Prevalence of Pathogenic and Potentially Pathogenic Inborn Error of Immunity Associated Variants in Children with Severe Sepsis.
Hyperinflammation
Inborn errors of immunity
Primary immunodeficiency
Sepsis
Journal
Journal of clinical immunology
ISSN: 1573-2592
Titre abrégé: J Clin Immunol
Pays: Netherlands
ID NLM: 8102137
Informations de publication
Date de publication:
02 2022
02 2022
Historique:
received:
27
09
2021
accepted:
15
11
2021
pubmed:
2
1
2022
medline:
5
3
2022
entrez:
1
1
2022
Statut:
ppublish
Résumé
Our understanding of inborn errors of immunity is increasing; however, their contribution to pediatric sepsis is unknown. 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. 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). 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.
Identifiants
pubmed: 34973142
doi: 10.1007/s10875-021-01183-4
pii: 10.1007/s10875-021-01183-4
pmc: PMC8720168
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
350-364Subventions
Organisme : NICHD NIH HHS
ID : RL1 HD107777
Pays : United States
Organisme : NIH HHS
ID : U10HD050012
Pays : United States
Organisme : NIH HHS
ID : U10HD049983
Pays : United States
Organisme : NIH HHS
ID : U10HD063108
Pays : United States
Organisme : NICHD NIH HHS
ID : RL1 HD107779
Pays : United States
Organisme : NICHD NIH HHS
ID : U10 HD049983
Pays : United States
Organisme : NIH HHS
ID : U10HD049981
Pays : United States
Organisme : NICHD NIH HHS
ID : U01 HD049934
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM108618
Pays : United States
Organisme : NIH HHS
ID : U10HD050096
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01GM108618
Pays : United States
Organisme : NHGRI NIH HHS
ID : K08 HG010490
Pays : United States
Organisme : NICHD NIH HHS
ID : 5U01HD049934-10S1
Pays : United States
Organisme : NIAID NIH HHS
ID : L30 AI147146
Pays : United States
Organisme : NIAID NIH HHS
ID : L30AI147146
Pays : United States
Organisme : NICHD NIH HHS
ID : K12HD047349
Pays : United States
Organisme : NICHD NIH HHS
ID : K12 HD047349
Pays : United States
Organisme : NIH HHS
ID : U10HD63106
Pays : United States
Organisme : NIH HHS
ID : U01HD049934
Pays : United States
Organisme : NIH HHS
ID : U10HD063114
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2021. The Author(s).
Références
Rudd KE, Johnson SC, Agesa KM, Shackelford KA, Tsoi D, Kievlan DR, et al. Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study. The Lancet. 2020;395:200–11.
doi: 10.1016/S0140-6736(19)32989-7
Casanova J-L. Severe infectious diseases of childhood as monogenic inborn errors of immunity. Proc Natl Acad Sci. 2015;112:201521651.
Schulert GS, Zhang M, Fall N, Husami A, Kissell D, Hanosh A, et al. Whole-Exome Sequencing Reveals Mutations in Genes Linked to Hemophagocytic Lymphohistiocytosis and Macrophage Activation Syndrome in Fatal Cases of H1N1 Influenza. J Infect Dis. 2016;213:1180–8. https://doi.org/10.1093/infdis/jiv550 .
doi: 10.1093/infdis/jiv550
pubmed: 26597256
Gaschignard J, Levy C, Chrabieh M, Boisson B, Bost-Bru C, Dauger S, et al. Invasive pneumococcal disease in children can reveal a primary immunodeficiency. Clin Infect Dis. 2014;59:244–51.
doi: 10.1093/cid/ciu274
Asgari S, McLaren PJ, Peake J, Wong M, Wong R, Bartha I, et al. Exome sequencing reveals primary immunodeficiencies in children with community-acquired Pseudomonas aeruginosa sepsis. Front immunol. 2016;7:357. https://doi.org/10.3389/fimmu.2016.00357 .
