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 Zuppa; Russel Banks; Ron W Reeder; Richard Holubkov; Daniel A Notterman; J Michael Dean; Joseph A Carcillo

doi:10.1007/s10875-021-01183-4

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

J Clin Immunol. 2022 Feb;42(2):350-364. doi: 10.1007/s10875-021-01183-4. Epub 2022 Jan 1.

Authors

Kate F Kernan¹, Lina Ghaloul-Gonzalez², Jerry Vockley², Janette Lamb³, Deborah Hollingshead³, Uma Chandran⁴, Rahil Sethi⁴, Hyun-Jung Park⁵, Robert A Berg⁶, David Wessel⁷, Murray M Pollack⁷, Kathleen L Meert^{8

9}, Mark W Hall¹⁰, Christopher J L Newth¹¹, John C Lin¹², Allan Doctor^{12

13}, Tom Shanley¹⁴, Tim Cornell^{14

15}, Rick E Harrison¹⁶, Athena F Zuppa⁶, Russel Banks¹⁷, Ron W Reeder¹⁷, Richard Holubkov¹⁷, Daniel A Notterman¹⁸, J Michael Dean¹⁷, Joseph A Carcillo¹⁹

Affiliations

¹ Division of Pediatric Critical Care Medicine, Department of Critical Care Medicine, Center for Critical Care Nephrology and Clinical Research Investigation and Systems Modeling of Acute Illness Center, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA. kate.kernan@chp.edu.
² Division of Genetic and Genomic Medicine, Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA.
³ Genomics Core Laboratory, University of Pittsburgh, Pittsburgh, PA, USA.
⁴ Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, PA, USA.
⁵ Department of Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
⁶ Department of Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁷ Division of Critical Care Medicine, Department of Pediatrics, Children's National Hospital, Washington, DC, USA.
⁸ Division of Critical Care Medicine, Department of Pediatrics, Children's Hospital of Michigan, Detroit, MI, USA.
⁹ Central Michigan University, Mt. Pleasant, MI, USA.
¹⁰ Division of Critical Care Medicine, Department of Pediatrics, The Research Institute at Nationwide Children's Hospital Immune Surveillance Laboratory, and Nationwide Children's Hospital, Columbus, OH, USA.
¹¹ Division of Pediatric Critical Care Medicine, Department of Anesthesiology and Pediatrics, Children's Hospital Los Angeles, Los Angeles, CA, USA.
¹² Division of Critical Care Medicine, Department of Pediatrics, St. Louis Children's Hospital, St. Louis, MO, USA.
¹³ Division of Pediatric Critical Care Medicine, The Center for Blood Oxygen Transport and Hemostasis, University of Maryland School of Medicine, MD, Baltimore, USA.
¹⁴ Division of Critical Care Medicine, Department of Pediatrics, C. S. Mott Children's Hospital, Ann Arbor, MI, USA.
¹⁵ Department of Pediatrics, Lucile Packard Children's Hospital Stanford, Stanford University, CA, Palo Alto, USA.
¹⁶ Division of Critical Care Medicine, Department of Pediatrics, Mattel Children's Hospital at University of California Los Angeles, Los Angeles, CA, USA.
¹⁷ Department of Pediatrics, University of Utah, Salt Lake City, UT, USA.
¹⁸ Department of Molecular Biology, Princeton University, Princeton, NJ, USA.
¹⁹ Division of Pediatric Critical Care Medicine, Department of Critical Care Medicine, Center for Critical Care Nephrology and Clinical Research Investigation and Systems Modeling of Acute Illness Center, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA.

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 [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).

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.

Keywords: Hyperinflammation; Inborn errors of immunity; Primary immunodeficiency; Sepsis.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Child
Exome Sequencing
Humans
Immunologic Deficiency Syndromes* / genetics
Phenotype
Prevalence
Sepsis* / epidemiology
Sepsis* / genetics

Abstract

Publication types

MeSH terms

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