Definition and epidemiology
Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis, a slow-growing, obligate aerobic, acid-fast bacillus. The infection exists in two forms: latent TB infection (LTBI), where organisms remain dormant without causing active disease, and active TB disease, characterized by symptomatic infection with bacterial replication and tissue damage.
TB remains a major global health problem, with an estimated 10 million new cases and 1.5 million deaths annually. Approximately 25% of the world's population has latent TB infection. Incidence is highest in Southeast Asia, Africa, and the Western Pacific regions. In high-income countries, TB disproportionately affects immigrants from endemic areas, homeless populations, prisoners, and immunocompromised individuals.
Pulmonary TB accounts for approximately 80% of cases in immunocompetent hosts. Extrapulmonary TB can affect any organ, with lymph nodes, pleura, genitourinary system, bones, joints, and meninges being the most common sites. Miliary TB represents hematogenous dissemination with multiorgan involvement.
- TB causes caseating granulomas; sarcoidosis causes non-caseating granulomas.
- Reactivation TB preferentially affects upper lobes (apical-posterior segments) due to high oxygen tension.
- Primary TB: Ghon focus + hilar lymph node = Ghon complex; calcified = Ranke complex.
- RIPE therapy for active TB: Rifampin, Isoniazid + pyridoxine, Pyrazinamide, Ethambutol for 2 months, then RIF + INH for 4 months.
- Sterile pyuria suggests genitourinary TB; perform AFB culture of early morning urine.
- TB meningitis: lymphocytic CSF with low glucose, high protein, basilar involvement, requires corticosteroids and 9-12 months treatment.
- Miliary TB shows diffuse 1-3 mm nodules on chest X-ray resembling millet seeds.
- GeneXpert MTB/RIF rapidly detects M. tuberculosis and rifampin resistance within hours.
Etiology and risk factors
Mycobacterium tuberculosis is transmitted via airborne droplet nuclei produced when individuals with active pulmonary or laryngeal TB cough, sneeze, speak, or sing. Particles less than 5 microns in diameter can remain suspended in air for hours and reach the alveoli when inhaled. TB is not transmitted through contact with surfaces, food, or casual contact.
Major risk factors for TB infection:
- Close contact with active TB cases (household members, healthcare workers)
- Immigration from or travel to high-prevalence countries
- Residence in congregate settings (prisons, homeless shelters, long-term care facilities)
- Healthcare workers, especially in high-burden settings
Risk factors for progression from latent to active TB:
- HIV infection (greatest risk factor, 20-30 times increased risk)
- Recent TB infection (within 2 years)
- Immunosuppressive medications (TNF-alpha inhibitors, corticosteroids, chemotherapy)
- Chronic kidney disease requiring dialysis
- Diabetes mellitus
- Malnutrition and vitamin D deficiency
- Substance abuse (alcohol, injection drug use)
- Silicosis
- Malignancies (especially hematologic)
- Post-transplant immunosuppression
- Extremes of age (children <5 years, elderly)
Only 5-10% of immunocompetent individuals with latent TB will develop active disease in their lifetime, with half progressing within the first 2 years after infection.
Pathophysiology
Following inhalation of droplet nuclei containing M. tuberculosis, bacilli reach the alveoli and are phagocytosed by alveolar macrophages. The bacteria can survive and replicate within macrophages by inhibiting phagosome-lysosome fusion. This initial infection, typically asymptomatic, is called the primary infection or Ghon focus.
Within 2-8 weeks, cell-mediated immunity develops as CD4+ T cells recognize mycobacterial antigens and activate macrophages, leading to granuloma formation. The granuloma consists of a central core of infected macrophages and multinucleated giant cells surrounded by lymphocytes and fibroblasts. In most cases, the immune response contains but does not eliminate the infection, resulting in latent TB. The primary Ghon focus combined with hilar lymph node involvement forms the Ghon complex (Ranke complex when calcified).
