Acquired cytomegalovirus in children: pathogen, bystander, or immune trainer?

Cytomegalovirus (CMV) is one of the most common infections worldwide, with acquisition occurring predominantly in early childhood (younger than 5 years). Although congenital CMV is a recognised cause of neurodevelopmental impairment, the consequences of postnatally acquired CMV in children remain poorly defined and are often assumed to be benign. However, accumulating evidence suggests that acquired CMV infection is biologically active even when clinically silent, with the capacity to shape immune ontogeny, influence immune responses to other pathogens and vaccines, and alter health trajectories across the life course. In this Review, we examine the epidemiology, transmission pathways, immune responses, and clinical consequences of acquired CMV infection in childhood. We synthesise evidence to evaluate whether acquired CMV acts as a driver of pathology, a neutral bystander, or a beneficial immune trainer. The effects of CMV are highly context-dependent, determined by the timing of acquisition, host immune maturity, maternal health, co-infections, and broader social and environmental factors. Evidence of harm is strongest in infants with heightened biological or contextual risk, such as infants born preterm and those living with or exposed to HIV, whereas effects in children who are immunocompetent are heterogeneous and often clinically silent. Acquired CMV should be understood as a context-dependent immune modifier rather than a uniformly benign or pathogenic infection. This reframing of acquired CMV has important implications for policy and research. Universal intervention is unlikely to be appropriate; instead, targeted CMV prevention and treatment strategies for populations at high risk of CMV infection and severe disease integrated into maternal and child health programmes could offer the greatest benefit. Defining high-risk populations and critical windows for intervention should be prioritised to translate emerging evidence into improvements in childhood morbidity and equity.