Inherited IFNAR1 Deficiency in a Child with Both Critical COVID-19 Pneumonia and Multisystem Inflammatory Syndrome

<jats:title>Abstract </jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>Inborn errors of immunity (IEI) and autoantibodies to type I interferons (IFNs) underlie critical COVID-19 pneumonia in at least 15% of the patients, while the causes of multisystem inflammatory syndrome in children (MIS-C) remain elusive.</jats:p> </jats:sec><jats:sec> <jats:title>Objectives</jats:title> <jats:p>To detect causal genetic variants in very rare cases with concomitant critical COVID-19 pneumonia and MIS-C.</jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>Whole exome sequencing was performed, and the impact of candidate gene variants was investigated. Plasma levels of cytokines, specific antibodies against the virus, and autoantibodies against type I IFNs were also measured.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>We report a 3-year-old child who died on day 56 of SARS-CoV-2 infection with an unusual clinical presentation, combining both critical COVID-19 pneumonia and MIS-C. We identified a large, homozygous loss-of-function deletion in <jats:italic>IFNAR1</jats:italic>, underlying autosomal recessive IFNAR1 deficiency.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusions</jats:title> <jats:p>Our findings confirm that impaired type I IFN immunity can underlie critical COVID-19 pneumonia, while suggesting that it can also unexpectedly underlie concomitant MIS-C. Our report further raises the possibility that inherited or acquired dysregulation of type I IFN immunity might contribute to MIS-C in other patients.</jats:p> </jats:sec>