Case series, case-control
Study population and setting
This study included 987 patients hospitalized with severe “life-threatening COVID-19 pneumonia” (defined as pneumonia with critical disease involving any organ system, requiring ICU admission) from multiple cohorts in several countries, along with 663 patients with SARS-CoV-2 infection with mild or no symptoms, and 1,127 healthy controls. Plasma and serum samples were obtained from participants, and these samples were tested for the presence of IgG auto-antibodies (Ab) against the type I interferons (IFNs) IFN-ɑ2 and IFN-ω. The authors tested whether these auto-Ab were neutralizing in vitro using plasma from patients with auto-Ab and healthy controls. A subset of samples from patients with auto-Ab to IFN-ɑ2 (n=22) were tested for the presence of auto-Ab to all 15 type I IFNs. Another subset of samples from patients with auto-Ab to IFN-ɑ2 (n=8) were tested to determine if they impaired the ability of IFN-ɑ2 to block SARS-CoV-2 infection in vitro. Finally, plasma concentrations of all 15 type I IFNs were measured among patients who had auto-Ab to these type I IFNs (n=41).
Summary of Main Findings
Among the 987 patients with severe COVID-19 pneumonia, 135 (13.7%) had IgG auto-Ab to IFN-ɑ2 and/or IFN-ω; these were also present in the two available samples from patients prior to SARS-CoV-2 infection. The prevalence of these auto-Ab against type I IFNs was estimated to be 0.33% (95% CI: 0.015% to 0.67%) in the healthy controls. In vitro, these antibodies were neutralizing for at least one type I IFN in 101 patients (10.1%), 95 (94%) of whom were male. All of the tested patients with auto-Ab to IFN-ɑ2 also had auto-Ab to all 13 type I INFs. The 8 plasma samples tested from patients with auto-Ab to IFN-ɑ2 were able to block the ability of IFN-ɑ2 to protect against infection from SARS-CoV-2 in vitro. Among the 41 patients tested who had auto-Ab to all 13 type I IFNs, 40 had no detectable levels of any type I INFs, and one had low levels. Among individuals with neutralizing auto-Ab against type I INFs, there was a predominance of males (94%), which was higher than the proportion of men among severe COVID-19 patients without these Ab (75%) and among those with mild or no symptoms (28%). One of the 7 women with auto-Ab to type I INFs had a condition in which cells activate only one X chromosome, providing evidence for X chromosome linkage.
This study considered evidence at multiple levels (prevalence in cases and controls, neutralizing effect in vitro, effect on ability of IFN-ɑ2 to block SARS-CoV-2 infection in vitro, plasma type I INF concentrations). The study population was large and included from diverse ethnicities and nationalities.
Only two samples were available from patients before SARS-CoV-2 infection, which limits the ability to conclude with certainty that auto-Ab production was not a consequence of severe disease. Demographic and clinical characteristics of patients and controls were not well described. Methods for selecting asymptomatic or paucisymptomatic controls were unclear.
This, along with an accompanying study in the same journal (Zhang et al.), is an important and novel piece of evidence; it is among the first to identify underlying variations in immune response that may cause severe COVID-19.
This review was posted on: 28 October 2020