Caseating granulomas are the pathologic hallmark of TB, characterized by central caseous (cheese-like) necrosis surrounded by epithelioid histiocytes, Langhans giant cells, and a lymphocytic rim. This differs from non-caseating granulomas seen in sarcoidosis.
Active TB disease occurs when host immunity fails to contain bacterial replication. This can happen during primary infection (progressive primary TB, more common in immunocompromised) or when latent infection reactivates (secondary/reactivation TB, typically in apical-posterior lung segments due to higher oxygen tension). Reactivation TB accounts for most adult cases in low-burden countries.
Miliary TB results from hematogenous dissemination, producing numerous small (millet seed-sized) granulomas throughout multiple organs, most visibly in lungs, liver, spleen, and bone marrow.
Clinical features
Pulmonary TB presents insidiously over weeks to months with:
- Chronic productive cough (>3 weeks) ± hemoptysis
- Fever (often low-grade, worse in evening)
- Night sweats (drenching, requiring clothing/sheet changes)
- Unintentional weight loss
- Malaise and fatigue
- Chest pain (suggests pleural involvement)
Hemoptysis can range from blood-streaked sputum to massive bleeding (Rasmussen aneurysm rupture). Physical examination may reveal post-tussive apical rales, but findings are often minimal despite extensive radiographic disease.
Extrapulmonary TB manifestations:
Tuberculous lymphadenitis
Most common form of extrapulmonary TB; presents as painless, progressive lymph node enlargement (cervical > mediastinal > axillary). Nodes may become fluctuant, drain spontaneously (scrofula), or form sinus tracts.
Pleural TB
Presents with pleuritic chest pain, dyspnea, and fever. Pleural effusion is typically unilateral and exudative with lymphocytic predominance.
TB meningitis
Subacute onset over 2-3 weeks with headache, fever, altered mental status, and meningismus. Basilar meningitis can cause cranial nerve palsies (CN VI most common). Complications include hydrocephalus, stroke, and tuberculomas.
Skeletal TB
Pott disease (spinal TB) presents with chronic back pain, vertebral collapse, kyphosis, and potential spinal cord compression. Peripheral arthritis most commonly affects weight-bearing joints (hip, knee).
Genitourinary TB
Chronic dysuria, hematuria, and flank pain. Sterile pyuria (white blood cells without bacterial growth on routine culture) is characteristic. Can cause infertility in both sexes.
Miliary TB
Presents with fever, weight loss, hepatosplenomegaly, and cytopenias. May have minimal respiratory symptoms despite diffuse lung involvement.
Pericardial TB
Presents as pericarditis or constrictive pericarditis with dyspnea, chest pain, and jugular venous distension.
Diagnosis
TB diagnosis requires high clinical suspicion combined with microbiological, radiologic, and/or histopathologic evidence.
Screening tests (detect TB infection, not active disease):
Tuberculin skin test (TST, Mantoux test): Intradermal injection of purified protein derivative (PPD). Read at 48-72 hours measuring induration (not erythema).
- ≥5 mm: HIV, recent TB contact, immunosuppressed, chest X-ray with TB findings
- ≥10 mm: immigrants from high-prevalence areas, high-risk congregate settings, healthcare workers, children <4 years
- ≥15 mm: persons with no known risk factors
Interferon-gamma release assays (IGRAs): Blood tests (QuantiFERON, T-SPOT) measuring T-cell response to TB antigens. More specific than TST (not affected by BCG vaccination), require single visit, but do not distinguish latent from active TB.
Diagnosis of active TB:
Microbiological confirmation (gold standard)
Sputum examination: Collect 3 samples (early morning preferred).
- Acid-fast bacilli (AFB) smear (Ziehl-Neelsen or auramine-rhodamine stain): rapid but low sensitivity (50-80%), cannot distinguish M. tuberculosis from non-tuberculous mycobacteria
- Culture (Lowenstein-Jensen or liquid media): gold standard, allows drug susceptibility testing, but slow (2-8 weeks)
- Nucleic acid amplification tests (NAAT, GeneXpert MTB/RIF): rapid molecular test detecting M. tuberculosis and rifampin resistance within hours, high sensitivity and specificity
Extrapulmonary samples: Tissue biopsy, pleural fluid, CSF, urine, depending on suspected site. CSF in TB meningitis shows lymphocytic pleocytosis, elevated protein, low glucose.
