Association of rare predicted loss-of-function variants of influenza-related type I IFN genes with critical COVID-19 pneumonia.

Zhang, Qian; Cobat, Aurélie; Bastard, Paul; Notarangelo, Luigi D; Su, Helen C; Abel, Laurent; Casanova, Jean-Laurent

To the Editor: Povysil G. et al. report that "rare loss-of-function (LOF) variants in type I interferon (IFN) immunity genes are not associated with severe COVID-19" (1). We disagree with the authors' interpretation of our data and their own (2), for six reasons: 1) Only predicted LOF (pLOF) variants are relevant for comparison between the two studies, because, unlike us, these authors did not test variants experimentally. The relevant proportion in our data is therefore not 24/659=3.5%, but 9/659= 1.36%, whereas theirs is 1/713=0.14%. 2) Our definitions of 'severe/critical' patients are different: we defined critical disease as severity grades 6-10 of the WHO scale (3), whereas they restricted their recruitment to grades 7-10 (i.e., excluding patients on high-flow oxygen, considered in our study). Their cohort of 'mild' cases may therefore include 'severe' COVID-19 cases (grade 6), such as perhaps their 'mild' TLR3 pLOF carrier. 3) Their 'controls' are subjects from the general population, without depletion of COVID-19 genetic risk factors, whereas we used pauci-/asymptomatic infected subjects (grades 1-3) as 'controls'. Consequently their power computation in Figure 1 is based on an incorrect hypothesis about the odds ratio, which would be expected to be lower when using general population controls (as they did), than when using pauci- and asymptomatic infected individuals (as we did). 4) The ethnic origin of the patients differs between the two studies: 58% of our 659 patients (and 8 of our 9 pLOF carriers) were European, versus only 10% of their 713 patients with severe disease (and their pLOF carrier is East Asian). 5) Age is a key factor neglected in their comparison: our sample was much younger (mean age: 51.8 years) than theirs (mean: 65.9 years), and seven of our nine pLOF carriers were < 60 years old. We performed a comparison stratified by age (<60/≥60 years), and no significant difference in pLOF proportion was found between the two studies, even ignoring the only patient carrying a pLOF they found (of unknown age): 7/458 in our sample vs. 0/192 in their sample (p=0.11, Fisher's exact test) for patients <60 years old, and 2/201 vs. 0/521 (p=0.07) for patients ≥60 years old. 6) Finally, and crucially, the authors did not exclude patients with autoantibodies against type I IFN, which account for at least 10% of critical cases and are much more frequent in patients > 60 years of age, particularly men (4).