.7%, all-cause mortality 0.4% at end of treatment
• Grade 3+ adverse events: 18.8% (4-month arm) vs. 19.3% (6-month arm) - similar safety

• Adults and adolescents ≥12 years
• Smear and culture-positive pulmonary DS-TB

• PLHIV with CD4 <100 cells/mm³ (6-month preferred)
• Children <12 years
• Pregnant, breastfeeding, or postpartum women
• Those who fail eligibility criteria for the pivotal trials

Note: A 2025 commentary in AJRCCM (Wilson et al., Mayo Clinic) urges caution in broad adoption of the 4-month regimen pending real-world evidence outside controlled trial settings.

PART 2: DRUG-RESISTANT TB (DR-TB) - 2025 WHO Guidelines

Definitions

Three Tiers of DR-TB Regimens (WHO 2025)

Tier 1 - Preferred: 6-Month All-Oral Regimens

BPaLM Evidence - TB-PRACTECAL Trial (Lancet Respir Med, 2024, PMID 37980911)

• Unfavorable outcomes: BPaLM 12% vs. standard care 41% (risk difference -29.2%, p<0.0001)
• Grade 3+ or serious adverse events: 23% vs. 48% (risk difference -25.2%)
• Deaths: 0 in BPaLM vs. 5 in standard care group
• Conclusion: BPaLM is both more effective and safer than standard of care

BPaLM Systematic Review (Silva et al., J Bras Pneumol, 2025, PMID 39813501)

• BPaLM reduced risk of unfavorable composite outcome (NNT = 7)
• Reduced early treatment discontinuation (NNT = 8)
• Reduced serious adverse events (NNT = 5)
• Better safety profile than standard of care

Tier 2: 9-Month All-Oral Short Regimens

Tier 3 - Last Resort: 18-20 Month Individualized Regimens

Drug Key (Abbreviations)

Isoniazid-Resistant TB (Hr-TB)

PART 3: SPECIAL SITUATIONS

TB-HIV Coinfection

• Start ART in all TB patients regardless of CD4 count (expanded 2025 recommendation)
• Preferred DS-TB regimen in PLHIV with CD4 <100 cells/mm³: 6-month 2HRZE/4HR
• The 4-month rifapentine-moxifloxacin regimen has been studied in PLHIV but the 6-month regimen is still preferred at very low CD4 counts
• For TBM in PLHIV: a recent placebo-controlled trial showed no survival benefit from adjunctive dexamethasone (unlike non-HIV patients)
• TB-IRIS: Occurs in 5-50% starting ART; high morbidity when CNS involvement

TB in Pregnancy

• 4-month rifapentine-moxifloxacin regimen is NOT recommended (women excluded from S31/A5349 trial)
• Standard 6-month 2HRZE/4HR is used
• Avoid: Pyrazinamide in first trimester per some guidelines; streptomycin (ototoxic to fetus); fluoroquinolones (teratogenic concern)

TB Meningitis

• 4-drug regimen (HRZE) for 2 months, then HR to complete 9-12 months total
• Adjunctive dexamethasone IV (0.4 mg/kg/day tapering over 6-8 weeks) - WHO-recommended for non-HIV TBM patients; reduces mortality
• Drugs with best CNS penetration: INH > PZA > rifampin > ethambutol

PART 4: NEW WHO 2025 MODULE 6 - TB AND UNDERNUTRITION (October 2025)

• Nutritional assessment and counselling for ALL people with TB and their household contacts (formal recommendation for the first time)
• Nutritional interventions for TB patients with undernutrition regardless of age, drug resistance status, pregnancy, or severity
• Food assistance to prevent TB in household contacts in food-insecure settings (based on RATIONS trial)

REAL-WORLD ADOPTION (WHO Global TB Report 2025)

SUMMARY COMPARISON TABLE

• WHO Global TB Report 2025 - DR-TB Treatment
• TB-PRACTECAL trial (Lancet Respir Med, 2024) - PMID 37980911
• BPaLM systematic review (J Bras Pneumol, 2025) - PMID 39813501
• ATS/CDC/ERS/IDSA 2025 clinical practice update (February 2025) - endorsing 4-month DS-TB regimen for eligible patients
• WHO Module 6: TB and Undernutrition (October 2025)