Cytomegalovirus Infection in Transplant Recipients: A Critical Narrative Review of Prevention Paradigms, Immune-Guided Management and the Evidentiary Limits of Current Practice

Abstract

Cytomegalovirus remains the most consequential opportunistic infection after solid organ and allogeneic haematopoietic cell transplantation, despite three decades of pharmacological and diagnostic advance. Licensing of letermovir and maribavir, the wide availability of quantitative nucleic acid testing calibrated to an international standard, and the maturation of assays measuring virus-specific cell-mediated immunity have altered practice substantially. Clinical outcomes have improved less than the expansion of the therapeutic and diagnostic armamentarium would predict, and the reasons for that mismatch are rarely examined directly. This critical narrative review evaluates the strength, internal consistency and methodological quality of the evidence underpinning contemporary cytomegalovirus management in transplant recipients. Literature was identified through systematic keyword searching of PubMed/MEDLINE and Crossref Metadata Search, supplemented by backward citation searching and registry-level verification of bibliographic records, covering publications from 1999 to the final search date. Five interlocking problems are examined: the instability of outcome definitions across successive consensus statements; residual interassay variability that limits the transferability of viral load thresholds between centres; the unresolved comparative standing of universal prophylaxis against pre-emptive therapy; the discordant randomised evidence on immune-guided prophylaxis duration; and the rapid emergence of drug resistance under agents with low genetic barriers. Evidence is strongest for the efficacy of letermovir in preventing early clinically significant infection and for the superiority of maribavir over conventional salvage therapy in refractory or resistant disease. Evidence is weakest, and frequently contradictory, on whether preventing detectable viraemia translates into improved survival, on the causal status of associations between viraemia and allograft outcomes, and on the clinical utility of currently available immune assays for individual-level decisions. The field requires trials powered for patient-centred outcomes rather than virological surrogates, prospective assay standardisation and evidence generation in populations and health systems that remain almost entirely unrepresented.