The inflammatory cytokine interleukin-6 (IL-6) is central to orchestrating the immune system.
The pathophysiological process underlying severe coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2, consists of an exaggerated host immune response and elevated circulating levels of inflammatory cytokines, including IL-6. 1 As such, immunomodulatory agents are being investigated for the treatment of COVID-19. Glucocorticoids may limit inflammation-mediated lung injury in patients with severe COVID-19, and consequently reduce progression to respiratory failure and death. The RECOVERY trial found that administration of dexamethasone resulted in lower 28-day mortality among hospitalized COVID-19 patients who were receiving either invasive mechanical ventilation or oxygen alone at randomization, but not among those who were not receiving any respiratory support. 2 Inhibition of IL-6 signaling may represent another potential immunomodulatory strategy for treating COVID-19, 3 and a recent meta-analysis of mean IL-6 concentrations demonstrated 2.9-fold higher levels in patients with complicated COVID-19 compared with patients with non-complicated disease. 4 Genetic variants that proxy inhibition of IL-6 signaling may be used as instrumental variables in the Mendelian randomization paradigm to investigate corresponding drug effects.
Here, we conducted a Mendelian randomization investigation to assess the potential effect of pharmacological inhibition of IL-6 signaling on susceptibility to COVID-19 and pneumonia.
Inhibition of IL-6 signaling was proxied using seven single-nucleotide polymorphisms within or adjacent to the IL6R gene region that were associated with C-reactive protein (CRP; downstream molecule of IL-6 signaling) levels at the genome-wide significance threshold in 204 402 individuals of European ancestry. 5 These genetic variants also had associations with fibrinogen, IL-6 and soluble IL-6 receptor in a pattern consistent with their effect on reducing IL-6 signaling. 5 . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint
The copyright holder for this this version posted September 18, 2020. . https://doi.org/10.1101/2020.09.15.20165886 doi: medRxiv preprint Summary-level genetic data for COVID-19 were acquired from: 1) The COVID-19
Host Genetics Initiative genome-wide association meta-analysis (round 3), 6 We performed summary data Mendelian randomization analysis using the inversevariance weighted method with multiplicative random-effects and accounting for correlations between genetic variants. Our results showed that genetically proxied inhibition of IL-6 signaling, scaled per 0.1 standard deviation lower CRP level, was associated with a reduced risk of COVID-19, but also with an increased risk of pneumonia ( Figure 1 ).
Our findings provide evidence supporting that inhibition of IL-6 signaling reduces susceptibility to COVID-19. Importantly, they go further to provide genetic evidence that inhibition of IL-6 signaling may also increase susceptibility to pneumonia. While we . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint
The copyright holder for this this version posted September 18, 2020. . https://doi.org/10.1101/2020.09.15.20165886 doi: medRxiv preprint considered a broad definition of pneumonia from any cause, our results may be of relevance to secondary lung infections that can complicate COVID-19. An adverse effect of IL-6 inhibition on risk of pneumonia risk is biologically plausible, and respiratory tract infections, including pneumonia, are a well-known complication of IL-6 signaling inhibition. 10 Respiratory disease is a main feature of severe COVID-19, and the potential of IL-6 signaling inhibitors to increase risk of pneumonia warrants vigilance and caution in their application to treat COVID-19. CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint
The copyright holder for this this version posted September 18, 2020. . https://doi.org/10.1101/2020.09.15.20165886 doi: medRxiv preprint