Skip to main content
Download PDF

Overall survival among patients with activated phosphoinositide 3-kinase delta syndrome (APDS)

Orphanet Journal of Rare Diseases volume 20, Article number: 212 (2025) Cite this article

Abstract

Background

This study aimed to describe overall survival (OS) of patients with APDS relative to the global population as well as among subsets of patients with concurrent lymphoma or hematopoietic stem cell transplant (HSCT) relative to the overall APDS population.

Methods

Patient-level data were extracted from a recent systematic literature review of 351 unique patients with APDS. OS was evaluated using the Kaplan-Meier method up to age 65 years. OS rate and corresponding 95% CI were reported at each decade of age. Global mortality estimates were obtained from World Health Organization life tables for 2019.

Results

Of the 351 patients with APDS (APDS1, 267 [76.1%]; APDS2, 83 [23.6%]; unspecified, 1 [0.3%]), 41 (11.7%) died. The OS rate was 25.0% (95% CI, 1.6–62.7%) by the last death event at 64 years of age. Starting at 12 years of age, the OS rate was numerically lower in patients with APDS relative to the global population (median OS, 64 vs. 75 years, respectively). Relative to the overall APDS population, OS rates were numerically similar in those who underwent HSCT (median OS, 64 years for both; p = 0.569), whereas OS rates were numerically lower in patients with concurrent lymphoma (median OS, 41 vs. 64 years, respectively; p = 0.109). Publication bias in source data was a possible limitation.

Conclusion

Reduced survival in patients with APDS suggests a high disease burden, particularly in those with concurrent lymphoma. These results highlight the unmet need for disease-modifying treatments for APDS.

Introduction

Activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS)—also known as p110 delta–activating variant causing senescent T cells, lymphadenopathy, and immunodeficiency (PASLI)—is an underrecognized, rare primary immunodeficiency (PID) that was first characterized in 2013 [1,2,3]. As an inborn error of immunity, APDS is caused by variants in one of two genes that encode subunits of PI3Kδ [3,4,5]. Gain-of-function mutations in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (PIK3CD) gene encoding the p110δ catalytic subunit of PI3Kδ lead to APDS1, and loss-of-function mutations in the phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) gene encoding the p85α regulatory subunit of PI3Kδ lead to APDS2 [1, 2, 4,5,6,7,8,9]. These genetic mutations result in overactivation of the PI3K/AKT/mTOR/S6K signaling pathway, which alters B-cell and T-cell growth, survival, proliferation, and differentiation, ultimately leading to immune deficiency and dysregulation [4,5,6, 9, 10].

Patients diagnosed with APDS exhibit a diverse range of symptoms that typically present in infancy or early childhood, with APDS1 and APDS2 often displaying similar clinical features [4, 11, 12]. Recurrent respiratory tract infections are nearly ubiquitous among patients with APDS and may be accompanied by other manifestations such as bronchiectasis, persistent herpesvirus infections, various viral and bacterial infections, non-neoplastic lymphoproliferation involving lymphadenopathy, splenomegaly and hepatomegaly, autoimmune and autoinflammatory conditions, neurodevelopmental issues, and growth deficiencies [4, 11, 12]. Additionally, concurrent lymphoma has been reported in up to 25% of patients with APDS [11,12,13]. Although some adults with APDS may be asymptomatic, many patients experience considerable morbidity, and infection-related fatalities have been documented in children and young adults with APDS [11].

Manifestations associated with APDS are variable and may be progressive and detrimental over time [4]. There are currently no treatment guidelines defining standard of care. Therapies for APDS can vary according to clinical manifestations and may include antimicrobial prophylaxis, mTOR inhibitors, immunomodulatory therapies, immunoglobulin replacement therapy, and splenectomy [4]. Notably, none of these treatment strategies target the underlying pathogenesis of APDS. Hematopoietic stem cell transplant (HSCT) has been used to treat APDS when severe immune deficiency is present. However, the risks of adverse events and mortality limit the clinical application of HSCT [4, 14,15,16]. In 2023, leniolisib, an oral selective PI3Kδ inhibitor, became the first and only treatment approved in the US for APDS after meeting both coprimary outcomes of reduction in index lymph node size and increase in the percentage of naïve to total B cells in the peripheral blood (p < 0.001 for both).

As APDS was only characterized within the last decade, there is a paucity of published literature on the clinical course of the disease, including the survival pattern of patients with APDS [5, 6]. Small cohort studies of APDS1 and APDS2 have reported 30-year overall survival rates of 86% and < 75%, respectively [12, 16], while a larger systematic literature review of 256 patients with APDS reported a 30-year overall survival rate of 74% [17]. However, these analyses did not contextualize the overall survival of patients with APDS relative to the general population or account for the impact of therapies.

To shed light on these gaps in the literature, this study estimated the overall survival of patients with APDS relative to the global population using patient-level data from a systematic literature review. Additional objectives were to describe overall survival by APDS subtype, in patients with concurrent lymphoma, and censoring for patients who were treated with HSCT.

Methods

Patient-level data were extracted via a systematic literature review that has been previously detailed [18]. Briefly, the systematic literature review followed the PICO (population, intervention, comparator, and outcome) principle (Table 1) [19]. A comprehensive literature search in PubMed and Embase databases was conducted from the time of each database’s inception to March 13, 2023, to identify relevant publications that included data on patients with APDS and their survival status [19, 20]. To be included in the study population, patients were required to have a reported APDS diagnosis or a first-degree relative with genetically confirmed APDS and at least 1 reported clinical sign consistent with APDS. When available, data on age at last observation, death, age at death, sex, APDS subtype (APDS1 or APDS2), concurrent lymphoma, HSCT, age at HSCT, and age at leniolisib initiation were extracted from the literature within the systematic literature review [1, 2, 7, 8, 11, 12, 15, 16, 21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120].

Table 1 PICO criteria
Full size table

Global mortality estimates were obtained from the World Health Organization (WHO) life tables for 2019 and were used to estimate overall survival for the global population [121].

Statistical analysis

Overall survival was evaluated using the Kaplan-Meier method and defined as the time from birth to the age of death due to any cause. The overall survival rate and corresponding 95% CIs were estimated up to 65 years of age, as the maximum age of death reported in the individual patient data was 64 years. Median overall survival was defined as the age when the overall survival rate of patients with APDS was 50%. To ensure that the overall survival rate in patients with APDS accounted for therapies used as supportive care, patients treated with leniolisib were censored at the age of leniolisib initiation. In the analysis that censored for HSCT, patients who underwent HSCT were censored at the age of transplant.

The overall survival rate of the global population was derived using the probability of dying (qx) at specific age intervals. Overall survival rates of the global population were calculated using the following formula:

$$\:{S}_{t}=\left(1-{q}_{x\left(t\right)}\right)\:\times\:\:{S}_{t-1}$$

Where St represents the overall survival rate at age interval t, qx(t) represents the probability of dying at time t, and St–1 represents the overall survival rate at the prior age interval. The overall survival rate at 0 years of age was imputed as 1.

