CMV is the most common pathogen detected after SOT and is associated with significant morbidity and in some cases may lead to death or graft loss [12]. Therefore, understanding the relationship between CMV and patient outcomes post-transplantation is critical. CMV infection has complicated SOT since the first procedure [13]. In a 1964 study by Hill RB et al, among the 61 SOT recipients included, 32 died (mainly kidney recipients), with a median survival post-transplant of only 36.5 days. Notably, autopsy findings revealed that 26 of these patients had active pulmonary infection, with CMV identified as the predominant pathogen in 58% of cases, suggesting a possible association between CMV pneumonitis and mortality [14]. In addition to direct effects related to organ-specific infections, later reports showed an association between CMV infection and acute or chronic graft rejection. In a pivotal study from Grattan MT et al, CMV infection was found to be associated with acute rejection and coronary artery disease in heart transplant recipients [15]. More recently, in a retrospective cohort study involving 192 kidney transplant recipients, patients with CMV disease had a significant likelihood of developing acute rejection after CMV infection or reactivation [16]. Additionally, in 2014 Stern and colleagues conducted a study involving 1414 recipients of heart, kidney, liver, or lung allografts, revealing an increased risk of biopsy-proven graft rejection within 4 weeks after CMV replication was detected [17].

Advances in screening, prophylactic antiviral therapy, and pre-emptive treatment have mitigated the impact of CMV disease on morbidity and mortality following SOT. However, although significant improvements have been made, in the current era, morbidity and mortality data related to CMV disease during organ transplantation remain variable despite advancements in antiviral treatments and the use of newer immunosuppressive drugs [18].

Likelihood of CMV infection in patients undergoing SOT is influenced by several factors. The most significant risk factor is the serological status of the donor (D) and recipient (R), determined by the presence or absence of anti-CMV antibodies. The highest risk of CMV infection occurs when an organ from a CMV-seropositive donor (D+) is transplanted into a CMV-seronegative recipient (R-), designated (D+/R-). Consequently, pre-transplant screening is widely acknowledged to be of paramount importance [19]. Additionally, the type of organ transplanted also affects the CMV risk, with lung transplant recipients facing the highest susceptibility, followed by heart, kidney, and liver recipients (Figure 1). Thus, the riskiest scenario regarding CMV infection involves lung transplantation from a seropositive donor to a seronegative recipient (D+/R-). The level of immunosuppression is also important to consider, with the administration of lymphocyte-depleting antibodies (i.e., anti-thymocyte globulin [ATG]) as induction and/or anti-rejection therapy also being associated with increased incidence of CMV, in seropositive recipients. Of note, risk stratification based on donor and recipient serology may only partially estimate the risk for CMV disease. Case 1 underscores the importance of considering all the factors associated with CMV infection (Figure 2), such as in a D+/R+ scenario in the presence of additional risk factors like the need for increased immunosuppression.

Given the profound implications of CMV disease in SOT recipients, effective CMV prevention strategies can enhance the success and improve the outcomes of transplant procedures. Two preventive strategies are available (Figure 3): universal prophylaxis (administration of antivirals to all patients at risk, starting within 10 days after transplant and continuing for at least 3 months and up to 12 months in D+/R- lung transplant recipients [duration dependent on organ transplanted and D/R serostatus]) or pre-emptive therapy (monitoring for DNAemia every week, followed by the administration of antivirals until at least two consecutive negative DNAemia tests are achieved or according to center-specific thresholds) [6]. Both strategies are effective in preventing CMV disease, with no consensus on the superiority of one over the other, but with prophylaxis preferred in lung transplants and pre-emptive therapy in liver [21–23]. The choice between universal prophylaxis and pre-emptive therapy will be driven by the expected relative benefits of each strategy (Table 1) as well as the clinical situation in the individual patient. As an illustration, in case 1, a patient (D+/R+) undergoing a heart transplant, who based on serology and transplanted organ could be considered to be at lower risk of CMV infection than a seronegative recipient and a candidate for pre-emptive therapy, received universal prophylaxis with valganciclovir due to the increased risk of CMV disease associated with potent immunosuppression (Table 1; Figure 2).

