Prevalence of Pathogenic and Potentially Pathogenic Inborn Error of Immunity Associated Variants in Children with Severe Sepsis

Kate F. Kernan; Lina Ghaloul-Gonzalez; Jerry Vockley; Janette Lamb; Deborah Hollingshead; Uma Chandran; Rahil Sethi; Hyun Jung Park; Robert A. Berg; David Wessel; Murray M. Pollack; Kathleen L. Meert; Mark W. Hall; Christopher J.L. Newth; John C. Lin; Allan Doctor; Tom Shanley; Tim Cornell; Rick E. Harrison; Athena F. Zuppa; Russel Banks; Ron W. Reeder; Richard Holubkov; Daniel A. Notterman; J. Michael Dean; Joseph A. Carcillo

doi:10.1007/s10875-021-01183-4

Prevalence of Pathogenic and Potentially Pathogenic Inborn Error of Immunity Associated Variants in Children with Severe Sepsis

Kate F. Kernan^*, Lina Ghaloul-Gonzalez, Jerry Vockley, Janette Lamb, Deborah Hollingshead, Uma Chandran, Rahil Sethi, Hyun Jung Park, Robert A. Berg, David Wessel, Murray M. Pollack, Kathleen L. Meert, Mark W. Hall, Christopher J.L. Newth, John C. Lin, Allan Doctor, Tom Shanley, Tim Cornell, Rick E. Harrison, Athena F. ZuppaRussel Banks, Ron W. Reeder, Richard Holubkov, Daniel A. Notterman, J. Michael Dean, Joseph A. Carcillo

^*Corresponding author for this work

Pediatrics

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

18 Scopus citations

Abstract

Purpose: Our understanding of inborn errors of immunity is increasing; however, their contribution to pediatric sepsis is unknown. Methods: We used whole-exome sequencing (WES) to characterize variants in genes related to monogenic immunologic disorders in 330 children admitted to intensive care for severe sepsis. We defined candidate variants as rare variants classified as pathogenic or potentially pathogenic in QIAGEN’s Human Gene Mutation Database or novel null variants in a disease-consistent inheritance pattern. We investigated variant correlation with infection and inflammatory phenotype. Results: More than one in two children overall and three of four African American children had immunodeficiency-associated variants. Children with variants had increased odds of isolating a blood or urinary pathogen (blood: OR 2.82, 95% CI: 1.12–7.10, p = 0.023, urine: OR: 8.23, 95% CI: 1.06–64.11, p = 0.016) and demonstrating increased inflammation with hyperferritinemia (ferritin ≥ 500 ng/mL, OR: 2.16, 95% CI: 1.28–3.66, p = 0.004), lymphopenia (lymphocyte count < 1000/µL, OR: 1.66, 95% CI: 1.06 – 2.60, p = 0.027), thrombocytopenia (platelet count < 150,000/µL, OR: 1.76, 95% CI: 1.12–2.76, p = 0.013), and CRP greater than 10 mg/dl (OR: 1.71, 95% CI: 1.10–2.68, p = 0.017). They also had increased odds of requiring extracorporeal membrane oxygenation (ECMO, OR: 4.19, 95% CI: 1.21–14.5, p = 0.019). Conclusion: Herein, we describe the genetic findings in this severe pediatric sepsis cohort and their microbiologic and immunologic significance, providing evidence for the phenotypic effect of these variants and rationale for screening children with life-threatening infections for potential inborn errors of immunity.

Original language	English (US)
Pages (from-to)	350-364
Number of pages	15
Journal	Journal of Clinical Immunology
Volume	42
Issue number	2
DOIs	https://doi.org/10.1007/s10875-021-01183-4
State	Published - Feb 2022

