Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study

Tanya I Coulter; Anita Chandra; Chris M Bacon; Judith Babar; James Curtis; Nick Screaton; John R Goodlad; George Farmer; Cathal Laurence Steele; Timothy Ronan Leahy; Rainer Doffinger; Helen Baxendale; Jolanta Bernatoniene; J David M Edgar; Hilary J Longhurst; Stephan Ehl; Carsten Speckmann; Bodo Grimbacher; Anna Sediva; Tomas Milota; Saul N Faust; Anthony P Williams; Grant Hayman; Zeynep Yesim Kucuk; Rosie Hague; Paul French; Richard Brooker; Peter Forsyth; Richard Herriot; Caterina Cancrini; Paolo Palma; Paola Ariganello; Niall Conlon; Conleth Feighery; Patrick J Gavin; Alison Jones; Kohsuke Imai; Mohammad A A Ibrahim; Gašper Markelj; Mario Abinun; Frédéric Rieux-Laucat; Sylvain Latour; Isabelle Pellier; Alain Fischer; Fabien Touzot; Jean-Laurent Casanova; Anne Durandy; Siobhan O Burns; Sinisa Savic; D S Kumararatne; Despina Moshous; Sven Kracker; Bart Vanhaesebroeck; Klaus Okkenhaug; Capucine Picard; Sergey Nejentsev; Alison M Condliffe; Andrew James Cant

doi:https://doi.org/10.1016/j.jaci.2016.06.021

Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study

Tanya I Coulter, Anita Chandra, Chris M Bacon, Judith Babar, James Curtis, Nick Screaton, John R Goodlad, George Farmer, Cathal Laurence Steele, Timothy Ronan Leahy, Rainer Doffinger, Helen Baxendale, Jolanta Bernatoniene, J David M Edgar, Hilary J Longhurst, Stephan Ehl, Carsten Speckmann, Bodo Grimbacher, Anna Sediva, Tomas MilotaSaul N Faust, Anthony P Williams, Grant Hayman, Zeynep Yesim Kucuk, Rosie Hague, Paul French, Richard Brooker, Peter Forsyth, Richard Herriot, Caterina Cancrini, Paolo Palma, Paola Ariganello, Niall Conlon, Conleth Feighery, Patrick J Gavin, Alison Jones, Kohsuke Imai, Mohammad A A Ibrahim, Gašper Markelj, Mario Abinun, Frédéric Rieux-Laucat, Sylvain Latour, Isabelle Pellier, Alain Fischer, Fabien Touzot, Jean-Laurent Casanova, Anne Durandy, Siobhan O Burns, Sinisa Savic, D S Kumararatne, Despina Moshous, Sven Kracker, Bart Vanhaesebroeck, Klaus Okkenhaug, Capucine Picard, Sergey Nejentsev, Alison M Condliffe, Andrew James Cant

Research output: Contribution to journal › Article › Academic › peer-review

320 Citations (Scopus)

Abstract

BACKGROUND: Activated phosphoinositide 3-kinase δ syndrome (APDS) is a recently described combined immunodeficiency resulting from gain-of-function mutations in PIK3CD, the gene encoding the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ).

OBJECTIVE: We sought to review the clinical, immunologic, histopathologic, and radiologic features of APDS in a large genetically defined international cohort.

METHODS: We applied a clinical questionnaire and performed review of medical notes, radiology, histopathology, and laboratory investigations of 53 patients with APDS.

RESULTS: Recurrent sinopulmonary infections (98%) and nonneoplastic lymphoproliferation (75%) were common, often from childhood. Other significant complications included herpesvirus infections (49%), autoinflammatory disease (34%), and lymphoma (13%). Unexpectedly, neurodevelopmental delay occurred in 19% of the cohort, suggesting a role for PI3Kδ in the central nervous system; consistent with this, PI3Kδ is broadly expressed in the developing murine central nervous system. Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60%). Increased IgM levels (78%), IgG deficiency (43%), and CD4 lymphopenia (84%) were significant immunologic features. No immunologic marker reliably predicted clinical severity, which ranged from asymptomatic to death in early childhood. The majority of patients received immunoglobulin replacement and antibiotic prophylaxis, and 5 patients underwent hematopoietic stem cell transplantation. Five patients died from complications of APDS.

CONCLUSION: APDS is a combined immunodeficiency with multiple clinical manifestations, many with incomplete penetrance and others with variable expressivity. The severity of complications in some patients supports consideration of hematopoietic stem cell transplantation for severe childhood disease. Clinical trials of selective PI3Kδ inhibitors offer new prospects for APDS treatment.

