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

• Published in: Journal of clinical immunology 2022-02, Vol.42 (2), p.350-364
• Main Authors: 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.
• Format: Article
• Language: English
• Subjects: Biomedical and Life Sciences; Biomedicine; Cell number; Child; Children; Exome Sequencing; Ferritin; Heredity; Humans; Immunity; Immunodeficiency; Immunologic Deficiency Syndromes - genetics; Immunological diseases; Immunology; Infectious Diseases; Inflammation; Internal Medicine; Lymphocytes; Lymphopenia; Medical Microbiology; Original; Original Article; Oxygenation; Pediatrics; Phenotype; Phenotypes; Point mutation; Prevalence; Sepsis; Sepsis - epidemiology; Sepsis - genetics; Thrombocytopenia
• ISSN: 0271-9142; 1573-2592
• DOI: 10.1007/s10875-021-01183-4

   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