Version May 2024
INTRODUCTION — Cytomegalovirus (CMV) is a globally widespread virus that becomes latent following primary infection but reactivates frequently and causes disease in kidney transplant recipients in the setting of immunocompromise. After kidney transplantation, CMV infection and disease are associated with increased risk of allograft failure and death; thus, CMV prevention strategies are commonly used in such patients. Preventive therapy decreases reactivation in the setting of latent infection in the transplant recipient and/or acquisition of acute infection in CMV-seronegative recipients of seropositive grafts. However, CMV disease may still occur despite preventive therapies, especially when they are not dosed adequately. It also occurs following discontinuation of preventive therapy.
The epidemiology, clinical manifestations, diagnosis, and treatment of CMV disease in kidney transplant recipients are reviewed here. The approach to the prevention of CMV infection in transplant recipients is discussed elsewhere. (See "Prevention of cytomegalovirus disease in kidney transplant recipients".)
The diagnosis of CMV infection and the epidemiology, clinical manifestations, and treatment of CMV infection and disease in immunocompetent adults are also presented separately:
●(See "Overview of diagnostic tests for cytomegalovirus infection".)
●(See "Approach to the diagnosis of cytomegalovirus infection".)
DEFINITIONS — Like other members of the herpesvirus family, CMV establishes latent infection after the resolution of acute (or primary) infection. Patients who are CMV seropositive have latent infection. Secondary, symptomatic disease may present later, reflecting either reactivation of latent CMV or, less commonly, reinfection with a novel exogenous strain. The risk of CMV reactivation is highest in the setting of systemic immunosuppression.
CMV can present in kidney transplant recipients as either CMV infection or CMV disease [1-3]:
●CMV infection – Defined as the presence of CMV replication in blood regardless of whether signs or symptoms are present.
●CMV disease – Defined as the presence of detectable CMV in a clinical specimen accompanied by other clinical manifestations.
CMV disease may present as either CMV syndrome (symptomatic viremia without evidence of tissue-invasive disease) or tissue-invasive CMV disease (eg, enteritis, colitis, hepatitis, nephritis, pneumonitis, meningitis, encephalitis, retinitis). (See 'Clinical manifestations' below.)
EPIDEMIOLOGY — The primary risk factor for CMV infection or disease is the CMV serostatus of the donor/recipient pair. Among United States kidney transplant recipients, approximately 18 percent are CMV-seronegative recipients of kidneys from CMV-seropositive donors (CMV D+/R-), 61 percent are CMV-seropositive patients (CMV R+), and 21 percent are CMV D-/R- [4-6]. The proportion of CMV D+/R- transplants has been increasing over time and is projected to continue to increase [6].
Both CMV D+/R- and CMV R+ patients are at substantial risk of CMV reactivation, but CMV D+/R- patients are at higher risk of developing CMV disease than CMV R+ patients [7-10]. In addition, among those with CMV reactivation, peak CMV loads are highest among CMV D+/R- patients [7]. In a study of the natural history of CMV before the era of effective CMV prevention in 477 kidney transplant recipients, active CMV infection occurred in 69 and 67 percent of CMV D+/R- and CMV R+ patients, respectively, and CMV disease occurred in 56 and 20 percent of CMV D+/R- and CMV R+ patients, respectively, within three months of transplantation [8]. Widespread adoption of CMV prevention strategies by transplant centers has changed the epidemiology of CMV infection after kidney transplantation. However, CMV disease remains common among transplant recipients but typically occurs later, after preventive therapy is stopped:
●In a single-center study of 176 CMV D+/R- patients who received prophylactic ganciclovir or valganciclovir for three months, 29 percent of patients developed CMV disease at a median of 61 days after stopping antiviral prophylaxis, of which 49 percent were CMV syndrome and 51 percent were tissue-invasive CMV disease [11].
●In a multicenter study of 15,848 United States kidney transplant recipients assembled using large administrative data, CMV disease occurring >100 days posttransplant was identified in 4 percent of patients, whereas CMV disease occurring <100 days posttransplant was identified in only 1.2 percent of patients [12].
These studies demonstrate that improved preventive strategies are needed.
Other risk factors for CMV infection and disease are discussed separately. (See "Prevention of cytomegalovirus disease in kidney transplant recipients", section on 'Risk factors for infection'.)
CLINICAL MANIFESTATIONS — CMV infection in kidney transplant recipients can manifest as CMV syndrome or tissue-invasive CMV disease [1,2,13]:
●CMV syndrome – Defined as the presence of detectable viral replication in blood accompanied by attributable symptoms and signs (eg, fever, malaise, arthralgia, leukopenia, thrombocytopenia) in the absence of tissue-invasive disease.
