Standardizing Care and Management of Cytomegalovirus Infections in Solid Organ Transplant Recipients: Highlights From the Fourth Consensus Guidelines

Cytomegalovirus (CMV) infection is one of the most common and clinically significant opportunistic infections developed after solid organ transplantation (SOT).1 CMV infection is associated with substantial morbidity, including retinitis, pneumonitis, hepatitis, graft dysfunction, and death. With the support of the Transplantation Society, a fourth consensus meeting with key global experts was convened in Montreal in 2024 to review, discuss, and update the CMV management guidelines for SOT recipients.2 This meeting was built on the foundation of the third CMV Consensus guideline published in 2018, integrating recent advances and evidence to improve the management of CMV infections. This guideline also addresses the global challenges in managing CMV disease, particularly in diverse healthcare settings. Since 2018, several advancements have been made in preventing, diagnosing, and treating CMV infections in SOT recipients. For example, letermovir, a CMV DNA terminase complex inhibitor, has shown promise in preventing CMV infection in high-risk recipients.3 Novel strategies for immunological monitoring have also been developed for high-risk individuals. Other therapeutic innovations, such as maribavir inhibiting UL 97 protein kinase4 and adoptive T-cell therapies,5 may help treat refractory CMV infections. Similar to the previous guidelines, the Grading of Recommendations Assessment, Development and Evaluation system was used to assess and rate the quality of the scientific evidence and inform the guideline development. This fourth iteration focused on several key updates. The guideline emphasized the need to ensure the CMV-quantitative nucleic acid testing assay is calibrated to the World Health Organization standards for diagnosis surveillance, preemptive treatment, and therapeutic monitoring.6 Although a change of CMV DNAemia >0.5 log10 IU/mL (3-fold) or 0.7 log10 IU/mL (5-fold) when the initial viral load is <3 log10 IU/mL is considered significant, a universal treatment threshold remains elusive. This reinforces the requirements for individual transplant centers to establish treatment thresholds based on the specific assays used in their laboratories, sample type, and D/R serology risk. Letermovir has been introduced as an alternative primary prophylaxis for kidney transplant recipients. In a multicenter trial of CMV prevention in high-risk kidney transplant recipients, 12 mo of letermovir prophylaxis was found to be noninferior to valganciclovir, but a considerable reduction in valganciclovir-related cytopenias.3 However, letermovir can interact with tacrolimus/cyclosporine and lacks activity against other herpesviruses, necessitating acyclovir prophylaxis. In addition, its limited availability and high costs also restrict its broader use. Although there is a consensus that prophylaxis is needed for medium- and high-risk recipients, the duration of prophylaxis depends on the recipients’ risk profile and the types of organs received. For example, 6 mo of prophylaxis is probably sufficient for most SOT recipients, but high-risk lung transplant recipients (D+R–) may require extended prophylaxis (up to 12 mo). Current evidence does not support indefinite prophylaxis after lung transplant, even in very high-risk recipients. Although there is a lack of strong evidence to support secondary prophylaxis (to prevent CMV recurrence), experts recommend 8–12 wk in high-risk situations. The key to successful prophylaxis (and treatment) is optimizing immunosuppression, ensuring timely CMV monitoring, and administering antiviral agents at the appropriate dosage. It is crucial to avoid underdosing valganciclovir or ganciclovir, as this can increase the risk of treatment failure, drug resistance, increased patient morbidity, and mortality. The current guideline recommends ganciclovir or valganciclovir as first-line treatment for CMV disease. Regarding second-line treatment, maribavir is added as an alternative option in patients with suspected ganciclovir resistance.4 However, its use is only recommended for those with confirmed UL 97 mutation, provided the patients have low viral load and no evidence of end-organ disease. Notably, maribavir is not recommended for patients with CMV retinitis and central nervous system disease because of its limited penetration into ocular tissues and the central nervous system.7 Foscarnet is the preferred treatment for clinically unwell patients with a high viral load and end-organ disease, particularly in cases with evidence of a UL 54 mutation alone or combined with UL 97 mutation. Ongoing monitoring is crucial for assessing treatment responses, detecting the emergence of antiviral resistance, and managing treatment intolerance. Emerging data suggest that SOT recipients may experience a lower risk of CMV infection when maintained on mammalian target of rapamycin inhibitors compared with patients treated with antiproliferative agents such as mycophenolate mofetil.8 Based on low certainty evidence, it is suggested that patients with low immunological risk who experience their first episode of CMV infection/disease should consider a conversion from an antiproliferative agent to mammalian target of rapamycin inhibitors. This strategy may reduce the risk of recurrent CMV infection while maintaining adequate immunosuppression. There is growing evidence for using CMV cell-mediated immune assays to risk-stratify patients.9 However, their widespread use is still hindered by limited evidence, availability, and lack of standardization to support their cost effectiveness and utility. Pediatric SOT transplant recipients are at a heightened risk of developing primary CMV disease and acquiring CMV infection from their donors, as many are CMV naive. Given that children were excluded from many comparative trials of prophylaxis, treatment, and monitoring, it is recommended that the general principles of prevention, treatment, and monitoring in adults also apply to children, but with some important distinctions. In view of the higher incidence of breakthrough CMV infections in children, monitoring for CMV DNAemia is suggested during prophylaxis. For children with refractory/resistant disease, maribavir is only recommended for children aged 12 y or older and weight ≥35 kg.10 There is insufficient evidence to recommend letermovir for preventing and treating CMV infection in pediatric SOT recipients. In summary, these updated consensus guidelines provide a detailed review and synthesis of the current evidence in preventing, managing, and monitoring CMV infections in SOT recipients. The guidelines offer evidence-based recommendations to guide best practices in CMV management, addressing important topics such as novel prophylactic strategies and newer interventions to treat resistance and refractory disease/infections, intending to provide a framework for standardizing CMV care and improving patient outcomes worldwide. More importantly, these recommendations are designed to be applicable across the global transplant communities, considering the needs, the healthcare infrastructure, and the economic status of the individual countries. This ensures that the guidelines are adaptable to diverse clinical settings, allowing equitable implementation in resource-rich and limited environments.

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