The aim of this study was to characterize the clinical manifestations, treatment responses, and prognostic indicators of activated PI3K-δ syndrome (APDS) in pediatric patients. Clinical data from three patients diagnosed with APDS in our department were retrospectively analyzed. All patients carried the same heterozygous E1021K (c.3061G > A) gain-of-function mutation in the PIK3CD gene. Immunoglobulin levels varied: IgM was normal or elevated, while IgG and IgA were normal or decreased, with the extent of change correlating with disease severity. All three children received anti-infective therapy, resulting in significant improvement in clinical symptoms and chest imaging findings. Bronchoscopic re-evaluation in Cases 1 and 2 showed marked regression of airway mucosal hyperplasia. Following diagnosis, Cases 1 and 2 received regular immunoglobulin replacement therapy, which reduced the frequency of infections. Case 2 was treated with rapamycin as targeted therapy, leading to significant improvement in hepatosplenomegaly. In conclusion, bronchoscopic detection of nodular lymphoid hyperplasia is a diagnostic hallmark of APDS. Progressive T-cell exhaustion and immunoglobulin dysregulation may serve as biomarkers of disease severity. Targeted therapy, such as rapamycin, demonstrates clinical efficacy. This case series underscores the variable expressivity of APDS even among individuals sharing the same pathogenic variant, emphasizing the need for personalized management.

Activated phosphoinositide 3-kinase delta syndrome (APDS) is an inborn error of immunity first described in 2013. With an estimated prevalence of 1-2 per 1,000,000 individuals, it is considered an ultra-rare disease. The aim of this survey was to explore the diagnostic and therapeutic challenges of patients with APDS from the patients` and physicians` perspective in Austria, Germany, and Switzerland. A qualitative case study approach was applied. Semi-structured interviews were conducted with six patients or legal guardians of children with APDS, and four clinical immunologists with direct experience in APDS care. Transcripts were analyzed using inductive content analysis. The interviews revealed a median diagnostic delay of several years, mainly due to the rarity and phenotypic heterogeneity of APDS and the involvement of multiple specialties prior to referral to an immunologist. Many patients initially received symptomatic treatment before an underlying immune disorder was suspected. Physicians emphasized the decisive role of genetic testing for confirmation, while patients frequently described the diagnosis as a "lucky coincidence". Both groups highlighted structural barriers including limited awareness, fragmented care, and delayed access to targeted therapy. Early recognition of APDS requires specific education across specialties, wider access to genetic testing, and the development of standardized diagnostic and disease activity tools. Strengthening interdisciplinary care pathways and timely initiation of APDS-specific therapy may substantially improve outcomes in this ultra-rare immunodeficiency.

Activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) is an ultra-rare, progressive disease characterised by immunodeficiency, immune dysregulation, and risk of malignancies. To further characterise the natural history of APDS, we analysed patient characteristics, manifestations, treatment use, and combinations of manifestations and combinations of treatments over time using longitudinal data from registration and follow-up visits in the European Society for Immunodeficiencies (ESID)-APDS registry. 140 patients were included (mean age: 17.7 years at registration; 19.1 years at last follow-up). Manifestation burden was high from childhood (patients experienced up to 9 manifestations by age 10). The number of treatments increased with age, with a 64 % probability of receiving ≥1 by age 10. Life-threatening APDS complications led to 13 deaths reported over 2.6 years' mean follow-up. These data highlight the chronic, progressive nature of APDS and its long-term impact on patients, with a high manifestation load and early mortality, despite widespread symptomatic treatment use.

Activated PI3Kδ Syndrome (APDS) is a rare inborn error of immunity characterized by recurrent infections, lymphoproliferation, and autoimmunity. It results from mutations in the phosphoinositide 3-kinase delta (PI3Kδ) signalling pathway, leading to either gain-of-function (APDS1) or loss-of-function (APDS2) phenotypes. Clinical presentation ranges from asymptomatic to severe, depending on the underlying genetic defect. Malignancy, particularly lymphoma, represents the most frequent and life-threatening complication. Due to overlapping features with other primary immunodeficiencies, APDS is often misdiagnosed as combined immunodeficiency. Early molecular testing, particularly genetic analysis, is therefore crucial for accurate diagnosis. Although management remains complex and heterogeneous, there is growing interest in targeted approaches, particularly PI3Kδ-specific therapy. We describe a 12-year-old boy with recurrent respiratory and ear infections since infancy, accompanied by persistent lymphadenopathy, hepatosplenomegaly, and thrombocytopenia. Initial immunological evaluation suggested combined immunodeficiency, and prophylactic antibiotics were initiated, but genetic testing was deferred due to mild clinical features and parental reluctance. Following multiple years of enduring symptoms, genetic investigation identified a PIK3CD mutation leading in a missense alteration p.Glu1021Lys, confirming APDS 1. The patient was subsequently commenced on immunoglobulin replacement therapy and consulted for consideration of immunosuppressive and targeted pathway blocker therapy. This case highlights the diagnostic challenges of APDS, arising from both overlapping clinical features with other immunodeficiencies and external factors such as cost and parental decision-making. Early genetic testing facilitates accurate diagnosis, and timely recognition of APDS enables appropriate management, including immunosuppressive, targeted therapies and, in selected cases, potentially curative hematopoietic stem cell transplantation.

Activated phosphoinositide 3-kinase delta syndrome (APDS) is an ultra-rare, underrecognized inborn error of immunity. This study aimed to identify outcomes important in evaluating APDS treatment effectiveness and percent change in specific outcomes indicating a clinically meaningful benefit. In this e-Delphi panel study, 28 globally based APDS experts used a 5-point Likert scale (Strongly Disagree to Strongly Agree) to indicate level of agreement that an outcome was an important measure of APDS treatment effectiveness in adult and pediatric patients at 3 and 6 months after treatment initiation. A threshold of ≥75% responding with "Agree" or "Strongly Agree" was considered consensus. Percent meaningful improvement in 6 outcomes was assessed and applied to APDS trial data (NCT02435173). Twenty-four panelists participated; e-Delphi rounds 1-5 were completed by 23, 21, 18, 17, and 16 panelists, respectively. Outcomes with the highest degree of consensus included lymph node size/volume, clinician overall impression of disease activity, antibiotic use, patient/caregiver-reported social outcomes and patient quality of life, hospitalizations, thrombocytopenia, spleen volume, lymphopenia, and anemia. Panelists indicated within-patient clinically meaningful improvements in adult patients ranged from median values of 20%-25% in lymph nodes, naïve B-cell to total B-cell ratio, spleen volume, hemoglobin, platelets, and lymphocytes at 3 months, and 25%-30% at 6 months. Panelists indicated within-patient clinically meaningful improvements in pediatric patients ranged from median values of 20%-27.5% at 3 months and 22.5%-45% at 6 months in the same 6 outcomes. In an application of responder thresholds, treatment with leniolisib resulted in significant and meaningful improvements in disease hallmarks, including lymph node size, spleen volume, and naïve B-cell ratio. This study provides expert consensus on outcomes important in assessing APDS treatment effectiveness and improvement thresholds in 6 treatment outcomes indicative of a clinically meaningful benefit. These outcomes may help optimize APDS treatment in the clinic.