Genetic and immunologic evaluation of children with inborn errors of immunity and severe or critical COVID-19

Abstract

Background: Most severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals are asymptomatic or only exhibit mild disease. In about 10% of cases, the infection leads to hypoxemic pneumonia, although it is much more rare in children.

Objective: We evaluated 31 young patients aged 0.5 to 19 years who had preexisting inborn errors of immunity (IEI) but lacked a molecular diagnosis and were later diagnosed with coronavirus disease 2019 (COVID-19) complications.

Methods: Genetic evaluation by whole-exome sequencing was performed in all patients. SARS-CoV-2-specific antibodies, autoantibodies against type I IFN (IFN-I), and inflammatory factors in plasma were measured. We also reviewed COVID-19 disease severity/outcome in reported IEI patients.

Results: A potential genetic cause of the IEI was identified in 28 patients (90.3%), including mutations that may affect IFN signaling, T- and B-cell function, the inflammasome, and the complement system. From tested patients 65.5% had detectable virus-specific antibodies, and 6.8% had autoantibodies neutralizing IFN-I. Five patients (16.1%) fulfilled the diagnostic criteria of multisystem inflammatory syndrome in children. Eleven patients (35.4%) died of COVID-19 complications. All together, at least 381 IEI children with COVID-19 have been reported in the literature to date. Although many patients with asymptomatic or mild disease may not have been reported, severe presentation of COVID-19 was observed in 23.6% of the published cases, and the mortality rate was 8.7%.

Conclusions: Young patients with preexisting IEI may have higher mortality than children without IEI when infected with SARS-CoV-2. Elucidating the genetic basis of IEI patients with severe/critical COVID-19 may help to develop better strategies for prevention and treatment of severe COVID-19 disease and complications in pediatric patients.

Keywords: COVID-19; Inborn errors of immunity; SARS-CoV-2; genetic diagnosis; immune response; multisystem inflammatory syndrome in children (MIS-C); primary immunodeficiency.

Fig 1

(A) Classification of IEI according to clinical diagnosis in 31 Iranian patients with severe or critical COVID-19. Auto inf, Autoinflammatory disorders; Imm dys, disease of immune dysregulation; Innate, innate immunodeficiency. (B) Correlation of specific IgG and IgM response against RBD of the spike protein in different categories of IEI patients. Genetic defects of solved IEI patients are depicted; color codes refer to clinical diagnosis of patients according to their initial immunologic profile.

Fig 2

Extended SARS-CoV-2–related pathway analysis for evaluation of the impact of complete inheritance pattern (purple) and potential modifying gene defects (red) within the IFN pathway, IL-1/inflammasome activation, NF-κB activation, and autoinflammatory response pathways in a schematic presentation of the epithelial cell of lung alveoli or innate immune cells. Asterisk indicates one IEI patient. Hem, Hemizygous; het, heterozygous variants; hom, homozygous variants. Details of mutations are shown in Table II and Table E1 and Table E2.

Fig 3

Heat map analysis of plasma level of the inflammatory proteins in IEI patients with severe or critical COVID-19. Each column represents a patient, and each row indicates a given protein measured. Green bars indicate patients with autoantibodies against IFN-I (Auto-Ab); red bars indicate IEI patients who presented with MIS-C. The color legend is presented as normalized protein expression (NPX) values, Olink Proteomics’ arbitrary unit on a log₂ scale. Details of measurement of each protein are shown in Table E4 and differentially expressed markers are depicted in Fig E5.

Fig 4

Systematic review of the literature on the frequency of severe and critical forms of COVID-19 in different entities of IEI patients based on IUIS classification. IEI phenocopies group refers to a group of patients with Good syndrome and somatic mutation in TNFRSF6. Details are shown in Table E5.

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