Measuring the effect of newborn screening on survival after haematopoietic cell transplantation for severe combined immunodeficiency: a 36-year longitudinal study from the Primary Immune Deficiency Treatment Consortium

Monica S. Thakar; Brent R. Logan; Jennifer M. Puck; Elizabeth A. Dunn; Rebecca H. Buckley; Morton J. Cowan; Richard J. O'Reilly; Neena Kapoor; Lisa Forbes Satter; Sung Yun Pai; Jennifer Heimall; Sharat Chandra; Christen L. Ebens; Deepak Chellapandian; Olatundun Williams; Lauri M. Burroughs; Blachy Davila Saldana; Ahmad Rayes; Lisa M. Madden; Shanmuganathan Chandrakasan; Jeffrey J. Bednarski; Kenneth B. DeSantes; Geoffrey D.E. Cuvelier; Pierre Teira; Alfred P. Gillio; Hesham Eissa; Alan P. Knutsen; Frederick D. Goldman; Victor M. Aquino; Evan B. Shereck; Theodore B. Moore; Emi H. Caywood; Mark T.Vander Lugt; Jacob Rozmus; Larisa Broglie; Lolie C. Yu; Ami J. Shah; Jeffrey R. Andolina; Xuerong Liu; Roberta E. Parrott; Jasmeen Dara; Susan Prockop; Caridad A. Martinez; Malika Kapadia; Soma C. Jyonouchi; Kathleen E. Sullivan; Jack J. Bleesing; Sonali Chaudhury; Aleksandra Petrovic; Michael D. Keller; Troy C. Quigg; Suhag Parikh; Shalini Shenoy; Christine Seroogy; Tamar Rubin; Hélène Decaluwe; John M. Routes; Troy R. Torgerson; Jennifer W. Leiding; Michael A. Pulsipher; Donald B. Kohn; Linda M. Griffith; Elie Haddad; Christopher C. Dvorak; Luigi D. Notarangelo

doi:10.1016/S0140-6736(23)00731-6

Measuring the effect of newborn screening on survival after haematopoietic cell transplantation for severe combined immunodeficiency: a 36-year longitudinal study from the Primary Immune Deficiency Treatment Consortium

Monica S. Thakar^*, Brent R. Logan, Jennifer M. Puck, Elizabeth A. Dunn, Rebecca H. Buckley, Morton J. Cowan, Richard J. O'Reilly, Neena Kapoor, Lisa Forbes Satter, Sung Yun Pai, Jennifer Heimall, Sharat Chandra, Christen L. Ebens, Deepak Chellapandian, Olatundun Williams, Lauri M. Burroughs, Blachy Davila Saldana, Ahmad Rayes, Lisa M. Madden, Shanmuganathan ChandrakasanJeffrey J. Bednarski, Kenneth B. DeSantes, Geoffrey D.E. Cuvelier, Pierre Teira, Alfred P. Gillio, Hesham Eissa, Alan P. Knutsen, Frederick D. Goldman, Victor M. Aquino, Evan B. Shereck, Theodore B. Moore, Emi H. Caywood, Mark T.Vander Lugt, Jacob Rozmus, Larisa Broglie, Lolie C. Yu, Ami J. Shah, Jeffrey R. Andolina, Xuerong Liu, Roberta E. Parrott, Jasmeen Dara, Susan Prockop, Caridad A. Martinez, Malika Kapadia, Soma C. Jyonouchi, Kathleen E. Sullivan, Jack J. Bleesing, Sonali Chaudhury, Aleksandra Petrovic, Michael D. Keller, Troy C. Quigg, Suhag Parikh, Shalini Shenoy, Christine Seroogy, Tamar Rubin, Hélène Decaluwe, John M. Routes, Troy R. Torgerson, Jennifer W. Leiding, Michael A. Pulsipher, Donald B. Kohn, Linda M. Griffith, Elie Haddad, Christopher C. Dvorak, Luigi D. Notarangelo

