Activated phosphoinositide 3-kinase (PI3K) δ Syndrome (APDS), caused by
autosomal dominant mutations in PIK3CD (APDS1) or
PIK3R1 (APDS2), is a heterogeneous primary immunodeficiency.
While initial cohort-descriptions summarized the spectrum of clinical and
immunological manifestations, questions about long-term disease evolution and
response to therapy remain. The prospective European Society for Immunodeficiencies
(ESID)-APDS registry aims to characterize the disease course, identify outcome
predictors, and evaluate treatment responses. So far, 77 patients have been recruited
(51 APDS1, 26 APDS2). Analysis of disease evolution in the first 68 patients
pinpoints the early occurrence of recurrent respiratory infections followed by
chronic lymphoproliferation, gastrointestinal manifestations, and cytopenias.
Although most manifestations occur by age 15, adult-onset and asymptomatic courses
were documented. Bronchiectasis was observed in 24/40 APDS1 patients who received a
CT-scan compared with 4/15 APDS2 patients. By age 20, half of the patients had
received at least one immunosuppressant, but 2–3 lines of immunosuppressive
therapy were not unusual before age 10. Response to rapamycin was rated by physician
visual analog scale as good in 10, moderate in 9, and poor in 7. Lymphoproliferation
showed the best response (8 complete, 11 partial, 6 no remission), while bowel
inflammation (3 complete, 3 partial, 9 no remission) and cytopenia (3 complete, 2
partial, 9 no remission) responded less well. Hence, non-lymphoproliferative
manifestations should be a key target for novel therapies. This report from the
ESID-APDS registry provides comprehensive baseline documentation for a growing cohort
that will be followed prospectively to establish prognostic factors and identify
patients for treatment studies.
Background
Vaccination prevents severe morbidity and mortality from COVID-19 in the general population. The immunogenicity and efficacy of SARS-CoV-2 vaccines in patients with antibody deficiency is poorly understood.
Objectives
COVID-19 in patients with antibody deficiency (COV-AD) is a multi-site UK study that aims to determine the immune response to SARS-CoV-2 infection and vaccination in patients with primary or secondary antibody deficiency, a population that suffers from severe and recurrent infection and does not respond well to vaccination.
Methods
Individuals on immunoglobulin replacement therapy or with an IgG less than 4 g/L receiving antibiotic prophylaxis were recruited from April 2021. Serological and cellular responses were determined using ELISA, live-virus neutralisation and interferon gamma release assays. SARS-CoV-2 infection and clearance were determined by PCR from serial nasopharyngeal swabs.
Results
A total of 5.6% (n = 320) of the cohort reported prior SARS-CoV-2 infection, but only 0.3% remained PCR positive on study entry. Seropositivity, following two doses of SARS-CoV-2 vaccination, was 54.8% (n = 168) compared with 100% of healthy controls (n = 205). The magnitude of the antibody response and its neutralising capacity were both significantly reduced compared to controls. Participants vaccinated with the Pfizer/BioNTech vaccine were more likely to be seropositive (65.7% vs. 48.0%, p = 0.03) and have higher antibody levels compared with the AstraZeneca vaccine (IgGAM ratio 3.73 vs. 2.39, p = 0.0003). T cell responses post vaccination was demonstrable in 46.2% of participants and were associated with better antibody responses but there was no difference between the two vaccines. Eleven vaccine-breakthrough infections have occurred to date, 10 of them in recipients of the AstraZeneca vaccine.
Conclusion
SARS-CoV-2 vaccines demonstrate reduced immunogenicity in patients with antibody deficiency with evidence of vaccine breakthrough infection.
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