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.
Division of Genetic and Genomic Medicine, Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA.
J Clin Immunol. 2022 Feb;42(2):350-364. doi: 10.1007/s10875-021-01183-4. Epub 2022 Jan 1.
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.
我们对先天性免疫缺陷的认识在不断提高；然而，其对儿科脓毒症的贡献尚不清楚。
我们使用外显子组测序（WES）对 330 名因严重脓毒症入住重症监护病房的儿童进行了与单基因免疫疾病相关基因的变异分析。我们将候选变异定义为 QIAGEN 人类基因突变数据库中归类为致病性或可能致病性的罕见变异，或在疾病一致遗传模式下的新型无功能变异。我们研究了变异与感染和炎症表型的相关性。
总体而言，超过一半的儿童和四分之三的非裔美国儿童存在与免疫缺陷相关的变异。有变异的儿童分离血液或尿液病原体的几率更高（血液：比值比 2.82，95%置信区间：1.12-7.10，p=0.023；尿液：比值比 8.23，95%置信区间：1.06-64.11，p=0.016），且表现出更高的炎症水平，包括铁蛋白升高（铁蛋白[Formula: see text]ng/ml，比值比 2.16，95%置信区间：1.28-3.66，p=0.004）、淋巴细胞减少（淋巴细胞计数<1000/µl，比值比 1.66，95%置信区间：1.06-2.60，p=0.027）、血小板减少（血小板计数<150,000/µl，比值比 1.76，95%置信区间：1.12-2.76，p=0.013）和 CRP 大于 10mg/dl（比值比 1.71，95%置信区间：1.10-2.68，p=0.017）。他们还需要体外膜肺氧合（ECMO）的几率更高（比值比 4.19，95%置信区间：1.21-14.5，p=0.019）。
在此，我们描述了这一严重儿科脓毒症队列的基因发现及其微生物学和免疫学意义，为这些变异的表型效应提供了证据，并为有生命危险感染的儿童筛查潜在的先天性免疫缺陷提供了依据。