Valganciclovir is the standard of care for CMV prophylaxis in the most at-risk donor−recipient category (D+/R-) [27]. However, prolonged exposure in the setting of universal prophylaxis can lead to drug toxicity, in particular leukopenia [27]. A recent study by Limaye and colleagues demonstrated that letermovir is non-inferior in effectiveness to valganciclovir for CMV prophylaxis in D+/R- kidney transplant recipients, but with lower rates of leukopenia or neutropenia, suggesting its potential as a preferred option in D+/R- kidney transplant patients [27]. Furthermore, the use of CMV immunoglobulin (CMVIg) in combination with antivirals in CMV prophylaxis may be beneficial in specific circumstances, especially in D+/R- recipients of thoracic organs [28–30]. A meta-analysis assessed CMV infection rates in SOT patients who received prophylactic CMVIg, revealing a lower incidence of CMV infection in this cohort. Specifically, the average CMV infection rate was 35.8% (95% CI: 33.4%–38.2%) among patients who received CMVIg, compared with 41.4% (95% CI: 38.6%–44.2%) in the control group not receiving CMVIg (p = 0.003) [28]. Despite these promising results, the use of CMVIg remains controversial due to the lack of recent interventional data on efficacy.

Unlike universal prophylaxis, a pre-emptive approach to CMV prevention requires regular monitoring for CMV viremia [6]. The quantitative nucleic acid amplification test detects and quantifies CMV DNA and is preferred over antigenemia. It has become the standard of care for diagnosing and monitoring post-transplant CMV infection [31]. Post-transplant monitoring typically occurs weekly during the first 3 months and then twice a month from months 3–6 as patients stabilize. Despite the international standardization of reporting all viral load values in IU/mL during the QNAT, a consensus around viral load thresholds remains a challenge because laboratory assays and matrix choices differ between centers. This leaves individual centers with the task of determining specific thresholds in their laboratories [26].

Studies have shown that an increase in viral load correlates with the occurrence of CMV disease [5]. Therefore, focusing on viral load trends over time is more useful and important for predicting disease development and guiding therapeutic decisions than using center-specific absolute viral load values, which lack standardization [5]. To illustrate this, in case 1, CMV DNA in the blood increased 10-fold in 2 weeks, which prompted treatment with an antiviral, granulocyte-colony stimulating factor (GCSF) and CMVIg. It is important to underline that DNAemia values from plasma and whole blood are not comparable [5], so it is crucial not to change tests or matrix choices during treatment and follow-up. Additionally, in our opinion, distinguishing the clinical significance of a viral load increase is complicated by free DNA release into plasma from infected cells, potentially leading to low-level or persistent DNAemia, which could be mistaken as an indication of active replication. In this context, assessment of late mRNAemia in the plasma could help identify episodes of active viral replication and could have the potential to shorten the duration of pre-emptive or prophylaxis strategies and aid the management of long-term infections, in particular when using drugs that inhibit CMV replication steps downstream of DNA polymerase, such as letermovir and maribavir [32]. Nevertheless, this tool is still undergoing investigation and validation.

The presence of CMV disease is possible even if all diagnostic criteria are not met and treatment should be initiated in such situations. Diagnostic criteria may vary depending on the organ involved, and relying solely on QNAT may not always be sufficient, particularly in GI tract-related CMV disease [33]. In the GI tract, end-organ disease can be evident (positive immunohistochemistry [IHC]) despite negative DNAemia [34]. Therefore, diagnosis of CMV GI disease requires the presence of upper and/or lower GI symptoms along with endoscopic evidence or laboratory confirmation of CMV infection [33]. Additionally, it is possible for biopsy samples to be taken from unaffected parts of the intestine in individuals with CMV GI disease. Confirmation of CMV pneumonia typically involves clinical signs and/or symptoms suggestive of pneumonia combined with laboratory confirmation of CMV in lung tissue [33]. In case 2, a lung transplant recipient exhibited CMV viremia but negative IHC results from an esophageal biopsy (Figure 4). Despite this negative IHC result for esophagitis, treatment for CMV disease was initiated in the patient. This decision was based on the fact that the patient had a clinical syndrome suggestive of CMV disease.

First-line treatment of CMV infection or disease is oral valganciclovir or intravenous ganciclovir, with the latter often preferred in cases of life-threatening CMV, very high viral loads, or when oral absorption of medication is a concern [6]. Valganciclovir is a prodrug of ganciclovir, with both inhibiting viral DNA polymerases. In addition, these drugs can lead to varying degrees of bone marrow suppression and subsequently, neutropenia [35]. Oral valganciclovir has a longer half-life than intravenous ganciclovir meaning prolonged exposure (or slower clearance) of the drug and its metabolites [36]. Therefore, oral valganciclovir would be expected to be associated with a greater degree of neutropenia than intravenous ganciclovir, which was evident in study WV15376 (11% vs. 13%, respectively) [36, 37]. Higher incidences of neutropenia may be observed in patients with decreased kidney function, as this leads to reduced clearance of ganciclovir and a prolonged terminal half-life [36]. Neutropenia is one of the most common adverse event associated with valganciclovir, as was reported in case 2 (Figure 4) [38]. In cases of valganciclovir-induced neutropenia, dose adjustments or discontinuation of therapy, as well as management of other drugs, may be necessary, particularly if neutrophil counts fall below pre-defined thresholds or clinical symptoms of infection arise. Close monitoring of blood counts, particularly neutrophil levels, is crucial during valganciclovir therapy to manage neutropenia-related complications promptly.