●Tissue-invasive CMV disease – Patients with tissue-invasive CMV disease have clinical symptoms and signs of end-organ disease (eg, enteritis, colitis, hepatitis, nephritis, pneumonitis, meningitis, encephalitis, retinitis). The diagnosis of tissue-invasive disease is discussed in more detail below and separately. (See 'Diagnosis' below and "Approach to the diagnosis of cytomegalovirus infection", section on 'Tissue-invasive disease'.)
The most common clinical manifestation of tissue-invasive CMV disease in kidney transplant recipients is gastrointestinal disease [11,14]. Among 26 CMV D+/R- kidney transplant recipients who developed CMV disease after completing three months of CMV prophylaxis, 21 (81 percent) had gastrointestinal disease, including one patient who had concurrent pneumonitis [11]. Two patients (8 percent) had CMV nephritis, and there was one case (4 percent) each of retinitis, pancreatitis, and hepatitis.
Patients with tissue-invasive CMV disease may present with any of the following syndromes:
●Gastrointestinal disease – Esophagitis, enteritis and/or colitis, dysphagia, nausea, vomiting, diarrhea, and/or abdominal pain. In a study of 26 solid organ transplant recipients (including 13 kidney transplant recipients) with CMV gastrointestinal disease, 7 (27 percent) had upper gastrointestinal disease, 16 (62 percent) had lower gastrointestinal disease, and 3 (12 percent) had both [14].
●Hepatitis – Aspartate aminotransferase and alanine aminotransferase elevation with CMV viremia in the absence of any other cause.
●Pancreatitis – Abdominal pain with elevated amylase and lipase in the setting of CMV viremia.
●Pneumonitis – Cough, shortness of breath, and pulmonary infiltrates on radiographic imaging plus CMV in bronchoalveolar lavage fluid.
●Meningoencephalitis – Headache, nuchal rigidity, mental status changes, or paralysis, plus CMV in cerebrospinal fluid.
●Retinitis – Retinal edema or hemorrhage as reported by an ophthalmologist. CMV retinitis can present with one or more discrete foci of retinal edema or necrosis, with or without retinal hemorrhage or inflammatory sheathing of retinal vessels on funduscopic examination [15].
●Nephritis – Kidney dysfunction in the presence of microbiologic and histologic features of CMV infection in a kidney biopsy specimen. (See "Clinical manifestations and diagnosis of acute interstitial nephritis", section on 'Clinical features'.)
DIAGNOSIS — The approach to diagnosis varies with the suspected clinical syndrome and site of infection. In general, quantitative polymerase chain reaction (PCR) is the preferred test for detecting CMV in blood [3]. Evidence of CMV infection at the affected site is required for other tissue-invasive disease (eg, CMV enteritis) [3].
Our approach to diagnosis is generally consistent with the 2018 international consensus guidelines on the management of CMV in solid organ transplantation [3]. (See "Clinical manifestations, diagnosis, and treatment of cytomegalovirus infection in lung transplant recipients", section on 'Society guideline links'.)
Asymptomatic viremia — The diagnosis of asymptomatic CMV viremia is typically made during routine CMV viral-load monitoring posttransplantation. Strategies for viral-load monitoring and interpretation of results are discussed separately. (See "Prevention of cytomegalovirus disease in kidney transplant recipients".)
Symptomatic disease
CMV syndrome — For patients with suspected CMV syndrome (eg, fever, malaise, leukopenia, and/or lymphocytosis in the absence of end-organ disease), we generally obtain a quantitative PCR (ie, viral load) from plasma or whole blood for diagnosis. Because viral-load testing is very sensitive [16,17], assays vary among institutions, and the clinical features of CMV syndrome are nonspecific, results should be interpreted carefully.
●In general, an elevated viral load in a patient with a clinically compatible syndrome (in whom other causes seem unlikely) is considered diagnostic. However, the significance of very low viral loads (ie, detectable but not quantifiable viral loads or viral loads near the lower limit of the assay) is not certain. Thus, we take the clinical context into account when deciding when to repeat the viral load for confirmation and/or starting antiviral treatment.
●A negative test result (eg, an undetectable viral load) is often sufficient to rule out CMV as the cause of a patient's symptoms. However, in some patients with tissue-invasive disease (particularly CMV enteritis), plasma and whole-blood viral loads can be undetectable despite CMV replication in tissue [18]. (See 'Tissue-invasive disease' below.)