Original language	English
Pages (from-to)	597-606.e4
Journal	Journal of allergy and clinical immunology
Volume	139
Issue number	2
DOIs	https://doi.org/10.1016/j.jaci.2016.06.021
Publication status	Published - Feb 2017
Externally published	Yes

Keywords

Adolescent
Adult
Animals
Antibiotic Prophylaxis
Child
Child, Preschool
Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors
Cohort Studies
Enzyme Inhibitors/therapeutic use
Female
Hematopoietic Stem Cell Transplantation
Herpesviridae Infections/genetics
Humans
Immunoglobulins, Intravenous/therapeutic use
Immunologic Deficiency Syndromes/genetics
Infant
International Cooperation
Lymphoproliferative Disorders/genetics
Male
Mice
Middle Aged
Mutation/genetics
Recurrence
Respiratory Tract Infections/genetics
Surveys and Questionnaires
Survival Analysis
Young Adult

Access to Document

https://doi.org/10.1016/j.jaci.2016.06.021

Cite this

Coulter, T. I., Chandra, A., Bacon, C. M., Babar, J., Curtis, J., Screaton, N., Goodlad, J. R., Farmer, G., Steele, C. L., Leahy, T. R., Doffinger, R., Baxendale, H., Bernatoniene, J., Edgar, J. D. M., Longhurst, H. J., Ehl, S., Speckmann, C., Grimbacher, B., Sediva, A., ... Cant, A. J. (2017). Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study. Journal of allergy and clinical immunology, 139(2), 597-606.e4. https://doi.org/10.1016/j.jaci.2016.06.021

@article{7f322f2f77cf42cb8c533ddbd776d992,

title = "Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study",

abstract = "BACKGROUND: Activated phosphoinositide 3-kinase δ syndrome (APDS) is a recently described combined immunodeficiency resulting from gain-of-function mutations in PIK3CD, the gene encoding the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ).OBJECTIVE: We sought to review the clinical, immunologic, histopathologic, and radiologic features of APDS in a large genetically defined international cohort.METHODS: We applied a clinical questionnaire and performed review of medical notes, radiology, histopathology, and laboratory investigations of 53 patients with APDS.RESULTS: Recurrent sinopulmonary infections (98%) and nonneoplastic lymphoproliferation (75%) were common, often from childhood. Other significant complications included herpesvirus infections (49%), autoinflammatory disease (34%), and lymphoma (13%). Unexpectedly, neurodevelopmental delay occurred in 19% of the cohort, suggesting a role for PI3Kδ in the central nervous system; consistent with this, PI3Kδ is broadly expressed in the developing murine central nervous system. Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60%). Increased IgM levels (78%), IgG deficiency (43%), and CD4 lymphopenia (84%) were significant immunologic features. No immunologic marker reliably predicted clinical severity, which ranged from asymptomatic to death in early childhood. The majority of patients received immunoglobulin replacement and antibiotic prophylaxis, and 5 patients underwent hematopoietic stem cell transplantation. Five patients died from complications of APDS.CONCLUSION: APDS is a combined immunodeficiency with multiple clinical manifestations, many with incomplete penetrance and others with variable expressivity. The severity of complications in some patients supports consideration of hematopoietic stem cell transplantation for severe childhood disease. Clinical trials of selective PI3Kδ inhibitors offer new prospects for APDS treatment.",

keywords = "Adolescent, Adult, Animals, Antibiotic Prophylaxis, Child, Child, Preschool, Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors, Cohort Studies, Enzyme Inhibitors/therapeutic use, Female, Hematopoietic Stem Cell Transplantation, Herpesviridae Infections/genetics, Humans, Immunoglobulins, Intravenous/therapeutic use, Immunologic Deficiency Syndromes/genetics, Infant, International Cooperation, Lymphoproliferative Disorders/genetics, Male, Mice, Middle Aged, Mutation/genetics, Recurrence, Respiratory Tract Infections/genetics, Surveys and Questionnaires, Survival Analysis, Young Adult",

