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. 2018 Mar 16:9:543.
doi: 10.3389/fimmu.2018.00543. eCollection 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  1   2 , Hassan Abolhassani  3   4 , Asghar Aghamohammadi  4 , Alessandro Aiuti  5 , Olga Aleinikova  6 , Catherine Bangs  7 , Safa Baris  8 , Federica Barzaghi  5 , Helen Baxendale  9 , Matthew Buckland  10 , Siobhan O Burns  10 , Caterina Cancrini  11   12 , Andrew Cant  13 , Pascal Cathébras  14 , Marina Cavazzana  15   16   17 , Anita Chandra  18   19 , Francesca Conti  11   12 , Tanya Coulter  20 , Lisa A Devlin  20 , J David M Edgar  20 , Saul Faust  21 , Alain Fischer  17   22   23 , Marina Garcia-Prat  24 , Lennart Hammarström  3 , Maximilian Heeg  1   2 , Stephen Jolles  25 , Elif Karakoc-Aydiner  8 , Gerhard Kindle  1 , Ayca Kiykim  8 , Dinakantha Kumararatne  17 , Bodo Grimbacher  1 , Hilary Longhurst  10 , Nizar Mahlaoui  22   26 , Tomas Milota  27 , Fernando Moreira  10 , Despina Moshous  17   22   23 , Anna Mukhina  28 , Olaf Neth  29 , Benedicte Neven  17   22   30 , Alexandra Nieters  1 , Peter Olbrich  29 , Ahmet Ozen  8 , Jana Pachlopnik Schmid  31 , Capucine Picard  32   33 , Seraina Prader  31 , William Rae  21 , Janine Reichenbach  31 , Stephan Rusch  1 , Sinisa Savic  32 , Alessia Scarselli  11   12 , Raphael Scheible  1 , Anna Sediva  27 , Svetlana O Sharapova  6 , Anna Shcherbina  28 , Mary Slatter  12 , Pere Soler-Palacin  24 , Aurelie Stanislas  15 , Felipe Suarez  23 , Francesca Tucci  5 , Annette Uhlmann  1 , Joris van Montfrans  34 , Klaus Warnatz  1 , Anthony Peter Williams  21 , Phil Wood  35 , Sven Kracker  16   17 , Alison Mary Condliffe  36 , Stephan Ehl  1   2
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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 et al. Front Immunol. .

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.

Keywords: PIK3CD; PIK3R1; activated phosphoinositide 3-kinase δ syndrome; natural history; rapamycin; registry.

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Figures

Figure 1
Figure 1
(A) Incidence of infections in APDS1 and APDS2 patients. (B) Incidence of manifestations of immune dysregulation in APDS1 and APDS2 patients. (C) Evolution of disease manifestations over time. Information regarding age at onset available for: respiratory infections n = 62/65, lymphoproliferation n = 59/59, gastrointestinal manifestations n = 33/35, cytopenia n = 20/21 patients. (D) Diagram showing the different types of benign lymphoproliferative manifestations. (E) Diagram showing the different blood lineages affected in patients with cytopenias.
Figure 2
Figure 2
(A) Use of treatment modalities over time. IGRT, immunoglobulin-replacement-treatment; IS, immunosuppressive drug; HSCT, hematopoietic stem cell transplantation. Information regarding age at first therapy available for: IGRT n = 28/44, steroid therapy n = 31/31, IS therapy n = 35/36, HSCT = 8/8. (B) Number of lines of immunosuppressive treatments (steroids, immunosuppressive drugs, rituximab) by the time of registration; red: patients who had undergone HSCT by the time of registration. (C) Response to rapamycin treatment. White: complete response; gray: partial response; black: no response; red: worsened or new manifestation; boxes with a diagonal: manifestation not present in this patient. CR, complete remission; PR, partial remission. Rapamycin stopped because of: *non-compliance, °inefficiency, ^side effects, §clinical trial. (D) Overall clinical benefit (Visual Analog Scale) according to physician’s evaluation.
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