^*Corresponding author for this work

Pediatrics

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

22 Scopus citations

Abstract

Background: Severe combined immunodeficiency (SCID) is fatal unless durable adaptive immunity is established, most commonly through allogeneic haematopoietic cell transplantation (HCT). The Primary Immune Deficiency Treatment Consortium (PIDTC) explored factors affecting the survival of individuals with SCID over almost four decades, focusing on the effects of population-based newborn screening for SCID that was initiated in 2008 and expanded during 2010–18. Methods: We analysed transplantation-related data from children with SCID treated at 34 PIDTC sites in the USA and Canada, using the calendar time intervals 1982–89, 1990–99, 2000–09, and 2010–18. Categorical variables were compared by χ² test and continuous outcomes by the Kruskal-Wallis test. Overall survival was estimated by the Kaplan-Meier method. A multivariable analysis using Cox proportional hazards regression models examined risk factors for HCT outcomes, including the variables of time interval of HCT, infection status and age at HCT, trigger for diagnosis, SCID type and genotype, race and ethnicity of the patient, non-HLA-matched sibling donor type, graft type, GVHD prophylaxis, and conditioning intensity. Findings: For 902 children with confirmed SCID, 5-year overall survival remained unchanged at 72%–73% for 28 years until 2010–18, when it increased to 87% (95% CI 82·1–90·6; n=268; p=0·0005). For children identified as having SCID by newborn screening since 2010, 5-year overall survival was 92·5% (95% CI 85·8–96·1), better than that of children identified by clinical illness or family history in the same interval (79·9% [69·5–87·0] and 85·4% [71·8–92·8], respectively [p=0·043]). Multivariable analysis demonstrated that the factors of active infection (hazard ratio [HR] 2·41, 95% CI 1·56–3·72; p<0·0001), age 3·5 months or older at HCT (2·12, 1·38–3·24; p=0·001), Black or African-American race (2·33, 1·56–3·46; p<0·0001), and certain SCID genotypes to be associated with lower overall survival during all time intervals. Moreover, after adjusting for several factors in this multivariable analysis, HCT after 2010 no longer conveyed a survival advantage over earlier time intervals studied (HR 0·73, 95% CI 0·43–1·26; p=0·097). This indicated that younger age and freedom from infections at HCT, both directly driven by newborn screening, were the main drivers for recent improvement in overall survival. Interpretation: Population-based newborn screening has facilitated the identification of infants with SCID early in life, in turn leading to prompt HCT while avoiding infections. Public health programmes worldwide can benefit from this definitive demonstration of the value of newborn screening for SCID. Funding: National Institute of Allergy and Infectious Diseases, Office of Rare Diseases Research, and National Center for Advancing Translational Sciences.

Original language	English (US)
Pages (from-to)	129-140
Number of pages	12
Journal	The Lancet
Volume	402
Issue number	10396
DOIs	https://doi.org/10.1016/S0140-6736(23)00731-6
State	Published - Jul 8 2023

