Moundir Abderrahmane, Aissaoui Ouissal, Akhrichi Nassima, Allaoui Abire, Benhsaien Ibtihal, Jouanguy Emmanuelle, Casanova Jean-Laurent, El Bakkouri Jalila, Ailal Fatima, Bousfiha Ahmed Aziz
Clinical Immunology, Inflammation and Allergy Laboratory (LICIA), Faculty of Medicine and Pharmacy, Hassan II University, Casablanca, Morocco.
Department of Internal Medicine, Cheikh Khalifa International University Hospital, Mohammed VI University of Health Sciences, Casablanca, Morocco.
Clin Exp Immunol. 2025 Jan 21;219(1). doi: 10.1093/cei/uxaf007.
Increasing evidence supports the involvement of inborn errors of immunity in severe infections, but little is known about the prevalence of these genetic defects in children with sepsis. Due to the limited understanding of the molecular and immunological mechanisms driving sepsis, genetic testing is rarely used in routine diagnostics to identify genetic susceptibility to the condition. We performed a prospective observational study on previously healthy children hospitalized for severe infections, including sepsis. Patients underwent immunophenotyping and whole-exome sequencing, followed by in silico analysis to identify potentially causal variants. We assembled a cohort of 194 previously healthy children, including 149 (77%) patients with severe infection and 45 (23%) with sepsis. Our cohort was marked by a high frequency of respiratory tract infections (35%), bloodstream infections (20%), and central nervous system infections (16%). The genetic investigation identified 28 potentially causal variants, 18 (64%) are classified as variants with uncertain significance, and 10 (36%) are likely pathogenic variants. Of 45 patients with sepsis, 6 (13%) had potentially causal genetic variants. Similarly, 22/149 (15%) patients with severe infection presented potentially causal genetic variants. Whole-exome sequencing predicted the impairment of various immune mechanistic pathways such as immune dysregulation defects, antibody deficiencies, and combined immunodeficiencies (18% each). We found no clear association between genetic variants and the studied parameters: organ failure, microbe identification, immunoglobulin levels, and lymphocyte subset numbers. Although whole-exome sequencing is a valuable tool for detecting inborn errors of immunity underlying sepsis and unexplained severe infections, it could be selectively recommended for patients with a strong clinical suspicion of genetic abnormalities, balancing its diagnostic value with its cost and complexity.
越来越多的证据支持遗传性免疫缺陷参与严重感染，但对于脓毒症患儿中这些基因缺陷的患病率知之甚少。由于对导致脓毒症的分子和免疫机制了解有限，基因检测在常规诊断中很少用于识别对该病症的遗传易感性。我们对因包括脓毒症在内的严重感染而住院的既往健康儿童进行了一项前瞻性观察研究。患者接受了免疫表型分析和全外显子组测序，随后进行了计算机分析以识别潜在的致病变异。我们组建了一个由194名既往健康儿童组成的队列，其中包括149名（77%）严重感染患者和45名（23%）脓毒症患者。我们的队列以呼吸道感染（35%）、血流感染（20%）和中枢神经系统感染（16%）的高发生率为特征。基因研究确定了28个潜在的致病变异，其中18个（64%）被归类为意义不明确的变异，10个（36%）为可能的致病变异。在45名脓毒症患者中，6名（13%）有潜在的致病变异。同样，149名严重感染患者中有22名（15%）存在潜在的致病变异。全外显子组测序预测了各种免疫机制途径的损害，如免疫调节缺陷、抗体缺乏和联合免疫缺陷（各占18%）。我们没有发现基因变异与所研究的参数之间存在明确关联：器官衰竭、微生物鉴定、免疫球蛋白水平和淋巴细胞亚群数量。虽然全外显子组测序是检测脓毒症和不明原因严重感染潜在遗传性免疫缺陷的有价值工具，但对于临床高度怀疑有基因异常的患者，可以在权衡其诊断价值与成本和复杂性后有选择地推荐使用。
