What are the diagnosis and treatment approaches for pulmonary and extrapulmonary tuberculosis (TB)?

Diagnosis and Treatment of Tuberculosis

Pulmonary Tuberculosis Diagnosis

For suspected pulmonary TB, obtain at least three respiratory specimens (preferably first morning sputum) for AFB smear microscopy, mycobacterial culture, and rapid molecular testing (Xpert MTB/RIF or NAAT), with culture being essential for drug susceptibility testing and definitive diagnosis. 1, 2

Specimen Collection Strategy

• When patients cannot spontaneously produce sputum, perform sputum induction with hypertonic saline as the first-line approach under appropriate infection control measures. 2
• Collect minimum three induced sputum specimens for AFB smears and mycobacterial cultures, as this provides diagnostic yield of approximately 70% when culture-confirmed TB is the reference standard. 1, 2
• First morning specimens have 12% greater sensitivity than spot specimens. 3

When Sputum Collection Fails

• Proceed to bronchoscopy with bronchoalveolar lavage (BAL) when induced sputum is unsuccessful or non-diagnostic. 1, 2
• For cavitary lesions, bronchial washings or lavage provide diagnostic material. 2
• Collect post-bronchoscopy sputum specimens from all patients undergoing bronchoscopy, as these may yield positive results even when BAL specimens are negative. 1, 2
• A single positive bronchoscopic specimen for M. tuberculosis in patients with classic symptoms and radiographic findings consistent with TB is adequate for diagnosis. 2

Molecular and Microbiologic Testing

• Perform rapid molecular drug susceptibility testing (Xpert MTB/RIF) on all respiratory specimens, as it provides both TB diagnosis and rifampin resistance detection with 95% sensitivity and 98% specificity. 1, 2
• The sensitivity for detecting isoniazid resistance is 90% with 99% specificity, confirming resistance but not excluding it. 1
• Mycobacterial culture remains essential because it distinguishes viable from non-viable organisms and allows complete drug susceptibility testing. 2
• Perform susceptibility testing for isoniazid, rifampin, and ethambutol on any positive culture. 2

Pediatric Pulmonary TB Diagnosis

• Collect gastric aspirates on three consecutive mornings, which provides diagnostic yield of 40-50% (up to 90% in infants). 1
• Sputum induction with bronchodilator yields 20-30%, while BAL yields 10-22%. 1
• Mycobacterial culture of respiratory specimens is suggested for all children suspected of having pulmonary TB. 1
• In low-incidence settings during recent contact investigations, microbiological confirmation may not be necessary for children with uncomplicated pulmonary TB if the source case has documented drug-susceptible TB. 1

Extrapulmonary Tuberculosis Diagnosis

For suspected extrapulmonary TB, obtain tissue or fluid samples from the affected site using biopsy, fine needle aspiration, or fluid aspiration, and perform rapid molecular testing (Xpert MTB/RIF), mycobacterial culture with drug susceptibility testing, AFB smear microscopy, and histopathological examination on all specimens. 1, 4

Specimen Collection and Processing

• Save biological material in normal saline for microbiological/molecular testing and in formalin for histopathology. 4
• Perform cell counts and chemistries on pleural, cerebrospinal, ascitic, and joint fluids, as these provide rapid information to guide further testing. 1
• Use imaging (ultrasound, CT, MRI, or PET-CT) to localize lesions, map disease extent, and identify optimal biopsy sites. 4

Molecular Testing Performance by Site

• Xpert MTB/RIF has highest sensitivity for lymph node specimens (90%), moderate sensitivity for cerebrospinal fluid (53%), and lowest sensitivity for pleural (30%) and peritoneal (32%) fluids. 5
• Overall pooled sensitivity is 75% with 98% specificity when compared to composite reference standard. 5
• A positive NAAT result is considered evidence of extrapulmonary TB to guide treatment decisions. 4

Adjunctive Diagnostic Tests

• Measure Adenosine Deaminase (ADA) levels in pleural, cerebrospinal, peritoneal, and pericardial fluid, with sensitivity of 79% and specificity of 91% for cerebrospinal fluid. 1
• Histological examination on tissue specimens has sensitivity ranging from 60-100% depending on the site. 1, 4
• When microbiological tests are negative, integrate clinical context, histopathology, ADA levels, and imaging findings together. 4

Treatment of Drug-Susceptible Pulmonary TB

Initiate treatment with the four-drug regimen (isoniazid, rifampin, pyrazinamide, and ethambutol) for 8 weeks intensive phase, followed by 16 weeks continuation phase with isoniazid and rifampin for drug-susceptible pulmonary TB. 6, 7

