What is the approach to diagnosis and treatment of Tuberculosis (TB)?

Diagnosis and Treatment of Tuberculosis

Diagnostic Approach

Collect three sputum specimens on different days for AFB smear microscopy, mycobacterial culture, and nucleic acid amplification testing (NAAT) in any patient with cough ≥3 weeks, particularly when accompanied by evening fever, night sweats, weight loss, or hemoptysis. 1

Clinical Suspicion Triggers

• Maintain a lower threshold for suspicion in high-risk populations: HIV-infected, immunosuppressed, foreign-born from endemic countries, homeless, and incarcerated individuals 1
• Classic symptoms include cough ≥3 weeks, evening fever, night sweats, weight loss, anorexia, and hemoptysis 1
• Chest radiography should show 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, as the first specimen has 53.8% sensitivity, the second adds 11.1%, and the third adds only 2-5% additional yield 2, 3
• Use sputum induction with hypertonic saline aerosol in patients unable to produce adequate sputum 3
• First morning specimens are 12% more sensitive than spot specimens, and concentrated specimens increase sensitivity by 18% 2
• Fluorescence microscopy is 10% more sensitive than conventional microscopy 2

Laboratory Testing Algorithm

• Process all specimens for AFB smear microscopy, mycobacterial culture (both liquid and solid media), and NAAT on at least the first diagnostic specimen 1, 2, 3
• Culture remains the gold standard for diagnosis, species identification, and drug susceptibility testing 1, 3
• 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 when culture-confirmed TB is the reference standard, but 40% of culture-positive cases are smear-negative 2, 3

Interpretation of PCR Results

• A single positive TB PCR with positive AFB smear is sufficient to presume TB and initiate treatment (positive predictive value >95%) 3
• When AFB smear is negative but PCR is positive, two or more positive PCR results are required to presume TB diagnosis pending culture confirmation 3
• Culture remains mandatory regardless of PCR results for drug susceptibility testing and genotyping 3

Culture-Negative TB Management

• When clinical and radiographic findings suggest TB but cultures remain negative, initiate empiric four-drug therapy and reassess at 2 months 1, 3
• If clinical or radiographic improvement is noted within 2 months and no other etiology is identified, treatment can be completed with an additional 2 months of isoniazid and rifampin (total 4 months) 4, 3
• HIV-infected patients with culture-negative pulmonary TB should be treated for a minimum of 6 months 4

Testing for Latent TB Infection (LTBI)

• Use tuberculin skin test (TST) and/or interferon-gamma release assay (IGRA) to diagnose LTBI, with a dual testing strategy recommended in medium/high TB prevalence settings 1
• IGRAs have advantages over TST, including no cross-reactivity with BCG vaccination and higher specificity in BCG-vaccinated populations 1
• Do not use TST or IGRA to diagnose active TB disease—these tests detect latent infection, not active disease 2, 3

Treatment of Active TB Disease

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. 4, 5, 6

Standard Treatment Regimens

Option 1 (Preferred): Daily isoniazid, rifampin, pyrazinamide, and ethambutol for 8 weeks followed by 16 weeks of isoniazid and rifampin daily or 2-3 times weekly 5

Option 2: Daily HREZ for 2 weeks followed by twice-weekly administration of the same drugs for 6 weeks, then twice-weekly isoniazid and rifampin for 16 weeks 5

Option 3: Three times weekly HREZ for 6 months 5

Dosing Guidelines

Adults:

• Isoniazid: 5 mg/kg up to 300 mg daily; or 15 mg/kg up to 900 mg twice or three times weekly 5
• All twice-weekly or three-times-weekly regimens should be administered by directly observed therapy (DOT) 5

Children:

• Isoniazid: 10-15 mg/kg up to 300 mg daily; or 20-40 mg/kg up to 900 mg twice or three times weekly 5
• Ethambutol should not be used in children whose visual acuity cannot be monitored 5

Directly Observed Therapy (DOT)

• DOT is recommended for all patients to ensure compliance and prevent drug-resistant TB 4, 5
• DOT involves observation of the patient by a healthcare provider or responsible person as the patient ingests anti-tuberculosis medications 4, 5
• A case manager should be assigned to each patient to ensure adequate education, continuous standard therapy, and contact evaluation 4

Special Populations

HIV-Infected Patients:

• The response of immunologically impaired hosts may not be as satisfactory as those with normal host responsiveness 5
• Screen antimycobacterial drug levels in patients with advanced HIV disease to prevent malabsorption and emergence of multidrug-resistant TB 5
• Appropriate adjustments with antiretroviral treatment should be made 6

Pregnant Women:

• Initial treatment should consist of isoniazid, rifampin, and ethambutol 5
• Streptomycin is contraindicated as it interferes with in utero ear development and may cause congenital deafness 5
• Routine use of pyrazinamide is not recommended due to inadequate teratogenicity data 5

Renal Insufficiency:

• Specific dosing adjustments are required for patients with renal insufficiency and end-stage renal disease 4
• Administer all drugs after hemodialysis to facilitate DOT and avoid premature drug removal 4
• Monitor serum drug concentrations in patients with renal failure taking cycloserine or ethambutol 4

Extrapulmonary TB

• Treat with the same 6-month regimen as pulmonary disease for all sites except meninges 4
• Tuberculous meningitis requires 9-12 months of treatment 4, 5, 6
• Spinal TB with neurological involvement requires up to 9 months of treatment 6
• Addition of corticosteroids is recommended for tuberculous pericarditis and tuberculous meningitis 4

Drug Susceptibility Testing

• Perform drug susceptibility testing on initial isolates from all patients to guide effective treatment 3, 6
• If bacilli become resistant, therapy must be changed to agents to which the bacilli are susceptible 5
• Multidrug-resistant TB (resistance to at least isoniazid and rifampin) requires individualized treatment based on susceptibility studies and consultation with a TB expert 5, 7

Monitoring and Follow-Up

• Monitor patients receiving TB medications at least monthly for drug toxicity and treatment response 4
• Liver damage arises in 2.4% of patients treated with standard regimens 8
• Concomitant administration of pyridoxine (B6) is recommended in malnourished patients and those predisposed to neuropathy (alcoholics and diabetics) 5
• Respiratory isolation should be applied for 3 weeks or until 3 negative bacilloscopy samples are obtained 6

Treatment of Latent TB Infection (LTBI)

• Before initiating LTBI treatment, bacteriologically positive or radiographically progressive tuberculosis must be excluded 5
• Preferred regimens include isoniazid in combination with rifapentine or rifampin for 3 months, or rifampin alone for 4 months 7
• Standard treatment with isoniazid alone is 300 mg daily for 6 months in adults, or 10 mg/kg (up to 300 mg daily) in children 5, 6
• In situations where adherence cannot be assured, use 20-30 mg/kg (not to exceed 900 mg) twice weekly under direct observation 5

Critical Pitfalls to Avoid

• Never rely on a single negative sputum specimen to exclude TB—three specimens are required 2, 3
• Do not exclude TB based on negative AFB smears alone—40% of culture-positive cases are smear-negative 2, 3
• Do not delay empiric treatment in high-suspicion cases while awaiting culture results 1, 2
• Do not use TST or IGRA to diagnose active TB disease 2, 3
• Do not assume non-infectiousness immediately after starting treatment 1
• Always collect specimens for culture and drug susceptibility testing before starting treatment 2, 3