What are the possible causes of miliary‑appearing pulmonary nodules on chest imaging and how should the work‑up be approached?

Miliary Shadows Differential Diagnosis

Primary Differential Diagnoses

Miliary tuberculosis remains the most common cause of miliary pulmonary nodules, accounting for approximately 28% of cases in the United States, followed by sarcoidosis (23%), silicosis (13%), metastatic malignancy (9%), and fungal infections including histoplasmosis (8%). 1

Infectious Etiologies

• Miliary tuberculosis presents with uniformly distributed small nodules (1-4 mm) throughout both lungs with random distribution in the secondary lobule, though chest radiography identifies only 59-69% of cases 2, 3
• Fungal infections, particularly histoplasmosis, account for 7.6% of miliary patterns and occur predominantly in HIV-positive patients (4 of 9 HIV patients in one series) 1
• Other infectious causes include Pneumocystis jiroveci pneumonia, Mycobacterium-avium complex, cryptococcosis, aspergillosis, and Epstein-Barr virus pneumonia 1

Non-Infectious Etiologies

• Sarcoidosis accounts for 22.6% of miliary patterns, though it typically presents with hilar/mediastinal lymphadenopathy and occurs in less than 1% of sarcoidosis cases as a pure miliary pattern 4, 1
• Metastatic malignancy from extrathoracic primary tumors (9.4%) or primary lung adenocarcinoma can produce identical miliary patterns and may mimic tuberculous disease clinically and radiologically 1, 5
• Occupational lung disease, specifically silicosis, represents 13.2% of miliary patterns 1
• Rare causes include hypersensitivity pneumonitis and histiocytosis 4, 1

Diagnostic Workup Algorithm

Initial Imaging Characterization

Obtain high-resolution CT chest without IV contrast using thin sections (≤1.5 mm) with multiplanar reconstructions to characterize nodule size, distribution, and associated findings. 6

• HRCT demonstrates small nodules (1-4 mm) with diffuse random distribution in miliary tuberculosis and detects nodules even when chest radiography appears normal 2
• Assess for associated findings: mediastinal/hilar lymphadenopathy (suggests sarcoidosis or tuberculosis), ground-glass attenuation, reticular opacities, or calcification patterns 4, 2
• Nodule profusion ranges from mild (45% of cases) to severe (28% of cases) in miliary tuberculosis 3

Microbiological and Tissue Diagnosis

Bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial biopsy should be performed early, as it provides 57% diagnostic yield in miliary tuberculosis and allows assessment for malignancy, fungi, and non-caseating granulomas. 1, 5

• Obtain BAL for AFB smear, mycobacterial culture, fungal culture, and cytology 4, 1
• Sputum AFB smear is positive in only 28% of miliary tuberculosis cases 1
• Transbronchial biopsy identifies non-caseating granulomas in sarcoidosis and malignant cells in metastatic disease 4, 5
• TB PCR testing on respiratory specimens provides rapid results but negative results do not exclude tuberculosis 5

Risk Stratification Based on Clinical Context

HIV status, occupational exposures, endemic fungal infection geography, and cancer history fundamentally alter the differential probability and must be assessed immediately. 1, 5

• In HIV-positive patients, histoplasmosis becomes a leading consideration (44% of HIV patients with miliary pattern) 1
• Silicosis requires occupational exposure history to silica dust 1
• Prior malignancy or constitutional symptoms with negative infectious workup mandate early consideration of metastatic disease 5
• TB endemic areas increase pre-test probability of tuberculous etiology 6, 5

Critical Diagnostic Pitfalls

Do not assume miliary shadows represent tuberculosis in TB-endemic areas without tissue diagnosis, as metastatic adenocarcinoma and other malignancies produce identical radiographic patterns and delay in diagnosis leads to disease progression and poor outcomes. 5

• Empiric anti-tuberculous therapy without microbiological or histological confirmation risks missing malignancy, particularly lung adenocarcinoma with spinal metastases mimicking Pott's disease 5
• Negative AFB sputum smear and TB PCR do not exclude miliary tuberculosis; bronchoscopy is required 1, 5
• Sarcoidosis with miliary pattern requires demonstration of non-caseating granulomas and negative fungal/AFB cultures before diagnosis 4
• Ground-glass attenuation may be the predominant HRCT finding rather than discrete nodules in some cases of miliary tuberculosis 2

Specific Radiographic Features

Nodules measuring 1-3 mm with uniform distribution throughout both lungs and random distribution within the secondary lobule on HRCT strongly suggest miliary tuberculosis, though this pattern is not pathognomonic. 2

• Sharply or poorly defined nodules ranging 1-4 mm diameter occur in miliary tuberculosis 2
• Diffuse or localized reticular opacities superimposed on nodules, especially in lower lung zones, may accompany miliary tuberculosis 2
• Mediastinal widening with miliary pattern suggests sarcoidosis or lymphoma 4
• Upper lobe predominance increases malignancy risk, though this finding has reduced diagnostic significance in Asia due to high TB prevalence 6