Standard Treatment Regimens (Three Options)

Option 1 (Preferred):

• Daily isoniazid, rifampin, and pyrazinamide for 8 weeks, followed by 16 weeks of isoniazid and rifampin daily or 2-3 times weekly. 6
• Add ethambutol or streptomycin to initial regimen until sensitivity to isoniazid and rifampin is demonstrated. 6
• The fourth drug is optional only if community isoniazid resistance is ≤4%. 6

Option 2:

• Daily isoniazid, rifampin, pyrazinamide, and streptomycin or ethambutol for 2 weeks, followed by twice weekly administration of same drugs for 6 weeks, then twice weekly isoniazid and rifampin for 16 weeks. 6

Option 3:

• Three times weekly with isoniazid, rifampin, pyrazinamide, and ethambutol or streptomycin for 6 months. 6

Dosing

Adults:

• Isoniazid: 5 mg/kg up to 300 mg daily, or 15 mg/kg up to 900 mg twice or three times weekly. 6

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. 6

Critical Treatment Principles

• All regimens given twice weekly or three times weekly must be administered by directly observed therapy (DOT). 6
• Never initiate single-drug therapy or add a single drug to a failing regimen, as this leads to drug resistance development. 2, 6
• Concomitant pyridoxine (B6) is recommended in malnourished patients and those predisposed to neuropathy (alcoholics, diabetics). 6

Treatment of Extrapulmonary TB

Apply the same 6-9 month short-course regimen used for pulmonary TB to most extrapulmonary forms, with 12-month therapy reserved for miliary TB, bone/joint TB, and tuberculous meningitis in infants and children. 6

Site-Specific Considerations

• For tuberculous meningitis, administer corticosteroids early in the disease course to decrease neurologic sequelae. 6
• For tuberculous pericarditis, corticosteroids prevent cardiac constriction. 6
• Surgery may be necessary to obtain specimens for diagnosis and treat constrictive pericarditis or spinal cord compression from Pott's disease. 6
• Response to treatment often must be judged on clinical and radiographic findings due to relative inaccessibility of disease sites. 6

Special Populations

HIV-Coinfected Patients

• The immunologically impaired host may not respond as satisfactorily as immunocompetent patients, requiring individualized therapeutic decisions. 6
• Screen antimycobacterial drug levels in patients with advanced HIV disease to prevent malabsorption and emergence of multidrug-resistant TB. 6
• Expedited diagnostic evaluation and low threshold for empiric treatment are recommended. 4

Pregnant Women

• Initial treatment regimen should consist of isoniazid, rifampin, and ethambutol (unless primary isoniazid resistance is unlikely). 6
• Streptomycin is contraindicated as it interferes with in utero ear development and may cause congenital deafness. 6
• Routine use of pyrazinamide is not recommended due to inadequate teratogenicity data. 6

Empiric Treatment Without Microbiologic Confirmation

Initiate multi-drug therapy immediately when clinical suspicion is HIGH (symptomatic or seriously ill patient) even before culture results are available, but defer empiric treatment in asymptomatic patients with only radiographic findings until microbiologic confirmation is obtained. 2, 3

When to Start Empiric Treatment

• For patients with high clinical suspicion based on radiographic findings (especially cavitary lesions) and symptoms, initiate empiric treatment with isoniazid, rifampin, pyrazinamide, and ethambutol even when initial smears are negative. 2
• Never treat based on radiology alone in asymptomatic patients, as radiology cannot determine TB activity or distinguish active disease from inactive TB, other infections, or malignancy. 3

Re-evaluation Protocol

• Perform thorough clinical and radiographic re-evaluation at 2 months of therapy to determine whether there has been response attributable to antituberculosis treatment. 2, 3
• If cultures remain negative but clinical or radiographic improvement occurs, continue treatment for culture-negative TB with additional 2 months of isoniazid and rifampin (total 4 months). 3

Multidrug-Resistant TB (MDR-TB)

For MDR-TB (resistance to at least isoniazid and rifampin), treatment must be based on susceptibility studies with consultation from a TB expert, as this presents difficult treatment problems requiring individualized approaches. 6, 7

Critical Pitfalls to Avoid

• Alternative diagnoses must be considered carefully before making presumptive diagnosis of culture-negative tuberculosis. 2
• Nontuberculous mycobacteria can present with cavitary lung disease and must be excluded through species identification if cultures become positive, as treatment differs substantially. 2, 3
• If bacilli become resistant, therapy must be changed to agents to which the bacilli are susceptible. 6
• Both suspected and confirmed cases of latent TB infection and TB disease must be reported to local or state health departments. 7