Tuberculosis

Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis, spread via airborne respiratory droplets, and remains a leading infectious cause of death globally despite effective chemotherapy. TB incidence in the United States is approximately 2.7 cases per 100,000 population, though rates vary significantly by geography, with higher endemicity in Asia, Africa, and parts of Latin America. The disease primarily affects the lungs (pulmonary TB) but can disseminate to virtually any organ system (extrapulmonary TB). Clinical significance is heightened by the emergence of multidrug-resistant (MDR) TB and extensively drug-resistant (XDR) TB, which require prolonged, toxic, and expensive treatment regimens. Understanding TB diagnosis and treatment is essential for board examinations, as cases present across diverse clinical contexts from latent infection to fulminant disseminated disease.

Mycobacterium tuberculosis is an obligate aerobic, slow-growing bacillus with a distinctive lipid-rich cell wall containing mycolic acids that confer remarkable environmental resistance and enable survival in macrophages. Transmission occurs through inhalation of aerosolized droplet nuclei (1-5 micrometers), which bypass upper airway defenses and lodge in distal alveoli. The organism's slow replication (doubling time 15-20 hours) contrasts sharply with other bacterial pathogens and directly explains the prolonged 6-9 month treatment courses required for cure.

Upon inhalation, tubercle bacilli are phagocytosed by alveolar macrophages but resist killing through multiple mechanisms: the mycolic acid cell wall prevents phagolysosome fusion, the organism produces catalase-peroxidase to neutralize reactive oxygen species, and secreted virulence factors (like the ESX-1 secretion system) induce macrophage death and necrosis rather than containment. The initial innate response triggers recruitment of more macrophages and dendritic cells, leading to granuloma formation—a hallmark pathological hallmark wherein activated macrophages (epithelioid cells) and lymphocytes wall off the organism. This granulomatous inflammation is essential for host control but also causes tissue damage and cavitation.

In most infected individuals (90%), innate and adaptive immunity contain the bacilli within granulomas, resulting in latent tuberculosis infection (LTBI). However, the mycobacterium does not die; it enters a dormant metabolic state characterized by downregulation of aerobic respiration and upregulation of the dormancy regulon (DosR), allowing years or decades of quiescence. The hypoxic environment within necrotic granulomas (oxygen tension <5 mmHg) is critical—it upregulates the DosR regulon, which encodes proteins enabling survival under stress, and simultaneously activates the stringent response and lipid catabolism for energy. In roughly 5-10% of infected individuals, reactivation occurs when immune control wanes (due to advancing age, immunosuppression, malnutrition, or secondary infection with HIV). During reactivation, bacilli exit dormancy, proliferate rapidly, and cause tissue necrosis. Cavitary disease develops when caseous necrosis erodes into airways, creating the ideal microenvironment for massive bacterial multiplication (up to 10^8 organisms per cavity) and efficient aerosolization to new hosts.

Dendritic cells present mycobacterial antigens (notably 85B, ESAT-6, and CFP-10) to T cells via MHC-I and MHC-II pathways, priming a predominantly Th1 and Th17 cell-mediated immune response. IFN-γ produced by Th1 cells activates macrophages via STAT1 signaling, enhancing bactericidal capacity through upregulation of reactive nitrogen intermediates (nitric oxide) and antimicrobial peptides. IL-17 from Th17 cells recruits additional neutrophils and promotes tissue remodeling. Critically, antibody responses (Th2/B cell) are minimally protective—tuberculin reactivity (delayed-type hypersensitivity) reflects this Th1 dominance and underlies the tuberculin skin test (TST). Breakdown of this Th1 response (as in HIV infection, TNF-α inhibitor use, or severe malnutrition) permits uncontrolled bacillary replication and progressive disease.

