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

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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 \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\ge 500$$\end{document} 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.

Supplementary Information

The online version contains supplementary material available at 10.1007/s10875-021-01183-4.

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Most cited references 44

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Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology

Sue Richards, Nazneen Aziz, Sherri Bale … (2015)

The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants. 1 In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next generation sequencing. By adopting and leveraging next generation sequencing, clinical laboratories are now performing an ever increasing catalogue of genetic testing spanning genotyping, single genes, gene panels, exomes, genomes, transcriptomes and epigenetic assays for genetic disorders. By virtue of increased complexity, this paradigm shift in genetic testing has been accompanied by new challenges in sequence interpretation. In this context, the ACMG convened a workgroup in 2013 comprised of representatives from the ACMG, the Association for Molecular Pathology (AMP) and the College of American Pathologists (CAP) to revisit and revise the standards and guidelines for the interpretation of sequence variants. The group consisted of clinical laboratory directors and clinicians. This report represents expert opinion of the workgroup with input from ACMG, AMP and CAP stakeholders. These recommendations primarily apply to the breadth of genetic tests used in clinical laboratories including genotyping, single genes, panels, exomes and genomes. This report recommends the use of specific standard terminology: ‘pathogenic’, ‘likely pathogenic’, ‘uncertain significance’, ‘likely benign’, and ‘benign’ to describe variants identified in Mendelian disorders. Moreover, this recommendation describes a process for classification of variants into these five categories based on criteria using typical types of variant evidence (e.g. population data, computational data, functional data, segregation data, etc.). Because of the increased complexity of analysis and interpretation of clinical genetic testing described in this report, the ACMG strongly recommends that clinical molecular genetic testing should be performed in a CLIA-approved laboratory with results interpreted by a board-certified clinical molecular geneticist or molecular genetic pathologist or equivalent.

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The mutational constraint spectrum quantified from variation in 141,456 humans

Konrad J. Karczewski, Laurent C. Francioli, Grace Tiao … (2021)

Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes that are crucial for the function of an organism will be depleted of such variants in natural populations, whereas non-essential genes will tolerate their accumulation. However, predicted loss-of-function variants are enriched for annotation errors, and tend to be found at extremely low frequencies, so their analysis requires careful variant annotation and very large sample sizes 1 . Here we describe the aggregation of 125,748 exomes and 15,708 genomes from human sequencing studies into the Genome Aggregation Database (gnomAD). We identify 443,769 high-confidence predicted loss-of-function variants in this cohort after filtering for artefacts caused by sequencing and annotation errors. Using an improved model of human mutation rates, we classify human protein-coding genes along a spectrum that represents tolerance to inactivation, validate this classification using data from model organisms and engineered human cells, and show that it can be used to improve the power of gene discovery for both common and rare diseases.

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Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study

Kristina Rudd, Sarah Charlotte Johnson, Kareha M Agesa … (2020)

Summary Background Sepsis is life-threatening organ dysfunction due to a dysregulated host response to infection. It is considered a major cause of health loss, but data for the global burden of sepsis are limited. As a syndrome caused by underlying infection, sepsis is not part of standard Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) estimates. Accurate estimates are important to inform and monitor health policy interventions, allocation of resources, and clinical treatment initiatives. We estimated the global, regional, and national incidence of sepsis and mortality from this disorder using data from GBD 2017. Methods We used multiple cause-of-death data from 109 million individual death records to calculate mortality related to sepsis among each of the 282 underlying causes of death in GBD 2017. The percentage of sepsis-related deaths by underlying GBD cause in each location worldwide was modelled using mixed-effects linear regression. Sepsis-related mortality for each age group, sex, location, GBD cause, and year (1990–2017) was estimated by applying modelled cause-specific fractions to GBD 2017 cause-of-death estimates. We used data for 8·7 million individual hospital records to calculate in-hospital sepsis-associated case-fatality, stratified by underlying GBD cause. In-hospital sepsis-associated case-fatality was modelled for each location using linear regression, and sepsis incidence was estimated by applying modelled case-fatality to sepsis-related mortality estimates. Findings In 2017, an estimated 48·9 million (95% uncertainty interval [UI] 38·9–62·9) incident cases of sepsis were recorded worldwide and 11·0 million (10·1–12·0) sepsis-related deaths were reported, representing 19·7% (18·2–21·4) of all global deaths. Age-standardised sepsis incidence fell by 37·0% (95% UI 11·8–54·5) and mortality decreased by 52·8% (47·7–57·5) from 1990 to 2017. Sepsis incidence and mortality varied substantially across regions, with the highest burden in sub-Saharan Africa, Oceania, south Asia, east Asia, and southeast Asia. Interpretation Despite declining age-standardised incidence and mortality, sepsis remains a major cause of health loss worldwide and has an especially high health-related burden in sub-Saharan Africa. Funding The Bill & Melinda Gates Foundation, the National Institutes of Health, the University of Pittsburgh, the British Columbia Children's Hospital Foundation, the Wellcome Trust, and the Fleming Fund.