doi: 10.3389/fimmu.2016.00357
pubmed: 27703454
pmcid: 5028722
van der Made CI, Simons A, Schuurs-Hoeijmakers J, van den Heuvel G, Mantere T, Kersten S, et al. Presence of genetic variants among young men with severe COVID-19. JAMA. 2020;324(7):663–73.
doi: 10.1001/jama.2020.13719
Meyts I, Bucciol G, Quinti I, Neven B, Fischer A, Seoane E, et al. Coronavirus disease 2019 in patients with inborn errors of immunity: an international study. J Allergy Clin Immunol. 2021;147:520–31.
doi: 10.1016/j.jaci.2020.09.010
Borghesi A, Trück J, Asgari S, Sancho-Shimizu V, Agyeman PKA, Bellos E, et al. Whole-exome sequencing for the identification of rare variants in primary immunodeficiency genes in children with sepsis: a prospective, population-based cohort study. Clin Infect Dis. 2020;71:E614–23.
doi: 10.1093/cid/ciaa290
Tangye SG, Al-Herz W, Bousfiha A, Chatila T, Cunningham-Rundles C, Etzioni A, et al. Human inborn errors of immunity: 2019 update on the classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol. 2020;40:24–64.
doi: 10.1007/s10875-019-00737-x
Taeubner J, Wieczorek D, Yasin L, Brozou T, Borkhardt A, Kuhlen M. Penetrance and expressivity in inherited cancer predisposing syndromes. Trends Cancer. 2018;4:718–28.
doi: 10.1016/j.trecan.2018.09.002
Petrikin JE, Cakici JA, Clark MM, Willig LK, Sweeney NM, Farrow EG, et al. The NSIGHT1-randomized controlled trial: rapid whole-genome sequencing for accelerated etiologic diagnosis in critically ill infants. NPJ Genom Med. 2018;3:6. https://doi.org/10.1038/s41525-018-0045-8 .
doi: 10.1038/s41525-018-0045-8
pubmed: 29449963
pmcid: 5807510
Saunders CJ, Miller NA, Soden SE, Dinwiddie DL, Noll A, Alnadi NA, et al. Rapid whole-genome sequencing for genetic disease diagnosis in neonatal intensive care units. Sci Transl Med. 2012. https://doi.org/10.1126/scitranslmed.3004041 .
doi: 10.1126/scitranslmed.3004041
pubmed: 23035047
pmcid: 4283791
Mestek-Boukhibar L, Clement E, Jones WD, Drury S, Ocaka L, Gagunashvili A, et al. Rapid Paediatric Sequencing (RaPS): comprehensive real-life workflow for rapid diagnosis of critically ill children. J Med Genet. 2018;11:721–8. https://doi.org/10.1136/jmedgenet-2018-105396 .
doi: 10.1136/jmedgenet-2018-105396
Sanford EF, Clark MM, Farnaes L, Williams MR, Perry JC, Ingulli EG, et al. Rapid whole genome sequencing has clinical utility in children in the PICU. Pediatr Crit Care Med. 2019. https://doi.org/10.1097/PCC.0000000000002056 .
doi: 10.1097/PCC.0000000000002056
pubmed: 31246743
pmcid: 6832787
Doughty L, Clark RSB, Kaplan SS, Sasser H, Carcillo J. sFas and sFas ligand and pediatric sepsis-induced multiple organ failure syndrome. Pediatr Res. 2002. https://doi.org/10.1203/00006450-200212000-00018 .
doi: 10.1203/00006450-200212000-00018
pubmed: 12438671
Park KJ, Lee W, Chun S, Min WK. The frequency of discordant variant classification in the human gene mutation database: a comparison of the American College of Medical Genetics and Genomics Guidelines and ClinVar. Lab Med. 2021;52:250–9.
doi: 10.1093/labmed/lmaa072
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. 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. Genet Med. 2015. https://doi.org/10.1038/gim.2015.30 .
doi: 10.1038/gim.2015.30
pubmed: 25834946
pmcid: 4544753
Felmet KA, Hall MW, Clark RSB, Jaffe R, Carcillo JA. Prolonged lymphopenia, lymphoid depletion, and hypoprolactinemia in children with nosocomial sepsis and multiple organ failure. J Immunol. 2005;174:3765–72.