Although quantitative PCR has limitations, it is the test of choice for the diagnosis [1,19,20]. In general, a quantitative PCR assay that is calibrated to the World Health Organization international standard (with results reported in international units/mL) should be used. Calibration to the international standard reduces some but not all variability among different assays and different institutional testing practices [21,22]. Because sample types (plasma versus whole blood), DNA extraction techniques, and other factors still vary among testing centers, it is important to use the same assay while monitoring an individual patient over time.
The optimal sample type (ie, whole blood versus plasma) for quantitative PCR testing has not been determined. Both assays are used in clinical practice but are not interchangeable [1,23]. Whole-blood assays may be more sensitive that plasma assays, while plasma assays appear to be more specific. Because the amount of virus detected differs between sample types, neither the sample type nor the assay used should be changed when monitoring patients. (See "Overview of diagnostic tests for cytomegalovirus infection", section on 'Whole blood versus plasma'.)
Historically, the CMV pp65 antigenemia assay was commonly used for the diagnosis of CMV syndrome, but this has now been largely supplanted by quantitative PCR. Serology (CMV IgG/IgM) should not be used to diagnose active CMV infection or disease in transplant recipients. (See "Overview of diagnostic tests for cytomegalovirus infection" and "Approach to the diagnosis of cytomegalovirus infection".)
Tissue-invasive disease — For patients with suspected CMV meningoencephalitis, a quantitative PCR should be obtained from the cerebrospinal fluid in addition to quantitative PCR from blood. Elevated peripheral CMV viral loads are generally corroborative but can be negative even in the presence of active tissue-invasive disease. We do not rely on quantitative PCR from other body sites, since viral shedding is common from the airways and gastrointestinal tract and because these tests lack standardization. We instead rely on biopsies followed by immunohistochemical staining for definitive diagnosis. (See "Approach to the diagnosis of cytomegalovirus infection", section on 'Testing based on type of disease'.)
The diagnosis of CMV retinitis requires examination by an experienced ophthalmologist; in some cases, sampling of the vitreous fluid is performed to confirm the diagnosis [24].
Determining disease severity — There are no established criteria for defining disease severity. However, the presence of either of the following generally indicate severe disease:
●Markedly elevated or rapidly rising viral loads – There is no established cutoff for a "high" or markedly elevated viral load. The performance characteristics of quantitative PCR assay vary. In general, transplant centers define their own viral load cutoffs for defining disease severity and/or need for treatment based on the performance of the assay used by their institution. As a general rule, viral loads that are >10,000 copies/mL are considered high, and those near or exceeding the upper limit of quantification are very high [19].
Similarly, there is no consensus definition of a rapidly rising viral load. However, a threefold rise in a viral load (for values in the midrange of the assay) and a fivefold rise (for values in the lower range of the assay) indicate a biologically meaningful increase in viral replication [19].
●Tissue-invasive disease – Tissue-invasive disease (eg, enterocolitis, pneumonitis, meningoencephalitis) is generally considered severe, particularly when there is clinical evidence of organ dysfunction. While viral loads are frequently high in patients with tissue-invasive disease, tissue invasive disease can occur without viremia.
Patients with tissue-invasive disease are typically diagnosed in hospital and require intravenous (IV) antiviral therapy. We often admit patients with markedly high viral or rapidly rising viral loads to hospital for initial IV therapy as well, particularly for those who are more heavily immunosuppressed, are CMV donor-positive/recipient-negative (D+/R-), or are at higher risk for rejection. (See 'Symptomatic disease' below.)
TREATMENT
Asymptomatic viremia — Most patients with asymptomatic CMV viremia require treatment, usually with a reduction in immunosuppression, antiviral therapy, or a combination of both. The rationale for treating patients with asymptomatic CMV infection (ie, preemptive therapy) is to decrease progression to CMV syndrome and tissue-invasive organ disease and to prevent indirect effects of CMV infection (eg, acute and chronic allograft rejection) (table 1)[8,25].
The diagnosis of asymptomatic CMV viremia is typically made during CMV viral-load monitoring posttransplantation. Because viral load assays vary among institutions, the specific viral load threshold that should trigger the need for treatment is typically determined by the individual transplant center.
●As a first step in management, we reduce immunosuppression by stopping the antimetabolite immunosuppressant (ie, mycophenolate or azathioprine) in all patients.
For patients with low viral loads (eg, near the lower limits of the assay), we repeat the polymerase chain reaction (PCR) test one week after stopping the antimetabolite to assess response and determine the need for antiviral therapy. If the patient continues to have evidence of active viral replication, we start antiviral therapy (usually valganciclovir 900 mg orally twice daily) even in the absence of symptoms. PCR should then be checked weekly until viremia resolves.
