Journal Pre-proof Genetic and immunological evaluation of children with inborn errors of immunity and severe or critical COVID-19

42 Background: Most SARS-CoV-2 infected individuals are asymptomatic or only show a mild disease. In about 43 10% of cases, the infection leads to hypoxemic pneumonia, although it is much more rare in children. 44 Objective: We evaluated 31 young patients (0.5-19 years) who had pre-existing inborn errors of immunity (IEI) 45 but lacked a molecular diagnosis and were later diagnosed with COVID-19 complications. 46 Methods: Genetic evaluation by whole-exome sequencing was performed in all patients. SARS-CoV-2 specific 47 antibodies, autoantibodies against type I interferons (IFNs) and inflammatory factors in plasma were measured. 48 We also reviewed COVID-19 disease severity/outcome in reported IEI patients. 49 Results: A potential genetic cause of the IEI was identified in 28 patients (90.3%), including mutations that 50 may affect IFN signaling, T and B cell function, the inflammasome, and the complement system. Fourteen of 51 the patients tested (66%) had detectable virus-specific antibodies and two patients (6.8%) had autoantibodies 52 neutralizing type-I IFNs. Five patients (16.1%) fulfilled the diagnostic criteria of multisystem inflammatory 53 syndrome in children (MIS-C). Eleven patients (35.4%) died due to COVID-19 complications. Altogether at 54 least 381 IEI children with COVID-19 have been reported in the literature till date. Although many 55 asymptomatic or mild patients may not have been reported, severe presentation of COVID-19 was observed in 56 23.6% of the published cases and the mortality rate was 8.7%. 57 Conclusion: Young patients with pre-existing IEI may have a higher mortality as compared to children without 58 IEI when infected with SARS-CoV-2. Elucidating the genetic basis of IEI patients with severe/critical COVID- 59 19 may help to develop better strategies for prevention and treatment of severe COVID-19 disease and 60 complications in pediatric patients. million controls indicated that in the normal population, the ABO , PPP1R15A and SLC6A20 loci impact susceptibility to infection, whereas, genetic variants in the immune-related/IFN pathways including TYK2, CXCR6, IFNAR2 and OAS loci infer progression to severe/critical COVID-19 59 . Moreover, whole-genome sequencing in 7,491 critically ill patients compared with 48,400 controls highlighted the importance of immune-related genes variants in IFN signaling ( IFNA10, IFNAR2, TYK2, IL10RB and PLSCR1 ), leucocyte differentiation ( BCL11A ), and myeloid cell adhesion ( SELE, ICAM5 and CD209 ), in the predisposition to critical COVID-19 60 . Our study reinforces the notion that genetic defects in the type I IFN pathway can lead to hypoxemic COVID-19 pneumonia, and furthermore suggests that additional pathways, such as lymphocyte development, the inflammasome and complement pathways, may also be associated with a severe/critical form of COVID-19. Autoantibodies against type I IFNs were detected in two (6.8%) of the investigated patients with IEI. It has been shown that monogenic inborn errors of type I IFN immunity underlie ~5% of patients with severe and critical COVID-19, as well as other selected severe viral infections or adverse effects of live-attenuated vaccines 61-68 . Furthermore, autoantibodies neutralizing type I IFNs are present in at least 15% of the severe cases in the general population 6, 22 . These findings show that type I IFNs are essential for protective immunity against SARS-CoV-2. The proportion of type I IFN autoantibody positivity of the investigated IEI patients was similar to that of adult non-IEI severe COVID-19 patients. Children with COVID-19 present higher mucosal the cases further studies are needed to evaluate the impact of different variants of concerns and different types of vaccines on this specific group of the systematic review performed on published as some papers may still be missing due to the search strategy and selected. our overall findings emphasize the need for a paradigm about