Of note, as highlighted in case 2, neutropenia should not automatically prompt discontinuation of valganciclovir. Bone marrow suppression and neutropenia can also be caused by CMV infection itself [39], making it essential to assess whether neutropenia is a direct consequence of CMV replication. This may involve evaluating CMV viral load by DNAemia or other diagnostic tests to confirm active CMV infection. Furthermore, it is imperative to consider and investigate other potential underlying conditions or factors that could contribute to neutropenia. These may include medications commonly used in transplant recipients, such as immunosuppressive or anti-infective agents (e.g., mTOR inhibitors, mycophenolic acid, trimethoprim sulfamethoxazole). Additionally, concomitant viral infections (e.g., Epstein−Barr virus, Human Herpesvirus-8 [although relatively infrequent], and Parvovirus B19, adenovirus), hematologic disorders, or nutritional deficiencies need to be excluded. Once other potential causes are excluded, the initial consideration can be granulocyte-colony stimulating factor (GCSF) administration, followed by a possible switch to an alternative drug with a more acceptable safety profile (Figure 4) [35]. It is not recommended to use foscarnet or cidofovir to overcome valganciclovir toxicity, given their less acceptable safety profiles. Although it is preferred to only use these drugs as an alternative to valganciclovir in case of documented ganciclovir resistance, guidelines recommend considering foscarnet in refractory CMV cases with severe clinical symptoms or life-threatening disease [6]. Where available, maribavir can be considered for refractory or ganciclovir resistant infection in cases of intermediate viral loads, or as second step approach after an initial short course with foscarnet [6]. This approach is likely to minimize the toxicity of foscarnet and the risk of maribavir resistance that may occur when treating high viral loads.

Tailoring treatment approaches to each clinical scenario is essential for optimizing patient care. Impaired kidney function can lead to decreased drug clearance and increased drug concentrations, potentially increasing the risk of drug toxicity [40]. Therefore, in cases of kidney impairment, treatment doses should be adjusted according to kidney function to minimize adverse events, as highlighted in case 1 (Figure 2). However, despite these recommendations, data from kidney transplant recipients suggest that as many as one-third of patients may be receiving a dose of valganciclovir that is too high [41]. Immunosuppressive drugs, including corticosteroids, calcineurin inhibitors (e.g., tacrolimus and cyclosporine), and in particular antimetabolites (e.g., mycophenolate mofetil or mycophenolic acid), inhibit the immune response by suppressing the activity of immune cells, including T cells and natural killer cells [42], thus hindering immune surveillance and the ability to combat CMV infection. Switching or reducing immunosuppressive therapy should be considered as an adjunct to antiviral therapy to improve treatment outcomes, as demonstrated in case 1 (Figure 2).

Monitoring CMV viral load and complete blood count should be conducted on a weekly basis to guide the duration of therapy. Treatment should continue for a minimum of 2 weeks, until DNAemia falls below the detection threshold and signs and symptoms of CMV disease are resolved [6]. As introduced above, DNAemia may not accurately reflect CMV disease status in all clinical situations and longer courses of treatment may be needed, for example, in the treatment of tissue-invasive GI disease and pneumonitis in lung transplant recipients [6]. If a patient fails to respond after the recommended treatment duration with (val)ganciclovir, maribavir could be considered as an alternative option (Figure 4). However, as outlined earlier, we advise caution when using maribavir in patients with a high viral load due to the potential risk of selecting a resistant mutant [43]. Treatment failure may result from a resistant/refractory CMV infection or low adherence. Therapeutic drug monitoring, although not generally recommended in current guidelines, can be helpful in cases of suspected low adherence, or to ensure optimal drug levels in cases of kidney insufficiency, although a valganciclovir concentration clearly predictive of CMV clearance has not been determined [44]. If treatment fails in an adherent patient who meets the criteria for refractory disease, testing for resistant CMV should be considered.