For most patients, we do not restart the antimetabolite upon resolution of viremia; however, we may reintroduce it at a lower dose in patients who are at a perceived increased risk of rejection. We monitor the blood for CMV replication with PCR at weekly intervals for four weeks to ensure that CMV does not reactivate at the lower antimetabolite dose. If CMV infection recurs, we discontinue the antimetabolite indefinitely. If CMV reactivation does not occur, we continue the antimetabolite at the reduced dose.
●Some transplant centers start an antiviral agent upon recognition of CMV reactivation, especially in CMV donor-positive/recipient-negative (D+/R-) patients or for patients with "higher" viral loads (cut-offs are not well defined and vary by center and by assay). Additional factors that help guide the decision to treat with antivirals include the intensity of immunosuppression (especially with cellular-depleting induction immunosuppressive therapies and treatment for rejection) and risks for disease (eg, CMV serostatus, with CMV-seronegative recipients [CMV R-] having the highest risk for rapid progression to disease). (See "Prevention of cytomegalovirus disease in kidney transplant recipients", section on 'Risk factors for infection'.)
Data evaluating the long-term impact of antimetabolite discontinuation following asymptomatic CMV viremia are limited. In a single-center retrospective study that included 52 adult kidney transplant recipients whose antimetabolite was discontinued in response to CMV viremia (defined as a CMV viral load ≥500 copies/mL), nearly all patients (98 percent) achieved clearance of viremia [26]. Five patients (10 percent) developed biopsy-proven acute rejection after antimetabolite discontinuation, with most cases of T cell-mediated rejection being low grade in severity. The median onset of rejection was greater than one year after antimetabolite discontinuation, suggesting that other factors may have contributed. There are insufficient data to recommend long-term discontinuation of the antimetabolite at this time.
Symptomatic disease — We treat all kidney transplant recipients with symptomatic CMV disease (either CMV syndrome or tissue-invasive disease) by decreasing immunosuppression and by providing antiviral therapy, as discussed below.
Reduction of immunosuppression — We reduce immunosuppression in all kidney transplant recipients with CMV disease. We typically stop the antimetabolite immunosuppressant (ie, mycophenolate or azathioprine). We usually do not restart it at the conclusion of CMV treatment (ie, when symptoms have resolved and PCR is undetectable or less than the lower limit of a sensitive assay), since we believe that CMV viremia is a sign of excessive immunosuppression. However, occasionally, among patients who are at increased risk of rejection (eg, those who have undergone retransplantation or have a prior history of rejection), we reintroduce the antimetabolite at a lower dose. We monitor the blood for CMV replication with PCR at weekly intervals for four weeks to ensure that CMV does not reactivate at the lower antimetabolite dose. If CMV recurs, we discontinue the antimetabolite indefinitely and restart treatment with antiviral therapy. If CMV reactivation does not occur, we continue the antimetabolite at the reduced dose.
Antiviral therapy — Ganciclovir or its oral derivative, valganciclovir, is the preferred agent for most patients with CMV viremia or CMV disease. Oral maribavir, intravenous (IV) foscarnet, and IV cidofovir are alternatives and are primarily used for patients with known or suspected infection with resistant or refractory CMV [27].
Choice of initial therapy — The selection of antiviral treatment is determined by the severity of illness, initial viral load, ability to tolerate oral medication, and the ability to administer IV therapies at home. The selection of antiviral therapy is not stratified depending upon whether the patient has CMV syndrome or tissue-invasive CMV disease (see 'Definitions' above). Both CMV syndrome and tissue-invasive disease may be associated with significant clinical manifestations and high viral loads.
●Severe disease – For patients with tissue-invasive disease (eg, pneumonitis, meningoencephalitis), high or rapidly rising viral loads, or moderate to severe gastrointestinal disease (with either diarrhea or nausea and vomiting that impair absorption), we suggest IV ganciclovir rather than oral valganciclovir. We administer ganciclovir 5 mg/kg IV every 12 hours, with dose adjustment for kidney function [1]. Note that while retinitis is a less common manifestation CMV disease in solid organ transplant recipients, we typically treat it with intravitreal antiviral therapy in addition to IV therapy. (See "Treatment of AIDS-related cytomegalovirus retinitis".)
IV ganciclovir has been shown to be effective against CMV infection in randomized trials in patients with HIV infection and in case series in kidney transplant recipients with severe CMV disease [28,29]. Side effects of ganciclovir include leukopenia, thrombocytopenia, and diarrhea.
