In an adult with a >2‑week cough, weight loss, night sweats, fever and possible hemoptysis, what are the clinical features and stages of tuberculosis, how should it be diagnosed, and what is the recommended treatment for drug‑susceptible and resistant disease?

Tuberculosis: Clinical Features, Diagnosis, and Treatment

Clinical Features and Presentation

Any adult presenting with cough lasting ≥2-3 weeks accompanied by fever, night sweats, weight loss, or hemoptysis should be evaluated for tuberculosis immediately. 1, 2, 3

Classic Pulmonary TB Symptoms

• Persistent productive cough (>2-3 weeks duration), often with sputum that may be blood-tinged or frankly bloody 2, 3
• Constitutional symptoms: fever (often evening/low-grade), drenching night sweats, unintentional weight loss, anorexia, and fatigue 1, 2
• Respiratory symptoms: chest pain, shortness of breath, and hemoptysis in advanced disease 2

Variations by Immune Status and Population

The clinical presentation varies dramatically based on immune competence:

• HIV-positive patients frequently present with atypical features including lower lobe infiltrates rather than classic upper lobe disease, less cavitation, and more subtle or absent classic symptoms 2
• Elderly patients are less likely to have fever, sweating, and hemoptysis, and more commonly show lower lung lesions without cavitation 2
• Immunocompromised patients may have minimal or completely atypical symptoms, making diagnosis particularly challenging 2

Radiographic Patterns

• Immunocompetent adults: upper lobe infiltrates with cavitation and contraction fibrosis are classic findings 2, 4
• HIV-infected patients: lower lobe infiltrates, hilar adenopathy, interstitial patterns, or even normal chest radiographs despite active disease 2

Clinical Stages and Infectiousness

Determining Infectiousness

Patients should be considered infectious if they are coughing, undergoing cough-inducing procedures, or have positive AFB sputum smears, particularly if not on chemotherapy, just started treatment, or showing poor response to therapy. 1

Key principles of infectiousness:

• Effective anti-TB therapy reduces infectiousness by decreasing cough, sputum production, and bacterial load, but the time to become non-infectious varies between patients 1
• Some TB patients are never infectious, while those with unrecognized or inadequately treated drug-resistant TB may remain infectious for weeks to months 1
• Isolation should continue until three consecutive negative sputum smears collected on different days are obtained AND clinical improvement is demonstrated 1

Diagnostic Approach

Initial Evaluation Algorithm

For any patient with cough ≥2-3 weeks plus additional symptoms (fever, night sweats, weight loss, hemoptysis), obtain chest radiograph; if suggestive of TB, immediately collect three sputum specimens on different days for AFB smear microscopy and mycobacterial culture. 1, 3

High-Risk Populations Requiring Lower Threshold

Maintain heightened suspicion in patients with:

• Recent TB exposure or positive TB infection test 2, 3
• HIV infection or other immunosuppression 1, 3
• Immigration from high-prevalence countries within 5 years 1
• Homelessness, incarceration history, or injection drug use 1, 3
• Medical risk factors: diabetes, chronic renal failure, prolonged corticosteroid use, malignancies, or weight >10% below ideal 1

Microbiological Diagnosis

Culture remains the gold standard for TB diagnosis and is mandatory for drug susceptibility testing. 3

Specimen Collection and Processing

• Collect at least three sputum specimens on different days, including at least one early-morning specimen 3
• Specimens should be liquefied, decontaminated, and concentrated before testing 3
• Both liquid and solid culture media should be used on all specimens 3

AFB Smear Microscopy

• Fluorescence microscopy on concentrated specimens is preferred over conventional methods 3
• Critical caveat: Negative AFB smears do NOT exclude TB—culture is essential 3
• AFB smear-negative, culture-positive TB occurs in 20-50% of pulmonary TB cases 3

Nucleic Acid Amplification Testing (NAAT)

Perform NAAT on at least one respiratory specimen to enable diagnosis within 1-2 days rather than waiting weeks for culture. 3

Interpretation algorithm based on combined AFB smear and NAAT results:

