AUTHOR=Maccari Maria Elena , Abolhassani Hassan , Aghamohammadi Asghar , Aiuti Alessandro , Aleinikova Olga , Bangs Catherine , Baris Safa , Barzaghi Federica , Baxendale Helen , Buckland Matthew , Burns Siobhan O. , Cancrini Caterina , Cant Andrew , Cathébras Pascal , Cavazzana Marina , Chandra Anita , Conti Francesca , Coulter Tanya , Devlin Lisa A. , Edgar J. David M. , Faust Saul , Fischer Alain , Prat Marina Garcia , Hammarström Lennart , Heeg Maximilian , Jolles Stephen , Karakoc-Aydiner Elif , Kindle Gerhard , Kiykim Ayca , Kumararatne Dinakantha , Grimbacher Bodo , Longhurst Hilary , Mahlaoui Nizar , Milota Tomas , Moreira Fernando , Moshous Despina , Mukhina Anna , Neth Olaf , Neven Benedicte , Nieters Alexandra , Olbrich Peter , Ozen Ahmet , Schmid Jana Pachlopnik , Picard Capucine , Prader Seraina , Rae William , Reichenbach Janine , Rusch Stephan , Savic Sinisa , Scarselli Alessia , Scheible Raphael , Sediva Anna , Sharapova Svetlana O. , Shcherbina Anna , Slatter Mary , Soler-Palacin Pere , Stanislas Aurelie , Suarez Felipe , Tucci Francesca , Uhlmann Annette , van Montfrans Joris , Warnatz Klaus , Williams Anthony Peter , Wood Phil , Kracker Sven , Condliffe Alison Mary , Ehl Stephan TITLE=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 JOURNAL=Frontiers in Immunology VOLUME=Volume 9 - 2018 YEAR=2018 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2018.00543 DOI=10.3389/fimmu.2018.00543 ISSN=1664-3224 ABSTRACT=

Activated phosphoinositide 3-kinase (PI3K) δ Syndrome (APDS), caused by autosomal dominant mutations in PIK3CD (APDS1) or PIK3R1 (APDS2), is a heterogeneous primary immunodeficiency. While initial cohort-descriptions summarized the spectrum of clinical and immunological manifestations, questions about long-term disease evolution and response to therapy remain. The prospective European Society for Immunodeficiencies (ESID)-APDS registry aims to characterize the disease course, identify outcome predictors, and evaluate treatment responses. So far, 77 patients have been recruited (51 APDS1, 26 APDS2). Analysis of disease evolution in the first 68 patients pinpoints the early occurrence of recurrent respiratory infections followed by chronic lymphoproliferation, gastrointestinal manifestations, and cytopenias. Although most manifestations occur by age 15, adult-onset and asymptomatic courses were documented. Bronchiectasis was observed in 24/40 APDS1 patients who received a CT-scan compared with 4/15 APDS2 patients. By age 20, half of the patients had received at least one immunosuppressant, but 2–3 lines of immunosuppressive therapy were not unusual before age 10. Response to rapamycin was rated by physician visual analog scale as good in 10, moderate in 9, and poor in 7. Lymphoproliferation showed the best response (8 complete, 11 partial, 6 no remission), while bowel inflammation (3 complete, 3 partial, 9 no remission) and cytopenia (3 complete, 2 partial, 9 no remission) responded less well. Hence, non-lymphoproliferative manifestations should be a key target for novel therapies. This report from the ESID-APDS registry provides comprehensive baseline documentation for a growing cohort that will be followed prospectively to establish prognostic factors and identify patients for treatment studies.