Abstract Introduction Immunoglobulin G4-related disease (IgG4-RD) is a rare, fibroinflammatory disorder histologically characterized by dense lymphoplasmacytic infiltration with increased IgG4-positive plasma cells, storiform fibrosis, and obliterative phlebitis. Alveolar macrophage pneumonia (AMP, previously known as desquamative interstitial pneumonia, DIP) is a rare form of idiopathic interstitial pneumonia that predominantly affects smokers. However, it can occur in nonsmokers in association with other exposures (e.g., occupational dusts) or connective tissue diseases (CTDs). The association between the two conditions is exceedingly rare and poorly understood. Herein, we report a case of unexplained progressive AMP in a former smoker, with features suggestive of co-existing IgG4-RD. Case A 69-year-old man with chronic obstructive pulmonary disease, MALT lymphoma of the thyroid (treated in 2008), and prostate cancer in remission since 2021, presented with progressive dyspnea and radiographic ground-glass opacities (GGOs) with mediastinal lymphadenopathy on serial CT imaging from 2021 to 2025. He denied rheumatologic symptoms or significant occupational exposures. Examination revealed inspiratory crackles without systemic findings. Pulmonary function testing showed a mixed obstructive and restrictive pattern. Autoimmune serologies demonstrated a positive ANA (1:320) and weakly positive rheumatoid factor. Serum IgG4 was elevated, and IgE markedly increased (2,700 IU/mL). CTD evaluation was otherwise negative. High-resolution CT revealed progressive upper-lobe-predominant GGOs with peripheral and bronchovascular distribution. Video-assisted thoracoscopic biopsy showed alveolar filling by macrophages, multinucleated giant cells, and scattered eosinophils, findings consistent with AMP and follicular bronchiolitis. Lymphoplasmacytic inflammation was present with up to 15 IgG4-positive plasma cells per high-power field (IgG4/IgG ratio 10%). Obliterative phlebitis was noted, but storiform fibrosis was absent. Discussion This case highlights a rare overlap between AMP and IgG4-RD. While AMP is classically smoking-related, persistence or progression years after smoking cessation should prompt consideration of alternative or co-existing inflammatory pathways. IgG4-RD is characterized by lymphoplasmacytic inflammation, obliterative phlebitis, and elevated serum IgG4 levels, but its pulmonary manifestations are heterogeneous, ranging from airway disease to interstitial pneumonias that can mimic desquamative or cellular NSIP patterns. In this patient, the presence of lymphoplasmacytic inflammation with obliterative phlebitis, elevated serum IgG4, and striking hyper-IgE raised suspicion of a subclinical IgG4-related process, despite an IgG4/IgG ratio 10% and the absence of storiform fibrosis. Previous reports described similar “IgG4-positive interstitial pneumonias” with DIP-like features and partial steroid responsiveness, suggesting that IgG4-driven immune dysregulation may amplify macrophage-rich alveolitis. Recognition of this overlap has important clinical implications, as it broadens the differential diagnosis of unexplained or progressive AMP beyond smoking-related injury. This abstract is funded by: none
Seedahmed et al. (Fri,) studied this question.