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

TitlePrevalence of Pathogenic and Potentially Pathogenic Inborn Error of Immunity Associated Variants in Children with Severe Sepsis.
Publication TypeJournal Article
Year of Publication2022
AuthorsKernan, KF, Ghaloul-Gonzalez, L, Vockley, J, Lamb, J, Hollingshead, D, Chandran, U, Sethi, R, Park, H-J, Berg, RA, Wessel, D, Pollack, MM, Meert, KL, Hall, MW, Newth, CJL, Lin, JC, Doctor, A, Shanley, T, Cornell, T, Harrison, RE, Zuppa, AF, Banks, R, Reeder, RW, Holubkov, R, Notterman, DA, J Dean, M, Carcillo, JA
JournalJ Clin Immunol
Volume42
Issue2
Pagination350-364
Date Published2022 02
ISSN1573-2592
KeywordsChild, Humans, Immunologic Deficiency Syndromes, Phenotype, Prevalence, Sepsis, Whole Exome Sequencing
Abstract

<p><b>PURPOSE: </b>Our understanding of inborn errors of immunity is increasing; however, their contribution to pediatric sepsis is unknown.</p><p><b>METHODS: </b>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.</p><p><b>RESULTS: </b>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 [Formula: see text] 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).</p><p><b>CONCLUSION: </b>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.</p>

DOI10.1007/s10875-021-01183-4
Alternate JournalJ Clin Immunol
PubMed ID34973142
PubMed Central IDPMC8720168
Grant ListRL1 HD107777 / HD / NICHD NIH HHS / United States
U10HD050012 / NH / NIH HHS / United States
U10HD049983 / NH / NIH HHS / United States
U10HD063108 / NH / NIH HHS / United States
RL1 HD107779 / HD / NICHD NIH HHS / United States
U10 HD049983 / HD / NICHD NIH HHS / United States
U10HD049981 / NH / NIH HHS / United States
U01 HD049934 / HD / NICHD NIH HHS / United States
R01 GM108618 / GM / NIGMS NIH HHS / United States
U10HD050096 / NH / NIH HHS / United States
R01GM108618 / GM / NIGMS NIH HHS / United States
K08 HG010490 / HG / NHGRI NIH HHS / United States
5U01HD049934-10S1 / HD / NICHD NIH HHS / United States
L30 AI147146 / AI / NIAID NIH HHS / United States
L30AI147146 / AI / NIAID NIH HHS / United States
K12HD047349 / HD / NICHD NIH HHS / United States
K12 HD047349 / HD / NICHD NIH HHS / United States
U10HD63106 / NH / NIH HHS / United States
U01HD049934 / NH / NIH HHS / United States
U10HD063114 / NH / NIH HHS / United States