Overall survival rates between groups of patients were compared using a log-rank test to determine whether differences in survival were statistically significant. Comparisons were made between the following groups: (1) patients with APDS1 versus APDS2 (2) patients with APDS with concurrent lymphoma versus without concurrent lymphoma, and (3) patients with APDS who received HSCT versus those who did not receive HSCT.

All analyses were conducted using SAS Enterprise Guide software Version 7.15 (SAS Institute, Cary, NC).

Results

Patient characteristics

Among 108 eligible publications from the systematic literature review (Fig. 1), 351 unique patients with APDS were identified: 267 patients (76.1%) with APDS1 and 83 patients (23.6%) with APDS2 (Table 2) [18]. One patient (0.3%) did not have a specified APDS subtype and was excluded from the stratified analyses. Overall, 171 patients (49%) were male, 135 (38%) were female, and 45 (13%) did not have sex reported. Lymphoma was reported in 43 patients (12.3%) with APDS. A total of 46 patients (13.1%) were reported to have undergone HSCT, of whom 6 patients were excluded from the censoring analysis, as the age at the time of the procedure was not reported. Leniolisib use was reported for 13 patients (3.7%), none of whom were treated with HSCT.

Fig. 1
figure 1

PRISMA flow diagram providing the review process. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses

Full size image
Table 2 Patient characteristicsa
Full size table

Overall survival

Of the 351 patients with APDS, 41 (11.7%) died, and the median overall survival was 64 years (Fig. 2). The estimated overall survival rate reached 25.0% (95% CI, 1.6–62.7%) by the last death event at 64 years of age. Starting from 12 years of age, the estimated overall survival of patients with APDS was numerically lower relative to the global population, with the estimated overall survival rate being 17.0% and 21.2% lower at 30 and 40 years of age, respectively. The median overall survival in the global population was 75 years.

Fig. 2
figure 2

Kaplan-Meier curve of overall survival in patients with APDS and the global population. APDS, activated phosphoinositide 3-kinase delta syndrome

Full size image

Among the 267 patients with APDS1, 31 (11.6%) died, and median overall survival was 64 years (Fig. 3A). The estimated overall survival rate among patients with APDS1 reached 27.1% (95% CI, 1.6–66.2%) by the last death event at 64 years of age. Starting from 11 years of age, the estimated overall survival of patients with APDS1 was numerically lower relative to the global population. At 30 and 40 years of age, the estimated overall survival rate was 15.0% and 18.9% lower, respectively, relative to the global population.

Fig. 3
figure 3

Kaplan-Meier curve of overall survival in patients with (A) APDS1 or (B) APDS2 and the global population, or (C) APDS1 versus APDS2. APDS, activated phosphoinositide 3-kinase delta syndrome

Full size image

Among the 83 patients with APDS2, 10 (12.0%) died, and median overall survival was not reached (Fig. 3B). The estimated overall survival rate among patients with APDS2 reached 55.6% (95% CI, 28.6–75.9%) by the last death event at 41 years of age. Starting at nearly 15 years of age, the estimated overall survival of patients with APDS2 was numerically lower relative to the global population. At 30 and 40 years of age, the estimated overall survival rate was 21.4% and 26.3% lower, respectively, relative to the global population. There was no significant difference in overall survival between patients with APDS1 and patients with APDS2 (p = 0.899) (Fig. 3C).

In the 43 patients with APDS and reported concurrent lymphoma, 13 (30.2%) died and the median overall survival was 41 years (Fig. 4A). Relative to the overall population of patients with APDS, the estimated overall survival of patients with APDS and concurrent lymphoma was numerically lower across nearly all ages. The estimated overall survival rate among patients with APDS and concurrent lymphoma reached 42.7% (95% CI, 17.9–65.7%) by the last death event at 41 years of age, relative to the estimated overall survival rate of 66.8% (95% CI, 53.7–76.9%) in the overall population of patients with APDS at the same age. Overall survival was further compared between the 43 patients with concurrent lymphoma and the 308 patients without concurrent lymphoma (Fig. 4B). Although the overall survival rate was observed to be up to 23.5% lower in patients with APDS and concurrent lymphoma compared with those without lymphoma, the difference between these two groups was not significant (p = 0.109).

Fig. 4
figure 4

Kaplan-Meier curve of overall survival in (A) patients with APDS and APDS with concurrent lymphoma or (B) patients with APDS with concurrent lymphoma versus without concurrent lymphoma. APDS, activated phosphoinositide 3-kinase delta syndrome

Full size image

Of 40 patients reported to have undergone HSCT and for whom an age at transplant was available, 5 (12.5%) died. The mean follow-up time between transplant and last reported age was 3.7 years (SD, 4.5; range, 0–16), with 16 (40%) and 9 (22.5%) patients having at least 3 and 5 years of follow-up after transplant, respectively. The overall survival of patients with APDS was largely consistent across ages after censoring for HSCT (Fig. 5A). The median overall survival of patients with APDS censored for HSCT was 64 years, consistent with the overall APDS population. Beginning at approximately 4 years of age, estimated overall survival when censoring for HSCT was numerically higher than the overall survival when not censoring for HSCT, with the largest difference in the estimated overall survival rate observed at 15 years of age (censored for HSCT, 92.3% [95% CI, 88.0–95.2%]; not censored for HSCT, 91.3% [95% CI, 86.8–94.3%]). Overall survival was also evaluated between the 46 patients with APDS who had undergone HSCT and those who had not (n = 305) (Fig. 5B). Although median overall survival among patients with APDS who had not undergone HSCT was 57 years and was not reached in those who had undergone HSCT, no significant difference was observed between these two groups (p = 0.569).

Fig. 5
figure 5

Kaplan-Meier curve of overall survival in (A) patients with APDS and censoring at age of HSCT or (B) patients with APDS with HSCT versus without HSCT. APDS, activated phosphoinositide 3-kinase delta syndrome; HSCT, hematopoietic stem cell transplant

Full size image

Discussion

Using individual data from 351 patients with APDS obtained via a systematic literature review, this study estimated a lower overall survival rate among the overall APDS population relative to the global population and across APDS subtype. Early mortality in patients with APDS was evidenced by a median overall survival of 64 years, an 11-year difference compared with 75 years in the global population. In addition, overall survival rates for patients with APDS were up to 28% lower than that of the global population, underscoring the significant morbidity of APDS that can lead to shorter lifespans. The estimated 30-year overall survival rate observed in this study (76.4%) aligns with a previous report of the 30-year overall survival rate in 256 patients with APDS (74%), among whom no significant difference in overall survival between APDS1 and APDS2 was also observed [17]. To our knowledge, our study provides the most current and comprehensive estimate of overall survival among patients with APDS [12, 16, 17].