author = "Coulter, {Tanya I} and Anita Chandra and Bacon, {Chris M} and Judith Babar and James Curtis and Nick Screaton and Goodlad, {John R} and George Farmer and Steele, {Cathal Laurence} and Leahy, {Timothy Ronan} and Rainer Doffinger and Helen Baxendale and Jolanta Bernatoniene and Edgar, {J David M} and Longhurst, {Hilary J} and Stephan Ehl and Carsten Speckmann and Bodo Grimbacher and Anna Sediva and Tomas Milota and Faust, {Saul N} and Williams, {Anthony P} and Grant Hayman and Kucuk, {Zeynep Yesim} and Rosie Hague and Paul French and Richard Brooker and Peter Forsyth and Richard Herriot and Caterina Cancrini and Paolo Palma and Paola Ariganello and Niall Conlon and Conleth Feighery and Gavin, {Patrick J} and Alison Jones and Kohsuke Imai and Ibrahim, {Mohammad A A} and Ga{\v s}per Markelj and Mario Abinun and Fr{\'e}d{\'e}ric Rieux-Laucat and Sylvain Latour and Isabelle Pellier and Alain Fischer and Fabien Touzot and Jean-Laurent Casanova and Anne Durandy and Burns, {Siobhan O} and Sinisa Savic and Kumararatne, {D S} and Despina Moshous and Sven Kracker and Bart Vanhaesebroeck and Klaus Okkenhaug and Capucine Picard and Sergey Nejentsev and Condliffe, {Alison M} and Cant, {Andrew James}",

year = "2017",

month = feb,

doi = "https://doi.org/10.1016/j.jaci.2016.06.021",

language = "English",

volume = "139",

pages = "597--606.e4",

journal = "Journal of allergy and clinical immunology",

issn = "0091-6749",

publisher = "Mosby Inc.",

number = "2",

}

Coulter, TI, Chandra, A, Bacon, CM, Babar, J, Curtis, J, Screaton, N, Goodlad, JR, Farmer, G, Steele, CL, Leahy, TR, Doffinger, R, Baxendale, H, Bernatoniene, J, Edgar, JDM, Longhurst, HJ, Ehl, S, Speckmann, C, Grimbacher, B, Sediva, A, Milota, T, Faust, SN, Williams, AP, Hayman, G, Kucuk, ZY, Hague, R, French, P, Brooker, R, Forsyth, P, Herriot, R, Cancrini, C, Palma, P, Ariganello, P, Conlon, N, Feighery, C, Gavin, PJ, Jones, A, Imai, K, Ibrahim, MAA, Markelj, G, Abinun, M, Rieux-Laucat, F, Latour, S, Pellier, I, Fischer, A, Touzot, F, Casanova, J-L, Durandy, A, Burns, SO, Savic, S, Kumararatne, DS, Moshous, D, Kracker, S, Vanhaesebroeck, B, Okkenhaug, K, Picard, C, Nejentsev, S, Condliffe, AM & Cant, AJ 2017, 'Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study', Journal of allergy and clinical immunology, vol. 139, no. 2, pp. 597-606.e4. https://doi.org/10.1016/j.jaci.2016.06.021

