Genetic testing can reveal a molecular diagnosis in 20–40% of patients with inborn errors of immunity (IEI) such as predominantly antibody deficiencies (PAD), though this varies by IEI type and other factors. In patients with PAD, we hypothesize that there are clinical and epidemiologic characteristics that predict the probability of determining a molecular etiology with genetic testing.
We analyzed clinical characteristics of all patients with PAD diagnoses seen by immunology at a tertiary care academic medical center who underwent genetic testing. Exclusion criteria included patients with other non-PAD IEI diagnoses and genetic testing that did not assess PAD genes. PAD diagnoses, infections, and comorbidities were determined using ICD9/10 codes.
We identified 640 patients, of which 42% were female and 69% identified as white, non-Hispanic, or Latino. Median age at PAD diagnosis was 6.0 years (interquartile range [IQR] 2, 10). The first immunology evaluation was in the inpatient setting in 43% of patients. Patients had non-mutually exclusive PAD diagnoses of hypogammaglobulinemia (75%); antibody deficiency with near-normal immunoglobulins or hyperimmunoglobulinemia (28%); other immunodeficiencies with PAD (25%); common variable immunodeficiency (24%); selective IgA deficiency (15%); and immunodeficiency with PAD, unspecified (14%). Median age at genetic testing was 7 years (IQR 3,13) and included whole exome (64%), immunodeficiency panel (32%), whole genome (6%), and single gene (4%) sequencing. The number of patients with genetic testing has increased thirteen-fold over the last ten years. Evaluation with whole-genome sequencing has increased ten-fold over the last three years. Infection diagnoses were identified in the majority of patients with bacterial (15%), viral (13%), and fungal (6.3%) etiologies most classified. Acute otitis media (28%), pneumonia (24%), and acute sinusitis (9%) were identified. Most common comorbidity diagnoses by organ system were blood and blood-forming organs (75%), respiratory (38%), skin and subcutaneous tissue (18%), and nervous system (12%). Noninfectious complications were identified with lymphoproliferation (13%), autoimmune conditions (6.6%), bronchiectasis (5.6%), pulmonary fibrosis or interstitial lung disease (2.8%), and enteritis or colitis (0.9%). Hematologic malignancy was seen in 1.3% of patients.
Future investigation will include assessing clinical predictors of determining a molecular etiology for predominantly antibody deficiencies in those undergoing genetic testing.