Despite preventive strategies and well-established antiviral therapies, managing refractory/resistant CMV infection in patients undergoing SOT remains a significant challenge. Resistant/refractory CMV infection is defined as the failure to respond after 14 days of appropriate treatment [45]. Table 2 provides an overview of the definitions for refractory and resistant CMV infection. Ensuring appropriate dosing of antivirals is essential in the management of CMV infection, as suboptimal dosing can lead to an increased risk of treatment failure and resistance development [6].

In case of resistant CMV infection, mutations in the UL97 gene are most frequent, while UL54 mutations typically arise after prolonged pre-treatment and may lead to cross-resistance with cidofovir and foscarnet [45]. A laboratory study conducted in 2023 revealed CMV drug resistance in approximately 30% (n = 826/2750) of samples from transplant recipients sent for genotyping [47]. The most common resistance mutations in the UL97 gene were for ganciclovir and maribavir accounting for 27.64% and 9.96% of samples, respectively [47]. However, reported rates of CMV drug resistance may vary across publications. The annual reported incidence rate of ganciclovir resistance was less than 1% in 80% of transplant centers but reached up to 10% in some, according to the 2022 ESOT survey [26] and a recent trial of maribavir in patients with refractory or resistant CMV infection has reported a resistance rate in the region of 25% [43, 48]. Risk factors for resistant/refractory CMV infection include younger age, D+/R- serostatus, lung transplant, recurrent CMV infection, ongoing viral replication, prolonged antiviral treatment, subtherapeutic antiviral levels, high viral loads, and severe immunosuppression [45, 49]. Additionally, administering belatacept increases the risk of refractory CMV infection compared with other immunosuppressants. Belatacept was unable to sustain viral control relative to tacrolimus in high-risk recipients (n = 60) [50].

The latest international treatment recommendations for managing resistant CMV infection, as outlined in the 2025 guidelines, involves first reducing immunosuppression if feasible, followed by administering foscarnet, cidofovir, or high-dose ganciclovir depending on disease severity and genetic mutation type [6]. However, there is limited evidence supporting the use of high-dose ganciclovir. Additionally, older antivirals pose significant toxicity concerns, with ganciclovir linked to neutropenia, and foscarnet and cidofovir associated with a high risk of acute kidney injuries and increased mortality [51, 52].

Maribavir, an oral benzimidazole riboside antiviral, inhibits the CMV UL97 protein kinase involved in viral maturation and egress [53]. It was approved for the treatment of resistant/refractory CMV infection in the UK and Europe in 2022, with approval in the USA granted in 2021 [54, 55]. Maribavir is considered a valid alternative treatment for resistant/refractory CMV due to its more favorable safety profile [52]. A phase 2 study showed that ≥400 mg of maribavir twice daily achieved CMV clearance in SOT patients with resistant/refractory CMV [56]. The results from this study led to a large prospective phase 3 study in SOT and hematopoietic stem cell transplantation recipients (n = 352) with refractory CMV infection: after 8 weeks of therapy, maribavir showed greater CMV DNAemia clearance and fewer treatment discontinuations due to treatment-emergent adverse events compared with investigator-assigned therapy (valganciclovir/ganciclovir, cidofovir, or foscarnet) [52]. The viral response rate was 55.7%, compared with 23.9% in the investigator-assigned therapy group [52]. However, among the patients who achieved CMV clearance by Week 8 in the maribavir group, 66.4% of patients experienced a loss of response by Week 16 [52]. Alternative strategies, such as a longer treatment duration, should be evaluated, while also acknowledging the continued relevance of the conventional drugs, foscarnet and cidofovir, depending on the individual patient situation. However, it is important to note that from 6 weeks, maribavir can lead to CMV mutations and resistance in recurrent infections [57], and resistance to valganciclovir and maribavir in the same patient has been reported [58].

Letermovir disrupts the viral terminase complex (pUL56) and is currently approved for prophylaxis in patients undergoing hematopoietic stem cell transplantation or high-risk (D+/R-) kidney transplantation [59, 60]. Due to its more favorable safety profile and reduced risk of CMV resistance compared with valganciclovir, letermovir is sometimes used off-label for the treatment of resistant CMV, as observed in case 3 (Figure 5) [27]. However, there are concerns regarding the higher risk of resistant mutations, especially in patients with high viral loads, making letermovir potentially unsuitable in such patients [61].