Radiologic findings
Primary TB: Hilar/mediastinal lymphadenopathy, Ghon complex, lower or middle lobe infiltrates, pleural effusion
Reactivation TB: Upper lobe (apical-posterior segments) infiltrates, cavitation (highly infectious), fibrosis, volume loss. Cavitary lesions strongly suggest active disease.
Miliary TB: Diffuse, bilateral, fine nodular (1-3 mm) infiltrates throughout both lungs
CT chest is more sensitive than plain radiographs for detecting small lesions, cavitation, and lymphadenopathy.
Histopathology
Caseating granulomas with acid-fast bacilli confirm TB. Biopsy with culture provides both histologic confirmation and organism isolation.
Differential diagnosis
For chronic cough and constitutional symptoms:
- Bacterial pneumonia: More acute onset, responds to typical antibiotics, different radiographic pattern
- Lung cancer: Weight loss, hemoptysis, but mass lesion on imaging, older age, smoking history
- Fungal infections (histoplasmosis, coccidioidomycosis, aspergillosis): Similar presentation, especially in endemic areas or immunocompromised; require fungal cultures
- Sarcoidosis: Non-caseating granulomas, bilateral hilar lymphadenopathy, negative AFB, elevated ACE levels
- Non-tuberculous mycobacterial infection: Acid-fast positive but culture distinguishes species; seen with underlying lung disease
- Lung abscess: Foul-smelling sputum, more acute presentation, air-fluid level on imaging
- Bronchiectasis: Chronic productive cough but different radiographic pattern (dilated airways)
For lymphadenopathy:
- Lymphoma (non-tender, rubbery nodes)
- Bacterial lymphadenitis (acute, tender)
- HIV-related lymphadenopathy (generalized)
- Cat-scratch disease (exposure history)
For meningitis:
- Bacterial meningitis (more acute, PMN predominance in CSF)
- Viral meningitis (more acute, normal glucose)
- Fungal meningitis (cryptococcal in HIV patients)
- Malignant meningitis (cancer history)
Management
TB management requires prolonged multidrug therapy to kill actively dividing bacilli, eliminate semi-dormant organisms, and prevent drug resistance. Treatment must be directly observed therapy (DOT) whenever possible to ensure adherence.
Active TB disease
Initial intensive phase (2 months): Four-drug regimen (RIPE):
- Rifampin
- Isoniazid (with pyridoxine/vitamin B6 to prevent peripheral neuropathy)
- Pyrazinamide
- Ethambutol
Continuation phase (4 months): Rifampin and Isoniazid (if drug-susceptible)
Total treatment duration: 6 months for drug-susceptible pulmonary TB. Extend to 9-12 months for TB meningitis, bone/joint TB, or extensive disease.
Drug-resistant TB
Multidrug-resistant TB (MDR-TB): Resistant to rifampin and isoniazid. Requires second-line agents for 18-24 months.
Extensively drug-resistant TB (XDR-TB): MDR-TB plus resistance to fluoroquinolones and second-line injectables. Treatment with newer agents like bedaquiline, linezolid, and delamanid.
Latent TB infection
Treat to prevent progression to active disease in high-risk individuals:
- Isoniazid for 9 months (preferred), or
- Rifampin for 4 months, or
- Isoniazid + rifapentine weekly for 3 months (short-course, DOT)
Indications for LTBI treatment: Positive TST/IGRA with recent infection, HIV, immunosuppression, close TB contact, or radiographic evidence of old healed TB.