Funding

This work was supported by the Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases (NIAID); the Office of Rare Diseases Research (ORDR), National Center for Advancing Translational Sciences (NCATS), the National Institutes of Health (NIH); Public Health Service, NIH, and an NIAID grant U54AI082973 (multiple principal investigators JMP, CCD, and EH); NIH, National Institute of Neurological Disorders and Stroke grant U54NS064808 and NCATS grant U01TR001263 (principal investigator J Krischer); and NIH, NIAID grant R13AI094943 (principal investigator JMP). The 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 is supported by the U54 grants listed here, along with support of the Pediatric Blood and Marrow Transplant Consortium Operations Center by the St Baldrick's Foundation and NIH, National Heart, Lung and Blood Institute (NHLBI) grant/cooperative agreement U10HL069254 (principal investigator M M Horowitz). Collaborative work of the PIDTC with the Center for International Blood and Marrow Transplant Research is supported by NIH, National Cancer Institute grant/cooperative agreement U24CA076518 (principal investigator B E Shaw), NHLBI and NIAID; and NIH, NHLBI grant/cooperative agreement U01HL069294; by contracts HHSH250201200016C and HHSH234200637015C with the Health Resources and Services Administration (HRSA/DHHS); and by grants N00014-13-1-0039 and N00014-14-1-0028 from the Office of Naval Research. LDN is supported by the Division of Intramural Research, NIH, NIAID grant 1 ZIA AI001222-02 (principal investigator LDN). S-YP is supported by the Intramural Research Program, NIH, National Cancer Institute, and the Center for Cancer Research. MJC is supported by the California Institute of Regenerative Medicine (CLIN2-10830 and CLIN2-09504) and NIAID grant U54AI082973. LFS is supported by NIAD R21 AI156583 and NCATS UG3 TR003908 and the William T Shearer Texas Children's Hospital Center for Human Immunobiology. MAP is supported by 1U01AI126612-01A1, P30CA040214, and 2UG1HL069254. EH is supported by the Bank of Montreal Chair of Pediatric Immunology. The content and opinions expressed are solely the responsibility of the authors and do not represent the official policy or position of the NIAID, ORDR, NCATS, NIH, HRSA, or any other agency of the US Government. We would like to thank Sharon Kidd, Kiana Soriano, and Alison Yip for project management and Helen Crawford for assistance in preparing the manuscript. We are indebted to all local study coordinators for collection of clinical data from PIDTC sites, clinical teams who provided care for patients, and all the patients and families who enrolled in our studies and have made this work possible. This work was supported by the Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases (NIAID); the Office of Rare Diseases Research (ORDR), National Center for Advancing Translational Sciences (NCATS), the National Institutes of Health (NIH); Public Health Service, NIH, and an NIAID grant U54AI082973 (multiple principal investigators JMP, CCD, and EH); NIH, National Institute of Neurological Disorders and Stroke grant U54NS064808 and NCATS grant U01TR001263 (principal investigator J Krischer); and NIH, NIAID grant R13AI094943 (principal investigator JMP). The 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 is supported by the U54 grants listed here, along with support of the Pediatric Blood and Marrow Transplant Consortium Operations Center by the St Baldrick's Foundation and NIH, National Heart, Lung and Blood Institute (NHLBI) grant/cooperative agreement U10HL069254 (principal investigator M M Horowitz). Collaborative work of the PIDTC with the Center for International Blood and Marrow Transplant Research is supported by NIH, National Cancer Institute grant/cooperative agreement U24CA076518 (principal investigator B E Shaw), NHLBI and NIAID; and NIH, NHLBI grant/cooperative agreement U01HL069294; by contracts HHSH250201200016C and HHSH234200637015C with the Health Resources and Services Administration (HRSA/DHHS); and by grants N00014-13-1-0039 and N00014-14-1-0028 from the Office of Naval Research. LDN is supported by the Division of Intramural Research, NIH, NIAID grant 1 ZIA AI001222-02 (principal investigator LDN). S-YP is supported by the Intramural Research Program, NIH, National Cancer Institute, and the Center for Cancer Research. MJC is supported by the California Institute of Regenerative Medicine (CLIN2-10830 and CLIN2-09504) and NIAID grant U54AI082973. LFS is supported by NIAD R21 AI156583 and NCATS UG3 TR003908 and the William T Shearer Texas Children's Hospital Center for Human Immunobiology. MAP is supported by 1U01AI126612-01A1, P30CA040214, and 2UG1HL069254. EH is supported by the Bank of Montreal Chair of Pediatric Immunology. The content and opinions expressed are solely the responsibility of the authors and do not represent the official policy or position of the NIAID, ORDR, NCATS, NIH, HRSA, or any other agency of the US Government. We would like to thank Sharon Kidd, Kiana Soriano, and Alison Yip for project management and Helen Crawford for assistance in preparing the manuscript. We are indebted to all local study coordinators for collection of clinical data from PIDTC sites, clinical teams who provided care for patients, and all the patients and families who enrolled in our studies and have made this work possible.