Funding

Supported, in part, by grant R01GM108618 (to Dr. Carcillo) from the National Institutes of General Medical Sciences, by grants K12HD047349, L30AI147146 (to Dr. Kernan), and 5U01HD049934-10S1 (to Dr. Carcillo) from the Eunice Kennedy Shriver National Institutes of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, and the following cooperative agreements: U10HD049983, U10HD050096, U10HD049981, U10HD063108, U10HD63106, U10HD063114, U10HD050012, and U01HD049934. Drs. Carcillo’s, Berg’s, Wessel’s, Pollack’s, Meert’s, Hall’s, Doctor’s, Cornell’s, Harrison’s, Zuppa’s, Reeder’s, Banks’s, and Holubkov’s institutions received funding from the National Institutes of Health (NIH). Drs. Carcillo’s, Newth’s, Shanley’s, and Dean’s institutions received funding from the National Institutes of Child Health and Human Development. Drs. Carcillo, Berg, Wessel, Polack, Meert, Hall, Newth, Doctor, Shanley, Cornell, Harrison, Zuppa, Reeder, Banks, Holubkov, Notterman, and Dean received support for article research from the NIH. Dr. Carcillo’s institution also received funding from the National Institutes of General Medical Sciences. Dr. Pollack disclosed that his research is supported by philanthropy from Mallinckrodt Pharmaceuticals. Dr. Hall received funding from Bristol Myers Squibb (for service on an advisory board) and La Jolla Pharmaceuticals (service as a consultant), both unrelated to the current submission. Dr. Newth received funding from Philips Research North America. Dr. Doctor’s institution received funding from the Department of Defense and Kalocyte. Dr. Shanley received funding from Springer Publishing, International Pediatric Research Foundation, and Pediatric Academic Societies. Dr. Cornell disclosed he is cofounder of PreDixon Bio. Dr. Holubkov received funding from Pfizer (Data Safety Monitoring Board [DSMB] member), Medimmune (DSMB member), Physicians Committee for Responsible Medicine (biostatistical consulting), DURECT Corporation (biostatistical consulting), Armaron Bio (DSMB past member), and St. Jude Medical (DSMB past member). Dr. Notterman and Dr. Kernan received funding from the National Institutes of Health. The remaining authors have disclosed that they do not have any potential conflicts of interest.

Keywords

Hyperinflammation
Inborn errors of immunity
Primary immunodeficiency
Sepsis

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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10.1007/s10875-021-01183-4

Cite this

Kernan, K. F., Ghaloul-Gonzalez, L., Vockley, J., Lamb, J., Hollingshead, D., Chandran, U., Sethi, R., Park, H. J., Berg, R. A., Wessel, D., Pollack, M. M., Meert, K. L., Hall, M. W., Newth, C. J. L., Lin, J. C., Doctor, A., Shanley, T., Cornell, T., Harrison, R. E., ... Carcillo, J. A. (2022). Prevalence of Pathogenic and Potentially Pathogenic Inborn Error of Immunity Associated Variants in Children with Severe Sepsis. Journal of Clinical Immunology, 42(2), 350-364. https://doi.org/10.1007/s10875-021-01183-4

@article{9a189c00b1824faf9fc910cb39a79703,

title = "Prevalence of Pathogenic and Potentially Pathogenic Inborn Error of Immunity Associated Variants in Children with Severe Sepsis",

abstract = "Purpose: Our understanding of inborn errors of immunity is increasing; however, their contribution to pediatric sepsis is unknown. Methods: We used whole-exome sequencing (WES) to characterize variants in genes related to monogenic immunologic disorders in 330 children admitted to intensive care for severe sepsis. We defined candidate variants as rare variants classified as pathogenic or potentially pathogenic in QIAGEN{\textquoteright}s Human Gene Mutation Database or novel null variants in a disease-consistent inheritance pattern. We investigated variant correlation with infection and inflammatory phenotype. Results: More than one in two children overall and three of four African American children had immunodeficiency-associated variants. Children with variants had increased odds of isolating a blood or urinary pathogen (blood: OR 2.82, 95% CI: 1.12–7.10, p = 0.023, urine: OR: 8.23, 95% CI: 1.06–64.11, p = 0.016) and demonstrating increased inflammation with hyperferritinemia (ferritin ≥ 500 ng/mL, OR: 2.16, 95% CI: 1.28–3.66, p = 0.004), lymphopenia (lymphocyte count < 1000/µL, OR: 1.66, 95% CI: 1.06 – 2.60, p = 0.027), thrombocytopenia (platelet count < 150,000/µL, OR: 1.76, 95% CI: 1.12–2.76, p = 0.013), and CRP greater than 10 mg/dl (OR: 1.71, 95% CI: 1.10–2.68, p = 0.017). They also had increased odds of requiring extracorporeal membrane oxygenation (ECMO, OR: 4.19, 95% CI: 1.21–14.5, p = 0.019). Conclusion: Herein, we describe the genetic findings in this severe pediatric sepsis cohort and their microbiologic and immunologic significance, providing evidence for the phenotypic effect of these variants and rationale for screening children with life-threatening infections for potential inborn errors of immunity.",

keywords = "Hyperinflammation, Inborn errors of immunity, Primary immunodeficiency, Sepsis",

author = "Kernan, {Kate F.} and Lina Ghaloul-Gonzalez and Jerry Vockley and Janette Lamb and Deborah Hollingshead and Uma Chandran and Rahil Sethi and Park, {Hyun Jung} and Berg, {Robert A.} and David Wessel and Pollack, {Murray M.} and Meert, {Kathleen L.} and Hall, {Mark W.} and Newth, {Christopher J.L.} and Lin, {John C.} and Allan Doctor and Tom Shanley and Tim Cornell and Harrison, {Rick E.} and Zuppa, {Athena F.} and Russel Banks and Reeder, {Ron W.} and Richard Holubkov and Notterman, {Daniel A.} and Dean, {J. Michael} and Carcillo, {Joseph A.}",

note = "Funding Information: Supported, in part, by grant R01GM108618 (to Dr. Carcillo) from the National Institutes of General Medical Sciences, by grants K12HD047349, L30AI147146 (to Dr. Kernan), and 5U01HD049934-10S1 (to Dr. Carcillo) from the Eunice Kennedy Shriver National Institutes of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, and the following cooperative agreements: U10HD049983, U10HD050096, U10HD049981, U10HD063108, U10HD63106, U10HD063114, U10HD050012, and U01HD049934. Funding Information: Drs. Carcillo{\textquoteright}s, Berg{\textquoteright}s, Wessel{\textquoteright}s, Pollack{\textquoteright}s, Meert{\textquoteright}s, Hall{\textquoteright}s, Doctor{\textquoteright}s, Cornell{\textquoteright}s, Harrison{\textquoteright}s, Zuppa{\textquoteright}s, Reeder{\textquoteright}s, Banks{\textquoteright}s, and Holubkov{\textquoteright}s institutions received funding from the National Institutes of Health (NIH). Drs. Carcillo{\textquoteright}s, Newth{\textquoteright}s, Shanley{\textquoteright}s, and Dean{\textquoteright}s institutions received funding from the National Institutes of Child Health and Human Development. Drs. Carcillo, Berg, Wessel, Polack, Meert, Hall, Newth, Doctor, Shanley, Cornell, Harrison, Zuppa, Reeder, Banks, Holubkov, Notterman, and Dean received support for article research from the NIH. Dr. Carcillo{\textquoteright}s institution also received funding from the National Institutes of General Medical Sciences. Dr. Pollack disclosed that his research is supported by philanthropy from Mallinckrodt Pharmaceuticals. Dr. Hall received funding from Bristol Myers Squibb (for service on an advisory board) and La Jolla Pharmaceuticals (service as a consultant), both unrelated to the current submission. Dr. Newth received funding from Philips Research North America. Dr. Doctor{\textquoteright}s institution received funding from the Department of Defense and Kalocyte. Dr. Shanley received funding from Springer Publishing, International Pediatric Research Foundation, and Pediatric Academic Societies. Dr. Cornell disclosed he is cofounder of PreDixon Bio. Dr. Holubkov received funding from Pfizer (Data Safety Monitoring Board [DSMB] member), Medimmune (DSMB member), Physicians Committee for Responsible Medicine (biostatistical consulting), DURECT Corporation (biostatistical consulting), Armaron Bio (DSMB past member), and St. Jude Medical (DSMB past member). Dr. Notterman and Dr. Kernan received funding from the National Institutes of Health. The remaining authors have disclosed that they do not have any potential conflicts of interest. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2022",

month = feb,

doi = "10.1007/s10875-021-01183-4",

language = "English (US)",

volume = "42",

pages = "350--364",

journal = "Journal of Clinical Immunology",

issn = "0271-9142",

publisher = "Springer",

number = "2",

}

Kernan, KF, Ghaloul-Gonzalez, L, Vockley, J, Lamb, J, Hollingshead, D, Chandran, U, Sethi, R, Park, HJ, Berg, RA, Wessel, D, Pollack, MM, Meert, KL, Hall, MW, Newth, CJL, Lin, JC, Doctor, A, Shanley, T, Cornell, T, Harrison, RE, Zuppa, AF, Banks, R, Reeder, RW, Holubkov, R, Notterman, DA, Dean, JM & Carcillo, JA 2022, 'Prevalence of Pathogenic and Potentially Pathogenic Inborn Error of Immunity Associated Variants in Children with Severe Sepsis', Journal of Clinical Immunology, vol. 42, no. 2, pp. 350-364. https://doi.org/10.1007/s10875-021-01183-4

TY - JOUR

T1 - Prevalence of Pathogenic and Potentially Pathogenic Inborn Error of Immunity Associated Variants in Children with Severe Sepsis

AU - Kernan, Kate F.

AU - Ghaloul-Gonzalez, Lina

AU - Vockley, Jerry

AU - Lamb, Janette

AU - Hollingshead, Deborah

AU - Chandran, Uma

AU - Sethi, Rahil

AU - Park, Hyun Jung

AU - Berg, Robert A.

AU - Wessel, David

AU - Pollack, Murray M.

AU - Meert, Kathleen L.

AU - Hall, Mark W.

AU - Newth, Christopher J.L.

AU - Lin, John C.

AU - Doctor, Allan

AU - Shanley, Tom

AU - Cornell, Tim

AU - Harrison, Rick E.

AU - Zuppa, Athena F.

AU - Banks, Russel

AU - Reeder, Ron W.

AU - Holubkov, Richard

AU - Notterman, Daniel A.

AU - Dean, J. Michael

AU - Carcillo, Joseph A.

N1 - Funding Information: Supported, in part, by grant R01GM108618 (to Dr. Carcillo) from the National Institutes of General Medical Sciences, by grants K12HD047349, L30AI147146 (to Dr. Kernan), and 5U01HD049934-10S1 (to Dr. Carcillo) from the Eunice Kennedy Shriver National Institutes of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, and the following cooperative agreements: U10HD049983, U10HD050096, U10HD049981, U10HD063108, U10HD63106, U10HD063114, U10HD050012, and U01HD049934. Funding Information: Drs. Carcillo’s, Berg’s, Wessel’s, Pollack’s, Meert’s, Hall’s, Doctor’s, Cornell’s, Harrison’s, Zuppa’s, Reeder’s, Banks’s, and Holubkov’s institutions received funding from the National Institutes of Health (NIH). Drs. Carcillo’s, Newth’s, Shanley’s, and Dean’s institutions received funding from the National Institutes of Child Health and Human Development. Drs. Carcillo, Berg, Wessel, Polack, Meert, Hall, Newth, Doctor, Shanley, Cornell, Harrison, Zuppa, Reeder, Banks, Holubkov, Notterman, and Dean received support for article research from the NIH. Dr. Carcillo’s institution also received funding from the National Institutes of General Medical Sciences. Dr. Pollack disclosed that his research is supported by philanthropy from Mallinckrodt Pharmaceuticals. Dr. Hall received funding from Bristol Myers Squibb (for service on an advisory board) and La Jolla Pharmaceuticals (service as a consultant), both unrelated to the current submission. Dr. Newth received funding from Philips Research North America. Dr. Doctor’s institution received funding from the Department of Defense and Kalocyte. Dr. Shanley received funding from Springer Publishing, International Pediatric Research Foundation, and Pediatric Academic Societies. Dr. Cornell disclosed he is cofounder of PreDixon Bio. Dr. Holubkov received funding from Pfizer (Data Safety Monitoring Board [DSMB] member), Medimmune (DSMB member), Physicians Committee for Responsible Medicine (biostatistical consulting), DURECT Corporation (biostatistical consulting), Armaron Bio (DSMB past member), and St. Jude Medical (DSMB past member). Dr. Notterman and Dr. Kernan received funding from the National Institutes of Health. The remaining authors have disclosed that they do not have any potential conflicts of interest. Publisher Copyright: © 2021, The Author(s).

