key: cord-1049712-p1f0pkcz authors: Paul, Griffiths title: Coronavirus disease 2019 as a syndemic date: 2021-01-19 journal: Rev Med Virol DOI: 10.1002/rmv.2212 sha: 2379107ae60104acb6b176e53040537e81dcc74b doc_id: 1049712 cord_uid: p1f0pkcz nan 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 , 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. 4 Several articles in this journal have documented this and considered some potential contributory factors worthy of further exploration. 5, 6 As reviewed by Teymoori-Rad and colleagues, deficiency of vitamin D is common and may have genetic predispositions. 5 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. 7 Vitamin D deficiency is associated with an excess of respiratory viral infections and a randomised controlled trial (RCT) supports clinical benefit from dietary supplementation. 8, 9 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. 5 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. 6, 10 Remarkably, most of these differentiated T-cells are specific for cytomegalovirus (CMV) and their abundance can be reduced by valganciclovir. 10, 11 This virus is acquired preferentially by people from non-Caucasian backgrounds and its prevalence increases with age. 12, 13 A study comparing monozygotic twins with dizygotic reported that most of the variance in immune parameters was non-hereditary and driven by CMV. 14 A recent publication shows that the prevalence of CMV IgG antibodies is higher among those with Covid-19 severe enough to require hospitalisation. 15 There is a known association between CMV and mortality in the general public and in stem cell transplant patients. [16] [17] [18] An RCT in the latter reports significantly reduced mortality from the CMV-specific antiviral drug letermovir. 19, 20 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. 21 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 This is an important parameter, and what the trial data safety monitoring board will be following closely, but much more is required. We need to see the protocol describing the inclusion and exclusion criteria, and descriptions of the ages and demographics of those recruited. We want to see the details of the intention to treat Intricate interplay between Covid-19 and cardiovascular diseases Covid-19 and kidney injury: Pathophysiology and molecular mechanisms Clotting disorder in severe acute respiratory syndrome coronavirus 2 Covid-19: time for a paradigm change Vitamin D and Covid-19: from potential therapeutic effects to unanswered questions Why the elderly appear to be more severely affected by COVID-19: the potential role of immunosenescence and CMV Hunninghake GW. Vitamin D decreases respiratory syncytial virus induction of NF-kappaB-linked chemokines and cytokines in airway epithelium while maintaining the antiviral state Association between serum 25-hydroxyvitamin D level and upper respiratory tract infection in the Third National Health and Nutrition Examination Survey High-dose monthly vitamin D for prevention of acute respiratory infection in older long-term care residents: a randomized clinical trial Latent cytomegalovirus (CMV) infection does not detrimentally alter T cell responses in the healthy old, but increased latent CMV carriage is related to expanded CMV-specific T cells Valganciclovir reduces T cell activation in HIV-infected individuals with incomplete CD4+ T cell recovery on antiretroviral therapy Seroprevalence of cytomegalovirus, Epstein Barr virus and varicella zoster virus among pregnant women in Bradford: a cohort study Epstein-Barr virus and varicella zoster virus infection in the first two years of life: a cohort study in Bradford Variation in the human immune system is largely driven by non-heritable influences Viral epitope profiling of COVID-19 patients reveals cross-reactivity and correlates of severity. Science Seropositivity to cytomegalovirus, inflammation, all-cause and cardiovascular diseaserelated mortality in the United States Seropositivity and higher immunoglobulin g antibody levels against cytomegalovirus are associated with mortality in the population-based European prospective investigation of Cancer-Norfolk cohort The impact of cytomegalovirus serostatus of donor and recipient before hematopoietic stem cell transplantation in the era of antiviral prophylaxis and preemptive therapy Letermovir prophylaxis for cytomegalovirus in hematopoietic-cell transplantation A mortality analysis of letermovir prophylaxis for cytomegalovirus (CMV) in CMV-seropositive recipients of allogeneic hematopoietic-cell transplantation Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet