What are the causes of diffuse interstitial infiltrates?

Causes of Diffuse Interstitial Infiltrates

Diffuse interstitial infiltrates have a broad differential diagnosis that can be systematically categorized into infectious, drug-related, inflammatory/autoimmune, malignant, and cardiac etiologies, with the specific cause determined by clinical context, timing, immune status, and radiologic patterns.

Infectious Causes

Opportunistic Infections (Immunocompromised Patients)

• Pneumocystis jirovecii pneumonia presents with diffuse bilateral perihilar infiltrates, ground-glass opacities with peripheral sparing, cysts, and septal thickening on CT 1
• Invasive fungal infections (Aspergillus, Blastomyces) manifest as nodular or cavitary lesions, particularly in patients receiving chemotherapy or immunosuppression 1, 2
• Mycobacterial infections (M. avium complex, M. kansasii) cause diffuse interstitial or reticulonodular infiltrates in HIV-positive patients, with apical involvement occurring in less than 10% of cases 3
• Viral pneumonias can produce diffuse interstitial patterns, particularly in immunocompromised hosts 1

Bacterial Pneumonia

• Atypical pneumonia patterns present with mononuclear inflammatory cell infiltrate in alveolar septa and interstitial tissue surrounding small parenchymal vessels 3
• Interstitial pneumonia patterns differ from lobar consolidation typical of bacterial pneumonia 3

Drug-Related Pneumonitis (DRP)

Immune Checkpoint Inhibitors and Targeted Therapies

• Drug-related pneumonitis presents with newly identified pulmonary parenchymal opacities in bilateral nonsegmental distribution with temporal association to drug initiation 3
• Common patterns include organizing pneumonia (OP), diffuse alveolar damage (DAD), cellular and fibrotic nonspecific interstitial pneumonia (NSIP), hypersensitivity pneumonitis (HP), and pulmonary eosinophilia 3
• Ground-glass opacities are characteristic radiologic findings 1
• Discontinuation of the offending drug is essential for management 1

Other Medications

• Antiarrhythmics, antihypertensives, antibiotics, anticonvulsants, methotrexate, and salicylates can cause drug-induced interstitial lung disease 3
• Methotrexate-related pneumonitis should be considered in patients with inflammatory bowel disease or rheumatologic conditions 3

Inflammatory and Autoimmune Causes

Idiopathic Interstitial Pneumonias

• Acute interstitial pneumonitis (AIP) presents with rapidly progressive diffuse pulmonary infiltrates, hypoxemia requiring mechanical ventilation, and organizing diffuse alveolar damage on biopsy 4
• Nonspecific interstitial pneumonia (NSIP) shows cellular or fibrotic patterns 3
• Organizing pneumonia (COP) demonstrates intraluminal plugs of granulation tissue in bronchioles extending into alveolar ducts with a characteristic "butterfly" pattern 3
• Lymphocytic interstitial pneumonia (LIP) shows monotonous sheets of lymphoplasmacytic cells expanding the interstitium 3
• Desquamative interstitial pneumonia (DIP) and respiratory bronchiolitis-ILD (RBILD) are smoking-related with predominance of macrophages containing smoking-related inclusions 3

Connective Tissue Disease-Associated ILD

• Inflammatory bowel disease can cause various interstitial lung patterns, most commonly organizing pneumonia, with development paralleling intestinal disease activity 3
• Granulomatous interstitial lung disease mimicking sarcoidosis occurs in Crohn's disease patients 3
• Other CTD-ILD patterns include usual interstitial pneumonia, eosinophilic pneumonia, and hypersensitivity pneumonitis 3

Hypersensitivity Pneumonitis

• Profuse centrilobular nodules, mosaic attenuation, and air-trapping on CT are characteristic 1
• Removal of the causative antigen is the primary intervention 1

Pulmonary Eosinophilia

• BAL cell differential with greater than 1% eosinophils represents an eosinophilic cellular pattern 3
• Acute eosinophilic pneumonia presents with rapidly progressive infiltrates 3

Malignant Causes

Pulmonary Lymphangitic Carcinomatosis

• Most commonly occurs with gastric, breast, lung, and pancreatic cancers 3
• Thickening of bronchovascular bundles and septae related to neoplastic cell proliferation, desmoplastic reaction, and lymphatic dilatation 3
• Can mimic drug-related pneumonitis or other benign conditions 5

Leukemic Infiltration

• Leukemic infiltration of the lungs causes diffuse early infiltrates in patients with acute leukemia undergoing remission induction therapy 6
• Diffuse malignant infiltration can mimic or coexist with interstitial lung disease 3

Metastatic Disease

• Diffuse interstitial infiltrative pattern of lung metastasis (e.g., malignant melanoma) can be confused with pulmonary edema or drug-induced pneumonitis 5

Cardiac and Vascular Causes

Pulmonary Edema

• Hydrostatic edema (cardiac or renal failure) causes expansion of connective tissue space around conducting airways, vessels, and interlobular septa 3
• Permeability edema (DAD pattern) shows alveolar space and interstitial edema with hyaline membrane formation 3
• Interstitial edema represents fluid accumulation in lung interstitium with pulmonary venous congestion, present in approximately 80% of acute heart failure cases 7
• Diuretics and optimization of cardiac function are recommended for treatment 1

Diffuse Alveolar Hemorrhage

• Injury to alveolar-capillary microcirculation (e.g., microscopic polyangiitis, ANCA-associated vasculitis) 3
• Presents with hemoptysis (in two-thirds of patients), anemia, and diffuse opacity on imaging 3
• Intra-alveolar hemorrhage with hemosiderin-laden macrophages on BAL 3

Radiation-Related

Radiation Pneumonitis

• Temporal relationship to radiation exposure (3-12 weeks after irradiation) 3
• Airspace and interstitial edema progressing to poorly defined consolidation, DAD, and type II cell hyperplasia 3
• Hypersensitivity pneumonitis or organizing pneumonia patterns can occur away from radiation portal 3

Key Diagnostic Considerations

BAL Cellular Analysis Patterns

• Lymphocytic pattern (>15% lymphocytes): sarcoidosis, hypersensitivity pneumonitis, drug-induced pneumonitis, organizing pneumonia 3
• Neutrophilic pattern (>3% neutrophils): idiopathic pulmonary fibrosis, acute interstitial pneumonia, connective tissue disease-ILD 3
• Eosinophilic pattern (>1% eosinophils): eosinophilic pneumonia, drug reactions, parasitic infections 3

Critical Pitfalls to Avoid

• Do not assume fungal isolates represent colonization in immunocompromised or elderly patients with chronic symptoms; BAL fluid cultures identified Pneumocystis jirovecii in 46% of patients initially diagnosed with drug-related pneumonitis 3
• Tumor infiltration (pulmonary lymphangitis, carcinomatous meningitis) can be revealed by immune checkpoint inhibitors and mimic pneumonitis 3
• Infectious organisms must be excluded through BAL fluid cultures before attributing infiltrates to non-infectious causes 3, 1
• In acute leukemia patients, diffuse early infiltrates may be caused by leukemic infiltration, pulmonary hemorrhage/edema, diffuse alveolar damage, viral pneumonia, or transfusion-related acute lung injury 6