Recessive inborn errors of type I IFN immunity in children with COVID-19 pneumonia

Abstract

Recessive or dominant inborn errors of type I interferon (IFN) immunity can underlie critical COVID-19 pneumonia in unvaccinated adults. The risk of COVID-19 pneumonia in unvaccinated children, which is much lower than in unvaccinated adults, remains unexplained. In an international cohort of 112 children (<16 yr old) hospitalized for COVID-19 pneumonia, we report 12 children (10.7%) aged 1.5–13 yr with critical (7 children), severe (3), and moderate (2) pneumonia and 4 of the 15 known clinically recessive and biochemically complete inborn errors of type I IFN immunity: X-linked recessive TLR7 deficiency (7 children) and autosomal recessive IFNAR1 (1), STAT2 (1), or TYK2 (3) deficiencies. Fibroblasts deficient for IFNAR1, STAT2, or TYK2 are highly vulnerable to SARS-CoV-2. These 15 deficiencies were not found in 1,224 children and adults with benign SARS-CoV-2 infection without pneumonia (P = 1.2 × 10−11) and with overlapping age, sex, consanguinity, and ethnicity characteristics. Recessive complete deficiencies of type I IFN immunity may underlie ∼10% of hospitalizations for COVID-19 pneumonia in children.

Impaired IL-23–dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency

“…We searched for biallelic variants, including at least one very rare or rare (frequencies <0.01 and <1%, respectively, in the general population) nonsynonymous or essential splice site variant of TYK2 (NM_003331) by WES in patients with unexplained mycobacterial or viral diseases. We identified and characterized 19 patients (15 of whom were new patients, the remaining patients having been described clinically; Sarrafzadeh et al, 2020 ; Zhang et al, 2022 ) from 16 families ( Fig. 1 and Table 1 ): P1 is homozygous for a previously reported 4-bp deletion in exon 4 (c.208_211:GCTTdel; p.C70Hfs*21; Minegishi et al, 2006 ); P2 is homozygous for a copy number variant consisting of a large deletion spanning exons 19–25 (g.10467969_10459969del; E19_25del; Fig.…”

“…Autosomal recessive (AR) complete TYK2 deficiency is characterized by mycobacterial and/or viral diseases ( Table 1 ; Fuchs et al, 2016 ; Guo et al, 2020 ; Kreins et al, 2015 ; Minegishi et al, 2006 ; Sarrafzadeh et al, 2020 ; Wu et al, 2020 ; Zhang et al, 2022 ). Only 15 patients with AR TYK2 deficiency from 13 families have been reported (including one for whom functional characterization is incomplete; Table 1 ; Fuchs et al, 2016 ; Guo et al, 2020 ; Kilic et al, 2012 ; Kreins et al, 2015 ; Minegishi et al, 2006 ; Sarrafzadeh et al, 2020 ; Wu et al, 2020 ; Zhang et al, 2022 ).…”

“…Autosomal recessive (AR) complete TYK2 deficiency is characterized by mycobacterial and/or viral diseases ( Table 1 ; Fuchs et al, 2016 ; Guo et al, 2020 ; Kreins et al, 2015 ; Minegishi et al, 2006 ; Sarrafzadeh et al, 2020 ; Wu et al, 2020 ; Zhang et al, 2022 ). Only 15 patients with AR TYK2 deficiency from 13 families have been reported (including one for whom functional characterization is incomplete; Table 1 ; Fuchs et al, 2016 ; Guo et al, 2020 ; Kilic et al, 2012 ; Kreins et al, 2015 ; Minegishi et al, 2006 ; Sarrafzadeh et al, 2020 ; Wu et al, 2020 ; Zhang et al, 2022 ). Nine of these patients had mycobacterial diseases, including BCG disease ( n = 6), EM disease ( n = 1), and tuberculosis (TB; n = 3), and five had unusually severe viral illnesses, including mucocutaneous herpes simplex virus 1 (HSV-1) infections ( n = 3), HSV-1 encephalitis (HSE; n = 1), cutaneous varicella-zoster virus (VZV; n = 2) or Molluscum contagiosum ( n = 1) infections, human parainfluenza type 3 virus (PIV3) pneumonia ( n = 1), COVID-19 pneumonia ( n = 4), influenza A pneumonia ( n = 1), and measles-mumps-rubella (MMR) vaccine disease ( n = 1; Fuchs et al, 2016 ; Guo et al, 2020 ; Kilic et al, 2012 ; Kreins et al, 2015 ; Minegishi et al, 2006 ; Sarrafzadeh et al, 2020 ; Wu et al, 2020 ; Zhang et al, 2022 ).…”

From rare disorders of immunity to common determinants of infection: Following the mechanistic thread

“…Based on previous discoveries of rare inherited TLR3, IRF7, STAT1, STAT2, and IRF9 deficiencies in children with life-threatening influenza pneumonia (Campbell et al, 2022;Le Voyer et al, 2021;Zhang, 2020a), rare autosomal IEI affecting TLR3-dependent type I IFN immunity were discovered in patients with life-threatening COVID-19 (Zhang et al, 2020). Remarkably, AR and complete defects of IFNAR1, IRF7, and TBK1 were found in previously healthy patients (Abolhassani et al, 2022;Khanmohammadi et al, 2022;Schmidt et al, 2021;Zhang et al, 2020Zhang et al, , 2022b. All these disorders, including the recessive defects, were rare, with genotype frequencies <10 À5 in the general population and probably <10 À3 in patients with critical disease (Zhang et al, 2020).…”

“…This redundancy was confirmed not only by reports of other patients with IFNAR1 or IRF7 deficiency ( Campbell et al., 2022 ) but also by the surprising observation of common loss-of-function (LOF) alleles of IFNAR1 and IFNAR2 in the Pacific and Arctic regions, respectively ( Bastard et al., 2022a ; Duncan et al., 2022 ). Recessive inborn errors of type I IFNs, including XR TLR7 and AR IFNAR1, STAT2, and TYK2 deficiencies, were even found in about 10% of international children hospitalized for COVID-19 pneumonia ( Zhang et al., 2022b ). Who would have predicted such a level of redundancy of type I IFNs and, in the case of IRF7 deficiency, of combined type I and III IFNs?…”