This is the first study to have demonstrated a significant correlation between IL-6 levels in matched healthy individuals and age-stratified mortality from COVID-19. Despite the format of data available for other variables deemed to be risk factors for increased mortality including sex, obesity and ethnicity6, not lending itself to statistical analysis, premorbid IL-6 in matched populations had similar higher levels when compared with mortality rates based on these risk factors. This suggests that IL-6 may have a far more important role in the pathogenesis of viral infection than previously thought. IL-6 upregulates cathepsin L production4, which then cleaves the virus, enabling it to infect pulmonary epithelial cells3. IL-6 also upregulates the Angiotensin II AT1 receptor17, and likely upregulates pulmonary epithelial cell ACE2 receptors, with a positive correlation between IL-6 and ACE2 levels in bronchioalveolar lavage (BAL) in patients with severe acute pulmonary inflammation5. Viral reproduction within pulmonary epithelial cells then recruits inflammatory cells which, in turn produce cytokines (as part of the “cytokine storm” phenomenon18) including IL-6. This could be expected to set up a noxious cycle between immune cells and pulmonary epithelium which the virus utilizes to enter cells and replicate. The principal predisposing factor could well be IL-6, with premorbid levels correlating with stratified mortality rates. There are other manifestations of this infection that could readily be attributed to IL-6. Levels of this interleukin are generally low in children, but there is a short spurt in early childhood19, correlating with a recently described severe COVID-19 manifestation in young children, a Kawasaki-like condition20. IL-6 is also thrombogenic, which may well account for this significant cause of death from the virus21. Intense exercise also produces large quantities of IL-622, which may account for the more severe clinical manifestations of infection amongst athletes23.
How can this be utilized to reduce mortality? The role of Vitamin D deficiency as a predictor for worse clinical outcomes remains the focus of investigation, although early results appear to support this contention10. What is unclear is whether Vitamin D exerts a general immune-enhancing effect, or whether it may have a specific role in prevention and treatment of COVID-19. The results herein reported point strongly to the latter, given that Vitamin D lowers immune cell production of IL-611. In addition to Vitamin D prescription, both prophylactic, and, potentially as a specific therapy18, there may well be other therapeutic strategies which could be deployed, including nutritional supplementation, such as ingesting Brazil nuts24, and administration of drugs which lower IL-6 production such as doxycycline25 and budesonide/formoterol26.
While the results of this work offer a rationale for the diverse clinical manifestations of COVID-19 and a range of therapeutic options for trial, this must be tempered by the limitations of my analysis. The data analysed were not strictly comparable, with premorbid data on IL-6 levels derived from different populations to those with mortality data. Further, only the age-stratified results are supported by statistical analysis as the other data on other factors including sex, ethnicity and obesity could not be assessed directly for statistical significance. While substantial premorbid data on IL-6 levels may never be obtainable in patients who die from COVID-19, prospective trials of therapeutic measures can certainly be undertaken, but, given that Vitamin D causes little harm if administered under clinical supervision, this study certainly supports its widespread prescription.
In conclusion, this study has demonstrated a highly significant correlation between premorbid IL-6 levels and mortality rates from COVID-19, accounting for a range of previously described clinical predictors and, potentially directing future therapeutic strategies.