Defining an Activated PI3K-delta Syndrome-like Endotype Within Broader Common Variable Immunodeficiency

Common variable immunodeficiency (CVID) is the most common symptomatic inborn error of immunity in the world. While the autoimmune and end-organ lympho-infiltrative complications that occur in patients with CVID continue to drive high morbidity and mortality, we lack available FDA-approved therapeutics to treat these noninfectious CVID-related complications. Previously, we used unbiased network clustering of noninfectious autoimmune and end-organ lympho-infiltrative complications to define a high-risk CVID patient endotype. Here, we asked whether this high-risk CVID patient endotype overlaps with the clinical spectrum of activated PI3K-delta syndrome (APDS), a rare inborn error of immunity that can clinically present as CVID and has an existing FDA-approved immunomodulator for disease management. Data including patient demographics, ICD-10 coded immunodeficiency diagnoses, ICD-10 coded noninfectious disease complications, and detailed immunophenotype were extracted from existing registry and research databases of 983 patients with predominantly antibody deficiency (PAD), which included 423 patients with CVID, and compared with 46 patients with APDS. Unbiased network clustering of noninfectious disease complications alone was sufficient to cluster APDS patients with high-risk CVID and PAD patient cohorts. Specifically, APDS patients clustered tightly with CVID patients with clinical evidence of splenomegaly, lymphadenopathy, autoimmune cytopenias, interstitial lung disease, liver disease, and gut lumen disease resembling celiac disease. Using the criterion of two or more autoimmune and end-organ lympho-infiltrative complications, we identified that 74% (N = 314) of CVID patients and 28% (N = 274) of PAD patients exhibited an ‘APDS-like’ phenotype. Future directions include overlapping patient immunophenotypes to determine how this impacts clinical clustering. Together, these data demonstrate that a significant proportion of CVID patients assessed at major tertiary care centers exhibit a spectrum of noninfectious autoimmune and end-organ lympho-infiltrative disease that closely resembles those observed in APDS and suggest a possible shared pathophysiology which may have therapeutic implications.