ASJC Scopus subject areas

General Medicine

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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Thakar, M. S., Logan, B. R., Puck, J. M., Dunn, E. A., Buckley, R. H., Cowan, M. J., O'Reilly, R. J., Kapoor, N., Satter, L. F., Pai, S. Y., Heimall, J., Chandra, S., Ebens, C. L., Chellapandian, D., Williams, O., Burroughs, L. M., Saldana, B. D., Rayes, A., Madden, L. M., ... Notarangelo, L. D. (2023). Measuring the effect of newborn screening on survival after haematopoietic cell transplantation for severe combined immunodeficiency: a 36-year longitudinal study from the Primary Immune Deficiency Treatment Consortium. The Lancet, 402(10396), 129-140. https://doi.org/10.1016/S0140-6736(23)00731-6

@article{0e0a36c8fa3244c8bc7f1ccb2d4d0639,

title = "Measuring the effect of newborn screening on survival after haematopoietic cell transplantation for severe combined immunodeficiency: a 36-year longitudinal study from the Primary Immune Deficiency Treatment Consortium",

abstract = "Background: Severe combined immunodeficiency (SCID) is fatal unless durable adaptive immunity is established, most commonly through allogeneic haematopoietic cell transplantation (HCT). The Primary Immune Deficiency Treatment Consortium (PIDTC) explored factors affecting the survival of individuals with SCID over almost four decades, focusing on the effects of population-based newborn screening for SCID that was initiated in 2008 and expanded during 2010–18. Methods: We analysed transplantation-related data from children with SCID treated at 34 PIDTC sites in the USA and Canada, using the calendar time intervals 1982–89, 1990–99, 2000–09, and 2010–18. Categorical variables were compared by χ2 test and continuous outcomes by the Kruskal-Wallis test. Overall survival was estimated by the Kaplan-Meier method. A multivariable analysis using Cox proportional hazards regression models examined risk factors for HCT outcomes, including the variables of time interval of HCT, infection status and age at HCT, trigger for diagnosis, SCID type and genotype, race and ethnicity of the patient, non-HLA-matched sibling donor type, graft type, GVHD prophylaxis, and conditioning intensity. Findings: For 902 children with confirmed SCID, 5-year overall survival remained unchanged at 72%–73% for 28 years until 2010–18, when it increased to 87% (95% CI 82·1–90·6; n=268; p=0·0005). For children identified as having SCID by newborn screening since 2010, 5-year overall survival was 92·5% (95% CI 85·8–96·1), better than that of children identified by clinical illness or family history in the same interval (79·9% [69·5–87·0] and 85·4% [71·8–92·8], respectively [p=0·043]). Multivariable analysis demonstrated that the factors of active infection (hazard ratio [HR] 2·41, 95% CI 1·56–3·72; p<0·0001), age 3·5 months or older at HCT (2·12, 1·38–3·24; p=0·001), Black or African-American race (2·33, 1·56–3·46; p<0·0001), and certain SCID genotypes to be associated with lower overall survival during all time intervals. Moreover, after adjusting for several factors in this multivariable analysis, HCT after 2010 no longer conveyed a survival advantage over earlier time intervals studied (HR 0·73, 95% CI 0·43–1·26; p=0·097). This indicated that younger age and freedom from infections at HCT, both directly driven by newborn screening, were the main drivers for recent improvement in overall survival. Interpretation: Population-based newborn screening has facilitated the identification of infants with SCID early in life, in turn leading to prompt HCT while avoiding infections. Public health programmes worldwide can benefit from this definitive demonstration of the value of newborn screening for SCID. Funding: National Institute of Allergy and Infectious Diseases, Office of Rare Diseases Research, and National Center for Advancing Translational Sciences.",