Further “proof of concept” studies are needed to determine the role of letermovir in treating refractory infections and whether CMVIg can enhance T-cell response. In specific cases, combining CMVIg with antivirals may present a more viable approach. CMVIg can provide an additional mechanism of action by modulating the immune response through various mechanisms, including CMV neutralization, dendritic cell maturation modulation, decreased T-cell activation, and decreased cytokine production [62]. Although it is only licensed for prophylactic use, some clinicians use CMVIg off-label to support the treatment of resistant CMV infection. For example, in case 3, CMVIg was added to off-label letermovir treatment for a patient with hypogammaglobulinemia and ganciclovir-resistant CMV infection (Figure 5). Despite the potential benefits of CMVIg, there is limited evidence supporting its off-label use in the treatment of CMV infections [63, 64].

The integration of CMI monitoring into the care pathway for CMV disease has the potential to revolutionize the management of CMV infection by offering a personalized approach to CMV management and enhanced care for individual patients [65]. CMI monitoring measures the production of interferon gamma, or other cytokines, produced by T cells in response to CMV antigens [66]. The level of CMI is commonly quantified using the ELISPOT or QuantiFERON-CMV assay [55]. Typically, a high CMI response indicates protection against CMV disease, whereas a low CMI response increases the risk of CMV reactivation or progression [66]. The impact of immunosuppressants on CMV-specific T-cell functionality varies [67], and by closely monitoring the immune response, preventive and curative strategies may be tailored appropriately [66, 68].

CMI monitoring can be used as a decision-making tool at various stages of the patient journey (Figure 6) [65]. Unlike serology, which may misrepresent the risk of CMV infection in some patients, particularly D+/R+ patients, CMI is primarily driven by T cells and does not rely on B-cell antibody production [70]. CMI monitoring can be useful for stratifying the risk of CMV infection [31, 71, 72]. with the absence of pre-existing CMV-specific CMI in the recipient increasing the risk of CMV infection [31, 73]. In a prospective multicenter study in D+/R+ kidney recipients deemed to be at high risk for CMV based on pretransplant CMI significantly higher CMV infection rates were observed compared with those considered to be at lower risk, regardless of whether prophylaxis or pre-emptive protocols were followed [74]. However, with some immunosuppressive regimens additional comprehensive profiling of cytokine and chemokine responses may improve the performance of CMV-specific CMI [67, 68].

In case 1, CMI monitoring was used to assess the necessity of CMVIg treatment. An indeterminate QuantiFERON-CMV result, typically interpreted as negative, suggested low or no overall immunity, including against CMV, prompting the initiation of CMVIg. Additionally, CMI monitoring could have guided the decision on universal prophylaxis initiation or earlier initiation of valganciclovir (Figure 2). This approach allows low-risk patients to avoid unnecessary CMV preventive therapy and minimize their exposure to antivirals, consequently decreasing the associated risk of adverse effects [66].

If CMI is positive, prophylaxis could be discontinued earlier as was demonstrated in a recent study in D+/R- kidney and liver transplant recipients receiving prophylactic valganciclovir [75] and a similar study in CMV seropositive kidney transplant recipients receiving ATG [76]. Thus, CMI measurements could be used to tailor the duration of prophylaxis, particularly in high-risk patients, aiming to reduce the risk of toxicity [66]. However, although no difference in CMV disease and replication has been shown in some studies [76], others have been unable to establish non-inferiority of this CMI-guided approach on CMV infection [75]. In patients with low-level DNAemia, CMI testing serves as an adjunctive tool to guide the decision to initiate curative treatment in symptomatic patients, and to determine its optimal duration, or to guide pre-emptive therapy in asymptomatic patients [66]. Interestingly, patients with an indeterminate result appear to be over-immunosuppressed and have a greater risk of CMV reactivation than those with a negative result [66], as observed in case 1 where the patient, a high-risk individual post-rabbit ATG (rATG) administration, exhibited an indeterminate result (Figure 2).

Despite the promising findings from several studies, the integration of CMI monitoring into routine clinical practice still faces challenges due to certain limitations. These include the lack of a clearly defined protective threshold, timings, and accessibility. Where CMI is not available, clinicians can refer to alternative indicators of global immunity, such as lymphocyte count or hypogammaglobulinemia. Low levels of lymphocytes and immunoglobulins may indicate the need for additional interventions in patients at risk of CMV disease.

Before CMV-specific CMI monitoring can be integrated into routine clinical practice, several questions regarding immune-guided CMV management must be addressed. These include understanding why current CMI monitoring has a poor predictive value for D+/R- patients, explaining the reasons behind the occurrence of CMV infections in some R+ patients despite a positive QuantiFERON test result, and exploring the mechanisms enabling certain CMI−CMV patients to control CMV infection following curative treatment. Addressing these questions is essential for optimizing the utility of CMI monitoring in personalized CMV management strategies.