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

ME Maccari, H Abolhassani, A Aghamohammadi, A Aiuti, O Aleinikova, C Bangs, S Baris, F Barzaghi, H Baxendale, M Buckland, SO Burns, C Cancrini, A Cant, P Cathébras, M Cavazzana, A Chandra, F Conti, T Coulter, LA Devlin, JDM EdgarS Faust, A Fischer, MG Prat, L Hammarström, M Heeg, S Jolles, E Karakoc-Aydiner, G Kindle, A Kiykim, D Kumararatne, B Grimbacher, H Longhurst, N Mahlaoui, T Milota, F Moreira, D Moshous, A Mukhina, O Neth, B Neven, A Nieters, P Olbrich, A Ozen, JP Schmid, C Picard, S Prader, W Rae, J Reichenbach, S Rusch, S Savic, A Scarselli, R Scheible, A Sediva, SO Sharapova, A Shcherbina, M Slatter, P Soler-Palacin, A Stanislas, F Suarez, F Tucci, A Uhlmann, Jv Montfrans, K Warnatz, AP Williams, P Wood, S Kracker, AM Condliffe, S Ehl

Research output: Contribution to journalArticle

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. © 2018 Maccari, et al.
Original languageEnglish
Article number543
JournalFrontiers in Immunology
Volume9
Issue number6
DOIs
Publication statusPublished - 2018

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1-Phosphatidylinositol 4-Kinase
Sirolimus
Registries
Immunosuppressive Agents
Therapeutics
Bronchiectasis
Visual Analog Scale
Respiratory Tract Infections
Documentation
Inflammation
Physicians
Mutation

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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. / Maccari, ME; Abolhassani, H; Aghamohammadi, A; Aiuti, A; Aleinikova, O; Bangs, C; Baris, S; Barzaghi, F; Baxendale, H; Buckland, M; Burns, SO; Cancrini, C; Cant, A; Cathébras, P; Cavazzana, M; Chandra, A; Conti, F; Coulter, T; Devlin, LA; Edgar, JDM; Faust, S; Fischer, A; Prat, MG; Hammarström, 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, JP; Picard, C; Prader, S; Rae, W; Reichenbach, J; Rusch, S; Savic, S; Scarselli, A; Scheible, R; Sediva, A; Sharapova, SO; Shcherbina, A; Slatter, M; Soler-Palacin, P; Stanislas, A; Suarez, F; Tucci, F; Uhlmann, A; Montfrans, Jv; Warnatz, K; Williams, AP; Wood, P; Kracker, S; Condliffe, AM; Ehl, S.

In: Frontiers in Immunology, Vol. 9, No. 6, 543, 2018.

Research output: Contribution to journalArticle

Maccari, ME, Abolhassani, H, Aghamohammadi, A, Aiuti, A, Aleinikova, O, Bangs, C, Baris, S, Barzaghi, F, Baxendale, H, Buckland, M, Burns, SO, Cancrini, C, Cant, A, Cathébras, P, Cavazzana, M, Chandra, A, Conti, F, Coulter, T, Devlin, LA, Edgar, JDM, Faust, S, Fischer, A, Prat, MG, Hammarström, 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, JP, Picard, C, Prader, S, Rae, W, Reichenbach, J, Rusch, S, Savic, S, Scarselli, A, Scheible, R, Sediva, A, Sharapova, SO, Shcherbina, A, Slatter, M, Soler-Palacin, P, Stanislas, A, Suarez, F, Tucci, F, Uhlmann, A, Montfrans, J, Warnatz, K, Williams, AP, Wood, P, Kracker, S, Condliffe, AM & Ehl, S 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', Frontiers in Immunology, vol. 9, no. 6, 543. https://doi.org/10.3389/fimmu.2018.00543
Maccari, ME ; Abolhassani, H ; Aghamohammadi, A ; Aiuti, A ; Aleinikova, O ; Bangs, C ; Baris, S ; Barzaghi, F ; Baxendale, H ; Buckland, M ; Burns, SO ; Cancrini, C ; Cant, A ; Cathébras, P ; Cavazzana, M ; Chandra, A ; Conti, F ; Coulter, T ; Devlin, LA ; Edgar, JDM ; Faust, S ; Fischer, A ; Prat, MG ; Hammarström, 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, JP ; Picard, C ; Prader, S ; Rae, W ; Reichenbach, J ; Rusch, S ; Savic, S ; Scarselli, A ; Scheible, R ; Sediva, A ; Sharapova, SO ; Shcherbina, A ; Slatter, M ; Soler-Palacin, P ; Stanislas, A ; Suarez, F ; Tucci, F ; Uhlmann, A ; Montfrans, Jv ; Warnatz, K ; Williams, AP ; Wood, P ; Kracker, S ; Condliffe, AM ; Ehl, S. / 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. In: Frontiers in Immunology. 2018 ; Vol. 9, No. 6.
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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. {\circledC} 2018 Maccari, et al.",
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T1 - 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

AU - Maccari, ME

AU - Abolhassani, H

AU - Aghamohammadi, A

AU - Aiuti, A

AU - Aleinikova, O

AU - Bangs, C

AU - Baris, S

AU - Barzaghi, F

AU - Baxendale, H

AU - Buckland, M

AU - Burns, SO

AU - Cancrini, C

AU - Cant, A

AU - Cathébras, P

AU - Cavazzana, M

AU - Chandra, A

AU - Conti, F

AU - Coulter, T

AU - Devlin, LA

AU - Edgar, JDM

AU - Faust, S

AU - Fischer, A

AU - Prat, MG

AU - Hammarström, L

AU - Heeg, M

AU - Jolles, S

AU - Karakoc-Aydiner, E

AU - Kindle, G

AU - Kiykim, A

AU - Kumararatne, D

AU - Grimbacher, B

AU - Longhurst, H

AU - Mahlaoui, N

AU - Milota, T

AU - Moreira, F

AU - Moshous, D

AU - Mukhina, A

AU - Neth, O

AU - Neven, B

AU - Nieters, A

AU - Olbrich, P

AU - Ozen, A

AU - Schmid, JP

AU - Picard, C

AU - Prader, S

AU - Rae, W

AU - Reichenbach, J

AU - Rusch, S

AU - Savic, S

AU - Scarselli, A

AU - Scheible, R

AU - Sediva, A

AU - Sharapova, SO

AU - Shcherbina, A

AU - Slatter, M

AU - Soler-Palacin, P

AU - Stanislas, A

AU - Suarez, F

AU - Tucci, F

AU - Uhlmann, A

AU - Montfrans, Jv

AU - Warnatz, K

AU - Williams, AP

AU - Wood, P

AU - Kracker, S

AU - Condliffe, AM

AU - Ehl, S

PY - 2018

Y1 - 2018

N2 - 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. © 2018 Maccari, et al.

AB - 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. © 2018 Maccari, et al.

U2 - 10.3389/fimmu.2018.00543

DO - 10.3389/fimmu.2018.00543

M3 - Article

VL - 9

JO - Frontiers in Immunology

JF - Frontiers in Immunology

SN - 1664-3224

IS - 6

M1 - 543

ER -