Chronic Pulmonary and Systemic Inflammatory Manifestations Associated with Interstitial Lung Disease in Patients with Common Variable Immunodeficiency

Rationale Interstitial (diffuse) lung disease (ILD) in common variable immunodeficiency (CVID) patients significantly impacts their quality of life and survival. We aimed to identify phenotypic characteristics associated with ILD in a large U.S. cohort of CVID patients. Methods We conducted a cross-sectional analysis of 1,470 CVID cases in the USIDNET registry. The primary outcome was physician-diagnosed ILD. Clinical characteristics were compared using chi-square or Wilcoxon–Mann–Whitney tests. Logistic regression evaluated associations between respiratory comorbidities, immunological features, extrapulmonary autoimmunity, and ILD. Results There were 103 CVID patients with known ILD (7%). Their median age was 47 years (IQR 25) compared with 50 years (IQR 38) in the non-ILD group, with a similar sex distribution, predominantly female (62.1% vs. 61%). Most ILD patients were asymptomatic for chronic respiratory symptoms, but dyspnea (15.5% vs. 3.6%, p < 0.001) and weight loss (14.6% vs. 7.1%, p = 0.007) were the most frequent symptoms. ILD patients had lower serum IgA levels (7 mg/dL vs. 29 mg/dL, p < 0.001) and CD3+, CD4+, CD8+, and CD19+ lymphocyte counts (p < 0.01). Chronic respiratory comorbidities associated with ILD included lung granulomas/multiple nodules (OR 16.75, 95% CI 9.23-30.39, p < 0.0001) and bronchiectasis (OR 3.1, 95% CI 1.9-5.1, p < 0.0001) independent of age. In contrast, upper airway inflammatory conditions and lower airway diseases (e.g., asthma and COPD) were not significantly associated. CVID patients with extrapulmonary immune dysregulation, including hepatosplenomegaly (OR 6.29, 95% CI 4.16-9.51, p < 0.0001), cytopenias (OR 3.9, 95% CI 2.59-5.88, p < 0.0001), inflammatory GI disease (OR 1.76, 95% CI 1.18-2.65, p = 0.006), and autoimmune endocrine disorders (OR 1.69, 95% CI 1.06-2.69, p = 0.028) also had an increased likelihood of ILD. No significant associations were observed between ILD and autoimmune skin or rheumatologic diseases. Conclusions CVID patients with ILD feature a severe phenotype characterized by a higher frequency of bronchiectasis, lung granulomas/nodules, reduced IgA, and T and B cells, as well as non-pulmonary immune dysregulation, particularly hematologic, GI, and endocrine manifestations. These findings highlight the need for targeted monitoring of lung disease in patients with these complications. Despite limitations (risk of recall/selection/attrition bias), our study provides valuable clinical insights into ILD in CVID patients and motivates further research into this highly relevant clinical problem.