{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:43:18Z","timestamp":1785436998660,"version":"3.56.0"},"reference-count":51,"publisher":"Rockefeller University Press","issue":"5","license":[{"start":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T00:00:00Z","timestamp":1785110400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,9,7]]},"abstract":"<jats:p>Activated phosphoinositide 3-kinase delta syndrome (APDS) is a form of common variable immunodeficiency (CVID) caused by gain-of-function variants in PIK3CD (APDS1) or loss-of-function variants in PIK3R1 (APDS2), resulting in hyperactivation of the PI3K\u03b4 pathway. Clinically, it is characterized by recurrent respiratory infections, lymphadenopathy, splenomegaly, and progressive airway destruction, often leading to bronchiectasis. Enteropathy, cytopenia, and immune dysregulation have also been observed in several patients. Some patients develop malignant lymphomas, which can be fatal. Prophylactic antimicrobial therapy and regular immunoglobulin replacement therapy are administered in a manner similar to that used for CVID. However, since excessive activation of the class IA phosphoinositide 3-kinase signaling pathway is the primary pathophysiology of APDS, mammalian target of rapamycin inhibitors and selective p110\u03b4 inhibitors are expected to be licensed therapies. Early diagnosis based on diagnostic clues specific to APDS, followed by prompt treatment, is expected to improve patient prognosis.<\/jats:p>","DOI":"10.70962\/jhi.20260054","type":"journal-article","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T06:21:34Z","timestamp":1783578094000},"update-policy":"https:\/\/doi.org\/10.70962\/jhi.crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["How I treat: Diagnostic clues and treatment for activated phosphoinositide 3-kinase delta syndrome"],"prefix":"10.70962","volume":"2","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8696-9378","authenticated-orcid":true,"given":"Hirokazu","family":"Kanegane","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05dqf9946","id-type":"ROR","asserted-by":"publisher"}],"name":"Graduate School of Medical and Dental Sciences, Institute of Science Tokyo 1 Department of Child Health and Development, , Tokyo,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3236-5098","authenticated-orcid":true,"given":"Dan","family":"Tomomasa","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05dqf9946","id-type":"ROR","asserted-by":"publisher"}],"name":"Graduate School of Medical and Dental Sciences, Institute of Science Tokyo 2 Department of Pediatrics and Developmental Biology, , Tokyo,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4622-5657","authenticated-orcid":true,"given":"Satoshi","family":"Okada","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03t78wx29","id-type":"ROR","asserted-by":"publisher"}],"name":"Hiroshima University Graduate School of Medicine and Health Sciences 3 Department of Pediatrics, , Hiroshima,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2026,7,27]]},"reference":[{"key":"2026072709341082100_bib1","doi-asserted-by":"publisher","first-page":"866","DOI":"10.1126\/science.1243292","article-title":"Phosphoinositide 3-kinase \u03b4 gene mutation predisposes to respiratory infection and airway damage","volume":"342","author":"Angulo","year":"2013","journal-title":"Science"},{"key":"2026072709341082100_bib2","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1038\/ni.2771","article-title":"Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110\u03b4 result in T cell senescence and human immunodeficiency","volume":"15","author":"Lucas","year":"2014","journal-title":"Nat. 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