Systematic literature reviews to identify epidemiological, clinical, economic and health-related quality of life evidence in activated PI3Kδ syndrome (APDS).

Background: Activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) is an ultra-rare inborn error of immunity, characterised by immunodeficiency and immune dysregulation. Having only been recognised in 2013, evidence on APDS is limited. We carried out four systematic literature reviews (SLRs) to identify and narratively synthesise evidence on the following for APDS: epidemiology (epidemiology SLR), clinical efficacy/safety of treatments (clinical SLR), cost-effectiveness and costs/healthcare (HCRU) associated with (economic SLR) and health-related quality of life (HRQoL) and utility data (HRQoL SLR) from a global perspective.

Methods: The Cochrane Collaboration and the University of York's Centre for Reviews and Dissemination (CRD) guidelines were followed. MEDLINE, Embase, the Cochrane Library, University of York CRD, conference proceedings and other grey literature were searched through to May 2023 for all SLRs, except the epidemiology SLR (searched to Nov 2021); economic databases were also searched for the economic and HRQoL SLRs. Eligible records were: primary epidemiology publications (epidemiology SLR), interventional/observational studies of treatments (clinical SLR), cost/HCRU studies/economic evaluations (economic SLR) and HRQoL/utility studies (HRQoL SLR) in people with APDS. Risk of bias was assessed using the Downs and Black checklist (clinical SLR) and the Drummond checklist (economic SLR).

Results: The numbers of unique relevant studies identified were: 0 (epidemiology SLR), 117 (clinical SLR; 87 reported on <5 patients), 2 (economic SLR) and 1 (HRQoL SLR). The clinical SLR reported symptomatic treatments to be only partially effective at controlling APDS manifestations, with variable tolerability. Outcome reporting was heterogeneous and inconsistent, with small sample sizes and patients receiving multiple treatments, limiting interpretation of results. The economic SLR reported a high direct cost of APDS. Additional HRQoL/utility studies are required to evaluate the clinical and HRQoL burden of APDS and the impact of therapies.

Conclusion: Four methodologically robust SLRs identified limited evidence on epidemiology, clinical outcomes, costs and HRQoL in APDS, reflecting its ultra-rare nature and recent recognition. This suggests a need for more rigorous data evaluating the clinical and economic effectiveness of APDS treatments. Outcome reporting was highly heterogeneous and inconsistent across studies, sample sizes were small and patients often received multiple treatments, limiting interpretation of results.