In this prospective study of community-dwelling older women aged 70–79 years, those in the highest quartile of CMV IgG antibody concentration had higher risks of 3-year incident frailty and 5-year mortality than those who were CMV seronegative. After adjustment for potential confounders, the highest quartile of CMV antibody concentration independently predicted a higher risk of 5-year mortality.
Given the high prevalence of CMV infection worldwide, a better understanding of its long-term clinical effect in immunocompetent adults has an important public health impact. A previous study, also nested in the Women's Health and Aging Study, showed an association between CMV IgG seropositivity and prevalent frailty (12
), the risk factors for which include older age, lower educational level, lower income, cigarette smoking, arthritis, chronic obstructive pulmonary disease, hypertension, diabetes, and cardiovascular disease (14
). However, the dichotomous antibody measurement precluded further examination of any dose-response effect of CMV infection. Our study clarifies that the previously reported association between CMV and frailty (12
) is strongest at the highest CMV antibody and highest IL-6 concentrations.
In immunocompetent humans, CMV maintains a lifelong infection through immunomodulatory mechanisms that evade viral clearance by the hosts (28
). It is unclear whether any potential effect of CMV infection on frailty or mortality risk for older women is the culmination of pathologic cellular and end-organ changes accumulated over life. To our knowledge, no definitive evidence exists to support the hypothesis that more frequent CMV reactivations, and thus more frequent antigenic stimuli, result in higher antibody titers. The observations that antibody titers increase over time in CMV shedders (17
) and are generally higher in older persons (18
) suggest that serum CMV IgG concentration could be a function of the cumulative frequency of viral reactivation. Therefore, it is conceivable that individuals who have higher CMV antibody concentrations have experienced either more frequent viral reactivations or a longer infection. A higher cumulative frequency of viral reactivation could in turn represent a proportionately higher cumulative inflammatory burden and pathologic insult, through such mechanisms as atherogenesis (30
) and local host-cell damage by a potent viral proinflammatory chemokine (31
). The effect of these insults integrated over time could then culminate in accelerated host death or the manifestation of frailty, which has been hypothesized to be the aggregate expression of subthreshold damages to multiple physiologic systems (32
The modifying effect of plasma IL-6 concentration on the relation between CMV infection and frailty suggests that any potential contribution of CMV to the pathogenesis of frailty is likely grounded in synergistic interaction with IL-6 production, consistent with the modifying effect of IL-6 on the association between CMV and cardiac mortality (33
). CMV infection increases IL-6 gene expression and production in peripheral blood mononuclear cells (34
). Our results suggest that the magnitudes of association between the highest CMV antibody concentration and prevalent frailty are higher at higher IL-6 concentrations. It can be envisioned, therefore, that any potential pathologic effect that CMV might exert on the development of host frailty requires the synergy of IL-6 production, induced by either inflammatory activation of non-CMV origin (32
) or CMV itself (31
). This requirement for high IL-6 concentration, and thus for the host genetic, physiologic, and environmental factors that might underlie elevation of this proinflammatory cytokine (35
), could explain why there is not a one-to-one correspondence between the highly prevalent CMV infection and frailty in older women. The lack of a statistically significant interaction between IL-6 and CMV in incident frailty and mortality analyses might result from inadequate power for our longitudinal samples, since there was a suggestion of effect modification by IL-6 on the associations of CMV with incident frailty and mortality.
It is possible that the higher mortality rate among women with the highest CMV antibody concentration could be mediated partially or completely by cardiovascular disease, known to be associated with high CMV antibody titer (8
). However, the association between CMV and mortality remained significant after adjusting for cardiovascular disease. After we excluded women with cardiovascular disease from the study sample, there remained a suggestion, although not definitive evidence, of a higher mortality risk for women in the highest quartile of CMV antibody concentration. Thus, although residual confounding is still possible, the significantly higher mortality risk for women with a high CMV antibody concentration could not be attributed completely to cardiovascular disease. Indeed, if CMV infection were responsible for the onset of frailty or accelerated death, there must be certain intermediary pathophysiologic changes, whether measureable clinically or presently not definable or quantifiable, that eventually result in the manifestation of frailty (32
) or accelerated death.
An alternative explanation can be offered for the association reported here of CMV IgG concentration with frailty and mortality. A higher frequency of CMV reactivation could be a bystander, rather than an initiator, of pathologic changes in human hosts. For example, production of tumor necrosis factor-α, as during the course of natural, non-CMV-related infections or inflammatory responses, could induce CMV reactivation (36
). Therefore, the data presented in this paper are also consistent with the alternative hypothesis that CMV reactivation, reflected in the higher antibody concentrations, is a by-product of non-CMV-related pathophysiologic changes in frail older women or those experiencing accelerated death.
This study has several strengths. It utilized a prospective, well-characterized cohort of community-dwelling older women (19, 20). The definition of frailty utilized in this study is a well-validated measure, collected by using objective and standardized tests (14
). In addition, multiple statistical models utilized in the longitudinal analysis ensured robustness of our results. Rigorous adjustment for socioeconomic factors minimized their potential confounding effects on the relation between CMV and the assessed outcomes. Finally, use of study-specific probability weights enables extrapolation of the results to a larger population (24
There are potential limitations to this study. The exact duration of persistent CMV infection could not be determined by measuring CMV antibody concentration. Serologic diagnosis of primary infection was not possible because of limited serum availability. CMV reactivation, optimally measured in immunocompetent humans by detecting CMV DNA in urine (29
), could not be determined because urine samples were not stored. Since a cellular response to CMV has been reported to be detected in seronegative individuals (37
), underdiagnosis of CMV infection was possible but should not have affected the internal validity of these findings. It is unclear whether long-term cryopreservation might affect the stability of serum CMV IgG antibody, but no loss of titer was observed for serum antibodies cryopreserved for 5 years and measured by immunoassay (38
). There might be differences between men and women in their immune response to CMV (39
); the investigation should be repeated with men. Finally, the follow-up duration of 3 years and 5 years might not adequately capture the long-term effect of CMV infection on the development of incident frailty or mortality, respectively, in older women. Nevertheless, the results of the present study offer the first known generalizable longitudinal data on the effect of CMV infection on mortality and frailty development in immunocompetent older women.
In summary, we demonstrated an association between high CMV IgG antibody concentration and prevalent frailty among women with a high plasma IL-6 concentration, and between high CMV IgG antibody concentration and 5-year mortality risk, independent of potential confounders. The mechanisms underlying these associations remain to be elucidated. These findings provide a strong rationale for well-designed longitudinal population studies investigating the long-term clinical effects and pathogenic mechanisms of persistent CMV infection, the collective results of which can guide public health efforts on potential preventive and therapeutic strategies for this widely prevalent infection.