In this study, a divergence in survival between patients with APDS and the global population was observed beginning in adolescence and sustained through adulthood. Nearly all patients with APDS (98%) experience their first symptoms of APDS in infancy or childhood at a median age of 2.0 years (range, birth to 22 years). In contrast, the median age of diagnosis is 13.4 years (range, 0–56 years) [18]. Delays in APDS diagnosis of a median 7.0 years (IQR, 3.4–14.0 years) and mean 10.6 years (range, 0–44 years) have been previously reported [18, 122]. The mortality implications of early onset of APDS manifestations coupled with delays in diagnosis and lack of effective early interventions are not fully understood. However, findings from our study suggest that timely diagnosis and effective management of APDS at first presentation of symptoms may improve survival in these patients but should be confirmed in future analyses of OS relative to the diagnostic timing.

Our findings also highlight the exacerbated mortality of patients with APDS and concurrent lymphoma, with a median overall survival of 41 years. The cumulative risk of lymphoid malignancy has been previously estimated to be as high as 78% at 40 years of age, and up to 62% of APDS fatalities may be attributable to lymphoma [12, 123]. In this study, the overall survival rate in patients with APDS and concurrent lymphoma was 42.7% at 41 years of age, compared with 66.8% in the overall APDS population at the same age. Although we did not observe a significant difference in overall survival between patients with APDS with and without concurrent lymphoma, an empirical assessment of the data suggests an accelerated decline in survival among patients with APDS and concurrent lymphoma relative to those without concurrent lymphoma and to the overall APDS population. Thus, our findings underscore the considerable influence of concurrent lymphoma on overall survival and emphasize the importance of focusing mitigation efforts on decreasing the incidence of lymphoma in patients with APDS.

Previous literature suggests that HSCT can reverse some phenotypes of APDS or achieve a cure; the reported overall survival rates after HSCT were 81% over follow-up periods ranging from 8 months to 16 years and 86% at 2 years [14, 15]. However, prior studies have also reported high rates of complications following HSCT, including graft instability or failure and severe infection [14,15,16]. In this study, we observed that the estimated overall survival of patients with APDS remained largely unchanged when censoring for HSCT. Moreover, no significant difference was noted when overall survival in patients with APDS who were reported to have undergone HSCT was compared with overall survival in those who had not. With the data available at the time of this analysis, our results suggest that HSCT may not provide a meaningful clinical benefit in survival in patients with APDS and ongoing evaluation is warranted. Further investigations are warranted to assess whether the benefits observed with HSCT outweigh the risk of adverse complications including graft failure or instability, poor graft function, graft vs. host disease, and mortality [14,15,16,17, 122].

The results of this study should be considered within the context of its limitations. First, this study relied on published data, potentially introducing publication bias. However, this study includes a large collection of publications describing patients with APDS across multiple countries to help mitigate bias. Secondly, age-related information in the literature predominantly focuses on early decades of life, resulting in fewer data available for the construction of Kaplan-Meier curves for later decades. Given the recent characterization of APDS in 2013 and a median age of diagnosis of 12 years, the distribution of age among patients with APDS observed in our study may be reflective of real-world trends [1, 2, 122]. Additionally, the follow-up time after HSCT was based on follow-up times noted in the literature. Therefore, the time between age at HSCT and last age observed may not have been sufficient to capture the long-term survival benefit associated with transplant. Likewise, literature references reported that only 13 patients received leniolisib, which precluded the assessment of the impact of leniolisib on overall survival. With the approval of leniolisib for treatment of APDS in 2023 by the US Food and Drug Administration, future studies may extend the present findings by evaluating its impact on mortality. Additionally, the creation of an International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) code for APDS (D81.82) in 2023 may also help identify patients for future analyses. Finally, due to lack of individual data for the global population, CIs for survival estimates could not be calculated in this population, and a statistical comparison of overall survival between the overall APDS population and global population was not feasible. Despite these limitations, our assessment of APDS mortality relative to the global population sheds light on the considerable burden of this disease. Moreover, our study assesses the largest number of patients with APDS for whom survival has been evaluated, increasing the generalizability of our findings to the broader APDS population, and it is the first study to evaluate the impact of concurrent lymphoma and HSCT on survival.

Conclusions

This study provides the most current and comprehensive estimate of overall survival in patients with APDS. Relative to the global population, the overall survival rate was lower among the overall APDS population and across APDS subtype, with no difference in mortality between APDS1 and APDS2. The observed lack of improvement in survival after HSCT warrants further investigation of the impact of this therapy in patients with APDS. Findings from this study indicate a high disease burden associated with APDS, particularly in patients with concurrent lymphoma, highlighting the unmet need for disease-modifying treatments to improve survival in this patient population.

Data availability

Data used within this manuscript are available in PubMed and Embase.

References

  1. Angulo I, Vadas O, Garçon F, Banham-Hall E, Plagnol V, Leahy TR, et al. Phosphoinositide 3-kinase δ gene mutation predisposes to respiratory infection and airway damage. Science. 2013;342(6160):866–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Lucas CL, Zhang Y, Venida A, Wang Y, Hughes J, McElwee J, et al. Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K. J Exp Med. 2014;211(13):2537–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Vanselow S, Wahn V, Schuetz C. Activated PI3Kδ syndrome - reviewing challenges in diagnosis and treatment. Front Immunol. 2023;14:1208567.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Coulter TI, Cant AJ. The treatment of activated PI3Kδ syndrome. Front Immunol. 2018;9:2043.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Michalovich D, Nejentsev S. Activated PI3 kinase delta syndrome: from genetics to therapy. Front Immunol. 2018;9:369.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Oh J, Garabedian E, Fuleihan R, Cunningham-Rundles C. Clinical manifestations and outcomes of activated phosphoinositide 3-kinase δ syndrome from the USIDNET cohort. J Allergy Clin Immunol Pract. 2021;9(11):4095–102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lucas CL, Kuehn HS, Zhao F, Niemela JE, Deenick EK, Palendira U, et al. Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency. Nat Immunol. 2014;15(1):88–97.

    Article  CAS  PubMed  Google Scholar 

  8. Deau MC, Heurtier L, Frange P, Suarez F, Bole-Feysot C, Nitschke P, et al. A human immunodeficiency caused by mutations in the PIK3R1 gene. J Clin Invest. 2014;124(9):3923–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Cant AJ, Chandra A, Munro E, Rao VK, Lucas CL. PI3Kδ pathway dysregulation and unique features of its inhibition by leniolisib in activated PI3Kδ syndrome and beyond. J Allergy Clin Immunol Pract. 2024;12(1):69–78.

    Article  CAS  PubMed  Google Scholar 

  10. Nunes-Santos CJ, Uzel G, Rosenzweig SD. PI3K pathway defects leading to immunodeficiency and immune dysregulation. J Allergy Clin Immunol. 2019;143(5):1676–87.

    Article  CAS  PubMed  Google Scholar 

  11. Coulter TI, Chandra A, Bacon CM, Babar J, Curtis J, Screaton N, et al. Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: a large patient cohort study. J Allergy Clin Immunol. 2017;139(2):597–606.e4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Elkaim E, Neven B, Bruneau J, Mitsui-Sekinaka K, Stanislas A, Heurtier L, et al. Clinical and immunologic phenotype associated with activated phosphoinositide 3-kinase δ syndrome 2: a cohort study. J Allergy Clin Immunol. 2016;138(1):210–8.e9.

    Article  CAS  PubMed  Google Scholar 

  13. Maccari ME, Abolhassani H, Aghamohammadi A, Aiuti A, Aleinikova O, Bangs C, et al. Disease evolution and response to rapamycin in activated phosphoinositide 3-kinase δ syndrome: the European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry. Front Immunol. 2018;9:543.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Dimitrova D, Nademi Z, Maccari ME, Ehl S, Uzel G, Tomoda T, et al. International retrospective study of allogeneic hematopoietic cell transplantation for activated PI3K-delta syndrome. J Allergy Clin Immunol. 2022;149(1):410–21.e7.

    Article  CAS  PubMed  Google Scholar 

  15. Nademi Z, Slatter MA, Dvorak CC, Neven B, Fischer A, Suarez F, et al. Hematopoietic stem cell transplant in patients with activated PI3K delta syndrome. J Allergy Clin Immunol. 2017;139(3):1046–9.

    Article  PubMed  Google Scholar 

  16. Okano T, Imai K, Tsujita Y, Mitsuiki N, Yoshida K, Kamae C, et al. Hematopoietic stem cell transplantation for progressive combined immunodeficiency and lymphoproliferation in patients with activated phosphatidylinositol-3-OH kinase δ syndrome type 1. J Allergy Clin Immunol. 2019;143(1):266–75.

    Article  CAS  PubMed  Google Scholar 

  17. Hanson J, Bonnen PE. Systematic review of mortality and survival rates for APDS. Clin Exp Med. 2024;24(1):17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Büsch K, Memmott HL, McLaughlin HM, Upton JEM, Harrington A. Genetic etiologies and outcomes in malignancy and mortality in activated phosphoinositide 3-kinase delta syndrome: a systematic review. Adv Ther.2025;42(2):752–771.

    Article  PubMed  Google Scholar 

  19. Methley AM, Campbell S, Chew-Graham C, McNally R, Cheraghi-Sohi S. PICO, PICOS and SPIDER: a comparison study of specificity and sensitivity in three search tools for qualitative systematic reviews. BMC Health Serv Res. 2014;14:579.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Zhou Z, Zondag T, Hermans M, van Hagen PM, van Laar JAM. Hemophagocytic lymphohistiocytosis in activated PI3K delta syndrome: an illustrative case report. J Clin Immunol. 2021;41(7):1656–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Conti F, Catelli A, Cifaldi C, Leonardi L, Mulè R, Fusconi M, et al. Case report: Hodgkin lymphoma and refractory systemic lupus erythematosus unveil activated phosphoinositide 3-kinase-δ syndrome 2 in an adult patient. Front Pediatr. 2021;9:702546.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Yin J, Ma J, Xia J, Cao Y, Li C. Activated PI3Kδ syndrome 1 mimicking systemic lupus erythematosus and secondary Sjögren’s syndrome-like phenotype without recurrent infections: a case report. Front Pediatr. 2022;10:1077324.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Ahmed AA, El Shahaway AA, Hussien SA. Activated PI3K-delta syndrome in an Egyptian pediatric cohort with primary immune deficiency. Allergol Immunopathol (Madr). 2020;48(6):686–93.

    Article  PubMed  Google Scholar 

  25. Baleydier F, Ranza E, Schäppi M, Rougemont AL, Merlini L, Ansari M, et al. Activated phosphoinositide 3 kinase delta syndrome (APDS): a primary immunodeficiency mimicking lymphoma. J Pediatr Hematol Oncol. 2019;41(8):e521–4.

    Article  PubMed  Google Scholar 

  26. Bloomfield M, Klocperk A, Zachova R, Milota T, Kanderova V, Sediva A. Natural course of activated phosphoinositide 3-kinase delta syndrome in childhood and adolescence. Front Pediatr. 2021;9:697706.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Bravo García-Morato M, García-Miñaúr S, Molina Garicano J, Santos Simarro F, Del Pino Molina L, López-Granados E, et al. Mutations in PIK3R1 can lead to APDS2, SHORT syndrome or a combination of the two. Clin Immunol. 2017;179:77–80.

    Article  PubMed  Google Scholar 

  28. Buchbinder D, Seppanen M, Rao VK, Uzel G, Nugent D. Clinical challenges: identification of patients with novel primary immunodeficiency syndromes. J Pediatr Hematol Oncol. 2018;40(5):e319–22.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Cansever M, Zietara N, Chiang SCC, Ozcan A, Yilmaz E, Karakukcu M, et al. A rare case of activated phosphoinositide 3-kinase delta syndrome (APDS) presenting with hemophagocytosis complicated with Hodgkin lymphoma. J Pediatr Hematol Oncol. 2020;42(2):156–9.

    Article  PubMed  Google Scholar 

  30. Ceraulo A, Malcus C, Durandy A, Picard C, Bertrand Y. Activated PI3-kinase δ syndrome: long-term follow-up after cord blood transplantation. J Clin Immunol. 2016;36(6):544–6.

    Article  PubMed  Google Scholar 

  31. Chiriaco M, Brigida I, Ariganello P, Di Cesare S, Di Matteo G, Taus F, et al. The case of an APDS patient: defects in maturation and function and decreased in vitro anti-mycobacterial activity in the myeloid compartment. Clin Immunol. 2017;178:20–8.

    Article  CAS  PubMed  Google Scholar 

  32. Craig M, Geng B, Wigby K, Phillips SA, Bakhoum C, Naheedy J, et al. Activated phosphoinositide 3-kinase δ syndrome associated with nephromegaly, growth hormone deficiency, bronchiectasis: a case report. Allergy Asthma Clin Immunol. 2022;18(1):15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Crank MC, Grossman JK, Moir S, Pittaluga S, Buckner CM, Kardava L, et al. Mutations in PIK3CD can cause hyper IgM syndrome (HIGM) associated with increased cancer susceptibility. J Clin Immunol. 2014;34(3):272–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Diaz N, Juarez M, Cancrini C, Heeg M, Soler-Palacín P, Payne A, et al. Seletalisib for activated PI3Kδ syndromes: open-label phase 1b and extension studies. J Immunol. 2020;205(11):2979–87.

    Article  CAS  PubMed  Google Scholar 

  35. Dominguez-Pinilla N, Allende LM, Rosain J, Gallego MDC, Chaves F, Deswarte C, et al. Disseminated abscesses due to Mycoplasma faucium in a patient with activated PI3Kδ syndrome type 2. J Allergy Clin Immunol Pract. 2018;6(5):1796–8.e2.

    Article  PubMed  Google Scholar 

  36. Donaldson SL, Purnell JC, Pavlidakey PG, Atkinson TP, Kissel R. Epidermodysplasia verruciformis in a young adult with activated PI3Kδ syndrome. JAAD Case Rep. 2019;5(2):195–7.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Dulau Florea AE, Braylan RC, Schafernak KT, Williams KW, Daub J, Goyal RK, et al. Abnormal B-cell maturation in the bone marrow of patients with germline mutations in PIK3CD. J Allergy Clin Immunol. 2017;139(3):1032–5.e6.

    Article  CAS  PubMed  Google Scholar 

  38. Edwards ESJ, Bier J, Cole TS, Wong M, Hsu P, Berglund LJ, et al. Activating PIK3CD mutations impair human cytotoxic lymphocyte differentiation and function and EBV immunity. J Allergy Clin Immunol. 2019;143(1):276–91.e6.

    Article  CAS  PubMed  Google Scholar 

  39. Elgizouli M, Lowe DM, Speckmann C, Schubert D, Hülsdünker J, Eskandarian Z, et al. Activating PI3Kδ mutations in a cohort of 669 patients with primary immunodeficiency. Clin Exp Immunol. 2016;183(2):221–9.

    Article  CAS  PubMed  Google Scholar 

  40. Ewertowska M, Grześk E, Urbańczyk A, Dąbrowska A, Bąbol-Pokora K, Łęcka M, et al. Activated phosphoinositide 3-kinase delta syndrome 1 and 2 (APDS 1 and APDS 2): similarities and differences based on clinical presentation in two boys. Allergy Asthma Clin Immunol. 2020;16:22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Fang S, Zeng A, Xu Q, Zhou L, Zhang Z, An Y, et al. Generation of human induced pluripotent stem cell line from peripheral blood mononuclear cells from an activated phosphoinositide 3-kinase δ syndrome patient. Stem Cell Res. 2022;62:102822.

    Article  CAS  PubMed  Google Scholar 

  42. Fox TA, Chakraverty R, Burns S, Carpenter B, Thomson K, Lowe D, et al. Successful outcome following allogeneic hematopoietic stem cell transplantation in adults with primary immunodeficiency. Blood. 2018;131(8):917–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Fuentes LA, Garkaby J, Scott O, Pachul JW, Dadi H, Vong L. Novel mutation in PIK3CD affecting the Ras-binding domain. LymphoSign J. 2022;9(1):11–6.

    Article  Google Scholar 

  44. Hartman HN, Niemela J, Hintermeyer MK, Garofalo M, Stoddard J, Verbsky JW, et al. Gain of function mutations of PIK3CD as a cause of primary sclerosing cholangitis. J Clin Immunol. 2015;35(1):11–4.

    Article  PubMed  Google Scholar 

  45. Hauck F, Magg T, Krolo A, Bilic I, Hirschmugl T, Laass M, et al. Variant PIK3R1 hypermorphic mutation and clinical phenotypes in a family with short statures, mild immunodeficiency and lymphoma. Klin Padiatr. 2017;229(3):113–7.

    Article  PubMed  Google Scholar 

  46. Heurtier L, Lamrini H, Chentout L, Deau MC, Bouafia A, Rosain J, et al. Mutations in the adaptor-binding domain and associated linker region of p110δ cause activated PI3K-δ syndrome 1 (APDS1). Haematologica. 2017;102(7):e278–81.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Hong Y, Nanthapisal S, Omoyinmi E, Olbrich P, Neth O, Speckmann C, et al. Secondary C1q deficiency in activated PI3Kδ syndrome type 2. Front Immunol. 2019;10:2589.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Hong CR, Lee S, Hong KT, Choi JY, Shin HY, Choi M, et al. Successful haploidentical transplantation with post-transplant cyclophosphamide for activated phosphoinositide 3-kinase δ syndrome. J Allergy Clin Immunol Pract. 2019;7(3):1034–7.e1.

    Article  PubMed  Google Scholar 

  49. Inglés-Ferrándiz M, Martin-Inaraja M, Herrera L, Villaverde M, Santos S, Vesga MA, et al. Generation, establishment and characterization of a pluripotent stem cell line (CVTTHi001-A) from primary fibroblasts isolated from a patient with activated PI3 kinase delta syndrome (APDS2). Stem Cell Res. 2020;49:102082.

    Article  PubMed  Google Scholar 

  50. Kang JM, Kim SK, Kim D, Choi SR, Lim YJ, Kim SK, et al. Successful sirolimus treatment for Korean patients with activated phosphoinositide 3-kinase δ syndrome 1: the first case series in Korea. Yonsei Med J. 2020;61(6):542–6.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Kannan JA, Dávila-Saldaña BJ, Zhang K, Filipovich AH, Kucuk ZY. Activated phosphoinositide 3-kinase δ syndrome in a patient with a former diagnosis of common variable immune deficiency, bronchiectasis, and lymphoproliferative disease. Ann Allergy Asthma Immunol. 2015;115(5):452–4.

    Article  PubMed  Google Scholar 

  52. Karanovic D, Michelow IC, Hayward AR, DeRavin SS, Delmonte OM, Grigg ME, et al. Disseminated and congenital toxoplasmosis in a mother and child with activated PI3-kinase δ syndrome type 2 (APDS2): case report and a literature review of toxoplasma infections in primary immunodeficiencies. Front Immunol. 2019;10:77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kracker S, Curtis J, Ibrahim MA, Sediva A, Salisbury J, Campr V, et al. Occurrence of B-cell lymphomas in patients with activated phosphoinositide 3-kinase δ syndrome. J Allergy Clin Immunol. 2014;134(1):233–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Kralickova P, Milota T, Litzman J, Malkusova I, Jilek D, Petanova J, et al. CVID-associated tumors: Czech nationwide study focused on epidemiology, immunology, and genetic background in a cohort of patients with CVID. Front Immunol. 2018;9:3135.

    Article  CAS  PubMed  Google Scholar 

  55. Kuhlen M, Hönscheid A, Loizou L, Nabhani S, Fischer U, Stepensky P, et al. De Novo PIK3R1 gain-of-function with recurrent sinopulmonary infections, long-lasting chronic CMV-lymphadenitis and microcephaly. Clin Immunol. 2016;162:27–30.

    Article  CAS  PubMed  Google Scholar 

  56. Larrauffie A, Syrykh C, Tavitian S, Comont T, Dion J. Activated PI3 kinase delta syndrome revealed by vasculitis and disseminated toxoplasmosis. J Clin Immunol. 2022;42(3):688–90.

    Article  PubMed  Google Scholar 

  57. Lawrence MG, Uzel G. 6-year-old boy with recurrent sinopulmonary infections and lymphadenopathy. J Allergy Clin Immunol Pract. 2015;3(3):461–3.e1. quiz 4–5.

    Article  PubMed  Google Scholar 

  58. Li GM, Liu HM, Guan WZ, Xu H, Wu BB, Feng JY, et al. A mutation in PIK3CD gene causing pediatric systemic lupus erythematosus: a case report. Med (Baltim). 2019;98(18):e15329.

    Article  CAS  Google Scholar 

  59. Lougaris V, Faletra F, Lanzi G, Vozzi D, Marcuzzi A, Valencic E, et al. Altered germinal center reaction and abnormal B cell peripheral maturation in PI3KR1-mutated patients presenting with HIGM-like phenotype. Clin Immunol. 2015;159(1):33–6.

    Article  CAS  PubMed  Google Scholar 

  60. Lu M, Gu W, Sheng Y, Wang J, Xu X. Case report: activating PIK3CD mutation in patients presenting with granulomatosis with polyangiitis. Front Immunol. 2021;12:670312.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Lugo Reyes SO, Solórzano Suárez A, Scheffler Mendoza SC, Xóchihua Díaz L, González Serrano ME, López Herrera G, et al. Activating de novo monoallelic variants causing inborn errors of immunity in two unrelated children born of HIV-seroconcordant couples. Aids. 2022;36(15):2121–8.

    Article  CAS  PubMed  Google Scholar 

  62. Luo Y, Xia Y, Wang W, Li Z, Jin Y, Gong Y, et al. Identification of a novel de novo gain-of-function mutation of PIK3CD in a patient with activated phosphoinositide 3-kinase δ syndrome. Clin Immunol. 2018;197:60–7.

    Article  CAS  PubMed  Google Scholar 

  63. Maffucci P, Filion CA, Boisson B, Itan Y, Shang L, Casanova JL, et al. Genetic diagnosis using whole exome sequencing in common variable immunodeficiency. Front Immunol. 2016;7:220.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Mandola AB, Dadi H, Reid B, Roifman CM. Novel heterozygous PIK3CD mutation presenting with only laboratory markers of combined immunodeficiency. LymphoSign J. 2020;7(2):49–55.

    Article  Google Scholar 

  65. Martínez-Saavedra MT, García-Gomez S, Domínguez Acosta A, Mendoza Quintana JJ, Páez JP, García-Reino EJ, et al. Gain-of-function mutation in PIK3R1 in a patient with a narrow clinical phenotype of respiratory infections. Clin Immunol. 2016;173:117–20.

    Article  PubMed  Google Scholar 

  66. Marzollo A, Bresolin S, Colavito D, Cani A, Gaio P, Bosa L, et al. Case report: intestinal nodular lymphoid hyperplasia as first manifestation of activated PI3Kδ syndrome due to a novel PIK3CD variant. Front Pediatr. 2021;9:703056.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Mettman D, Thiffault I, Dinakar C, Saunders C. Immunodeficiency-associated lymphoid hyperplasia as a cause of intussusception in a case of activated PI3K-δ syndrome. Front Pediatr. 2017;5:71.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Moreno-Corona N, Chentout L, Poggi L, Thouenon R, Masson C, Parisot M, et al. Two monogenetic disorders, activated PI3-kinase-δ syndrome 2 and Smith-Magenis syndrome, in one patient: case report and a literature review of neurodevelopmental impact in primary immunodeficiencies associated with disturbed PI3K signaling. Front Pediatr. 2021;9:688022.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Nakagawa R, Takasawa K, Yeh TW, Imai K, Kashimada K, Morio T. Type 1 diabetes mellitus associated with activated phosphatidylinositol 3-kinase delta syndrome, type 2. J Diabetes. 2018;10(5):421–2.

    Article  PubMed  Google Scholar 

  70. Nguyen Y, Rosain J, Aguilar C, Picard C, Malphettes M. Long-term follow-up of an activated PI3K-δ syndrome 2 in patient presenting with an agammaglobulinemia phenotype. Ann Allergy Asthma Immunol. 2018;121(6):739–40.e1.

    Article  PubMed  Google Scholar 

  71. Orf K, Abbas A, Abdel-Aziz K, Burns SO. Transverse myelitis in a patient with activated phosphoinositide 3-kinase δ syndrome type 1. Clin Immunol. 2020;219:108552.

    Article  CAS  PubMed  Google Scholar 

  72. Petrovski S, Parrott RE, Roberts JL, Huang H, Yang J, Gorentla B, et al. Dominant splice site mutations in PIK3R1 cause hyper IgM syndrome, lymphadenopathy and short stature. J Clin Immunol. 2016;36(5):462–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Pham MN, Cunningham-Rundles C. Evaluation of lymphoproliferative disease and increased risk of lymphoma in activated phosphoinositide 3 kinase delta syndrome: a case report with discussion. Front Pediatr. 2018;6:402.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Qiu L, Wang Y, Tang W, Yang Q, Zeng T, Chen J, et al. Activated phosphoinositide 3-kinase δ syndrome: a large pediatric cohort from a single center in China. J Clin Immunol. 2022;42(4):837–50.

    Article  CAS  PubMed  Google Scholar 

  75. Wang Y, Yang Q, Chen X, Tang W, Zhou L, Chen Z, et al. Phenotypic characterization of patients with activated PI3Kδ syndrome 1 presenting with features of systemic lupus erythematosus. Genes Dis. 2021;8(6):907–17.

    Article  CAS  PubMed  Google Scholar 

  76. Rae W, Gao Y, Ward D, Mattocks CJ, Eren E, Williams AP. A novel germline gain-of-function variant in PIK3CD. Clin Immunol. 2017;181:29–31.

    Article  CAS  PubMed  Google Scholar 

  77. Rae W, Ramakrishnan KA, Gao Y, Ashton-Key M, Pengelly RJ, Patel SV, et al. Precision treatment with sirolimus in a case of activated phosphoinositide 3-kinase δ syndrome. Clin Immunol. 2016;171:38–40.

    Article  CAS  PubMed  Google Scholar 

  78. Ramirez L, Tamayo W, Ale H. APDS2 and SHORT syndrome in a teenager with PIK3R1 pathogenic variant. J Clin Immunol. 2020;40(7):1020–5.

    Article  CAS  PubMed  Google Scholar 

  79. Rao VK, Webster S, Dalm V, Šedivá A, van Hagen PM, Holland S, et al. Effective “activated PI3Kδ syndrome”-targeted therapy with the PI3Kδ inhibitor leniolisib. Blood. 2017;130(21):2307–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Rivalta B, Amodio D, Milito C, Chiriaco M, Di Cesare S, Giancotta C, et al. Case report: EBV chronic infection and lymphoproliferation in four APDS patients: the challenge of proper characterization, therapy, and follow-up. Front Pediatr. 2021;9:703853.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Rowane MJ, Callahan MA, Schend JE, Rowane MP, Hostoffer RW. Structural abnormalities and osteopathic considerations in primary immunodeficiencies. J Osteopath Med. 2023;123(4):195–9.

    Article  PubMed  Google Scholar 

  82. Ruiz-García R, Vargas-Hernández A, Chinn IK, Angelo LS, Cao TN, Coban-Akdemir Z, et al. Mutations in PI3K110δ cause impaired natural killer cell function partially rescued by rapamycin treatment. J Allergy Clin Immunol. 2018;142(2):605–17.e7.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Sanchez Clemente N, Penner J, Breuer J, Ip W, Booth C. Case report: a severe paediatric presentation of COVID-19 in APDS2 immunodeficiency. Front Immunol. 2022;13:881259.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Saunders JL, O’Connor MG, Machogu EM. Nasal nitric oxide may not differentiate primary ciliary dyskinesia from certain primary immunodeficiencies. Pediatr Pulmonol. 2022;57(9):2269–72.