author = "Thakar, {Monica S.} and Logan, {Brent R.} and Puck, {Jennifer M.} and Dunn, {Elizabeth A.} and Buckley, {Rebecca H.} and Cowan, {Morton J.} and O'Reilly, {Richard J.} and Neena Kapoor and Satter, {Lisa Forbes} and Pai, {Sung Yun} and Jennifer Heimall and Sharat Chandra and Ebens, {Christen L.} and Deepak Chellapandian and Olatundun Williams and Burroughs, {Lauri M.} and Saldana, {Blachy Davila} and Ahmad Rayes and Madden, {Lisa M.} and Shanmuganathan Chandrakasan and Bednarski, {Jeffrey J.} and DeSantes, {Kenneth B.} and Cuvelier, {Geoffrey D.E.} and Pierre Teira and Gillio, {Alfred P.} and Hesham Eissa and Knutsen, {Alan P.} and Goldman, {Frederick D.} and Aquino, {Victor M.} and Shereck, {Evan B.} and Moore, {Theodore B.} and Caywood, {Emi H.} and Lugt, {Mark T.Vander} and Jacob Rozmus and Larisa Broglie and Yu, {Lolie C.} and Shah, {Ami J.} and Andolina, {Jeffrey R.} and Xuerong Liu and Parrott, {Roberta E.} and Jasmeen Dara and Susan Prockop and Martinez, {Caridad A.} and Malika Kapadia and Jyonouchi, {Soma C.} and Sullivan, {Kathleen E.} and Bleesing, {Jack J.} and Sonali Chaudhury and Aleksandra Petrovic and Keller, {Michael D.} and Quigg, {Troy C.} and Suhag Parikh and Shalini Shenoy and Christine Seroogy and Tamar Rubin and H{\'e}l{\`e}ne Decaluwe and Routes, {John M.} and Torgerson, {Troy R.} and Leiding, {Jennifer W.} and Pulsipher, {Michael A.} and Kohn, {Donald B.} and Griffith, {Linda M.} and Elie Haddad and Dvorak, {Christopher C.} and Notarangelo, {Luigi D.}",

note = "Publisher Copyright: {\textcopyright} 2023 Elsevier Ltd",

year = "2023",

month = jul,

day = "8",

doi = "10.1016/S0140-6736(23)00731-6",

language = "English (US)",

volume = "402",

pages = "129--140",

journal = "The Lancet",

issn = "0140-6736",

publisher = "Elsevier Limited",

number = "10396",

}

Thakar, MS, Logan, BR, Puck, JM, Dunn, EA, Buckley, RH, Cowan, MJ, O'Reilly, RJ, Kapoor, N, Satter, LF, Pai, SY, Heimall, J, Chandra, S, Ebens, CL, Chellapandian, D, Williams, O, Burroughs, LM, Saldana, BD, Rayes, A, Madden, LM, Chandrakasan, S, Bednarski, JJ, DeSantes, KB, Cuvelier, GDE, Teira, P, Gillio, AP, Eissa, H, Knutsen, AP, Goldman, FD, Aquino, VM, Shereck, EB, Moore, TB, Caywood, EH, Lugt, MTV, Rozmus, J, Broglie, L, Yu, LC, Shah, AJ, Andolina, JR, Liu, X, Parrott, RE, Dara, J, Prockop, S, Martinez, CA, Kapadia, M, Jyonouchi, SC, Sullivan, KE, Bleesing, JJ, Chaudhury, S, Petrovic, A, Keller, MD, Quigg, TC, Parikh, S, Shenoy, S, Seroogy, C, Rubin, T, Decaluwe, H, Routes, JM, Torgerson, TR, Leiding, JW, Pulsipher, MA, Kohn, DB, Griffith, LM, Haddad, E, Dvorak, CC & Notarangelo, LD 2023, 'Measuring the effect of newborn screening on survival after haematopoietic cell transplantation for severe combined immunodeficiency: a 36-year longitudinal study from the Primary Immune Deficiency Treatment Consortium', The Lancet, vol. 402, no. 10396, pp. 129-140. https://doi.org/10.1016/S0140-6736(23)00731-6

Measuring the effect of newborn screening on survival after haematopoietic cell transplantation for severe combined immunodeficiency: a 36-year longitudinal study from the Primary Immune Deficiency Treatment Consortium. / Thakar, Monica S.; Logan, Brent R.; Puck, Jennifer M. et al.
In: The Lancet, Vol. 402, No. 10396, 08.07.2023, p. 129-140.

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

TY - JOUR

T1 - Measuring the effect of newborn screening on survival after haematopoietic cell transplantation for severe combined immunodeficiency

T2 - a 36-year longitudinal study from the Primary Immune Deficiency Treatment Consortium

AU - Thakar, Monica S.

AU - Logan, Brent R.

AU - Puck, Jennifer M.

AU - Dunn, Elizabeth A.

AU - Buckley, Rebecca H.

AU - Cowan, Morton J.

AU - O'Reilly, Richard J.

AU - Kapoor, Neena

AU - Satter, Lisa Forbes

AU - Pai, Sung Yun

AU - Heimall, Jennifer

AU - Chandra, Sharat

AU - Ebens, Christen L.

AU - Chellapandian, Deepak

AU - Williams, Olatundun

AU - Burroughs, Lauri M.

AU - Saldana, Blachy Davila

AU - Rayes, Ahmad

AU - Madden, Lisa M.

AU - Chandrakasan, Shanmuganathan

AU - Bednarski, Jeffrey J.

AU - DeSantes, Kenneth B.

AU - Cuvelier, Geoffrey D.E.

AU - Teira, Pierre

AU - Gillio, Alfred P.

AU - Eissa, Hesham

AU - Knutsen, Alan P.

AU - Goldman, Frederick D.

AU - Aquino, Victor M.

AU - Shereck, Evan B.

AU - Moore, Theodore B.

AU - Caywood, Emi H.

AU - Lugt, Mark T.Vander

AU - Rozmus, Jacob

AU - Broglie, Larisa

AU - Yu, Lolie C.

AU - Shah, Ami J.

AU - Andolina, Jeffrey R.

AU - Liu, Xuerong

AU - Parrott, Roberta E.

AU - Dara, Jasmeen

AU - Prockop, Susan

AU - Martinez, Caridad A.

AU - Kapadia, Malika

AU - Jyonouchi, Soma C.

AU - Sullivan, Kathleen E.

AU - Bleesing, Jack J.

AU - Chaudhury, Sonali

AU - Petrovic, Aleksandra

AU - Keller, Michael D.

AU - Quigg, Troy C.

AU - Parikh, Suhag

AU - Shenoy, Shalini

AU - Seroogy, Christine

AU - Rubin, Tamar

AU - Decaluwe, Hélène

AU - Routes, John M.

AU - Torgerson, Troy R.

AU - Leiding, Jennifer W.

AU - Pulsipher, Michael A.

AU - Kohn, Donald B.

AU - Griffith, Linda M.

AU - Haddad, Elie

AU - Dvorak, Christopher C.

AU - Notarangelo, Luigi D.

PY - 2023/7/8

Y1 - 2023/7/8

N2 - Background: Severe combined immunodeficiency (SCID) is fatal unless durable adaptive immunity is established, most commonly through allogeneic haematopoietic cell transplantation (HCT). The Primary Immune Deficiency Treatment Consortium (PIDTC) explored factors affecting the survival of individuals with SCID over almost four decades, focusing on the effects of population-based newborn screening for SCID that was initiated in 2008 and expanded during 2010–18. Methods: We analysed transplantation-related data from children with SCID treated at 34 PIDTC sites in the USA and Canada, using the calendar time intervals 1982–89, 1990–99, 2000–09, and 2010–18. Categorical variables were compared by χ2 test and continuous outcomes by the Kruskal-Wallis test. Overall survival was estimated by the Kaplan-Meier method. A multivariable analysis using Cox proportional hazards regression models examined risk factors for HCT outcomes, including the variables of time interval of HCT, infection status and age at HCT, trigger for diagnosis, SCID type and genotype, race and ethnicity of the patient, non-HLA-matched sibling donor type, graft type, GVHD prophylaxis, and conditioning intensity. Findings: For 902 children with confirmed SCID, 5-year overall survival remained unchanged at 72%–73% for 28 years until 2010–18, when it increased to 87% (95% CI 82·1–90·6; n=268; p=0·0005). For children identified as having SCID by newborn screening since 2010, 5-year overall survival was 92·5% (95% CI 85·8–96·1), better than that of children identified by clinical illness or family history in the same interval (79·9% [69·5–87·0] and 85·4% [71·8–92·8], respectively [p=0·043]). Multivariable analysis demonstrated that the factors of active infection (hazard ratio [HR] 2·41, 95% CI 1·56–3·72; p<0·0001), age 3·5 months or older at HCT (2·12, 1·38–3·24; p=0·001), Black or African-American race (2·33, 1·56–3·46; p<0·0001), and certain SCID genotypes to be associated with lower overall survival during all time intervals. Moreover, after adjusting for several factors in this multivariable analysis, HCT after 2010 no longer conveyed a survival advantage over earlier time intervals studied (HR 0·73, 95% CI 0·43–1·26; p=0·097). This indicated that younger age and freedom from infections at HCT, both directly driven by newborn screening, were the main drivers for recent improvement in overall survival. Interpretation: Population-based newborn screening has facilitated the identification of infants with SCID early in life, in turn leading to prompt HCT while avoiding infections. Public health programmes worldwide can benefit from this definitive demonstration of the value of newborn screening for SCID. Funding: National Institute of Allergy and Infectious Diseases, Office of Rare Diseases Research, and National Center for Advancing Translational Sciences.