• AFB smear positive + NAAT positive: Presume TB and begin four-drug treatment immediately (positive predictive value >95%) 3
• AFB smear negative + NAAT positive: Use clinical judgment; if two or more specimens are NAAT-positive, presume TB pending culture 3
• AFB smear positive + NAAT negative: Test for PCR inhibitors immediately and obtain additional specimen; if no inhibitors detected and repeat remains smear-positive/NAAT-negative, presume nontuberculous mycobacterial infection 3

Important limitation: Current NAAT tests detect only 50-80% of AFB smear-negative, culture-positive pulmonary TB, so negative results do not exclude TB 3

Radiographic Evaluation

• Chest radiography is essential but cannot establish TB diagnosis alone 3, 4
• CT scanning is useful when chest radiograph is normal but clinical suspicion remains high, or to differentiate TB from other diseases 4

Testing for Latent TB Infection (LTBI)

Use tuberculin skin test (TST) and/or interferon-gamma release assay (IGRA) to diagnose LTBI, with dual testing strategy recommended in medium/high TB prevalence settings. 3

• IGRAs have advantages over TST: no cross-reactivity with BCG vaccination and higher specificity in BCG-vaccinated populations 3
• TST interpretation: ≥5mm induration is positive in high-risk individuals (HIV-infected, recent TB contacts, immunosuppressed) 5
• Critical caveat: TST and IGRA should NEVER be used to diagnose active TB disease—only for latent infection 3

Culture-Negative Pulmonary TB

When clinical and radiographic findings strongly suggest TB but cultures remain negative, initiate empiric four-drug therapy and reassess at 2 months. 3

Treatment of Drug-Susceptible TB

The standard treatment for new cases of drug-susceptible pulmonary TB is 2 months of isoniazid, rifampin, ethambutol, and pyrazinamide (HREZ), followed by 4 months of isoniazid and rifampin (HR). 5, 6

Treatment Phases

Intensive Phase (First 2 Months)

• Four drugs: Isoniazid + Rifampin + Pyrazinamide + Ethambutol 5, 6
• This combination prevents emergence of drug resistance 5

Continuation Phase (Next 4 Months)

• Two drugs: Isoniazid + Rifampin, based on susceptibility testing results 5, 6

Special Duration Considerations

• TB meningitis: Extend treatment to 12 months 5
• Spinal TB with neurological involvement: Treat for 9 months 5
• Silicosis-associated TB: Extend treatment duration 5

Drug Susceptibility Testing

Perform antibiogram to first-line drugs on all initial isolations from new patients to guide appropriate therapy. 5

Treatment of Latent TB Infection (LTBI)

Preferred regimens include isoniazid combined with rifapentine or rifampin for 3 months, or rifampin alone for 4 months. 6

Alternative regimen:

• Isoniazid alone for 6 months (standard historical regimen) 5

Before initiating LTBI treatment, active TB must be excluded through clinical history, physical examination, and chest radiograph. 1, 3

Treatment of Drug-Resistant TB

Consultation with a TB expert is mandatory if drug-resistant TB is suspected or confirmed. 6

Drug-resistant TB requires:

• Modified regimens based on specific resistance patterns
• Longer treatment duration
• Second-line drugs with greater toxicity
• Close monitoring for adverse effects

Critical Pitfalls to Avoid

• Never exclude TB based on negative AFB smears alone—culture is mandatory 3
• Never delay treatment in high-suspicion cases while awaiting culture results 3
• Never rely on a single negative sputum specimen 3
• Never use TST or IGRA to diagnose active TB disease—these tests only detect infection, not active disease 3
• Never assume non-infectiousness immediately after starting treatment—isolation requires three negative sputum smears on different days plus clinical improvement 1, 3
• Never delay specimen collection to await NAAT results 3

Infection Control and Reporting

• Respiratory isolation should be applied for 3 weeks or until 3 negative AFB smears are obtained 5
• Both suspected and confirmed cases of LTBI and TB disease must be reported to local or state health departments 6