The diagnosis of severe combined immunodeficiency: Implementation of the PIDTC 2022 Definitions

Christopher C. Dvorak; Elie Haddad; Jennifer Heimall; Elizabeth Dunn; Morton J. Cowan; Sung Yun Pai; Neena Kapoor; Lisa Forbes Satter; Rebecca H. Buckley; Richard J. O'Reilly; Sharat Chandra; Jeffrey J. Bednarski; Olatundun Williams; Ahmad Rayes; Theodore B. Moore; Christen L. Ebens; Blachy J. Davila Saldana; Aleksandra Petrovic; Deepak Chellapandian; Geoffrey D.E. Cuvelier; Mark T. Vander Lugt; Emi H. Caywood; Shanmuganathan Chandrakasan; Hesham Eissa; Frederick D. Goldman; Evan Shereck; Victor M. Aquino; Kenneth B. Desantes; Lisa M. Madden; Holly K. Miller; Lolie Yu; Larisa Broglie; Alfred Gillio; Ami J. Shah; Alan P. Knutsen; Jeffrey P. Andolina; Avni Y. Joshi; Paul Szabolcs; Malika Kapadia; Caridad A. Martinez; Roberta E. Parrot; Kathleen E. Sullivan; Susan E. Prockop; Roshini S. Abraham; Monica S. Thakar; Jennifer W. Leiding; Donald B. Kohn; Michael A. Pulsipher; Linda M. Griffith; Luigi D. Notarangelo; Jennifer M. Puck

doi:10.1016/j.jaci.2022.10.021

The diagnosis of severe combined immunodeficiency: Implementation of the PIDTC 2022 Definitions

Christopher C. Dvorak, Elie Haddad, Jennifer Heimall, Elizabeth Dunn, Morton J. Cowan, Sung Yun Pai, Neena Kapoor, Lisa Forbes Satter, Rebecca H. Buckley, Richard J. O'Reilly, Sharat Chandra, Jeffrey J. Bednarski, Olatundun Williams, Ahmad Rayes, Theodore B. Moore, Christen L. Ebens, Blachy J. Davila Saldana, Aleksandra Petrovic, Deepak Chellapandian, Geoffrey D.E. CuvelierMark T. Vander Lugt, Emi H. Caywood, Shanmuganathan Chandrakasan, Hesham Eissa, Frederick D. Goldman, Evan Shereck, Victor M. Aquino, Kenneth B. Desantes, Lisa M. Madden, Holly K. Miller, Lolie Yu, Larisa Broglie, Alfred Gillio, Ami J. Shah, Alan P. Knutsen, Jeffrey P. Andolina, Avni Y. Joshi, Paul Szabolcs, Malika Kapadia, Caridad A. Martinez, Roberta E. Parrot, Kathleen E. Sullivan, Susan E. Prockop, Roshini S. Abraham, Monica S. Thakar, Jennifer W. Leiding, Donald B. Kohn, Michael A. Pulsipher, Linda M. Griffith, Luigi D. Notarangelo, Jennifer M. Puck

Pediatric Blood & Marrow Transplant & Cellular Therapy

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

13 Scopus citations

Abstract

Background: Shearer et al in 2014 articulated well-defined criteria for the diagnosis and classification of severe combined immunodeficiency (SCID) as part of the Primary Immune Deficiency Treatment Consortium's (PIDTC's) prospective and retrospective studies of SCID. Objective: Because of the advent of newborn screening for SCID and expanded availability of genetic sequencing, revision of the PIDTC 2014 Criteria was needed. Methods: We developed and tested updated PIDTC 2022 SCID Definitions by analyzing 379 patients proposed for prospective enrollment into Protocol 6901, focusing on the ability to distinguish patients with various SCID subtypes. Results: According to PIDTC 2022 Definitions, 18 of 353 patients eligible per 2014 Criteria were considered not to have SCID, whereas 11 of 26 patients ineligible per 2014 Criteria were determined to have SCID. Of note, very low numbers of autologous T cells (<0.05 × 10⁹/L) characterized typical SCID under the 2022 Definitions. Pathogenic variant(s) in SCID-associated genes was identified in 93% of patients, with 7 genes (IL2RG, RAG1, ADA, IL7R, DCLRE1C, JAK3, and RAG2) accounting for 89% of typical SCID. Three genotypes (RAG1, ADA, and RMRP) accounted for 57% of cases of leaky/atypical SCID; there were 13 other rare genotypes. Patients with leaky/atypical SCID were more likely to be diagnosed at more than age 1 year than those with typical SCID lacking maternal T cells: 20% versus 1% (P < .001). Although repeat testing proved important, an initial CD3 T-cell count of less than 0.05 × 10⁹/L differentiated cases of typical SCID lacking maternal cells from leaky/atypical SCID: 97% versus 7% (P < .001). Conclusions: The PIDTC 2022 Definitions describe SCID and its subtypes more precisely than before, facilitating analyses of SCID characteristics and outcomes.

