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.

中文翻译：

---

巨细胞病毒感染的直接和间接后果以及接种疫苗的潜在好处。

免疫功能低下的患者会发生巨细胞病毒（CMV）的主动感染，并可能产生导致终末器官疾病的高病毒载量。这类患者的病史很复杂，许多经验丰富的医生推测，CMV可能还会导致不良的临床结果。1989年，鲍勃·鲁宾（Bob Rubin）博士创造了“间接作用”一词来描述病毒与患者之间的这种潜在关系。例子包括心脏移植术后或有潜在HIV感染的患者加速动脉粥样硬化，重症监护病房入院后患者需要通气的天数，老年人免疫衰老的发展以及包括普通人群在内的许多患者的死亡率。很难区分CMV是造成这种多样化病理的原因，还是仅具有良性旁观者效应。但是，将患者招募到具有抗CMV活性的抗病毒药物的安慰剂对照随机试验中，具有这样的潜力。本文介绍了迄今为止已进行的研究，并强调了干细胞移植后的死亡率（不归因于CMV终末器官疾病）最近已成为CMV的第一个被证实的间接作用，因为letemovir大大降低了非复发性死亡。然后讨论了CMV疫苗的含义。人们已经预测，如果疫苗可以减少CMV终末器官疾病，那么它们将具有很高的成本效益。卫生计划人员现在应该考虑通过降低CMV的间接影响来进一步提高成本效益。提供了一种评估这种可能性的原型方案，以促进本领域的讨论。本文构成了有关DNA病毒感染的预防和治疗的在线研讨会的一部分，该研讨会专门纪念Mark Prichard。