What is the recommended diagnostic work‑up and first‑line treatment for an adult presenting with miliary tuberculosis (fever, night sweats, weight loss, dry cough, dyspnea, and diffuse millet‑seed nodules on chest radiograph)?

Miliary Tuberculosis: Diagnostic Work-Up and First-Line Treatment

Immediate Diagnostic Approach

For an adult presenting with suspected miliary tuberculosis, immediately obtain three sputum specimens for AFB smear microscopy, mycobacterial culture, and molecular testing (Xpert MTB/RIF), and if sputum is negative or unobtainable, proceed directly to bronchoscopy with bronchial brushings and/or transbronchial biopsy—not just washings—as these have diagnostic yields of 27-78% and 32-75% respectively. 1

Initial Specimen Collection Strategy

• Sputum induction should be the first respiratory sampling method if the patient cannot spontaneously expectorate sputum 1
• Obtain three sputum specimens for:
  • AFB smear microscopy 2
  • Mycobacterial culture with drug susceptibility testing 2
  • Molecular testing (Xpert MTB/RIF or line probe assay) 3, 4

When to Proceed to Bronchoscopy

If induced sputum is AFB smear-negative or cannot be obtained, flexible bronchoscopy is indicated 1, 3

Critical technical points for miliary TB bronchoscopy:

• Bronchial brushings and/or transbronchial biopsy (TBB) are essential—the yield from washings alone is substantially lower 1, 3
• Bronchial brushings yield: 27-78% 1, 3
• Transbronchial biopsy yield: 32-75% 1, 3
• For critically ill patients requiring rapid presumptive diagnosis, transbronchial biopsy is both necessary and appropriate to identify histopathologic findings consistent with TB 1
• Collect postbronchoscopy sputum specimens for AFB smear and culture (yield: 9-73% for smears, 35-71% for cultures) 1

Additional Diagnostic Maneuvers

• Fundus examination for choroidal tubercles is pathognomonic when present (found in 8-13% of cases) 4, 5, 6, 7
• Blood cultures should be obtained (positive in 20% of cases) 6
• Bone marrow biopsy shows granulomas in 82% of cases and is less invasive than liver biopsy 6
• Liver biopsy demonstrates granulomas in 100% of cases but carries higher complication risk 6, 7

Baseline Laboratory Assessment

Before initiating treatment:

• Baseline liver function tests (AST, ALT, bilirubin) due to hepatotoxicity risk from isoniazid, rifampin, and pyrazinamide 2
• Complete blood count (anemia present in 76-86%, pancytopenia in 8-12%) 6, 7
• Tuberculin skin test (though only positive in 29-32% of miliary TB cases) 6, 7

First-Line Treatment Regimen

Initiate the standard 6-month four-drug regimen immediately upon clinical suspicion without waiting for culture confirmation, as untreated miliary TB is uniformly fatal. 1, 8, 3, 5

Standard Treatment Protocol

Intensive Phase (2 months):

• Isoniazid
• Rifampin
• Pyrazinamide
• Ethambutol 8, 2, 3

Continuation Phase (4 months minimum):

• Isoniazid
• Rifampin 8, 2, 3

Critical Treatment Duration Modifications

Extend treatment to 9-12 months total in these specific scenarios:

• Miliary TB with CNS involvement (tuberculous meningitis) 1, 8, 3
• Disseminated or miliary TB in children 8
• HIV-infected patients (minimum 9 months) 1, 8

The evidence for 6-month treatment in uncomplicated miliary TB comes from extrapolation of pulmonary TB data, as randomized controlled trials specifically for miliary TB are sparse 4, 9. However, the standard 6-month regimen shows good response rates in clinical practice 4, 5.

Adjunctive Corticosteroid Therapy

Add corticosteroids (dexamethasone or prednisolone) for 6-8 weeks if CNS involvement is present 3

Monitoring During Treatment

Clinical Monitoring Schedule

• Monthly clinical assessments at minimum to evaluate treatment response and adverse effects 2, 3
• Fever should resolve within 21 days in 90% of cases—persistent fever beyond this warrants investigation 6
• Monthly sputum cultures until two consecutive specimens are negative 2

Laboratory Monitoring

• Liver function tests every 2-4 weeks during treatment due to high hepatotoxicity risk 2, 3
• Monitor for drug-induced liver injury, which poses significant treatment challenges 9, 5

Critical Pitfalls to Avoid

Never delay treatment to obtain tissue diagnosis in critically ill patients—empiric therapy based on clinical and radiographic suspicion is lifesaving 1, 5

Never add a single drug to a failing regimen, as this rapidly leads to acquired drug resistance 8

Never discontinue therapy without consulting a TB specialist if complications arise 2

Directly Observed Therapy

Directly observed therapy (DOT) should be used for all patients with miliary TB, as compliance is the major determinant of treatment outcome and prevents emergence of drug resistance 1, 2

Prognostic Factors

Independent predictors of mortality include:

• Advanced age 6
• Low serum albumin 6
• Altered mental status 6, 7
• Male sex 7
• Absence of typical miliary pattern on chest X-ray 7
• Failure to initiate anti-TB treatment 7

Overall mortality ranges from 17-18% even with treatment, underscoring the importance of early diagnosis and immediate therapy initiation 6, 7