Monitoring
- Baseline: hepatic enzymes, bilirubin, creatinine, CBC, HIV test, visual acuity/color vision (ethambutol)
- Monthly: clinical assessment, adverse effects, adherence
- Sputum AFB smears at 2 months (should convert to negative)
- Hepatic monitoring if baseline abnormal or symptoms develop
Special populations
HIV-TB coinfection: Start TB treatment first, then initiate antiretroviral therapy (ART) within 2 weeks (within 2 days if CD4 <50). Monitor for immune reconstitution inflammatory syndrome (IRIS).
Pregnancy: Treat active TB with rifampin, isoniazid, ethambutol (avoid pyrazinamide per WHO guidelines, though some use it). Treat LTBI postpartum unless high risk.
Children: Adjust dosing by weight; treat miliary TB and TB meningitis with corticosteroids.
Adjunctive corticosteroids
Indicated for TB meningitis and pericarditis to reduce mortality and complications. Typically dexamethasone or prednisolone tapered over 6-8 weeks.
Infection control
Airborne precautions (negative-pressure room, N95 respirators) until sputum AFB-negative on three consecutive samples. Public health notification and contact tracing are mandatory.
Complications and prognosis
Complications of untreated or inadequately treated TB:
- Respiratory: Massive hemoptysis (Rasmussen aneurysm), bronchiectasis, chronic pulmonary aspergillosis (aspergilloma in old cavities), pulmonary fibrosis, cor pulmonale, pneumothorax
- Neurologic: Hydrocephalus, stroke, tuberculomas, cranial nerve palsies, seizures, permanent neurologic deficits from TB meningitis
- Cardiovascular: Constrictive pericarditis, pericardial effusion with tamponade
- Renal: Chronic kidney disease, ureteral strictures, hydronephrosis, bladder contracture
- Skeletal: Vertebral collapse, spinal cord compression, chronic osteomyelitis, joint destruction
- Drug toxicity: Hepatitis (isoniazid, rifampin, pyrazinamide), optic neuritis (ethambutol), peripheral neuropathy (isoniazid), hyperuricemia (pyrazinamide)
- Drug resistance: Develops with poor adherence or inadequate treatment regimens
- Immune reconstitution inflammatory syndrome (IRIS): Paradoxical worsening when starting ART in HIV-TB coinfection
Prognosis:
With appropriate treatment, cure rates exceed 95% for drug-susceptible pulmonary TB. Treatment success decreases with drug resistance: MDR-TB cure rates approximately 60%, XDR-TB approximately 30-50%. Mortality is highest with TB meningitis (15-30% even with treatment), miliary TB, and HIV coinfection.
Untreated active TB has approximately 50% mortality. Poor prognostic factors include HIV coinfection, extremes of age, malnutrition, extensive drug resistance, delayed diagnosis, and extrapulmonary dissemination.
Relapse rates after successful treatment are 3-5% within 2 years. Risk factors for relapse include HIV, extensive disease, cavitary disease, delayed culture conversion, and non-adherence.
Prevention:
- BCG vaccination (Bacille Calmette-Guérin) provides partial protection against severe TB in children (meningitis, miliary TB) but efficacy is variable for pulmonary TB in adults
- Screening and treatment of latent TB in high-risk populations
- Infection control measures in healthcare settings
- Contact tracing and prophylaxis for exposed individuals
- Addressing social determinants: poverty, overcrowding, malnutrition
RIPE for first-line TB drugs: Rifampin, Isoniazid, Pyrazinamide, Ethambutol. Remember SPINE for TB complications: Sputum (hemoptysis), Pott disease, Immune reconstitution, Neurotoxicity (drugs), Ethambutol optic neuritis.
Practice questions
1. A 34-year-old man from India presents with a 2-month history of productive cough, fever, night sweats, and 10-kg weight loss. He is HIV-positive with a CD4 count of 180 cells/μL. Chest X-ray shows a right upper lobe cavitary lesion. Sputum acid-fast bacilli smear is positive. Which of the following is the most appropriate initial management?