TY - JOUR

T1 - Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome

T2 - A large patient cohort study

AU - Coulter, Tanya I

AU - Chandra, Anita

AU - Bacon, Chris M

AU - Babar, Judith

AU - Curtis, James

AU - Screaton, Nick

AU - Goodlad, John R

AU - Farmer, George

AU - Steele, Cathal Laurence

AU - Leahy, Timothy Ronan

AU - Doffinger, Rainer

AU - Baxendale, Helen

AU - Bernatoniene, Jolanta

AU - Edgar, J David M

AU - Longhurst, Hilary J

AU - Ehl, Stephan

AU - Speckmann, Carsten

AU - Grimbacher, Bodo

AU - Sediva, Anna

AU - Milota, Tomas

AU - Faust, Saul N

AU - Williams, Anthony P

AU - Hayman, Grant

AU - Kucuk, Zeynep Yesim

AU - Hague, Rosie

AU - French, Paul

AU - Brooker, Richard

AU - Forsyth, Peter

AU - Herriot, Richard

AU - Cancrini, Caterina

AU - Palma, Paolo

AU - Ariganello, Paola

AU - Conlon, Niall

AU - Feighery, Conleth

AU - Gavin, Patrick J

AU - Jones, Alison

AU - Imai, Kohsuke

AU - Ibrahim, Mohammad A A

AU - Markelj, Gašper

AU - Abinun, Mario

AU - Rieux-Laucat, Frédéric

AU - Latour, Sylvain

AU - Pellier, Isabelle

AU - Fischer, Alain

AU - Touzot, Fabien

AU - Casanova, Jean-Laurent

AU - Durandy, Anne

AU - Burns, Siobhan O

AU - Savic, Sinisa

AU - Kumararatne, D S

AU - Moshous, Despina

AU - Kracker, Sven

AU - Vanhaesebroeck, Bart

AU - Okkenhaug, Klaus

AU - Picard, Capucine

AU - Nejentsev, Sergey

AU - Condliffe, Alison M

AU - Cant, Andrew James

PY - 2017/2

Y1 - 2017/2

N2 - BACKGROUND: Activated phosphoinositide 3-kinase δ syndrome (APDS) is a recently described combined immunodeficiency resulting from gain-of-function mutations in PIK3CD, the gene encoding the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ).OBJECTIVE: We sought to review the clinical, immunologic, histopathologic, and radiologic features of APDS in a large genetically defined international cohort.METHODS: We applied a clinical questionnaire and performed review of medical notes, radiology, histopathology, and laboratory investigations of 53 patients with APDS.RESULTS: Recurrent sinopulmonary infections (98%) and nonneoplastic lymphoproliferation (75%) were common, often from childhood. Other significant complications included herpesvirus infections (49%), autoinflammatory disease (34%), and lymphoma (13%). Unexpectedly, neurodevelopmental delay occurred in 19% of the cohort, suggesting a role for PI3Kδ in the central nervous system; consistent with this, PI3Kδ is broadly expressed in the developing murine central nervous system. Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60%). Increased IgM levels (78%), IgG deficiency (43%), and CD4 lymphopenia (84%) were significant immunologic features. No immunologic marker reliably predicted clinical severity, which ranged from asymptomatic to death in early childhood. The majority of patients received immunoglobulin replacement and antibiotic prophylaxis, and 5 patients underwent hematopoietic stem cell transplantation. Five patients died from complications of APDS.CONCLUSION: APDS is a combined immunodeficiency with multiple clinical manifestations, many with incomplete penetrance and others with variable expressivity. The severity of complications in some patients supports consideration of hematopoietic stem cell transplantation for severe childhood disease. Clinical trials of selective PI3Kδ inhibitors offer new prospects for APDS treatment.

AB - BACKGROUND: Activated phosphoinositide 3-kinase δ syndrome (APDS) is a recently described combined immunodeficiency resulting from gain-of-function mutations in PIK3CD, the gene encoding the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ).OBJECTIVE: We sought to review the clinical, immunologic, histopathologic, and radiologic features of APDS in a large genetically defined international cohort.METHODS: We applied a clinical questionnaire and performed review of medical notes, radiology, histopathology, and laboratory investigations of 53 patients with APDS.RESULTS: Recurrent sinopulmonary infections (98%) and nonneoplastic lymphoproliferation (75%) were common, often from childhood. Other significant complications included herpesvirus infections (49%), autoinflammatory disease (34%), and lymphoma (13%). Unexpectedly, neurodevelopmental delay occurred in 19% of the cohort, suggesting a role for PI3Kδ in the central nervous system; consistent with this, PI3Kδ is broadly expressed in the developing murine central nervous system. Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60%). Increased IgM levels (78%), IgG deficiency (43%), and CD4 lymphopenia (84%) were significant immunologic features. No immunologic marker reliably predicted clinical severity, which ranged from asymptomatic to death in early childhood. The majority of patients received immunoglobulin replacement and antibiotic prophylaxis, and 5 patients underwent hematopoietic stem cell transplantation. Five patients died from complications of APDS.CONCLUSION: APDS is a combined immunodeficiency with multiple clinical manifestations, many with incomplete penetrance and others with variable expressivity. The severity of complications in some patients supports consideration of hematopoietic stem cell transplantation for severe childhood disease. Clinical trials of selective PI3Kδ inhibitors offer new prospects for APDS treatment.

KW - Adolescent

KW - Adult

KW - Animals

KW - Antibiotic Prophylaxis

KW - Child

KW - Child, Preschool

KW - Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors

KW - Cohort Studies

KW - Enzyme Inhibitors/therapeutic use

KW - Female

KW - Hematopoietic Stem Cell Transplantation

KW - Herpesviridae Infections/genetics

KW - Humans

KW - Immunoglobulins, Intravenous/therapeutic use

KW - Immunologic Deficiency Syndromes/genetics

KW - Infant

KW - International Cooperation

KW - Lymphoproliferative Disorders/genetics

KW - Male

KW - Mice

KW - Middle Aged

KW - Mutation/genetics

KW - Recurrence

KW - Respiratory Tract Infections/genetics

KW - Surveys and Questionnaires

KW - Survival Analysis

KW - Young Adult

U2 - https://doi.org/10.1016/j.jaci.2016.06.021

DO - https://doi.org/10.1016/j.jaci.2016.06.021

M3 - Article

C2 - 27555459

SN - 0091-6749

VL - 139

SP - 597-606.e4

JO - Journal of allergy and clinical immunology

JF - Journal of allergy and clinical immunology

IS - 2

ER -