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 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 Genetic 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 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 10mg/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 phenotypic effect of these variants and rationale for screening children with life-threatening infection for potential inborn errors of immunity.