Frontiers in Immunology (Mar 2018)

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

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

DOI
https://doi.org/10.3389/fimmu.2018.00543
Journal volume & issue
Vol. 9

Abstract

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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.

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