Pulmonary Manifestations of Immune Dysregulation in CTLA-4
Haploinsufficiency and LRBA Deficiency
Abstract
Objective: The primary immunodeficiency syndromes of cytotoxic T
lymphocyte-associated protein 4 (CTLA-4) haploinsufficiency and
lipopolysaccharide-responsive and beige-like anchor protein (LRBA)
deficiency present with multisystem immune dysregulation. The aim of
this study was to characterize and compare the pulmonary manifestations
of these two diseases. Methods: We retrospectively analyzed the
pulmonary clinical, radiologic, and histopathologic characteristics of 6
patients with CTLA-4 haploinsufficiency and 4 patients with LRBA
deficiency with pulmonary involvement followed at a large tertiary care
center. Results: Chronic respiratory symptoms were more frequent in
patients with LRBA deficiency versus CTLA-4 haploinsufficiency (4/4
versus 1/6). Cough was the most common respiratory symptom.
Abnormalities in pulmonary exam and pulmonary function testing were more
frequent in LRBA deficiency (4/4, 2/4) compared to CTLA-4
haploinsufficiency (1/6, 2/6). Chest CT findings included mediastinal
lymphadenopathy (4/4 in LRBA deficiency versus 1/4 in CTLA-4
haploinsufficiency), pulmonary nodules (4/4, 3/4), ground-glass
opacification (4/4, 3/4), and bronchiectasis (3/4, 1/4). Lymphocytic
inflammation, concentrated bronchovasculocentrically and paraseptally,
was observed in all patients who had lung biopsies (N=3 with LRBA
deficiency; N=3 with CTLA-4 haploinsufficiency). Granulomas were seen in
all patients with CTLA-4 haploinsufficiency and in no patients with LRBA
deficiency. Conclusion: Despite phenotypic overlap amongst these
diseases, LRBA deficiency demonstrated greater severity of pulmonary
disease, indicated by respiratory symptoms, pulmonary exam, and
intrathoracic radiologic findings. Lymphocytic inflammation is a key
histologic feature of both of these disorders. Pediatric pulmonologists
should suspect these disorders in the appropriate clinical,
radiological, and pathological context to better diagnose and treat
these patients.