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

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


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 languageEnglish
Pages (from-to)350-364
Number of pages15
JournalJournal of Clinical Immunology
Issue number2
StatePublished - Feb 2022


  • Hyperinflammation
  • Inborn errors of immunity
  • Primary immunodeficiency
  • Sepsis


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