●Mild or moderate disease – For patients with mild (ie, those with minimal signs and symptoms) to moderate (ie, CMV syndrome without organ-specific involvement or high or rapidly rising viral load) CMV disease who are expected to have good absorption of oral medications, we suggest oral valganciclovir rather than IV ganciclovir. We administer valganciclovir 900 mg orally twice daily, with dose adjustment for kidney function.
Oral valganciclovir has good oral bioavailability and spares patients from the risks and costs of central venous access; however, the drug's absorption relies on enterocyte metabolism of the prodrug, which can be variable in people with gastrointestinal tract disease, resulting in low or variable levels.
In a trial of 321 solid organ transplant recipients with mild to moderate CMV disease who were randomly assigned to either 900 mg of oral valganciclovir or 5 mg/kg of IV ganciclovir twice daily for 21 days, rates of viremia eradication (45 versus 48 percent, respectively) and treatment success (77 versus 80 percent, respectively) were comparable between the two groups [30]. However, the study excluded patients with life-threatening illness, extremely high viral loads, or severe tissue-invasive gastrointestinal disease. Moreover, most patients were CMV seropositive (CMV R+) and therefore had preexisting anti-CMV immunity, which may have resulted in less severe disease.
Patients who do not respond to reduction of immunosuppression and to initial antiviral therapy may require an alternative regimen, further reduction of immunosuppression, and/or adjunctive treatment with cytomegalovirus immune globulin (CytoGam, CMV Ig) or intravenous immune globulin (IVIG). (See 'Refractory or drug-resistant CMV' below.)
Duration of therapy — The duration of therapy depends upon the severity of disease, as well as the clinical and virologic response to treatment. We generally treat until both symptoms and CMV viremia have resolved (ie, CMV is undetectable or lower than the limits of a sensitive assay in two quantitative PCR tests drawn one week apart). The typical duration of therapy is 21 days but is often longer, particularly for patients with tissue invasive disease [3]. We also monitor periodically for recurrence with quantitative PCR following completion of therapy, particularly for high-risk patients.
Whether antiviral therapy should be continued once symptoms and viremia are resolved is uncertain. Some clinicians treat patients with a one- to three-month course of oral valganciclovir at 900 mg once daily (adjusted for kidney function) to prevent relapse [1]; this reduced dose of valganciclovir is sometimes referred to as secondary prophylaxis. However, this approach is not taken universally and international consensus guidelines do not recommend secondary prophylaxis because of uncertain efficacy [3]. No randomized trials have evaluated the efficacy of secondary prophylaxis. However, in a retrospective cohort study of 170 solid organ transplant recipients (including 79 kidney transplant recipients), secondary prophylaxis was associated with decreased relapse rates when compared with no prophylaxis (22 versus 26 percent; hazard ratio [HR] 0.19, 95% CI 0.05–0.69) [31]. The benefit of secondary prophylaxis did not extend beyond six weeks of antiviral prophylaxis use.
Monitoring while on therapy — In all patients receiving antiviral therapy for CMV disease, we perform the following monitoring:
●Viral load – We monitor the CMV viral load with weekly PCR testing to assess the response to therapy and monitor for drug resistance. Either whole blood or plasma can be used for baseline measurements and monitoring of CMV viral load, but the same sample, assay, and laboratory should be used to ensure comparability [23].
A decrease in the viral load generally correlates with a clinical response to treatment [32,33]. In one study that included 267 solid organ transplant recipients with CMV disease, weekly decreases in viral load were demonstrated in most patients receiving antiviral therapy; however, a baseline viral load greater than 18,200 international units/mL and detectable viremia after 21 days of treatment were associated with delayed resolution of CMV disease [32]. These findings may not be generalizable, since patients with severe tissue-invasive CMV disease or high baseline viremia were excluded.
Monitoring the viral load is also a useful approach for assessing the likelihood of drug resistance. Markers suggestive of CMV resistance include a rising viral load, rebounding viral load, and a persistently elevated viral load (eg, no decline in viral load over a two-week period) in the setting of adequate doses of antiviral therapy. When antiviral drug-resistant CMV infection or disease is suspected, a genotypic assay for drug resistance should be performed [34]. (See "Approach to the diagnosis of cytomegalovirus infection", section on 'Resistance testing'.)
Monitoring the viral load after completion of therapy can be useful in detecting recurrences rapidly. This may be considered in patients at high risk of recurrence, such as patients with high initial peak viral load, recent allograft rejection requiring increased immunosuppressive therapy, and multiple past recurrences.