2. A 28-year-old woman presents with severe headache, fever, and confusion for 10 days. She has no significant past medical history. Lumbar puncture shows opening pressure of 25 cm H₂O, glucose 25 mg/dL (serum 90 mg/dL), protein 180 mg/dL, and 200 WBC/μL with 85% lymphocytes. Acid-fast bacilli are seen on CSF smear. In addition to antitubercular therapy, which of the following should be administered?
3. A 45-year-old homeless man with a history of alcohol abuse presents with chronic cough and hemoptysis. Chest X-ray shows bilateral upper lobe infiltrates with cavitation. Sputum culture grows Mycobacterium tuberculosis resistant to rifampin and isoniazid. He was previously treated for TB 3 years ago but admits he stopped medications after 2 months. What is the most likely explanation for his current condition?
Frequently asked questions
What causes tuberculosis?
Tuberculosis is caused by Mycobacterium tuberculosis, a slow-growing acid-fast bacillus transmitted through airborne droplets when an infected person coughs, sneezes, or speaks. Only about 5-10% of infected immunocompetent individuals develop active disease, while others develop latent infection. Risk factors for progression to active TB include HIV infection, immunosuppressive medications, diabetes, malnutrition, and recent infection within the past two years.
What are the first symptoms of tuberculosis?
The earliest symptoms of tuberculosis typically develop insidiously over weeks to months and include chronic cough lasting more than three weeks, low-grade fever (often worse in the evening), night sweats that are drenching enough to require changing clothes or sheets, and unintentional weight loss. Many patients also experience fatigue and malaise. As the disease progresses, the cough may become productive with blood-streaked sputum (hemoptysis), and chest pain may develop if the pleura becomes involved.
How is tuberculosis diagnosed?
TB diagnosis combines clinical suspicion with microbiological, radiologic, and histopathologic evidence. The gold standard is culture of M. tuberculosis from sputum or other clinical specimens, though this takes weeks. Acid-fast bacilli smears provide rapid but less sensitive results. Molecular tests like GeneXpert MTB/RIF detect TB and rifampin resistance within hours. Chest X-ray typically shows upper lobe infiltrates and cavitation in reactivation TB. Tuberculin skin test and interferon-gamma release assays detect TB infection but cannot distinguish latent from active disease. Biopsy showing caseating granulomas with acid-fast bacilli confirms the diagnosis.
Is tuberculosis curable?
Yes, tuberculosis is curable with appropriate antibiotic treatment. Drug-susceptible pulmonary TB has cure rates exceeding 95% with standard six-month treatment using rifampin, isoniazid, pyrazinamide, and ethambutol. However, treatment requires strict adherence to the full course of multiple medications. Drug-resistant TB is more challenging, with cure rates of approximately 60% for multidrug-resistant TB and 30-50% for extensively drug-resistant TB, requiring prolonged treatment lasting 18-24 months with second-line agents. Latent TB infection can be effectively treated to prevent progression to active disease.
Tuberculosis vs pneumonia — what is the difference?
Tuberculosis and bacterial pneumonia differ in onset, duration, causative organisms, and treatment. Pneumonia typically presents acutely over days with high fever, productive cough, and pleuritic chest pain, caused by bacteria like Streptococcus pneumoniae, and responds to standard antibiotics within days. TB has insidious onset over weeks to months with chronic cough, low-grade fever, night sweats, and weight loss, caused by Mycobacterium tuberculosis, requiring months of multidrug therapy. Radiographically, pneumonia shows lobar or segmental consolidation in any lung zone, while reactivation TB characteristically affects upper lobes with cavitation. TB is diagnosed with acid-fast staining and culture, whereas pneumonia diagnosis relies on routine bacterial culture and clinical response.
Key drugs
Related conditions and differentials
Sources and further reading
StatPearls (NCBI Bookshelf)MedlinePlusWHO ICD-10: A15-A19
Educational content for medical students, prepared by the WhiteCoat Pro editorial team with AI assistance; every page is reviewed by a second AI model for factual errors. It is not medical advice and does not replace the product label, local guidelines or a clinician.