Last updated March 15, 2022

Cytomegalovirus In Solid Organ Transplant Recipients

Recommendations

RISK FACTORS AND STRATIFICATION

All organ donors and transplant candidates should be tested for baseline CMV immune status using CMV‐IgG serology prior to transplantation. (High, Strong)
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The combined interpretation of CMV‐IgG serology in the organ donor and transplant recipient should be used to categorize post‐transplant CMV risk and guide CMV prevention strategies. (High, Strong)
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  • CMV‐seronegative recipients who receive an organ from CMV‐seropositive donor (D+/R−) are at highest risk of CMV disease after transplantation.
(High, Strong)
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Transplant candidates who are CMV‐seronegative during the initial pretransplant evaluation should have repeat CMV serology immediately prior to transplantation. (Low, Strong)
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A serologic assay that measures CMV‐IgG is recommended. (High, Strong)
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Unless clinically indicated (ie, if primary CMV infection is suspected), CMV‐IgM is not routinely recommended due to potential for false‐positivity. (Low, Strong)

CMV‐IgM false-positivity may lead to erroneous assignment of risk profile (eg, recipient is miscategorized as CMV D+/R+ instead of D+/R−), and resulting in severe clinical consequences.

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Recent blood transfusion or receipt of immunoglobulins and other blood products should be considered in the interpretation of CMV serology, as they may cause false‐positive results due to passive transfer of CMV antibodies. (Low, Strong)

The clinical consequences for miscategorizing D+/R− as a D+/R+ due to falsepositive results can be severe.

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For organ donors and transplant candidates with borderline or indeterminate CMV‐IgG serology results, the assignment of baseline serologic status should consider the “highest‐risk” scenario for CMV prevention purposes. (Low, Strong)
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If a donor CMV‐IgG serology is borderline or indeterminate, it should be considered as positive. (Low, Strong)
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If the recipient CMV‐IgG is borderline or indeterminate, the result should be considered in the context of donor serology, as described below. (Low, Strong)
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If donor CMV serology is positive, the recipient with borderline or indeterminate CMV‐IgG will be considered CMV‐seronegative (ie, CMV D+/R−). (Low, Strong)
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If donor CMV serology is negative, the recipient with borderline or indeterminate CMV‐IgG will be considered CMV‐seropositive. (Low, Strong)
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CMV‐specific T‐cell immune responses may be assessed in transplant candidates prior to transplantation to determine baseline CMV immune status, (Low, Weak)

but the role of CMV‐specific T-cell assay as a predictor of the risk of CMV after transplantation remains under clinical investigation.