AB - Background: Severe combined immunodeficiency (SCID) is fatal unless durable adaptive immunity is established, most commonly through allogeneic haematopoietic cell transplantation (HCT). The Primary Immune Deficiency Treatment Consortium (PIDTC) explored factors affecting the survival of individuals with SCID over almost four decades, focusing on the effects of population-based newborn screening for SCID that was initiated in 2008 and expanded during 2010–18. Methods: We analysed transplantation-related data from children with SCID treated at 34 PIDTC sites in the USA and Canada, using the calendar time intervals 1982–89, 1990–99, 2000–09, and 2010–18. Categorical variables were compared by χ2 test and continuous outcomes by the Kruskal-Wallis test. Overall survival was estimated by the Kaplan-Meier method. A multivariable analysis using Cox proportional hazards regression models examined risk factors for HCT outcomes, including the variables of time interval of HCT, infection status and age at HCT, trigger for diagnosis, SCID type and genotype, race and ethnicity of the patient, non-HLA-matched sibling donor type, graft type, GVHD prophylaxis, and conditioning intensity. Findings: For 902 children with confirmed SCID, 5-year overall survival remained unchanged at 72%–73% for 28 years until 2010–18, when it increased to 87% (95% CI 82·1–90·6; n=268; p=0·0005). For children identified as having SCID by newborn screening since 2010, 5-year overall survival was 92·5% (95% CI 85·8–96·1), better than that of children identified by clinical illness or family history in the same interval (79·9% [69·5–87·0] and 85·4% [71·8–92·8], respectively [p=0·043]). Multivariable analysis demonstrated that the factors of active infection (hazard ratio [HR] 2·41, 95% CI 1·56–3·72; p<0·0001), age 3·5 months or older at HCT (2·12, 1·38–3·24; p=0·001), Black or African-American race (2·33, 1·56–3·46; p<0·0001), and certain SCID genotypes to be associated with lower overall survival during all time intervals. Moreover, after adjusting for several factors in this multivariable analysis, HCT after 2010 no longer conveyed a survival advantage over earlier time intervals studied (HR 0·73, 95% CI 0·43–1·26; p=0·097). This indicated that younger age and freedom from infections at HCT, both directly driven by newborn screening, were the main drivers for recent improvement in overall survival. Interpretation: Population-based newborn screening has facilitated the identification of infants with SCID early in life, in turn leading to prompt HCT while avoiding infections. Public health programmes worldwide can benefit from this definitive demonstration of the value of newborn screening for SCID. Funding: National Institute of Allergy and Infectious Diseases, Office of Rare Diseases Research, and National Center for Advancing Translational Sciences.

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UR - http://www.scopus.com/inward/citedby.url?scp=85164261929&partnerID=8YFLogxK

U2 - 10.1016/S0140-6736(23)00731-6

DO - 10.1016/S0140-6736(23)00731-6

M3 - Article

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AN - SCOPUS:85164261929

SN - 0140-6736

VL - 402

SP - 129

EP - 140

JO - The Lancet

JF - The Lancet

IS - 10396

ER -

Measuring the effect of newborn screening on survival after haematopoietic cell transplantation for severe combined immunodeficiency: a 36-year longitudinal study from the Primary Immune Deficiency Treatment Consortium

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