doi: 10.4049/jimmunol.174.6.3765
Bennett TD, Hayward KN, Farris RW, Ringold S, Wallace CA, Brogan TV. Very high serum ferritin levels are associated with increased mortality and critical care in pediatric patients. Pediatr Crit Care Med. 2011;12:e233–6.
doi: 10.1097/PCC.0b013e31820abca8
Sekhon SS, Roy V. Thrombocytopenia in adults: a practical approach to evaluation and management. South Med J. 2006;99:491–8.
doi: 10.1097/01.smj.0000209275.75045.d4
Lobo SMA, Lobo FRM, Peres Bota D, Lopes-Ferreira F, Soliman HM, Mélot C, et al. C-reactive protein levels correlate with mortality and organ failure in critically ill patients. Chest. 2003;123:2043–9.
doi: 10.1378/chest.123.6.2043
Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alföldi J, Wang Q, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581:434–43.
doi: 10.1038/s41586-020-2308-7
Osborne AJ, Breno M, Borsa NG, Bu F, Frémeaux-Bacchi V, Gale DP, et al. Statistical validation of rare complement variants provides insights into the molecular basis of atypical hemolytic uremic syndrome and C3 glomerulopathy. J Immunol. 2018;200:2464–78.
doi: 10.4049/jimmunol.1701695
Geerlings MJ, Volokhina EB, de Jong EK, van de Kar N, Pauper M, Hoyng CB, et al. Genotype-phenotype correlations of low-frequency variants in the complement system in renal disease and age-related macular degeneration. Clin Genet. 2018;94:330–8.
doi: 10.1111/cge.13392
Besbas N, Gulhan B, Soylemezoglu O, Ozcakar ZB, Korkmaz E, Hayran M, et al. Turkish pediatric atypical hemolytic uremic syndrome registry: initial analysis of 146 patients. BMC Nephrol. 2017;18:6.
doi: 10.1186/s12882-016-0420-6
Fidalgo T, Martinho P, Pinto CS, Oliveira AC, Salvado R, Borràs N, et al. Combined study of ADAMTS13 and complement genes in the diagnosis of thrombotic microangiopathies using next-generation sequencing. Res Pract Thromb Haemost. 2017;1:69–80.
doi: 10.1002/rth2.12016
Schramm EC, Roumenina LT, Rybkine T, Chauvet S, Vieira-Martins P, Hue C, et al. Mapping interactions between complement C3 and regulators using mutations in atypical hemolytic uremic syndrome. Blood. 2015. https://doi.org/10.1182/blood-2014-10-609073 .
doi: 10.1182/blood-2014-10-609073
pubmed: 25608561
pmcid: 4392009
Chapin J, Eyler S, Smith R, Tsai H-M, Laurence J. Complement factor H mutations are present in ADAMTS13-deficient, ticlopidine-associated thrombotic microangiopathies. Blood. 2013;121:4012–3.
doi: 10.1182/blood-2013-03-487694
Zhang T, Lu J, Liang S, Chen D, Zhang H, Zeng C, et al. Comprehensive analysis of complement genes in patients with atypical hemolytic uremic syndrome. Am J Nephrol. 2016;43:160–9.
doi: 10.1159/000445127
Mørk N, Kofod-Olsen E, Sørensen KB, Bach E, Ørntoft TF, Østergaard L, et al. Mutations in the TLR3 signaling pathway and beyond in adult patients with herpes simplex encephalitis. Genes Immun. 2015;16:552–66.
doi: 10.1038/gene.2015.46
Nedjai B, Hitman GA, Church LD, Minden K, Whiteford ML, McKee S, et al. Differential cytokine secretion results from p65 and c-Rel NF-κB subunit signaling in peripheral blood mononuclear cells of TNF receptor-associated periodic syndrome patients. Cell Immunol. 2011;268:55–9.
