Activated PI3Kδ syndrome - reviewing challenges in diagnosis and treatment

Abstract

Activated PI3Kδ syndrome (APDS) is a rare inborn error of immunity (IEI) characterized primarily by frequent infections, lymphoproliferation and autoimmunity. Since its initial description in 2013, APDS has become part of the growing group of nearly 500 IEIs affecting various components of the immune system. The two subtypes of APDS - APDS1 and APDS2 - are caused by variants in the PIK3CD and PIK3R1 genes, respectively. Due to the rarity of the disease and the heterogeneous clinical picture, many patients are not diagnosed until years after symptom onset. Another challenge is the large number of PIK3CD and PIK3R1 variants whose functional significance for developing APDS is inconclusive. Treatment of APDS has so far been mostly symptom-oriented with immunoglobulin replacement therapy, immunosuppressive therapies and antibiotic or antiviral prophylaxes. Additionally, allogeneic stem cell transplantation as well as new targeted therapies are options targeting the root cause that may improve patients' quality of life and life expectancy. However, the clinical course of the disease is difficult to predict which complicates the choice of appropriate therapies. This review article discusses diagnostic procedures and current and future treatment options, and highlights the difficulties that physicians, patients and their caretakers face in managing this complex disease. This article is based on cohort studies, the German and US guidelines on the management of primary immunodeficiencies as well as on published experience with diagnosis and compiled treatment experience for APDS.

Keywords: APDS; IEI; PID; inborn errors of immunity; primary immunodeficiency; rare disease; stem cell transplantation; targeted therapy.

Figure 1

Schematic overview of typical signs, symptoms and affected organ systems in most APDS patients. Created with BioRender.com^©.

Figure 2

Simplified diagram of the PI3K signaling pathway in B cells and T cells, and targets for directed drug therapy. Other pathways also involving Pi3K (via IL-4R or CXCR5) are not depicted. Signaling events are extensively discussed in the text. Abbreviations: BCR, B cell receptor; TCR, T-cell receptor; Igα, CD79a; Igβ, CD79b; BCAP PI(*)P2, Phosphatidylinositol-*-bisphosphate; PI(*)P3, Phosphatidylinositol-*-trisphosphate; SH2, Src homology 2 domain; SHIP, SH2 domain-containing inositol-5-phosphatase; PTEN, phosphatase and tensin homologue; AKT, a SH2 containing serine/threonine kinase; TSC1-2 RHEB, RAS homologue enriched in brain; mTORC1, mTOR complex 1; S6K1, Ribosomal protein S6 kinase beta-1; FOXO1, Forkhead Box O1.

Figure 3

Variants in PIK3CD and PIK3R1 linked to APDS (52). (A) Linear depiction of p110δ and p85α proteins with confirmed, APDS-causing variants (B) Partial crystal structure of Homo sapiens p110δ (grey, positions commonly affected in APDS1 in yellow) in complex with part of the SH2 domains of Bos taurus p85α (green, positions commonly deleted in APDS2 in yellow), frequent APDS variants are indicated in yellow (MMDB-ID: 5DXU; image created with iCn3D webtool) (54). (C) Consequences of gene variants in p110δ (APDS1) and p85α (APDS2) on the PI3Kδ complex. iSH2, inter SH2 domain; cSH2, C-terminal SH2; nSH2, N-terminal SH2 domain; SH2, Src homology 2 domain.

Figure 4

Diagnostic workflow for suspected APDS patients. In all cases with increased susceptibility to infections an appropriate workup for a possible IEI is indicated. If a diagnosis is established genetic tests should follow. If one or more other clinical findings are present in addition to infections, genetic tests should follow independent from an IEI diagnosis.