    Article  PubMed  Google Scholar 

  85. Schworer SA, Francis OL, Johnson SM, Smith BD, Gold SH, Smitherman AB, et al. Autoimmune cytopenia as an early and initial presenting manifestation in activated PI3 kinase delta syndrome: case report and review. J Pediatr Hematol Oncol. 2021;43(8):281–7.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Segundo GRS, Takano OA, Moraes LSL, Nadaf M, Fernandes SJ, Ochs HD, et al. Paternal gonadal mosaicism as cause of a puzzling inheritance pattern of activated PI3-kinase delta syndrome. Ann Allergy Asthma Immunol. 2017;119(6):564–6.

    Article  PubMed  Google Scholar 

  87. Stray-Pedersen A, Sorte HS, Samarakoon P, Gambin T, Chinn IK, Coban Akdemir ZH, et al. Primary immunodeficiency diseases: genomic approaches delineate heterogeneous Mendelian disorders. J Allergy Clin Immunol. 2017;139(1):232–45.

    Article  PubMed  Google Scholar 

  88. Su G, Lai J, Zhu J, Zhang D, Hou J, Xu Y, et al. Analysis of five cases of monogenic lupus related to primary immunodeficiency diseases. Inflamm Res. 2021;70(10–12):1211–6.

    Article  CAS  PubMed  Google Scholar 

  89. Sugiyama M, Iguchi A, Yamada M, Terashita Y, Ohshima J, Cho Y, et al. Successful bone marrow transplantation in two sisters with activated phosphoinositide 3-kinase δ syndrome 2. Bone Marrow Transpl. 2017;52(12):1678–80.

    Article  CAS  Google Scholar 

  90. Sun B, Zhou S, Yang H, Zhou J, Leng X, Zhang W, et al. Tofacitinib as a possible treatment for arthritis in an APDS2 patient. Rheumatology (Oxford). 2023;62(3):e39–41.

    Article  PubMed  Google Scholar 

  91. Szczawińska-Popłonyk A, Bernat-Sitarz K, Schwartzmann E, Piechota M, Badura-Stronka M. Clinical and immunological assessment of APDS2 with features of the SHORT syndrome related to a novel mutation in PIK3R1 with reduced penetrance. Allergol Immunopathol (Madr). 2022;50(4):1–9.

    Article  PubMed  Google Scholar 

  92. Takeda AJ, Zhang Y, Dornan GL, Siempelkamp BD, Jenkins ML, Matthews HF, et al. Novel PIK3CD mutations affecting N-terminal residues of p110δ cause activated PI3Kδ syndrome (APDS) in humans. J Allergy Clin Immunol. 2017;140(4):1152–6.e10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Tessarin G, Rossi S, Baronio M, Gazzurelli L, Colpani M, Benvenuto A et al. Activated phosphoinositide 3-kinase delta syndrome 1: clinical and immunological data from an Italian cohort of patients. J Clin Med. 2020;9(10).

  94. Thauland TJ, Pellerin L, Ohgami RS, Bacchetta R, Butte MJ. Case study: mechanism for increased follicular helper T cell development in activated PI3K delta syndrome. Front Immunol. 2019;10:753.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Valencic E, Grasso AG, Conversano E, Lucafò M, Piscianz E, Gregori M, et al. Theophylline as a precision therapy in a young girl with PIK3R1 immunodeficiency. J Allergy Clin Immunol Pract. 2018;6(6):2165–7.

    Article  PubMed  Google Scholar 

  96. Wallace JG, Zambrano-Rodas P, Córdova-Calderón W, Estrada-Turriate S, Mendoza-Quispe D, Limache Ontiveros Y, et al. Dysregulated actin dynamics in activated PI3Kδ syndrome. Clin Immunol. 2020;210:108311.

    Article  CAS  PubMed  Google Scholar 

  97. Wang W, Min Q, Lai N, Csomos K, Wang Y, Liu L, et al. Cellular mechanisms underlying B cell abnormalities in patients with gain-of-function mutations in the PIK3CD gene. Front Immunol. 2022;13:890073.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Wentink M, Peeters D, van der Burg M, Vermont C, Duijts L, Driessen GJ. A 3-year-old girl with a mediastinal mass. Chest. 2019;155(1):e13–6.

    Article  PubMed  Google Scholar 

  99. Wentink M, Dalm V, Lankester AC, van Schouwenburg PA, Schölvinck L, Kalina T, et al. Genetic defects in PI3Kδ affect B-cell differentiation and maturation leading to hypogammaglobulineamia and recurrent infections. Clin Immunol. 2017;176:77–86.

    Article  CAS  PubMed  Google Scholar 

  100. Williams SN. Endoscopic airway manifestations in a pediatric patient with activated PI3K-delta syndrome. Pediatr Pulmonol. 2020;55(11):2836–7.

    Article  PubMed  Google Scholar 

  101. Yang X, Xi R, Bai J, Pan Y. Successful haploidentical hematopoietic stem cell transplantation for activated phosphoinositide 3-kinase δ syndrome: case report and literature review. Med (Baltim). 2023;102(5):e32816.

    Article  CAS  Google Scholar 

  102. Yazdani R, Hamidi Z, Babaha F, Azizi G, Fekrvand S, Abolhassani H, et al. PIK3R1 mutation associated with hyper IgM (APDS2 syndrome): a case report and review of the literature. Endocr Metab Immune Disord Drug Targets. 2019;19(7):941–58.

    Article  CAS  PubMed  Google Scholar 

  103. Yin Z, Tian X, Zou R, He X, Chen K, Zhu C. Case report: first occurrence of plasmablastic lymphoma in activated phosphoinositide 3-kinase δ syndrome. Front Immunol. 2021;12:813261.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Zhang X, Wang J, Zhu K, Jin Y, Fu H, Mao J. Activated phosphoinositide 3-kinase delta syndrome misdiagnosed as anti-neutrophil cytoplasmic antibody-associated vasculitis: a case report. J Int Med Res. 2021;49(5):3000605211013222.

    Article  PubMed  Google Scholar 

  105. Zhang Q, Ma H, Ma J, Wang D, Zhao Y, Wang T, et al. Clinical and genetic analysis of immunodeficiency-related diseases associated with PIK3CD mutations. Pediatr Investig. 2018;2(4):257–62.

    Article  PubMed  Google Scholar 

  106. Ye X, Maglione PJ, Wehr C, Li X, Wang Y, Abolhassani H, et al. Genomic characterization of lymphomas in patients with inborn errors of immunity. Blood Adv. 2022;6(18):5403–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Asano T, Okada S, Tsumura M, Yeh TW, Mitsui-Sekinaka K, Tsujita Y, et al. Enhanced AKT phosphorylation of circulating B cells in patients with activated PI3Kδ syndrome. Front Immunol. 2018;9:568.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Inoue M, Isoda T, Yamashita M, Tomoda T, Inoue K, Okano T, et al. Cytomegalovirus laryngitis in primary combined immunodeficiency diseases. J Clin Immunol. 2021;41(1):243–7.

