The direct and indirect consequences of cytomegalovirus infection and potential benefits of vaccination.

Active infection with cytomegalovirus (CMV) occurs in patients who are immunocompromised and may produce the high viral loads required to cause end-organ disease. Such patients have complex medical histories and many experienced physicians have speculated that CMV may, additionally, contribute to adverse clinical outcomes. In 1989, Dr Bob Rubin coined the term "indirect effects" to describe this potential relationship between virus and patient. Examples include accelerated atherosclerosis in patients after heart transplant or with underlying HIV infection, the number of days patients require ventilation after admission to intensive care units, the development of immunosenescence in the elderly and mortality in many groups of patients, including the general population. It is difficult to distinguish between CMV acting as causal contributor to such diverse pathology or simply having a benign bystander effect. However, recruitment of patients into placebo-controlled randomised trials of antiviral drugs with activity against CMV offers such a potential. This article describes the studies that have been conducted to date and emphasises that mortality after stem cell transplant (not attributed to CMV end-organ disease) has recently become the first proven indirect effect of CMV now that letermovir has significantly reduced non-relapse deaths. The implications for CMV vaccines are then discussed. Vaccines are already predicted to be highly cost-effective if they can reduce CMV end-organ disease. Health planners should now consider that cost effectiveness is likely to be enhanced further through reduction of the indirect effects of CMV. A prototype scheme for assessing this possibility is provided in order to stimulate discussion within the field. This article forms part of an online symposium on the prevention and therapy of DNA virus infections, dedicated to the memory of Mark Prichard.