Original language	English (US)
Pages (from-to)	547-555.e5
Journal	Journal of Allergy and Clinical Immunology
Volume	151
Issue number	2
DOIs	https://doi.org/10.1016/j.jaci.2022.10.021
State	Published - Feb 2023

Bibliographical note

Funding Information:
The work was supported by the Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases (NIAID); and the Office of Rare Diseases Research (ORDR), National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Bethesda, Md: grant number U54AI082973 (MPI: J.M.P., C.C.D., and E.H.); and grant numbers U54NS064808 and U01TR001263 (PI: J.K.). The Primary Immunodeficiency Treatment Consortium (PIDTC) is a part of the Rare Diseases Clinical Research Network of ORDR, NCATS. The collaborative work of the PIDTC with the Pediatric Transplantation and Cellular Therapy Consortium (PTCTC) is supported by the U54 grants listed, along with support of the PTCTC Operations Center by the St. Baldrick’s Foundation and grant number U10HL069254 (PI: M.M.H.). Collaborative work of the PIDTC with the Center for International Blood and Marrow Transplant Research is supported by grant number U24CA076518 (PI: B.E.S.); grant number U01HL069294 (PI: M.M.H.); contract numbers HHSH250201200016C and HHSH234200637015C with the Health Resources and Services Administration , Department of Health and Human Services; and grant numbers N00014-13-1-0039 and N00014-14-1-0028 from the Office of Naval Research . M.J.C. and J.M.P. are supported by the California Institute of Regenerative Medicine (grant no. CLIN2-10830). M.A.P. is supported by grant numbers 1U01AI126612-01A1, P30CA040214, and 2UG1HL069254. S.Y.P. is supported by funding from the Intramural Research Program, NIH, National Cancer Institute , Center for Cancer Research. L.D.N. is supported by the Division of Intramural Research, NIAID, and NIH (grant no. ZIA AI001222-07 to PI L.D.N.).

Publisher Copyright:
© 2022 The Authors

Keywords

Omenn syndrome
SCID
Severe combined immunodeficiency
leaky/atypical SCID
newborn screening
typical SCID

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10.1016/j.jaci.2022.10.021

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Dvorak, C. C., Haddad, E., Heimall, J., Dunn, E., Cowan, M. J., Pai, S. Y., Kapoor, N., Satter, L. F., Buckley, R. H., O'Reilly, R. J., Chandra, S., Bednarski, J. J., Williams, O., Rayes, A., Moore, T. B., Ebens, C. L., Davila Saldana, B. J., Petrovic, A., Chellapandian, D., ... Puck, J. M. (2023). The diagnosis of severe combined immunodeficiency: Implementation of the PIDTC 2022 Definitions. Journal of Allergy and Clinical Immunology, 151(2), 547-555.e5. https://doi.org/10.1016/j.jaci.2022.10.021

Dvorak, CC, Haddad, E, Heimall, J, Dunn, E, Cowan, MJ, Pai, SY, Kapoor, N, Satter, LF, Buckley, RH, O'Reilly, RJ, Chandra, S, Bednarski, JJ, Williams, O, Rayes, A, Moore, TB, Ebens, CL, Davila Saldana, BJ, Petrovic, A, Chellapandian, D, Cuvelier, GDE, Vander Lugt, MT, Caywood, EH, Chandrakasan, S, Eissa, H, Goldman, FD, Shereck, E, Aquino, VM, Desantes, KB, Madden, LM, Miller, HK, Yu, L, Broglie, L, Gillio, A, Shah, AJ, Knutsen, AP, Andolina, JP, Joshi, AY, Szabolcs, P, Kapadia, M, Martinez, CA, Parrot, RE, Sullivan, KE, Prockop, SE, Abraham, RS, Thakar, MS, Leiding, JW, Kohn, DB, Pulsipher, MA, Griffith, LM, Notarangelo, LD & Puck, JM 2023, 'The diagnosis of severe combined immunodeficiency: Implementation of the PIDTC 2022 Definitions', Journal of Allergy and Clinical Immunology, vol. 151, no. 2, pp. 547-555.e5. https://doi.org/10.1016/j.jaci.2022.10.021

