Pulmonary Histopathology Findings in Patients With STAT3 Gain of Function Syndrome

Abstract

Introduction and Aim Multiorgan autoimmunity and interstitial lung disease (ILD) are reported in patients with STAT3 GOF syndrome. Results We present lung histopathology findings in 3 such children, two of whom underwent wedge biopsies with adequate diagnostic material. Wedge biopsies showed interstitial cellular expansion with linear and nodular aggregates of CD8 positive T lymphocytes, plasma cells, and histiocytes; consistent with lymphocytic interstitial pneumonia pattern (LIP). CD4+ T cells and CD20+ B cells were present but infrequent in the interstitium. FOXP3 cells ranged from 0-5%. Focal interstitial and intraalveolar histiocytes were also seen. Neutrophils and eosinophils were rare/absent. Non-occlusive peribronchial lymphoid aggregates showed equal T and B cells; likely reactive in nature. Pulmonary vessels appeared normal without vasculitis or hypertensive change. There was no interstitial or subepithelial fibrosis or organizing pneumonia. Interlobular septa and visceral pleura were unremarkable. Conclusion Children with multi-system autoimmune disorders with ILD should be investigated for STAT3 GOF syndrome. Lung wedge biopsies are more informative than transbronchial biopsies, if a tissue sampling is indicated. CD8 dominant T cell inflammation seems to be a key driver of ILD. Although interstitial fibrosis was not seen in our small sample, longer follow up is needed to understand the natural history.

Early‐onset, fatal interstitial lung disease in STAT3 gain‐of‐function patients

“…Chest CT scans displayed GGOs, cystic lesions and bronchiectasis at varying degrees. Histopathologic examination revealed either a cellular NSIP or LIP pattern, both of which have been reported in one or three STAT3 GOF individuals respectively 6,7 . Interstitial fibrosis, as seen in patient 3, has not been observed in a recently published, detailed histopathologic report of two cases 7 .…”

“…Histopathologic examination revealed either a cellular NSIP or LIP pattern, both of which have been reported in one or three STAT3 GOF individuals respectively. 6,7 Interstitial fibrosis, as seen in patient 3, has not been observed in a recently published, detailed histopathologic report of two cases. 7 BAL cytology suggested moderate lymphocytic inflammation with large predominance of CD8 expressing lymphocytes in all three patients.…”

“…6,7 Interstitial fibrosis, as seen in patient 3, has not been observed in a recently published, detailed histopathologic report of two cases. 7 BAL cytology suggested moderate lymphocytic inflammation with large predominance of CD8 expressing lymphocytes in all three patients. Such lymphocytosis with inverted CD4/CD8 ratio in BAL is, however, not disease-specific and has for example been reported in paediatric patients suffering from hypersensitivity pneumonitis.…”