Real-world evidence of mortality and survival rates in 256 individuals with APDS

Activated Phosphoinositide 3-kinase Delta Syndrome (APDS) is a rare genetic disorder that presents clinically as a primary immunodeficiency. Clinical presentation of APDS includes severe, recurrent infections, lymphoproliferation, lymphoma and other cancers, autoimmunity and enteropathy. Autosomal dominant variants in two independent genes have been demonstrated to cause APDS. Pathogenic variants in PIK3CD and PIK3R1 , both of which encode components of the PI3-kinase, have been identified in subjects with APDS. APDS1 is caused by gain of function (GOF) variants in the PIK3CD gene while loss of function (LOF) variants in PIK3R1 have been reported to cause APDS2. We conducted a review of the medical literature and identified 256 individuals who had a molecular diagnosis for APDS as well as age at last report; 193 individuals with APDS1 and 63 with APDS2. A Kaplan-Meier survival analysis for APDS showed the conditional survival rate at the age of 20 was 87%, age 30 was 74%, age 40 and 50 were 68%. Review of causes of death showed that the most common cause of death was lymphoma, followed by complications from HSCT. The mortality data suggests that the standard of care treatment for APDS, immunoglobulin replacement therapy, appears to prevent most deaths due to severe infection, however, new treatments are needed to mitigate the risk of death from lymphoma and other cancers. This analysis based on real world evidence gathered from the medical literature is the largest study of survival for APDS to date. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study did not receive any funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The source data used in this study were all openly available prior to the initiation of this study. All data was extracted from publications indexed in PubMed. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors