Prevalence of Pathogenic and Potentially Pathogenic Inborn Error of Immunity Associated Variants in Children with Severe Sepsis.
Author
Kernan, Kate FGhaloul-Gonzalez, Lina
Vockley, Jerry
Lamb, Janette
Hollingshead, Deborah
Chandran, Uma
Sethi, Rahil
Park, Hyun-Jung
Berg, Robert A
Wessel, David
Pollack, Murray M
Meert, Kathleen L
Hall, Mark W
Newth, Christopher J L
Lin, John C
Doctor, Allan
Shanley, Tom
Cornell, Tim
Harrison, Rick E
Zuppa, Athena F
Banks, Russel
Reeder, Ron W
Holubkov, Richard
Notterman, Daniel A
Dean, J Michael
Carcillo, Joseph A
Date
2022-01-01Journal
Journal of Clinical ImmunologyPublisher
Springer NatureType
Article
Metadata
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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. © 2021, The Author(s).Rights/Terms
© 2021. The Author(s).Identifier to cite or link to this item
http://hdl.handle.net/10713/17633ae974a485f413a2113503eed53cd6c53
10.1007/s10875-021-01183-4
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