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LABORATORY DIAGNOSIS

CMV quantitative nucleic acid amplification test (QNAT) is the laboratory method of choice for rapid diagnosis of CMV infection in blood after solid organ transplant (SOT). (High, Strong)
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  • CMV QNAT is the preferred laboratory method for CMV surveillance to guide preemptive therapy.
(High, Strong)
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pp65 antigenemia is an alternative laboratory method for surveillance and diagnosis of CMV infection after SOT. (High, Strong)
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CMV QNAT assays should be calibrated using the WHO International Reference Standard. (High, Strong)
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Studies should report CMV viral load in IU/ml using QNAT assays that have been calibrated to the WHO International Reference Standard. (High, Strong)
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Even if viral loads are reported in IU/ml, the viral load values are not similar among CMV QNAT assays, and should not be interpreted interchangeably during clinical care. (High, Strong)
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Transplant centers are encouraged to derive specific viral load thresholds depending on the CMV QNAT assay they use and the population at risk. (High, Strong)
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CMV QNAT for surveillance and diagnosis should be performed using the same assay. (High, Strong)
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  • In reporting viral load values, the name of the CMV QNAT assay should be specified.
(High, Strong)
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Whole blood and plasma are the recommended clinical samples for the detection of CMV replication by QNAT in the peripheral blood. (High, Strong)
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CMV viral load is higher in whole blood than in plasma. CMV monitoring should only use one sample type (plasma only or whole blood only). (High, Strong)
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CMV QNAT in BAL fluid may be used for the diagnosis of probable CMV pneumonia, but the viral load threshold to suggest end‐organ lung disease vs asymptomatic shedding needs to be defined. (Low, Weak)
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CMV QNAT of CSF may be used for the diagnosis of probable central nervous system CMV disease. (High, Strong)
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CMV QNAT of urine sample should not be used for diagnosis and surveillance in adult CMV R+ SOT recipients. (Low, Strong)
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The diagnosis of CMV syndrome should be supported by the demonstration of CMV by QNAT in whole blood or plasma. (High, Strong)
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CMV QNAT of whole blood or plasma may also be used as a surrogate method for the diagnosis of probable end‐organ CMV disease, when the risk of performing invasive procedure such as biopsy is prohibitive. (Moderate, Strong)
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A negative CMV QNAT in the blood does not completely rule out the presence of end‐organ CMV disease, particularly among CMV R+ SOT recipients with gastrointestinal disease. (Moderate, Strong)
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The diagnosis of most end‐organ CMV diseases should be confirmed by histopathology. (High, Strong)
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  • Histopathology with or without immunohistochemical staining remains as the standard method for definitive diagnosis of most end‐organ CMV diseases.
(High, Strong)
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Patients suspected to have end‐organ CMV disease but with negative QNAT in blood or negative pp65 antigenemia should have tissue biopsy and histopathology to confirm the clinical suspicion of CMV disease. (Moderate, Strong)
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Histopathology is not necessary for the diagnosis of CMV retinitis. A detailed ophthalmologic examination by expert ophthalmologist is sufficient. (High, Strong)
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  • Only in atypical cases, the demonstration of CMV by NAT in vitreous fluid is suggested.
(High, Strong)
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Viral culture of blood and urine has limited clinical utility for prediction, diagnosis, and management of CMV disease in adult SOT patients and is not recommended in routine practice. (High, Strong)
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CMV‐IgM and ‐IgG serology should not be used for the diagnosis of CMV disease after SOT. (High, Strong)
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Immunologic monitoring after SOT may be used to stratify the risk of CMV disease.

Absolute lymphocyte count and CD4+/CD8+ T‐cell subsets may be used to stratify the risk of CMV disease after SOT, but specific lymphocyte thresholds will need to be clinically validated. (Low, Weak)
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Hypogammaglobulinemia is associated with CMV disease, and measurement of total immunoglobulin G levels may be used to assess the risk. (Low, Weak)
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Measures of global (nonspecific) and CMV‐specific CD8+ and/ or CD4+ T cells may be used to stratify the risk of CMV disease after SOT. (Moderate, Strong)
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PREVENTION

Antiviral prophylaxis may be given to any “at‐risk” SOT recipient to prevent CMV infection and disease after transplantation. (High, Strong)
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Valganciclovir is the preferred drug for antiviral prophylaxis in adults. Alternative drug options for antiviral prophylaxis are intravenous ganciclovir (which entails the need for vascular access) and, for kidney recipients only, high‐dose valacyclovir (2 g PO qid). (, )
(level of evidence varies depending on transplant type)
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Despite US FDA caution, valganciclovir is the recommended drug for CMV prophylaxis in liver recipients. (High, Strong)
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The use of low‐dose (“mini‐dose”) valganciclovir is not recommended, particularly in CMV D+/R− SOT recipients. (High, Strong)
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Unselected IVIg and CMV‐Ig may be used, but only as an adjunct to antiviral therapy in lung, heart, and intestinal transplant recipients. (Low, Weak)
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Antiviral prophylaxis should generally be started within the first 10 days after transplantation. (High, Strong)
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The duration of antiviral prophylaxis varies depending on the CMV donor and recipient serologies and the transplant types. (, )
(level of evidence varies depending on serologies and transplant type)
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CMV D+/R−: Antiviral prophylaxis for 6 months is recommended for CMV D+/R− kidney recipients, (High, Strong)
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  • 3 months to 6 months for CMV D+/R− heart, liver, and pancreas recipients,

(, )

(level of evidence varies)

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  • 6‐12 months for CMV D+/R− lung recipients,
(, Strong)

(moderate to high)