●Blood cell counts – Bone marrow suppression, in particular leukopenia, appears to be the most significant and common adverse event associated with ganciclovir and valganciclovir. Given the risk, we check a complete blood count with a differential weekly while patients are on therapy.
When leukopenia occurs, the dose of ganciclovir or valganciclovir should not be reduced, given the risk of promoting resistance with prolonged exposure to subtherapeutic levels of the antiviral [13]. Patients should be evaluated for other potential causes of leukopenia (eg, mycophenolate, trimethoprim-sulfamethoxazole). It is also important to note that CMV itself can cause leukopenia (including both neutropenia and lymphopenia) and thrombocytopenia and that these abnormalities often improve with antiviral therapy. The addition of granulocyte colony-stimulating factor should be considered before discontinuing ganciclovir or valganciclovir. (See "Ganciclovir and valganciclovir: An overview", section on 'Bone marrow suppression'.)
●Kidney function – We check a serum creatinine weekly to assess kidney function since a decline in kidney function may require adjusting the dose of ganciclovir or valganciclovir.
Refractory or drug-resistant CMV — Refractory CMV disease is defined as persistent and/or progressive infection despite antiviral agents and reduction of immunosuppression and can be due to ganciclovir resistance. Ganciclovir resistance should be suspected in patients who have rising or persistently elevated viral loads despite treatment with appropriately dosed ganciclovir for more than two weeks (see 'Monitoring while on therapy' above). It occurs in 1 to 2 percent of kidney transplant recipients with CMV infection or disease and typically develops in CMV D+/R- patients [34,35]. Ganciclovir resistance is a spectrum and ranges from 2- to 10-fold increases in CMV inhibitory concentrations, depending on the mechanism(s) of resistance [36].
Resistance testing — When ganciclovir-resistant infection or disease is suspected, genotype testing should be performed to identify specific resistance mutations. Common resistance mutations include those in the genes that encode UL97 phosphotransferase, which performs the initial phosphorylation of ganciclovir (which is required for its antiviral activity), and the viral DNA polymerase gene UL54. (See "Overview of diagnostic tests for cytomegalovirus infection", section on 'Resistance testing'.)
●More than 80 percent of resistant isolates have UL97 mutations clustered at codons 460, 520, and 590 to 607 [35,37]. These "canonical" UL97 mutations are M460V/I, H520Q, C592G, A594V, L595S, and C603W. UL97 mutations confer 5- to 10-fold increases in CMV inhibitory concentrations. Occasionally, UL97 mutations that confer low-grade resistance occur.
●UL54 mutations are much less common and confer various patterns of cross-resistance depending on the specific mutation [38]. UL54 mutations located in the exonuclease domains and region V confer dual ganciclovir-cidofovir resistance. UL54 mutations that are located at and between regions II and III confer foscarnet resistance [34]. Unlike UL97 mutations, UL54 mutations are not limited to a short list of "canonical" mutations and therefore require more extensive sequencing for elucidation.
●A significant number of patients with clinically ganciclovir-resistant CMV disease have no detectable mutation.
Treatment of drug-resistant CMV
●Choice of antiviral therapy – Antiviral therapies for patients with ganciclovir-resistant or refractory CMV include maribavir, foscarnet, and cidofovir.
•Maribavir – An oral drug that inhibits UL97 phosphotransferase and stops viral maturation and egress. Maribavir is active against CMV with UL97 and UL54 mutations. Maribavir is dosed at 400 mg orally twice daily for eight weeks. Dysgeusia is a frequent side effect, and maribavir cannot be coadministered with ganciclovir or valganciclovir. Key advantages of maribavir over other agents are lack of bone marrow and kidney toxicity. Due to a drug interaction with calcineurin inhibitors and mammalian (mechanistic) target of rapamycin (mTOR) inhibitors, close monitoring of these immunosuppressive agents is required. Resistance to maribavir has also been reported to emerge while on therapy [39].
•Foscarnet – A pyrophosphate analog that inhibits viral replication by selectively binding to viral DNA polymerase and requires IV administration. Foscarnet is active against CMV with UL97 and UL54 mutations. Foscarnet is dosed at 60 mg/kg IV every 8 hours or 90 mg/kg every 12 hours, with dose adjustment for kidney function impairment. Foscarnet is highly nephrotoxic and patients should receive pre- and postinfusion hydration, and close monitoring of electrolytes, creatinine, magnesium, and phosphorus is essential given that acute kidney injury is common with foscarnet. (See "Foscarnet: An overview", section on 'Toxicity'.)
