Clinical Manifestations and Outcomes of Activated Phosphoinositide 3-Kinase δ Syndrome from the USIDNET Cohort

Abstract

Background: Activated phosphoinositide 3-kinase δ syndrome is a combined primary immunodeficiency characterized by gain-of-function mutations in PIK3CD and PIK3R1. Activated phosphoinositide 3-kinase δ syndrome demonstrates a large range of phenotypes including respiratory and herpesvirus infections, lymphadenopathy, autoimmunity, and developmental delay.

Objective: To describe clinical phenotypes and disease outcomes of a large activated phosphoinositide 3-kinase δ syndrome cohort from the United States Immunodeficiency Network Registry.

Methods: A total of 38 patients were enrolled in the United States Immunodeficiency Network Registry, and 2 additional patients were obtained from the Clinical Immunology Division at Mount Sinai Hospital. Each patient's demographic characteristics, disease complications, genetic studies, laboratory data, therapeutic interventions, and clinical outcomes were reviewed.

Results: There was a high frequency of respiratory infections (70.0% pneumonia) and herpesvirus infections (37.5%). Bronchiectasis was observed in 45.0% of patients. Lymphadenopathy was common (52.5%), and 12.5% of patients developed lymphoma. Neurological and developmental findings were common: 20.0% had developmental delay, 15.0% had seizures, and 10.0% had dysmorphic features. Asthma was more common in PIK3CD compared with PIK3R1 patients (63.6% vs 14.3%). More subjects with PIK3CD had CD3 lymphopenia compared with the PIK3R1 cohort. Seven patients underwent hematopoietic stem cell transplantation. One patient died from infectious complications.

Conclusions: This is the first cohort comparing clinical manifestations in PIK3CD and PIK3R1 patients from the USIDNET Registry. Similar frequencies of respiratory and herpesvirus infections, lymphadenopathy, and developmental delay were observed compared with previous cohort studies. However, a higher frequency of asthma and CD3 lymphopenia in the PIK3CD cohort compared with the PIK3R1 cohort was observed.

Keywords: Activated phosphoinositide 3-kinase δ syndrome; Combined immunodeficiency; Phosphoinositide 3-kinase δ.

Figure 1.. Quantitative Immunoglobulins*

*Laboratory values are first available entry into the USIDNET registry and may not represent baseline values. The first available Immunoglobulin G (IgG) level at data entry ranged from 30 to 2153 mg/dL, with a median value of 881 mg/dL. 32.5% of patients presented with an IgG of less than 700 mg/dL. 53.8% of patients had a low immunoglobulin A (IgA) and 23.1% of patients had a low immunoglobulin M (IgM) based on normal age ranges. 53.8% of patients had high IgM values (greater than 230 mg/dL). There were no statistically significant differences between the PIK3CD cohort compared to the PIK3R1 cohort.

Figure 2.. Lymphocyte Values*

*Laboratory values are first available entry into the USIDNET registry and may not represent baseline values. CD4 lymphopenia (77.8%) was more pronounced than cytotoxic CD8 lymphopenia (44.4%). The PIK3CD cohort demonstrated a greater degree of CD3 lymphopenia when compared to the PIK3R1 cohort. The degree of CD4 and CD8 lymphopenia was also greater in the PIK3CD cohort compared to the PIK3R1 cohort.

Figure 3.. Clinical Features.

Clinical features are identified separately for PIK3CD and PIK3R1 patients. The most common clinical features were benign lymphoid hyperplasia, asthma, gastrointestinal disease, and bronchiectasis.

Figure 4.. Procedures and Surgeries

APDS patients are medically complex, with 75.0% of patients requiring at least one surgery or major procedure. On average, 3.8 procedures were performed per patient. The most common procedures were tympanostomy tubes, tonsillectomy/adenoidectomy, and bronchoscopy.