Why the elderly appear to be more severely affected by COVID‐19: The potential role of immunosenescence and CMV

Summary The significantly higher mortality rates seen in the elderly compared with young children during the coronavirus disease 2019 (Covid‐19) pandemic is likely to be driven in part by an impaired immune response in older individuals. Cytomegalovirus (CMV) seroprevalence approaches 80% in the elderly. CMV has been shown to accelerate immune ageing by affecting peripheral blood T cell phenotypes and increasing inflammatory mediated cytokines such as IL‐6. The elderly with pre‐existing but clinically silent CMV infection may therefore be particularly susceptible to severe Covid‐19 disease and succumb to a cytokine storm which may have been promoted by CMV. Here, we evaluate the potential role of CMV in those with severe Covid‐19 disease and consider how this relationship can be investigated in current research studies.


| INTRODUCTION
The outbreak of coronavirus disease 2019  caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) appears to cause the highest morbidity and mortality in adults aged over 70 years. 1,2 One of the earliest and largest epidemiological studies in children with  showed that only 112 (5.6%) of 2143 children had severe disease (defined as hypoxia), 13 (0.6%) developed respiratory or multiorgan failure or acute respiratory distress syndrome (ARDS). 3 In China, there have been no reports of children succumbing to Covid-19. The reasons why children appear to develop less severe disease than adults is perplexing and likely multifactorial.
A range of environmental factors (greater transmission in cases who travel or in the workplace, increased contact with sick cases, cigarette smokers) and underlying health conditions (hypertension, diabetes and chronic respiratory disease) have been associated with severe Covid-19 disease and death. 2 All of these factors are more common in older adults than in children. The host immune response is also likely to play a pivotal role in accelerating disease progression in elderly individuals infected with SARS-CoV-2.
T cells have a crucial role in controlling viral infections. A central process in immunological ageing (also called immunosenescence) is reduction in thymic activity. 4,5 Cytomegalovirus (CMV) seroprevalence increases with age and approaches 80% by the age of 70 years in northern Europe. 6,7 In the elderly, CMV causes clonal T cell proliferation, reduction in naïve T cell diversity which in turn may lead to reduced capacity for immune responses to novel viral infections such as SARS-CoV-2. This article will consider the potential role of CMV in those with severe COVID-19 disease.

| CMV AND PREDISPOSITION TO RESPIRATORY VIRAL INFECTIONS
As aged T cells die, the thymus replenishes the T cell pool with naïve T cells. However, thymic output is reduced by 99% in 70 year olds compared with newborns. 8 CMV infection drives compensatory memory T cell proliferation which ensures that overall T cell numbers do not decline significantly as we age. Very large CMV specific T cell responses in older people have parallels to the phenomenon of CMV induced T cell memory inflation seen in preclinical models. 9,10 The accumulation of terminally differentiated memory T cells and reduction in naïve CD8+ T-cells in the elderly due to thymic involution is associated with influenza vaccine failure in older people. 11,12 A prospective Canadian study of residents aged over 65 years in 32 nursing homes found high T-reg and high CMV reactive CD4+ T cells were predictive of risk of respiratory viral infections. 13 In the OCTO and NONA Immune studies in Scandinavia, CMV seropositivity and the associated CD8 T cell expansions (inverted CD4:CD8 ratio) were linked to excess mortality in later life. 14,15 Although these findings are not universally consistent, they have been reproduced in other careful large scale epidemiology studies, for example, the EPIC study which associated high levels of CMV-specific IgG with mortality. 16 Although the impact of CMV on the CD8+ T cell compartment can be dramatic, whether CD8+ T cell expansion plays a direct causal role or is a marker for lack of immune control of CMV in such populations is not fully established. 17 Multiple small cohort studies have attempted to evaluate the impact of CMV on the immunogenicity of influenza vaccines. [18][19][20][21] A study of 54 recipients of an intradermal influenza vaccine showed that CMV seropositivity was linked to reduced immune responses in individuals over the age of 60 years. 20 The reduced effectiveness seen in this study appeared to be mediated by late differentiated CD4 T cells.
A separate study in adults of all ages showed that CMV seropositive individuals over the age of 60 years had impaired B cell predictive biomarkers to influenza vaccine response. 18 These data highlight that chronic CMV infections may have impaired humoral antibody responses.
In contrast, a study of 731 residents in long term residential facilities showed that CMV serostatus did not influence pre or post influenza vaccination geometric mean antibody titer (GMT). 21 Similarly, Wald and colleagues, showed that CMV serostatus had no impact on H1N1 influenza vaccine antibody responses in elderly individuals. 19 Finally, a study of 348 individuals aged between 50 and 70 years, showed that CMV infection did not impair pneumococcal vaccine responses. 22 Thus, overall, CMV seropositivity (with high levels of IgG) and the linked changes in bulk T cell populations appear to correlate with disease risk amongst the elderly ( Figure 1). Assessment of CMV serologic and cellular immune responses in SARS-CoV-2 infected individuals and in healthy aged matched controls is required to assess whether there is a relationship between CMV infection (including reactivation) and severity of Covid-19 disease. These data may also help us understand the potential effectiveness of any vaccine against SARS-CoV-2 in populations with high CMV seropositivity and thus inform future vaccine implementation.

| CONCLUSION
Covid-19 has disproportionately affected the elderly with significantly higher rates of mortality than in children. This observation has been