What is the differential diagnosis for reticulonodular opacities on a computed tomography (CT) chest?

Differential Diagnosis for Reticulonodular Opacities on CT Chest

Reticulonodular opacities on CT chest represent a pattern of interstitial lung disease with a broad differential that must be systematically approached by considering distribution, associated findings, and clinical context to distinguish between fibrotic, inflammatory, infectious, neoplastic, and occupational etiologies.

Idiopathic Interstitial Pneumonias

Idiopathic Pulmonary Fibrosis (IPF/UIP Pattern)

• Patchy, predominantly peripheral, subpleural, bibasal reticular abnormalities with limited ground glass opacity are characteristic 1
• Traction bronchiectasis, bronchiolectasis, and subpleural honeycombing develop in areas of severe involvement 1
• When ground glass opacity exceeds 30% of lung involvement, consider alternative diagnoses rather than IPF 1, 2
• HRCT diagnosis by experienced observers achieves approximately 90% accuracy for UIP pattern 1

Nonspecific Interstitial Pneumonia (NSIP)

• Bilateral symmetric ground glass opacities or bilateral air space consolidation with temporally uniform appearance distinguishes this from IPF 1
• Reticular opacities present but honeycombing is rare 1
• Better prognosis than IPF with 15-20% mortality at 5 years and most patients improve with corticosteroids 1

Desquamative Interstitial Pneumonitis (DIP)

• Extensive ground glass opacities (>30% lung involvement) are typical 1, 2
• Occurs in current or former cigarette smokers 1
• Better prognosis than IPF with approximately 70% survival at 10 years 1

Respiratory Bronchiolitis-Interstitial Lung Disease (RBILD)

• Diffuse fine reticular or nodular interstitial opacities with hazy opacities on HRCT 1, 2
• Centrilobular nodules often present 2
• Associated with current or former cigarette smoking 1

Connective Tissue Disease-Related ILD

• Scleroderma and rheumatoid arthritis commonly produce CT appearances similar to IPF 1
• High titers of anti-nuclear antibodies (>1:160) or rheumatoid factor suggest underlying connective tissue disease 1
• Bilateral basal reticular pattern characteristic 1

Occupational and Environmental Exposures

Asbestosis

• CT appearance similar to IPF but distinguished by parenchymal bands of fibrosis and pleural plaques 1
• Bilateral basal reticular pattern 1

Hypersensitivity Pneumonitis (Subacute/Chronic)

• Reticular opacity or honeycombing often lacking the bibasilar predominance seen in IPF 1
• Centrilobular nodules, middle and upper lobe predominance, and absence of honeycombing favor HP over IPF 1
• Ground glass opacities without basal or peripheral predominance 1, 2
• The "three-density pattern" (hypoattenuating, normal, and hyperattenuating lobules in close proximity) is highly specific for fibrotic HP 2

Drug-Related Pneumonitis

• Temporal relationship between drug exposure and onset of disease is critical for diagnosis 1
• Multiple patterns possible including NSIP, organizing pneumonia (OP), diffuse alveolar damage (DAD), HP pattern, and pulmonary eosinophilia 1
• Common culprits include molecular targeting agents (EGFR-TKIs, mTOR inhibitors) and immune checkpoint inhibitors 1
• Improvement with drug cessation supports diagnosis 1

Infectious Etiologies

Tuberculosis with HIV Co-infection

• Bilateral medium-to-coarse reticulonodular opacities often associated with hilar and mediastinal adenopathy 3
• Chest radiographs improve with appropriate tuberculosis therapy in HIV-positive patients 3
• Worsening radiographs during treatment indicate superimposed infection rather than treatment failure 3

Atypical Infections

• Consider Pneumocystis jirovecii pneumonia, particularly in immunocompromised patients on drugs like everolimus 1
• BAL fluid cultures essential for excluding infectious organisms before attributing findings to drug toxicity 1

Neoplastic Processes

Epithelioid Hemangioendothelioma

• Multiple pulmonary reticulonodular opacities represent one of three thoracic CT patterns 4
• Malignant features (multiplicity, hepatic/bone involvement, lymphangitic spread) despite histologically benign appearance 4

Benign Metastasizing Leiomyomatosis

• Extensive diffuse reticulonodular opacities in women with history of uterine leiomyomas 5
• Histologically benign smooth muscle proliferation with very low mitotic rate 5

Lymphangitic Carcinomatosis

• Reticulonodular pattern from tumor spread along lymphatic channels 4
• Consider in patients with known primary malignancy

Metastatic Colorectal Cancer

• Reticulonodular opacities with enlarged lymph nodes can represent metastatic disease 6
• EGFR mutations may be present and respond to targeted therapy 6

Rare Genetic Disorders

Hermansky-Pudlak Syndrome

• Diffuse interstitial shadows with reticulonodular opacities in bilateral lung fields 7
• Associated with oculocutaneous albinism and platelet dysfunction 7
• Ceroid-like materials in alveolar macrophages on biopsy 7

Sarcoidosis

• Can mimic IPF on CT with reticular opacities 1
• Typically shows lymphadenopathy and upper/mid-lung predominance distinguishing it from IPF

Critical Diagnostic Approach

Distribution Pattern Analysis

• Peripheral and basal predominance: IPF, asbestosis, connective tissue disease 1
• Upper and mid-lung predominance: Hypersensitivity pneumonitis, sarcoidosis 1
• Diffuse bilateral symmetric: NSIP, drug-related pneumonitis 1

Associated CT Features to Identify

• Honeycombing: IPF (common), NSIP (rare) 1
• Traction bronchiectasis with ground glass: Always indicates fibrosis 1, 2
• Centrilobular nodules: Hypersensitivity pneumonitis, RBILD 1, 2
• Pleural plaques: Asbestosis 1
• Lymphadenopathy: Sarcoidosis, tuberculosis, malignancy 1, 3

Clinical Context Integration

• Smoking history: DIP, RBILD 1
• Occupational exposures: Asbestosis, hypersensitivity pneumonitis 1
• Medication history: Drug-related pneumonitis 1
• Systemic symptoms: Connective tissue disease, infection 1, 3
• Prior malignancy: Metastatic disease, lymphangitic spread 4, 6

Common Pitfalls to Avoid

• Do not diagnose IPF when ground glass opacity exceeds 30% of lung involvement—this suggests DIP, NSIP, or drug-related pneumonitis instead 1, 2
• Do not attribute worsening radiographs to treatment failure in tuberculosis patients—investigate for superimposed infection 3
• Do not overlook drug-related pneumonitis—always obtain detailed medication history including recent initiation of molecular targeting agents or immunotherapy 1
• Do not rely solely on CT pattern—multidisciplinary integration of clinical, radiologic, and when necessary, pathologic findings is essential 1
• Do not miss infectious causes—obtain BAL with cultures before attributing findings to non-infectious etiologies, especially in immunocompromised patients 1