•Cidofovir – Another viral DNA polymerase inhibitor, it is also highly nephrotoxic. Cidofovir can also cause uveitis [40]. It is active against CMV with UL97 mutations but not against CMV with UL54 mutations. Cidofovir can be dosed at 1 mg/kg IV three times a week. Alternatively, cidofovir can be given as 5 mg/kg IV weekly for two weeks as induction therapy and then 5 mg/kg every other week. Cidofovir should be given with aggressive hydration, and probenecid use should be considered. (See "Cidofovir: An overview", section on 'Toxicity'.)
Selection among antiviral agents is guided by disease severity and the results of genotypic testing (see 'Resistance testing' above):
•UL97 gene mutations – The approach to management varies among experts. Some experts use maribavir for most patients because it has been shown to be more effective and has a lower side effect profile in one randomized trial [41]. However, maribavir has not been well studied in patients with severe disease or high viral load. Resistance has also been reported to emerge while on therapy, including in those with UL97 mutations [39]. Other experts select among maribavir, foscarnet, and cidofovir based upon disease severity, viral load, and other patient-specific factors. Clinical experience is greater with foscarnet compared with maribavir.
In a phase 3 trial comparing eight weeks of maribavir or investigator-assigned therapy (valganciclovir/ganciclovir, foscarnet, or cidofovir) in 352 hematopoietic cell or solid organ transplant recipients with refractory CMV infection or disease (with or without documented antiviral resistance), symptom control and viremia clearance rates were higher in the maribavir group (19 versus 10 percent and 56 versus 24 percent, respectively) [41]. Of note, only six percent of patients in either arm had a high viral load (>91000 international units/mL) at baseline. Treatment-emergent adverse events were similar between the groups; however, patients on maribavir had less acute kidney injury compared with those on foscarnet (9 versus 21 percent) and less neutropenia compared with those on valganciclovir/ganciclovir (9 versus 34 percent).
•UL54 mutations – The approach to management is similar to that for UL97 mutations. However, we avoid cidofovir since CMV strains harboring this mutation are often resistant to cidofovir as well as ganciclovir. Maribavir has an entirely different mechanism of action.
•No detectable mutations – For patients with no detectable mutations, we often increase the dose of ganciclovir to 7.5 mg/kg IV twice daily and recheck a viral load in one week rather than switching to another agent.
Letermovir (a viral terminase inhibitor that is US Food and Drug Administration approved for CMV prevention in allogeneic hematopoietic cell transplant recipients) has been used in combination with another antiviral agent for salvage therapy. Letermovir is not approved for refractory or resistant CMV, and optimal dosing has not yet been determined. Given its low barrier to resistance, letermovir is not approved for this indication and should not be used for patients with higher viral loads. It should be given in combination with other antiviral agents because of its low barrier to resistance [42]. While letermovir is not reliable nor approved for the treatment of resistant or refractory CMV disease in organ transplant recipients, letermovir has an oral formulation and lacks bone marrow toxicity; thus, some centers do treat patients with low-level viremia (<1000 international units/mL) with letermovir when other agents cannot be tolerated [43].
●Reduction of immunosuppression – For all patients with drug-resistant CMV, we reduce maintenance immunosuppression more stringently than we do among patients without drug resistance. In addition to stopping the antimetabolite (ie, mycophenolate or azathioprine), we lower the dose of prednisone and then the calcineurin inhibitor.
●Adjunctive therapies for patients with life-threatening disease – Patients with life-threatening disease (such as CMV pneumonitis) that progresses despite antiviral agents and reduction of immunosuppression agents may be treated with cytomegalovirus immune globulin (CytoGam, CMV Ig) or IVIG, irrespective of the mutation that is identified and even if no mutation is identified. Among such patients, the potential benefits may outweigh potential harms (infusion reactions, kidney failure, fluid overload, aseptic meningitis) and cost. However, CMV Ig and IVIG adjunctive therapies have not been studied in well-designed, randomized trials [1]. Evidence on the use of CMV Ig and IVIG in solid organ transplant recipients is limited to small, uncontrolled and retrospective case series published prior to the advent of current immunosuppressive and antiviral strategies [44-46].
PROGNOSIS — CMV disease increases allograft loss and mortality:
●In a single-center study of 51 CMV donor-positive/recipient-negative (D+/R-) patients who developed CMV disease after stopping antiviral prophylaxis (49 percent with CMV syndrome and 51 percent with tissue-invasive CMV disease), CMV disease was associated with a 2.8-fold increased risk of allograft loss or death whereas CMV syndrome was not [11].
