LAUSR

It seems that human nature has not changed much over the past third of a millennium. Contemporary newspapers are replete with photographs of people ignoring advice about social distancing. Many, but not all, of these are young; consistent with the perception by adolescents of their own immortality, coupled with a desire for immediate gratification, even at the risk of future consequences. As anticipated by Pepys, these consequences are often not visited upon the generation that took the initial risks. The plague currently affecting us is coronavirus disease 2019 (Covid‐19), found more frequently than expected in senior citizens, males and in people of non‐Caucasian background. The causative agent, SARS‐CoV‐2 is a generally mild virus acquired by the respiratory route that spreads systemically. It tends to wreak havoc in the lungs, kidneys, heart and clotting systems of people who are old and/ or have comorbidities, particularly diabetes, obesity and hypertension.1‐3 A failure of the immune system to control initial infection is compounded by the tendency of the senescent immune system to switch into inflammatory overdrive. Several articles in this journal have documented this and considered some potential contributory factors worthy of further exploration. As reviewed by Teymoori‐Rad and colleagues, deficiency of vitamin D is common and may have genetic predispositions. The active form of this multifunctional hormone increases the level of IkBalpha that restrains inflammation triggered by NFkB signalling which, in in vitro experiments, is achieved without increasing the quantity of respiratory syncytial virus infection. Vitamin D deficiency is associated with an excess of respiratory viral infections and a randomised controlled trial (RCT) supports clinical benefit from dietary supplementation. Full anabolism to the active form of vitamin D is effected by sunlight, so people with darker skin colour may have increased risks of deficiency. Immune senescence has multiple components, including atrophy of the thymus in early adulthood and the progressive acquisition of immunocommitted T‐cells as individuals experience multiple virus infections as they age. Remarkably, most of these differentiated T‐cells are specific for cytomegalovirus (CMV) and their abundance can be reduced by valganciclovir. This virus is acquired preferentially by people from non‐Caucasian backgrounds and its prevalence increases with age. A study comparing monozygotic twins with dizygotic reported that most of the variance in immune parameters was non‐hereditary and driven by CMV. A recent publication shows that the prevalence of CMV IgG antibodies is higher among those with Covid‐19 severe enough to require hospitalisation. There is a known association between CMV and mortality in the general public and in stem cell transplant patients.16‐18 An RCT in the latter reports significantly reduced mortality from the CMV‐specific antiviral drug letermovir. Rather than considering these vitamin D and CMV candidates as competitors with SARS‐CoV‐2 for causality of mortality, we should be considering that they and other factors could be interacting in a complex web of Venn diagrams to deliver this end. Covid‐19 should thus be thought of as a multifactorial syndemic caused by contributions from multiple overlapping epidemics. As well as the biological factors mentioned above, candidates include the social epidemics of diabetes, obesity (sometimes combined into the term diabesity), social deprivation and racial prejudice that conspire to leave many at risk of disease living in crowded conditions and working in people‐facing occupations. Add in inadequate financial provision to take time off work when they become exposed to individuals with SARS‐CoV‐2 and it becomes clear how many interactions may conspire to sustain the pandemic. Potentially, action taken against any single component of a syndemic could reduce the severity of disease and could deliver results rapidly because licensed treatments exist for them already. The interactions within a syndemic are so complex that placebo‐ controlled RCTs are essential. Several RCTs are underway to determine if supplementation with vitamin D can reduce the severity of Covid‐19 but, despite the body of evidence summarised above, I could not find any RCTs evaluating anti‐CMV therapy in the setting of Covid‐19 on Clintrials.org. Fortunately, help is on its way with four vaccines that have provided remarkable protection in Phase 3 RCTs against the initiating SARS‐CoV‐2 (BioNTech/Pfizer; Gamaleya Center/Russian Direct Investment Fund; Moderna; Oxford University/AstraZeneca)