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Author and article information

Contributors

Kate F. Kernan:

ORCID: http://orcid.org/0000-0002-6337-841X

kate.kernan@chp.edu

Journal

Journal ID (nlm-ta): J Clin Immunol

Journal ID (iso-abbrev): J Clin Immunol

Title: Journal of Clinical Immunology

Publisher: Springer US (New York )

ISSN (Print): 0271-9142

ISSN (Electronic): 1573-2592

Publication date (Electronic): 1 January 2022

Publication date PMC-release: 1 January 2022

Pages: 1-15

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

[2 ]Division of Genetic and Genomic Medicine, Department of Pediatrics, Children’s Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA USA

[3 ]GRID grid.21925.3d, ISNI 0000 0004 1936 9000, Genomics Core Laboratory, , University of Pittsburgh, ; Pittsburgh, PA USA

[4 ]GRID grid.21925.3d, ISNI 0000 0004 1936 9000, Department of Biomedical Informatics, , University of Pittsburgh, ; Pittsburgh, PA USA

[5 ]GRID grid.21925.3d, ISNI 0000 0004 1936 9000, Department of Genetics, Graduate School of Public Health, , University of Pittsburgh, ; Pittsburgh, PA USA

[6 ]GRID grid.239552.a, ISNI 0000 0001 0680 8770, Department of Anesthesiology and Critical Care Medicine, , Children’s Hospital of Philadelphia, ; Philadelphia, PA USA

[7 ]GRID grid.239560.b, ISNI 0000 0004 0482 1586, Division of Critical Care Medicine, Department of Pediatrics, , Children’s National Hospital, ; Washington, DC USA

[8 ]GRID grid.414154.1, ISNI 0000 0000 9144 1055, Division of Critical Care Medicine, Department of Pediatrics, , Children’s Hospital of Michigan, ; Detroit, MI USA

[9 ]GRID grid.253856.f, ISNI 0000 0001 2113 4110, Central Michigan University, ; Mt. Pleasant, MI USA

[10 ]GRID grid.240344.5, ISNI 0000 0004 0392 3476, 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 ]GRID grid.239546.f, ISNI 0000 0001 2153 6013, Division of Pediatric Critical Care Medicine, Department of Anesthesiology and Pediatrics, , Children’s Hospital Los Angeles, ; Los Angeles, CA USA

[12 ]GRID grid.416775.6, ISNI 0000 0000 9953 7617, Division of Critical Care Medicine, Department of Pediatrics, , St. Louis Children’s Hospital, ; St. Louis, MO USA

[13 ]GRID grid.411024.2, ISNI 0000 0001 2175 4264, Division of Pediatric Critical Care Medicine, The Center for Blood Oxygen Transport and Hemostasis, , University of Maryland School of Medicine, ; MD Baltimore, USA

[14 ]GRID grid.413177.7, ISNI 0000 0001 0386 2261, Division of Critical Care Medicine, Department of Pediatrics, , C. S. Mott Children’s Hospital, ; Ann Arbor, MI USA

[15 ]GRID grid.168010.e, ISNI 0000000419368956, Department of Pediatrics, Lucile Packard Children’s Hospital Stanford, , Stanford University, ; CA Palo Alto, USA

[16 ]GRID grid.19006.3e, ISNI 0000 0000 9632 6718, Division of Critical Care Medicine, Department of Pediatrics, , Mattel Children’s Hospital at University of California Los Angeles, ; Los Angeles, CA USA

[17 ]GRID grid.223827.e, ISNI 0000 0001 2193 0096, Department of Pediatrics, University of Utah, ; Salt Lake City, UT USA

[18 ]GRID grid.16750.35, ISNI 0000 0001 2097 5006, Department of Molecular Biology, Princeton University, ; Princeton, NJ USA

Author information

Kate F. Kernan http://orcid.org/0000-0002-6337-841X

Article

Publisher ID: 1183

DOI: 10.1007/s10875-021-01183-4

PMC ID: 8720168

PubMed ID: 34973142

SO-VID: 9ed23acd-a646-4ad3-93ba-c8577f50feb6

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 27 September 2021

Date accepted : 15 November 2021

Funding

Funded by: National Institute of General Medical Sciences

Award ID: R01GM108618

Award Recipient : Joseph A. Carcillo

Funded by: FundRef http://dx.doi.org/10.13039/100009633, Eunice Kennedy Shriver National Institute of Child Health and Human Development;

Award ID: K12HD047349

Award ID: 5U01HD049934-10S1

Award Recipient : Kate F. Kernan Joseph A. Carcillo

Funded by: FundRef http://dx.doi.org/10.13039/100000016, U.S. Department of Health and Human Services;

Award ID: U10HD049983

Award ID: U10HD050096

Award ID: U10HD049981

Award ID: U10HD063108

Award ID: U10HD63106

Award ID: U10HD063114

Award ID: U10HD050012

Award ID: U01HD049934

Funded by: FundRef http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;

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

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Abstract

Purpose

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Conclusion

Supplementary Information

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Most cited references 44

Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology

The mutational constraint spectrum quantified from variation in 141,456 humans

Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study

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