●In a multicenter study of 15,848 United States kidney transplant recipients assembled using large administrative data, CMV disease occurring >100 days posttransplant was identified in 4 percent of patients, and CMV disease occurring <100 days posttransplant was identified in 1.2 percent of patients. In multivariable analysis, CMV disease occurring 101 to 365 days posttransplant and CMV disease occurring >365 days posttransplant were associated with a 1.5- and 2.1-fold increased risk of death, respectively [12].
●In a cohort study of over 1400 solid-organ transplant recipients, including over 900 kidney transplant recipients, CMV viremia was associated with an increased risk of biopsy-proven rejection within 4 weeks of the detection of viremia [47]. The hazard ratio for rejection following kidney transplantation was 1.58 (95% CI, 1.16-2.16).
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cytomegalovirus in solid organ transplant recipients".)
SUMMARY AND RECOMMENDATIONS
●Overview – Cytomegalovirus (CMV) is a herpesvirus that causes lifelong latent infection. In most patients, latent infection is benign and asymptomatic. In the setting of immunocompromise, latent infection can reactivate and cause symptomatic disease. In transplant recipients, CMV reactivation is also associated with allograft rejection and other indirect effects (table 1). (See 'Epidemiology' above and 'Prognosis' above.)
●Clinical manifestations – CMV can present in kidney transplant recipients as either CMV infection or CMV disease.
•CMV infection is defined as detection of CMV replication in the blood regardless of whether signs or symptoms are present.
•CMV disease is defined as the presence of CMV in a clinical specimen accompanied by other clinical manifestations (eg, fever, malaise, arthralgia, leukopenia, thrombocytopenia).
•CMV disease may be either CMV syndrome (symptomatic viremia without evidence of tissue-invasive disease) or tissue-invasive CMV disease (eg, enteritis, colitis, hepatitis, nephritis, pneumonitis, meningitis, encephalitis, retinitis). (See 'Clinical manifestations' above.)
●Diagnosis – The approach to diagnosis varies with the suspected clinical syndrome and site of infection. In general, CMV quantitative polymerase chain reaction (ie, viral-load testing, nucleic acid amplification testing) is the preferred test for detecting viremia. Evidence of CMV infection at the affected site is required for the diagnosis of other tissue-invasive CMV diseases (eg, CMV meningitis). (See 'Diagnosis' above.)
●Treatment
•Asymptomatic viremia – For kidney transplant recipients with asymptomatic CMV viremia, we stop the antimetabolite immunosuppressant (ie, azathioprine or mycophenolate) as a first step in management.
For most patients with low viral loads (eg, near the lower limits of the assay), we monitor the viral load weekly following the reduction in immunosuppression to determine whether antiviral treatment is needed. However, practice varies by transplant centers, many start antiviral therapy when viremia is detected, particularly in patients with higher viral loads or other risk factors for severe disease. (See 'Asymptomatic viremia' above.)
•Symptomatic disease – For kidney transplant recipients with symptomatic CMV disease (either CMV syndrome or tissue-invasive disease), we stop the antimetabolite immunosuppressant (ie, azathioprine or mycophenolate) and provide antiviral therapy. The choice of agent depends upon the severity of the clinical manifestations and level of viremia (see 'Choice of initial therapy' above):
-For patients with tissue-invasive illness (eg, pneumonitis, meningoencephalitis), high or rapidly rising viral loads, or moderate to severe gastrointestinal disease, we suggest intravenous (IV) ganciclovir rather than oral valganciclovir (Grade 2C). The dose of ganciclovir is 5 mg/kg IV every 12 hours (adjusted for kidney function).
-For patients with mild or moderate CMV disease who are expected to have good absorption of oral medications, we suggest oral valganciclovir rather than IV ganciclovir (Grade 2C). The dose of valganciclovir is 900 mg orally twice daily (adjusted for kidney function).
We generally continue one of the antiviral regimens until the clinical signs and symptoms of CMV disease have completely resolved and there is no evidence of CMV viremia in two blood polymerase chain reaction (PCR) tests at least one week apart. The typical duration of therapy is 21 days but is often longer, particularly for patients with tissue invasive disease. (See 'Duration of therapy' above.)
•Refractory or drug-resistant CMV – For patients whose viral loads fail to decline while on therapy, we test for ganciclovir resistance. Antiviral selection varies based on the specific mutation detected and disease severity. (See 'Refractory or drug-resistant CMV' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges William M Bennett, MD, who contributed to earlier versions of this topic review.
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