    Article  PubMed  Google Scholar 

  109. Olbrich P, Lorenz M, Cura Daball P, Lucena JM, Rensing-Ehl A, Sanchez B, et al. Activated PI3Kδ syndrome type 2: two patients, a novel mutation, and review of the literature. Pediatr Allergy Immunol. 2016;27(6):640–4.

    Article  PubMed  Google Scholar 

  110. Goto F, Uchiyama T, Nakazawa Y, Imai K, Kawai T, Onodera M. Persistent impairment of T-cell regeneration in a patient with activated PI3K δ syndrome. J Clin Immunol. 2017;37(4):347–50.

    Article  CAS  PubMed  Google Scholar 

  111. Tsujita Y, Mitsui-Sekinaka K, Imai K, Yeh TW, Mitsuiki N, Asano T, et al. Phosphatase and tensin homolog (PTEN) mutation can cause activated phosphatidylinositol 3-kinase δ syndrome-like immunodeficiency. J Allergy Clin Immunol. 2016;138(6):1672–80.e10.

    Article  CAS  PubMed  Google Scholar 

  112. Lougaris V, Baronio M, Moratto D, Tampella G, Gazzurelli L, Facchetti M, et al. A novel monoallelic gain of function mutation in p110δ causing atypical activated phosphoinositide 3-kinase δ syndrome (APDS-1). Clin Immunol. 2019;200:31–4.

    Article  CAS  PubMed  Google Scholar 

  113. Saettini F, Pelagatti MA, Sala D, Moratto D, Giliani S, Badolato R, et al. Early diagnosis of PI3Kδ syndrome in a 2 years old girl with recurrent otitis and enlarged spleen. Immunol Lett. 2017;190:279–81.

    Article  CAS  PubMed  Google Scholar 

  114. Rivalta B, Amodio D, Giancotta C, Santilli V, Pacillo L, Zangari P, et al. Case report: successful treatment with monoclonal antibodies in one APDS patient with prolonged SARS-CoV-2 infection not responsive to previous lines of treatment. Front Immunol. 2022;13:891274.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Serra I, Manusama OR, Kaiser FMP, Floriano II, Wahl L, van der Zalm C, et al. Activated PI3Kδ syndrome, an immunodeficiency disorder, leads to sensorimotor deficits recapitulated in a murine model. Brain Behav Immun Health. 2021;18:100377.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Wang Y, Chen X, Yang Q, Tang W, Jia Y, Zhou L, et al. E1021K homozygous mutation in PIK3CD leads to activated PI3K-delta syndrome 1. J Clin Immunol. 2020;40(2):378–87.

    Article  CAS  PubMed  Google Scholar 

  117. Bucciol G, Willems L, Hauben E, Uyttebroeck A, Proesmans M, Meyts I. Thyroid carcinoma in a child with activated phosphoinositide 3-kinase δ syndrome: somatic effect of a germline mutation. J Clin Immunol. 2017;37(5):422–6.

    Article  CAS  PubMed  Google Scholar 

  118. Lougaris V, Baronio M, Castagna A, Tessarin G, Rossi S, Gazzurelli L, et al. Paediatric MAS/HLH caused by a novel monoallelic activating mutation in p110δ. Clin Immunol. 2020;219:108543.

    Article  CAS  PubMed  Google Scholar 

  119. Yagasaki H, Hirai M, Kanezawa K, Ueno M, Hao H, Masuda S, et al. Successful treatment for diffuse large B-cell lymphoma in a Japanese adolescent with PIK3CD germ-line mutation: stem cell transplantation after reduced-intensity conditioning. Ann Hematol. 2022;101(7):1617–9.

    Article  CAS  PubMed  Google Scholar 

  120. Wang Y, Wang W, Liu L, Hou J, Ying W, Hui X, et al. Report of a Chinese cohort with activated phosphoinositide 3-kinase δ syndrome. J Clin Immunol. 2018;38(8):854–63.

    Article  CAS  PubMed  Google Scholar 

  121. World Health Organization. Life tables: Life tables by WHO region Global. Accessed October 17, 2023. https://apps.who.int/gho/data/view.searo.LIFEREGIONGLOBAL

  122. Jamee M, Moniri S, Zaki-Dizaji M, Olbrich P, Yazdani R, Jadidi-Niaragh F, et al. Clinical, immunological, and genetic features in patients with activated PI3Kδ syndrome (APDS): a systematic review. Clin Rev Allergy Immunol. 2020;59(3):323–33.

    Article  CAS  PubMed  Google Scholar 

  123. Carpier JM, Lucas CL. Epstein-Barr virus susceptibility in activated PI3Kδ syndrome (APDS) immunodeficiency. Front Immunol. 2017;8:2005.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

Medical writing and editorial assistance was provided by Precision AQ of Bethesda, MD and was funded by Pharming Healthcare, Inc, according to the Good Publication Practice guideline.

Funding

This study was sponsored by Pharming Healthcare, Inc.

Author information

Authors and Affiliations

  1. Groupe d’analyse, Ltée, Montréal, Québec, Canada

    Malena Mahendran, Ramya Ramasubramanian, Guillaume Germain & François Laliberté

  2. Clinical Immunology and Allergy, Department of Pediatrics, The Hospital For Sick Children, Toronto, ON, Canada

    Julia E. M. Upton

  3. Department of Pediatrics, University of Toronto, Toronto, ON, Canada

    Julia E. M. Upton

  4. Pharming Healthcare, Inc, Warren, NJ, USA

    Heidi L. Memmott & Amanda Harrington

  5. KJM Büsch Consulting GmbH, Büsch, Switzerland

    Katharina Büsch

Authors
  1. Malena Mahendran
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Julia E. M. Upton
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Ramya Ramasubramanian
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Heidi L. Memmott
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Guillaume Germain
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Katharina Büsch
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. François Laliberté
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Amanda Harrington
    View author publications

    You can also search for this author inPubMed Google Scholar

Contributions

AH, MM, RR, GG, and FL contributed to the study concept and design. AH, MM, RR, HLM, GG, FL, and KB contributed to data acquisition and analysis. JEMU contributed to data analysis. All authors contributed to data interpretation, provided critical feedback during manuscript development, and approved the final manuscript for publication.

Corresponding author

Correspondence to Amanda Harrington.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

AH and HLM are employees of Pharming Healthcare, Inc. JEMU reports consulting for and steering committee membership with Pharming Healthcare, Inc, both outside of the current work, advising fees from Pfizer and Bausch Health, speaker fees from AstraZeneca, clinical trial funding (to institution) from Regeneron and Sanofi, and drug donation for clinical trial use from Novartis. KB is an employee of KJM Büsch Consulting GmbH. MM, RR, GG, and FL are employees of Groupe d’analyse, Ltée, a consulting company that received research funding from Pharming Healthcare, Inc, to conduct this study.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mahendran, M., Upton, J.E.M., Ramasubramanian, R. et al. Overall survival among patients with activated phosphoinositide 3-kinase delta syndrome (APDS). Orphanet J Rare Dis 20, 212 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13023-025-03734-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13023-025-03734-z

Keywords

Orphanet Journal of Rare Diseases

ISSN: 1750-1172