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

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    Author
    Kernan, Kate F
    Ghaloul-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
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    Date
    2022-01-01
    Journal
    Journal of Clinical Immunology
    Publisher
    Springer Nature
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1007/s10875-021-01183-4
    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. © 2021, The Author(s).
    Rights/Terms
    © 2021. The Author(s).
    Keyword
    Hyperinflammation
    Inborn errors of immunity
    Primary immunodeficiency
    Sepsis
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/17633
    ae974a485f413a2113503eed53cd6c53
    10.1007/s10875-021-01183-4
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