How is tuberculosis diagnosed and treated?

Diagnosis and Treatment of Tuberculosis

Diagnostic Approach

For any patient with suspected TB, immediately collect three sputum specimens on different days for AFB smear microscopy, mycobacterial culture, and nucleic acid amplification testing (NAAT), as culture remains the gold standard and is essential for drug susceptibility testing. 1, 2

When to Suspect TB

• Consider TB in patients with cough lasting ≥3 weeks, particularly when accompanied by evening fever, night sweats, weight loss, anorexia, or hemoptysis 1, 2
• Maintain a lower threshold for suspicion in high-risk populations: HIV-infected, immunosuppressed, foreign-born from endemic countries, homeless, and incarcerated individuals 1, 2
• Classic chest radiography findings include apical cavitary lesions, infiltrates, lymphadenopathy, or pleural effusions, though findings may be atypical in immunocompromised patients 1, 2

Specimen Collection Protocol

• Collect three sputum specimens 8-24 hours apart, with at least one early morning specimen 2
• The first specimen has 53.8% sensitivity, the second adds 11.1%, and the third adds only 2-5% additional yield 2
• First morning specimens are 12% more sensitive than spot specimens, and concentrated specimens increase sensitivity by 18% 2
• Use sputum induction with hypertonic saline aerosol in patients unable to produce adequate sputum 2
• For children aged <10 years who cannot produce sputum, perform early morning gastric aspirate with expected yield of 50% 3

Laboratory Testing Strategy

• Process all specimens for AFB smear microscopy (preferably fluorescence microscopy, which is 10% more sensitive), mycobacterial culture on both liquid and solid media, and NAAT on at least the first diagnostic specimen 1, 2
• Culture is mandatory for species identification and drug susceptibility testing 3, 1, 2
• NAAT (GeneXpert MTB/RIF) provides results within 1 day and simultaneously detects rifampin resistance, with 96.3% sensitivity and 81.3% specificity in smear-negative cases 2
• Three AFB smears have approximately 70% sensitivity, but 40% of culture-positive cases are smear-negative 2

Critical pitfall: Never rely on a single negative sputum specimen or negative AFB smears alone to exclude TB—40% of culture-positive cases are smear-negative 1, 2

Treatment Initiation Decision Algorithm

High Clinical Suspicion or Seriously Ill Patient

If suspicion of tuberculosis is high or the patient is seriously ill, initiate combination chemotherapy immediately, often before AFB smear results are known and usually before mycobacterial culture results have been obtained 3

• A positive AFB smear provides strong inferential evidence for TB diagnosis 3
• Continue treatment to complete standard course if diagnosis is confirmed by culture or positive NAAT 3

AFB Smears and Cultures Negative

• If no other diagnosis is established and PPD-tuberculin skin test is positive (≥5 mm induration), initiate empirical combination chemotherapy 3
• If clinical or radiographic response occurs within 2 months and no other diagnosis established, diagnose culture-negative pulmonary TB and continue treatment with additional 2 months of isoniazid and rifampin to complete total of 4 months 3
• If no clinical or radiographic response by 2 months, stop treatment and consider other diagnoses including inactive tuberculosis 3

Low Clinical Suspicion

• Treatment can be deferred until mycobacterial culture results are known and comparison chest radiograph is available (usually within 2 months) 3

Critical pitfall: Do not delay empiric treatment in high-suspicion cases while awaiting culture results 2

Standard Treatment Regimen for Drug-Susceptible TB

Initiate isoniazid, rifampin, pyrazinamide, and ethambutol (HREZ) for 2 months followed by isoniazid and rifampin for 4 additional months (total 6 months) in all new cases of drug-susceptible pulmonary TB 3, 2, 4

Initial Phase (2 Months)

• Isoniazid, rifampin, pyrazinamide, and ethambutol daily 3, 2
• Perform repeat smear and culture when 2 months of treatment completed 3