@article{170986708e974c7bb7a315d6c404e107,

title = "The diagnosis of severe combined immunodeficiency: Implementation of the PIDTC 2022 Definitions",

abstract = "Background: Shearer et al in 2014 articulated well-defined criteria for the diagnosis and classification of severe combined immunodeficiency (SCID) as part of the Primary Immune Deficiency Treatment Consortium's (PIDTC's) prospective and retrospective studies of SCID. Objective: Because of the advent of newborn screening for SCID and expanded availability of genetic sequencing, revision of the PIDTC 2014 Criteria was needed. Methods: We developed and tested updated PIDTC 2022 SCID Definitions by analyzing 379 patients proposed for prospective enrollment into Protocol 6901, focusing on the ability to distinguish patients with various SCID subtypes. Results: According to PIDTC 2022 Definitions, 18 of 353 patients eligible per 2014 Criteria were considered not to have SCID, whereas 11 of 26 patients ineligible per 2014 Criteria were determined to have SCID. Of note, very low numbers of autologous T cells (<0.05 × 109/L) characterized typical SCID under the 2022 Definitions. Pathogenic variant(s) in SCID-associated genes was identified in 93% of patients, with 7 genes (IL2RG, RAG1, ADA, IL7R, DCLRE1C, JAK3, and RAG2) accounting for 89% of typical SCID. Three genotypes (RAG1, ADA, and RMRP) accounted for 57% of cases of leaky/atypical SCID; there were 13 other rare genotypes. Patients with leaky/atypical SCID were more likely to be diagnosed at more than age 1 year than those with typical SCID lacking maternal T cells: 20% versus 1% (P < .001). Although repeat testing proved important, an initial CD3 T-cell count of less than 0.05 × 109/L differentiated cases of typical SCID lacking maternal cells from leaky/atypical SCID: 97% versus 7% (P < .001). Conclusions: The PIDTC 2022 Definitions describe SCID and its subtypes more precisely than before, facilitating analyses of SCID characteristics and outcomes.",

keywords = "Omenn syndrome, SCID, Severe combined immunodeficiency, leaky/atypical SCID, newborn screening, typical SCID",

author = "Dvorak, {Christopher C.} and Elie Haddad and Jennifer Heimall and Elizabeth Dunn and Cowan, {Morton J.} and Pai, {Sung Yun} and Neena Kapoor and Satter, {Lisa Forbes} and Buckley, {Rebecca H.} and O'Reilly, {Richard J.} and Sharat Chandra and Bednarski, {Jeffrey J.} and Olatundun Williams and Ahmad Rayes and Moore, {Theodore B.} and Ebens, {Christen L.} and {Davila Saldana}, {Blachy J.} and Aleksandra Petrovic and Deepak Chellapandian and Cuvelier, {Geoffrey D.E.} and {Vander Lugt}, {Mark T.} and Caywood, {Emi H.} and Shanmuganathan Chandrakasan and Hesham Eissa and Goldman, {Frederick D.} and Evan Shereck and Aquino, {Victor M.} and Desantes, {Kenneth B.} and Madden, {Lisa M.} and Miller, {Holly K.} and Lolie Yu and Larisa Broglie and Alfred Gillio and Shah, {Ami J.} and Knutsen, {Alan P.} and Andolina, {Jeffrey P.} and Joshi, {Avni Y.} and Paul Szabolcs and Malika Kapadia and Martinez, {Caridad A.} and Parrot, {Roberta E.} and Sullivan, {Kathleen E.} and Prockop, {Susan E.} and Abraham, {Roshini S.} and Thakar, {Monica S.} and Leiding, {Jennifer W.} and Kohn, {Donald B.} and Pulsipher, {Michael A.} and Griffith, {Linda M.} and Notarangelo, {Luigi D.} and Puck, {Jennifer M.}",

