TBK1 and TNFRSF13B mutations and an autoinflammatory disease in a child with lethal COVID-19

Abstract

Among children, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are typically mild. Here, we describe the case of a 3.5-year-old girl with an unusually severe presentation of coronavirus disease (COVID-19). The child had an autoinflammatory disorder of unknown etiology, which had been treated using prednisolone and methotrexate, and her parents were half cousins of Turkish descent. After 5 days of nonspecific viral infection symptoms, tonic-clonic seizures occurred followed by acute cardiac insufficiency, multi-organ insufficiency, and ultimate death. Trio exome sequencing identified a homozygous splice-variant in the gene TBK1, and a homozygous missense variant in the gene TNFRSF13B. Heterozygous deleterious variants in the TBK1 gene have been associated with severe COVID-19, and the variant in the TNFRSF13B gene has been associated with common variable immunodeficiency (CVID). We suggest that the identified variants, the autoinflammatory disorder and its treatment, or a combination of these factors probably predisposed to lethal COVID-19 in the present case.

Outcomes of SARS-CoV-2 infection among children and young people with pre-existing rheumatic and musculoskeletal diseases

“…Three patients died with PCR confirmed SARS-CoV-2 ( table 2 ). One death in a female <5 years old with a pre-existing auto-inflammatory syndrome (unknown disease activity status), on low-dose glucocorticoids and methotrexate (described in further detail elsewhere 12 ). Two deaths occurred in subjects from lower-resource areas who were diagnosed with SLE around the same time as they developed COVID-19 (one with SLE manifestations recognised at the time of COVID-19 presentation, another with preceding SLE manifestations but not yet diagnosed).…”

The Immune Response to SARS-CoV-2 Vaccination: Insights Learned From Adult Patients With Common Variable Immune Deficiency

“…Few data are available on genetic factors associated with the impaired SARS-CoV-2 response in CVID. A CVID patient with NF-kB2 loss-of-function variant who developed severe COVID-19 and a patient with TBK1 and TNFRSF13B mutations and an auto-inflammatory disease with lethal COVID-19 were reported ( 9 , 10 ).…”

Host genetics of pediatric SARS-CoV-2 COVID-19 and multisystem inflammatory syndrome in children

“…Although the full loss of p90phox activity causes chronic granulomatous disease, this patient's variant reduced but did not eliminate the neutrophil respiratory burst [ 37 ▪ ]. Finally, homozygous TBK1 and TNFRSF13B mutations were recently identified in a 3-year-old girl with fatal COVID-19 and a history of autoimmune disease [ 39 ]. Notably, TBK1 is a known regulator of the type I IFN pathway, and homozygous variants were recently reported in a child with systemic autoinflammation [ 40 ] (Table 1 ).…”