doi: 10.1016/j.cellimm.2011.02.007
Kernan KF, Ghaloul-Gonzalez L, Shakoory B, Kellum JA, Angus DC, Carcillo JA. Adults with septic shock and extreme hyperferritinemia exhibit pathogenic immune variation. Genes Immun. 2019. https://doi.org/10.1038/s41435-018-0030-3 .
doi: 10.1038/s41435-018-0030-3
pubmed: 29977033
Davila S, Wright VJ, Khor CC, Sim KS, Binder A, Breunis WB, et al. Genome-wide association study identifies variants in the CFH region associated with host susceptibility to meningococcal disease. Nat Genet. 2010;42:772–6.
doi: 10.1038/ng.640
Van Den Broek B, Van Der Flier M, De Groot R, De Jonge MI, Langereis JD. Common genetic variants in the complement system and their potential link with disease susceptibility and outcome of invasive bacterial infection. J Innate Immun. 2020;12:131–41.
doi: 10.1159/000500545
Bu F, Borsa N, Gianluigi A, Smith RJH. Familial atypical hemolytic uremic syndrome: a review of its genetic and clinical aspects. Clin Dev Immunol. 2012;2012:370426.
doi: 10.1155/2012/370426
Tang L, Wang HF, Lu X, Jian XR, Jin B, Zheng H, et al. Common genetic risk factors for venous thrombosis in the Chinese population. Am J Hum Genet. 2013;92:177–87.
doi: 10.1016/j.ajhg.2012.12.013
Mohlin FC, Gros P, Mercier E, Gris JCR, Blom AM. Analysis of C3 gene variants in patients with idiopathic recurrent spontaneous pregnancy loss. Front Immunol. 2018. https://doi.org/10.3389/fimmu.2018.01813 .
doi: 10.3389/fimmu.2018.01813
pubmed: 30405598
pmcid: 6207586
Fang CJ, Fremeaux-Bacchi V, Liszewski MK, Pianetti G, Noris M, Goodship THJ, et al. Membrane cofactor protein mutations in atypical hemolytic uremic syndrome (aHUS), fatal Stx-HUS, C3 glomerulonephritis, and the HELLP syndrome. Blood. 2008;111:624–32.
doi: 10.1182/blood-2007-04-084533
Crovetto F, Borsa N, Acaia B, Nishimura C, Frees K, Smith RJH, et al. The genetics of the alternative pathway of complement in the pathogenesis of HELLP syndrome. J Matern Fetal Neonatal Med. 2012;25:2322–5.
doi: 10.3109/14767058.2012.694923
Liu J, Tan Y, Zhang J, Zou L, Deng G, Xu X, et al. C5aR, TNFa and FGL2 contribute to coagulation and complement activation in virus-induced fulminant hepatitis. J Hepatol. 2015;62:354–62.
doi: 10.1016/j.jhep.2014.08.050
Verma D, Särndahl E, Andersson H, Eriksson P, Fredrikson M, Jönsson J-I, et al. The Q705K polymorphism in NLRP3 is a gain-of-function alteration leading to excessive interleukin-1β and IL-18 production. PloS one. 2012;7:e34977.
doi: 10.1371/journal.pone.0034977
Aksentijevich I, Putnam CD, Remmers EF, Mueller JL, Le J, Kolodner RD, et al. The clinical continuum of cryopyrinopathies: novel CIAS1 mutations in North American patients and a new cryopyrin model. Arthritis Rheum. 2007;56:1273–85.
doi: 10.1002/art.22491
Koc B, Oktenli C, Bulucu F, Karadurmus N, Sanisoglu SY, Gul D. The rate of pyrin mutations in critically ill patients with systemic inflammatory response syndrome and sepsis: a pilot study. J Rheumatol. 2007;34:2070–5.
pubmed: 17696266
Zhang Q, Liu Z, Moncada-Velez M, Chen J, Ogishi M, Bigio B, et al. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science. 2020. https://doi.org/10.1126/science.abd4570 .
doi: 10.1126/science.abd4570
pubmed: 33335060
pmcid: 7880903