Disease evolution and response to rapamycin in Activated Phosphoinositide 3-Kinase delta syndrome: the european society for immunodeficiencies-Activated Phosphoinositide 3-Kinase d syndrome registry

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.

Metadata

Item Type:	Article
Authors/Creators:	Maccari, M.E. Abolhassani, H. Aghamohammadi, A. Aiuti, A. Aleinikova, O. Bangs, C. Baris, S. Barzaghi, F. Baxendale, H. Buckland, M. Burns, S.O. Cancrini, C. Cant, A. Cathebras, P. Cavazzana, M. Chandra, A. Conti, F. Coulter, T. Devlin, L.A. Edgar, J.D.M. Faust, S. Fischer, A. Prat, M.G. Hammarstrom, L. Heeg, M. Jolles, S. Karakoc-Aydiner, E. Kindle, G. Kiykim, A. Kumararatne, D. Grimbacher, B. Longhurst, H. Mahlaoui, N. Milota, T. Moreira, F. Moshous, D. Mukhina, A. Neth, O. Neven, B. Nieters, A. Olbrich, P. Ozen, A. Schmid, J.P. Picard, C. Prader, S. Rae, W. Reichenbach, J. Rusch, S. Savic, S. Scarselli, A. Scheible, R. Sediva, A. Sharapova, S.O. Shcherbina, A. Slatter, M. Soler-Palacin, P. Stanislas, A. Suarez, F. Tucci, F. Uhlmann, A. van Montfrans, J. Warnatz, K. Williams, A.P. Wood, P. Kracker, S. Condliffe, A.M. Ehl, S.
Copyright, Publisher and Additional Information:	© 2018 Maccari, Abolhassani, Aghamohammadi, Aiuti, Aleinikova, Bangs, Baris, Barzaghi, Baxendale, Buckland, Burns, Cancrini, Cant, Cathébras, Cavazzana, Chandra, Conti, Coulter, Devlin, Edgar, Faust, Fischer, Prat, Hammarström, Heeg, Jolles, Karakoc-Aydiner, Kindle, Kiykim, Kumararatne, Grimbacher, Longhurst, Mahlaoui, Milota, Moreira, Moshous, Mukhina, Neth, Neven, Nieters, Olbrich, Ozen, Schmid, Picard, Prader, Rae, Reichenbach, Rusch, Savic, Scarselli, Scheible, Sediva, Sharapova, Shcherbina, Slatter, Soler-Palacin, Stanislas, Suarez, Tucci, Uhlmann, van Montfrans, Warnatz, Williams, Wood, Kracker, Condliffe and Ehl. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Keywords:	activated phosphoinositide 3-kinase delta syndrome; PIK3CD; PIK3R1; registry; natural history; rapamycin
Dates:	Published: 16 March 2018
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Infection, Immunity and Cardiovascular Disease The University of Sheffield > Sheffield Teaching Hospitals
Depositing User:	Symplectic Sheffield
Date Deposited:	06 Apr 2018 12:32
Last Modified:	06 Apr 2018 12:32
Published Version:	https://doi.org/10.3389/fimmu.2018.00543
Status:	Published
Publisher:	Frontiers Media
Refereed:	Yes
Identification Number:	10.3389/fimmu.2018.00543
Related URLs:	Author
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:129346

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Disease evolution and response to rapamycin in Activated Phosphoinositide 3-Kinase delta syndrome: the european society for immunodeficiencies-Activated Phosphoinositide 3-Kinase d syndrome registry

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