The necrotic center of granulomas results from direct macrophage apoptosis triggered by mycobacterial virulence factors, particularly the ESX-1 secretion system's ESAT-6 protein. This necrosis creates a caseous (cheese-like) environment rich in lipids and mycolic acids, which supports bacillary growth and is the source of the bacilli expelled in sputum. Large cavities (>4 cm) in the upper lobes (apical-posterior segments of upper lobes and superior segments of lower lobes—areas of highest oxygen tension) contain the highest bacillary burden and are the most infectious lesions.

In pulmonary TB, organisms multiply within pneumocytes and alveolar macrophages, causing inflammation, parenchymal destruction, and cavitation. In miliary TB (hematogenous dissemination), bacilli seed distant organs via erosion into a blood vessel within a caseous focus (Simon focus), resulting in diffuse seeding of lungs and potentially any organ. Extrapulmonary TB (10-15% of cases) occurs via lymphatic or hematogenous spread and includes meningitis (with obliterative vasculitis causing stroke risk), pericarditis (with tamponade risk), and osteoarticular disease (spinal involvement with abscess formation and kyphosis).

Primary TB typically follows within 6-12 months of initial infection, especially in children, individuals with impaired cell-mediated immunity, and those with recent TB exposure. Reactivation TB (also called secondary TB) represents breakdown of previously established latent infection and accounts for the majority (85-90%) of active TB cases in low-incidence countries; it typically occurs years to decades after initial infection.

Impairs Th1 immunity and increases TB risk 3-fold; hyperglycemia impairs neutrophil and macrophage function. TB-DM coinfection complicates management and is associated with higher treatment failure rates.

Uremia depresses cell-mediated immunity; dialysis patients have 10-25 fold increased risk.

Deficiencies in protein, micronutrients (vitamins A, D, zinc), and caloric insufficiency impair Th1 differentiation and macrophage activation. BMI <18.5 kg/m² is associated with doubled TB risk.

Approximately 30% of contacts of sputum-positive TB cases become infected; risk is highest for young children (<5 years old), household members, and those in crowded settings (homeless shelters, prisons, healthcare facilities).

TB incidence is highest in sub-Saharan Africa, South Asia, and Southeast Asia. Immigration from high-burden countries is a risk factor in low-incidence regions. Genotyping studies show most cases in developed countries represent reactivation of remote infections acquired prior to immigration.

Cardinal Symptom: Chronic Cough

Classically productive and persistent (lasting >3 weeks is concerning for TB), initially dry but progressing to sputum production. The pathophysiology involves irritation of mucosa by inflammation and cavitary lesions eroding into airways. In early disease, cough may be mild and attributed to other causes, delaying diagnosis.

Constitutional Symptoms

Fever (typically low-grade, 37-38.5°C, often afternoon/evening predominance) results from macrophage production of TNF-α, IL-1, and IL-6 in response to mycobacterial antigens. Night sweats (drenching, requiring bed clothes changes) occur due to hypothalamic dysregulation from endogenous pyrogens; these are often the most bothersome symptom. Weight loss and anorexia reflect systemic inflammation and metabolic effects of TNF-α. Malaise and fatigue accompany chronic infection.

Hemoptysis

Occurs in 5-30% of pulmonary TB cases, typically from cavitary disease with vascular erosion or bronchial artery involvement. The presence of hemoptysis suggests more advanced disease and higher infectivity.

Chest Pain

Pleuritic chest pain indicates pleural involvement; TB pleuritis occurs in 20-30% of cases and results from granulomatous inflammation of the visceral and parietal pleura. Pain is typically sharp, worse with deep inspiration and coughing.

Upper Lobe Consolidation

Dullness to percussion, increased tactile fremitus, and bronchial breath sounds over apical-posterior lung fields reflect the predilection of TB for well-oxygenated apical segments. Crackles (fine, mid-to-late inspiratory) occur early; wheezing may develop if airways are involved.

Cavitary Disease

Large cavities may produce distinctive amphoric breathing (hollow, echo-like), though this is rarely heard clinically. Cavity walls may occasionally be palpable as localized dullness.