note = "Funding Information: The work was supported by the Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases (NIAID); and the Office of Rare Diseases Research (ORDR), National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Bethesda, Md: grant number U54AI082973 (MPI: J.M.P., C.C.D., and E.H.); and grant numbers U54NS064808 and U01TR001263 (PI: J.K.). The Primary Immunodeficiency Treatment Consortium (PIDTC) is a part of the Rare Diseases Clinical Research Network of ORDR, NCATS. The collaborative work of the PIDTC with the Pediatric Transplantation and Cellular Therapy Consortium (PTCTC) is supported by the U54 grants listed, along with support of the PTCTC Operations Center by the St. Baldrick{\textquoteright}s Foundation and grant number U10HL069254 (PI: M.M.H.). Collaborative work of the PIDTC with the Center for International Blood and Marrow Transplant Research is supported by grant number U24CA076518 (PI: B.E.S.); grant number U01HL069294 (PI: M.M.H.); contract numbers HHSH250201200016C and HHSH234200637015C with the Health Resources and Services Administration , Department of Health and Human Services; and grant numbers N00014-13-1-0039 and N00014-14-1-0028 from the Office of Naval Research . M.J.C. and J.M.P. are supported by the California Institute of Regenerative Medicine (grant no. CLIN2-10830). M.A.P. is supported by grant numbers 1U01AI126612-01A1, P30CA040214, and 2UG1HL069254. S.Y.P. is supported by funding from the Intramural Research Program, NIH, National Cancer Institute , Center for Cancer Research. L.D.N. is supported by the Division of Intramural Research, NIAID, and NIH (grant no. ZIA AI001222-07 to PI L.D.N.). Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2023",

month = feb,

doi = "10.1016/j.jaci.2022.10.021",

language = "English (US)",

volume = "151",

pages = "547--555.e5",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Mosby Inc.",

number = "2",

}

TY - JOUR

T1 - The diagnosis of severe combined immunodeficiency

T2 - Implementation of the PIDTC 2022 Definitions

AU - Dvorak, Christopher C.

AU - Haddad, Elie

AU - Heimall, Jennifer

AU - Dunn, Elizabeth

AU - Cowan, Morton J.

AU - Pai, Sung Yun

AU - Kapoor, Neena

AU - Satter, Lisa Forbes

AU - Buckley, Rebecca H.

AU - O'Reilly, Richard J.

AU - Chandra, Sharat

AU - Bednarski, Jeffrey J.

AU - Williams, Olatundun

AU - Rayes, Ahmad

AU - Moore, Theodore B.

AU - Ebens, Christen L.

AU - Davila Saldana, Blachy J.

AU - Petrovic, Aleksandra

AU - Chellapandian, Deepak

AU - Cuvelier, Geoffrey D.E.

AU - Vander Lugt, Mark T.

AU - Caywood, Emi H.

AU - Chandrakasan, Shanmuganathan

AU - Eissa, Hesham

AU - Goldman, Frederick D.

AU - Shereck, Evan

AU - Aquino, Victor M.

AU - Desantes, Kenneth B.

AU - Madden, Lisa M.

AU - Miller, Holly K.

AU - Yu, Lolie

AU - Broglie, Larisa

AU - Gillio, Alfred

AU - Shah, Ami J.

AU - Knutsen, Alan P.

AU - Andolina, Jeffrey P.

AU - Joshi, Avni Y.

AU - Szabolcs, Paul

AU - Kapadia, Malika

AU - Martinez, Caridad A.

AU - Parrot, Roberta E.

AU - Sullivan, Kathleen E.

AU - Prockop, Susan E.

AU - Abraham, Roshini S.

AU - Thakar, Monica S.

AU - Leiding, Jennifer W.

AU - Kohn, Donald B.

AU - Pulsipher, Michael A.

AU - Griffith, Linda M.

AU - Notarangelo, Luigi D.

AU - Puck, Jennifer M.

N1 - Funding Information: The work was supported by the Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases (NIAID); and the Office of Rare Diseases Research (ORDR), National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Bethesda, Md: grant number U54AI082973 (MPI: J.M.P., C.C.D., and E.H.); and grant numbers U54NS064808 and U01TR001263 (PI: J.K.). The Primary Immunodeficiency Treatment Consortium (PIDTC) is a part of the Rare Diseases Clinical Research Network of ORDR, NCATS. The collaborative work of the PIDTC with the Pediatric Transplantation and Cellular Therapy Consortium (PTCTC) is supported by the U54 grants listed, along with support of the PTCTC Operations Center by the St. Baldrick’s Foundation and grant number U10HL069254 (PI: M.M.H.). Collaborative work of the PIDTC with the Center for International Blood and Marrow Transplant Research is supported by grant number U24CA076518 (PI: B.E.S.); grant number U01HL069294 (PI: M.M.H.); contract numbers HHSH250201200016C and HHSH234200637015C with the Health Resources and Services Administration , Department of Health and Human Services; and grant numbers N00014-13-1-0039 and N00014-14-1-0028 from the Office of Naval Research . M.J.C. and J.M.P. are supported by the California Institute of Regenerative Medicine (grant no. CLIN2-10830). M.A.P. is supported by grant numbers 1U01AI126612-01A1, P30CA040214, and 2UG1HL069254. S.Y.P. is supported by funding from the Intramural Research Program, NIH, National Cancer Institute , Center for Cancer Research. L.D.N. is supported by the Division of Intramural Research, NIAID, and NIH (grant no. ZIA AI001222-07 to PI L.D.N.). Publisher Copyright: © 2022 The Authors