PY - 2022/2

Y1 - 2022/2

N2 - Purpose: Our understanding of inborn errors of immunity is increasing; however, their contribution to pediatric sepsis is unknown. Methods: We used whole-exome sequencing (WES) to characterize variants in genes related to monogenic immunologic disorders in 330 children admitted to intensive care for severe sepsis. We defined candidate variants as rare variants classified as pathogenic or potentially pathogenic in QIAGEN’s Human Gene Mutation Database or novel null variants in a disease-consistent inheritance pattern. We investigated variant correlation with infection and inflammatory phenotype. Results: More than one in two children overall and three of four African American children had immunodeficiency-associated variants. Children with variants had increased odds of isolating a blood or urinary pathogen (blood: OR 2.82, 95% CI: 1.12–7.10, p = 0.023, urine: OR: 8.23, 95% CI: 1.06–64.11, p = 0.016) and demonstrating increased inflammation with hyperferritinemia (ferritin ≥ 500 ng/mL, OR: 2.16, 95% CI: 1.28–3.66, p = 0.004), lymphopenia (lymphocyte count < 1000/µL, OR: 1.66, 95% CI: 1.06 – 2.60, p = 0.027), thrombocytopenia (platelet count < 150,000/µL, OR: 1.76, 95% CI: 1.12–2.76, p = 0.013), and CRP greater than 10 mg/dl (OR: 1.71, 95% CI: 1.10–2.68, p = 0.017). They also had increased odds of requiring extracorporeal membrane oxygenation (ECMO, OR: 4.19, 95% CI: 1.21–14.5, p = 0.019). Conclusion: Herein, we describe the genetic findings in this severe pediatric sepsis cohort and their microbiologic and immunologic significance, providing evidence for the phenotypic effect of these variants and rationale for screening children with life-threatening infections for potential inborn errors of immunity.

AB - Purpose: Our understanding of inborn errors of immunity is increasing; however, their contribution to pediatric sepsis is unknown. Methods: We used whole-exome sequencing (WES) to characterize variants in genes related to monogenic immunologic disorders in 330 children admitted to intensive care for severe sepsis. We defined candidate variants as rare variants classified as pathogenic or potentially pathogenic in QIAGEN’s Human Gene Mutation Database or novel null variants in a disease-consistent inheritance pattern. We investigated variant correlation with infection and inflammatory phenotype. Results: More than one in two children overall and three of four African American children had immunodeficiency-associated variants. Children with variants had increased odds of isolating a blood or urinary pathogen (blood: OR 2.82, 95% CI: 1.12–7.10, p = 0.023, urine: OR: 8.23, 95% CI: 1.06–64.11, p = 0.016) and demonstrating increased inflammation with hyperferritinemia (ferritin ≥ 500 ng/mL, OR: 2.16, 95% CI: 1.28–3.66, p = 0.004), lymphopenia (lymphocyte count < 1000/µL, OR: 1.66, 95% CI: 1.06 – 2.60, p = 0.027), thrombocytopenia (platelet count < 150,000/µL, OR: 1.76, 95% CI: 1.12–2.76, p = 0.013), and CRP greater than 10 mg/dl (OR: 1.71, 95% CI: 1.10–2.68, p = 0.017). They also had increased odds of requiring extracorporeal membrane oxygenation (ECMO, OR: 4.19, 95% CI: 1.21–14.5, p = 0.019). Conclusion: Herein, we describe the genetic findings in this severe pediatric sepsis cohort and their microbiologic and immunologic significance, providing evidence for the phenotypic effect of these variants and rationale for screening children with life-threatening infections for potential inborn errors of immunity.

KW - Hyperinflammation

KW - Inborn errors of immunity

KW - Primary immunodeficiency

KW - Sepsis

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JF - Journal of Clinical Immunology

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ER -

Prevalence of Pathogenic and Potentially Pathogenic Inborn Error of Immunity Associated Variants in Children with Severe Sepsis

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