Lymphadenitis

Regional lymph node enlargement may be apparent, particularly cervical nodes in primary TB or if there is lymphatic spread.

Patients often appear chronically ill with weight loss evident. Pallor may suggest anemia from chronic disease. Finger clubbing, though nonspecific, can develop with chronic suppurative disease.

TB Meningitis

Typically presents subacutely (over 2-4 weeks) with fever, headache, neck stiffness, and altered mental status. Cranial nerve palsies (especially CN VI and VII) occur due to basilar inflammation and vasculitis. This is a medical emergency with high mortality (20-25% even with treatment) and requires prompt CSF analysis and imaging.

TB Pericarditis

Presents with chest pain, dyspnea, and signs of pericardial effusion or tamponade. Pericardial involvement occurs in 1-2% of TB cases but has high mortality if untreated.

Skeletal TB (Poncet's Disease when articular)

Spinal TB (Pott disease) is the most common skeletal manifestation; gradual vertebral body destruction with kyphosis and potential spinal cord compression. Presents with localized back pain and progressive neurological deficit. Non-spinal skeletal TB causes insidious joint inflammation, typically weight-bearing joints.

Lymph Node TB

Hilar/mediastinal lymphadenopathy dominates in primary TB, especially in children and immunocompromised hosts. Can cause bronchial obstruction and atelectasis.

Abdominal TB

Peritonitis, ileitis, and mesenteric lymphadenitis present with chronic abdominal pain, ascites, and malabsorption. Diagnosis often delayed due to nonspecific presentation.

TB Lymphadenitis

Cervical lymph nodes most commonly involved (scrofula); firm, rubbery, sometimes suppurative nodes. May discharge through skin (TB verrucosa cutis).

Military TB

Acute hematogenous dissemination, typically following primary infection or immunosuppression. Presents with high fever, respiratory symptoms, and radiographic pattern of myriad 1-2 mm nodules throughout both lungs ("millet seed" appearance). Mortality high without prompt treatment.

Endobronchial TB

Erosion of caseous material directly into airways; presents with cough, sometimes dyspnea. Sputum smear may be positive. Risk of bronchial stenosis and obstruction.

TB Empyema

Rupture of caseous focus into pleural space; massive pyogenic reaction with large pleural effusion and potential for loculation and fibrosis.

Progressive Primary TB

More common in young children and immunocompromised; primary infection progresses to active disease with minimal latency period.

Detailed history should identify TB risk factors (prior exposure, immunosuppression, recent immigration, healthcare worker status, homeless/incarcerated, substance use) and symptom duration (≥3 weeks of cough is concerning). Asking specifically about night sweats, weight loss, and fever patterns strengthens pretest probability. Duration of symptoms <3 weeks makes TB less likely but does not exclude it, particularly in immunocompromised patients.

The TST uses purified protein derivative (PPD)—a concentrate of Mycobacterium tuberculosis antigens—injected intradermally. Induration (hardness, measured in millimeters, not erythema) measured at 48-72 hours reflects Th1-mediated delayed-type hypersensitivity.

TST sensitivity is 80-90% in immunocompetent persons with active TB but markedly lower (<50%) in HIV-infected patients with CD4 <200 cells/μL. Specificity is complicated by prior BCG vaccination (which causes false-positive TST) and non-tuberculous mycobacteria (NTM) exposure.

Tests such as QuantiFERON-TB Gold In-Tube measure IFN-γ release by T cells in response to TB-specific antigens (ESAT-6, CFP-10, TB7.7). Advantages include superior specificity (not affected by BCG), no booster effect on serial testing, and ability to differentiate TB from NTM. Sensitivity approaches 90% in active TB. IGRAs are increasingly preferred for latent TB screening, particularly in BCG-vaccinated populations. However, sensitivity decreases in severe immunosuppression (CD4 <50 cells/μL in HIV patients).

Sputum is heat-fixed, stained with carbol fuchsin, and examined by light