PY - 2023/2

Y1 - 2023/2

N2 - Background: Shearer et al in 2014 articulated well-defined criteria for the diagnosis and classification of severe combined immunodeficiency (SCID) as part of the Primary Immune Deficiency Treatment Consortium's (PIDTC's) prospective and retrospective studies of SCID. Objective: Because of the advent of newborn screening for SCID and expanded availability of genetic sequencing, revision of the PIDTC 2014 Criteria was needed. Methods: We developed and tested updated PIDTC 2022 SCID Definitions by analyzing 379 patients proposed for prospective enrollment into Protocol 6901, focusing on the ability to distinguish patients with various SCID subtypes. Results: According to PIDTC 2022 Definitions, 18 of 353 patients eligible per 2014 Criteria were considered not to have SCID, whereas 11 of 26 patients ineligible per 2014 Criteria were determined to have SCID. Of note, very low numbers of autologous T cells (<0.05 × 109/L) characterized typical SCID under the 2022 Definitions. Pathogenic variant(s) in SCID-associated genes was identified in 93% of patients, with 7 genes (IL2RG, RAG1, ADA, IL7R, DCLRE1C, JAK3, and RAG2) accounting for 89% of typical SCID. Three genotypes (RAG1, ADA, and RMRP) accounted for 57% of cases of leaky/atypical SCID; there were 13 other rare genotypes. Patients with leaky/atypical SCID were more likely to be diagnosed at more than age 1 year than those with typical SCID lacking maternal T cells: 20% versus 1% (P < .001). Although repeat testing proved important, an initial CD3 T-cell count of less than 0.05 × 109/L differentiated cases of typical SCID lacking maternal cells from leaky/atypical SCID: 97% versus 7% (P < .001). Conclusions: The PIDTC 2022 Definitions describe SCID and its subtypes more precisely than before, facilitating analyses of SCID characteristics and outcomes.

AB - Background: Shearer et al in 2014 articulated well-defined criteria for the diagnosis and classification of severe combined immunodeficiency (SCID) as part of the Primary Immune Deficiency Treatment Consortium's (PIDTC's) prospective and retrospective studies of SCID. Objective: Because of the advent of newborn screening for SCID and expanded availability of genetic sequencing, revision of the PIDTC 2014 Criteria was needed. Methods: We developed and tested updated PIDTC 2022 SCID Definitions by analyzing 379 patients proposed for prospective enrollment into Protocol 6901, focusing on the ability to distinguish patients with various SCID subtypes. Results: According to PIDTC 2022 Definitions, 18 of 353 patients eligible per 2014 Criteria were considered not to have SCID, whereas 11 of 26 patients ineligible per 2014 Criteria were determined to have SCID. Of note, very low numbers of autologous T cells (<0.05 × 109/L) characterized typical SCID under the 2022 Definitions. Pathogenic variant(s) in SCID-associated genes was identified in 93% of patients, with 7 genes (IL2RG, RAG1, ADA, IL7R, DCLRE1C, JAK3, and RAG2) accounting for 89% of typical SCID. Three genotypes (RAG1, ADA, and RMRP) accounted for 57% of cases of leaky/atypical SCID; there were 13 other rare genotypes. Patients with leaky/atypical SCID were more likely to be diagnosed at more than age 1 year than those with typical SCID lacking maternal T cells: 20% versus 1% (P < .001). Although repeat testing proved important, an initial CD3 T-cell count of less than 0.05 × 109/L differentiated cases of typical SCID lacking maternal cells from leaky/atypical SCID: 97% versus 7% (P < .001). Conclusions: The PIDTC 2022 Definitions describe SCID and its subtypes more precisely than before, facilitating analyses of SCID characteristics and outcomes.

KW - Omenn syndrome

KW - SCID

KW - Severe combined immunodeficiency

KW - leaky/atypical SCID

KW - newborn screening

KW - typical SCID

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The diagnosis of severe combined immunodeficiency: Implementation of the PIDTC 2022 Definitions

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