Continuation Phase (4 Months)

• If cavities were seen on initial chest radiograph OR acid-fast smear is positive at completion of 2 months, continue isoniazid and rifampin daily or twice weekly for 4 months to complete total of 6 months 3
• If no cavitation on initial radiograph AND smear-negative at 2 months, continue for 4 months 3

Directly Observed Therapy (DOT)

Directly observed therapy is recommended for all patients to ensure compliance and prevent drug-resistant TB 2, 4

• DOT involves observation of the patient by a healthcare provider or responsible person as the patient ingests anti-tuberculosis medications 2, 4
• A case manager should be assigned to each patient to ensure adequate education, continuous standard therapy, and contact evaluation 2

Critical pitfall: Doses of rifampin greater than 600 mg given once or twice weekly have resulted in higher incidence of adverse reactions including "flu syndrome," hematopoietic reactions, and renal failure 5

Special Populations and Sites

HIV-Infected Patients

• Treat with same 6-month regimen as HIV-negative patients 2
• HIV-infected patients with culture-negative pulmonary TB should be treated for minimum of 6 months 2
• Patients co-infected with HIV may have malabsorption problems; screening of antimycobacterial drug levels may be necessary to prevent emergence of multidrug-resistant TB 4

Extrapulmonary TB

• Treat with same 6-month regimen as pulmonary disease for all sites except meninges 2
• Tuberculous meningitis requires 9-12 months of treatment 2, 4
• Addition of corticosteroids is recommended for tuberculous pericarditis and tuberculous meningitis 2

Pregnant Women

• Initial treatment regimen should consist of isoniazid and rifampin 4
• Ethambutol should be included unless primary isoniazid resistance is unlikely (isoniazid resistance rate documented to be less than 4%) 4
• Streptomycin is contraindicated in pregnancy as it interferes with in utero development of the ear and may cause congenital deafness 4
• Routine use of pyrazinamide is not recommended in pregnancy because of inadequate teratogenicity data 4

Children

• Treat with same regimen as adults, with weight-based dosing 3, 2
• Ethambutol should not be used in children whose visual acuity cannot be monitored 4
• Military tuberculosis, bone/joint tuberculosis, and tuberculous meningitis in infants and children should receive 12-month therapy 4

Patients with Renal Insufficiency

• Specific dosing adjustments are required for patients with renal insufficiency and end-stage renal disease 2
• Administer all drugs after hemodialysis to facilitate DOT and avoid premature drug removal 2
• Monitor serum drug concentrations in patients with renal failure taking cycloserine or ethambutol 2

Monitoring During Treatment

• Monitor sputum cultures monthly until two consecutive specimens are culture-negative 6
• Reassess patient within 4 weeks to evaluate improvement in symptoms and physical exam 6
• Repeat chest radiograph if previous abnormalities were present to assess response 6
• Total dose of streptomycin should not exceed 120 g over course of therapy unless there are no other therapeutic options 7
• In patients older than 60 years of age, streptomycin should be used at reduced dosage due to risk of increased toxicity 7

Multi-Drug Resistant TB (MDR-TB)

Multiple-drug resistant tuberculosis (resistance to at least isoniazid and rifampin) requires individualized treatment based on susceptibility studies, and consultation with a TB expert is mandatory 4

• Never add a single drug to a failing regimen, as this can rapidly lead to acquired resistance 6
• If treatment failure is suspected, start empirical retreatment immediately without waiting for culture results if AFB smears are positive or clinical suspicion is high 6

Respiratory Isolation

Place persons with suspected or confirmed smear-positive pulmonary or laryngeal TB in respiratory isolation until noninfectious 3

• Persons with pulmonary or laryngeal TB can transmit M. tuberculosis through aerosolization of bacilli in infectious droplet nuclei produced by coughing or sneezing 3
• Nosocomial transmission has been clearly documented in multiple investigations 3