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  • and 6 months for CMV D+/R− intestinal and composite tissue allograft recipients.
(Low, Weak)
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CMV R+: Antiviral prophylaxis for 3 months is recommended for CMV R+ kidney, heart, liver, and pancreas recipients, (High, Strong)
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  • 6‐12 months for CMV R+ lung recipients,
(, Strong)
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and 3‐6 months for CMV R+ intestinal and composite tissue allograft transplant recipients. (Low, Weak)
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The use of CMV‐specific T‐cell immune measures to guide the duration of antiviral prophylaxis has been suggested, but this remains investigational. (Low, Weak)
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CMV‐specific prophylaxis is not recommended for CMV D−/R−SOT recipients. (High, Strong)
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HSV1‐ or HSV2‐seropositive CMV D−/R− SOT recipients should receive antiviral prophylaxis for prevention of herpes simplex infection (eg, acyclovir, valacyclovir, famciclovir). (High, Strong)

Please refer to the HSV guidelines.

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If blood transfusion is indicated, CMV D−/R− should receive CMV‐negative blood or leuko‐depleted blood products. (High, Strong)
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For the prevention of postprophylaxis delayed‐onset CMV disease:

CMV QNAT at least once weekly for 3 months may be considered for surveillance to detect CMV replication after completion of antiviral prophylaxis. (Low, Strong)

Detection of CMV DNA above a predefined threshold should be preemptively treated with valganciclovir or intravenous ganciclovir.

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Transplant recipients should be counseled of the risk of postprophylaxis delayed‐onset CMV disease upon discontinuation of antiviral prophylaxis. (Low, Strong)
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Close clinical follow‐up is highly recommended. (Low, Strong)
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Measures of lymphopenia (Low, Weak)
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and impairment in global (nonspecific) and CMV‐specific T‐cell responses (Moderate, Strong)
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at the end of antiviral prophylaxis may be used to assess the risk of postprophylaxis delayed‐onset CMV disease.

CMV serology at the end of antiviral prophylaxis has limited role in assessing the risk of postprophylaxis delayed‐onset CMV disease and is not routinely recommended. (Low, Weak)
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Antiviral prophylaxis with valganciclovir or intravenous ganciclovir should be given to patients receiving lymphocyte‐depleting anti‐lymphocyte antibodies for the treatment of rejection. (High, Strong)
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The optimal duration of antiviral prophylaxis after treatment of rejection with lymphocyte‐depleting drug is not known, but has been given for 1‐3 months. (Moderate, Weak)
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Preemptive therapy

Preemptive therapy may be used for effective prevention of CMV disease in SOT recipients. (, Strong)
(moderate to high)
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Preemptive therapy is clinically useful for the prevention of CMV disease in CMV R+ kidney, liver, pancreas, and heart recipients. (High, Strong)
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Preemptive therapy is effective for the prevention of CMV disease in CMV D+/R− liver and kidney patients, as long as personnel and logistics of close surveillance and follow‐up (ie, CMV QNAT results are available on the same day of testing) are available. (High, Strong)
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  • If these are not available, antiviral prophylaxis is preferred for D+/R− liver and kidney recipients.
(High, Strong)
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Preemptive therapy is not recommended for prevention of CMV disease in CMV D+/R− and R+ lung, (High, Strong)
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  • and it is less preferred for CMV D+/R− heart recipients.
(Low, Weak)
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Antiviral prophylaxis is preferred over preemptive therapy for lung and heart recipients. (, Strong)
(moderate to high)
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Preemptive therapy is less preferred after intestinal and composite tissue allograft transplantation. (Low, Weak)
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Preemptive therapy may be considered as alternative approach to CMV prevention in patients with acute rejection treated with anti‐lymphocyte antibody. (Low, Weak)
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  • or high-dose steroids.
(Low, Weak)
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The laboratory test recommended for CMV monitoring to guide preemptive therapy is CMV QNAT (preferred) or a pp65 antigenemia assay. (High, Strong)
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The recommended monitoring frequency is at least once weekly and the duration is at least 12 weeks after transplantation. (High, Strong)
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  • The duration of CMV QNAT monitoring may be extended longer for patients considered at highly immune suppressed status, or CMV‐specific T cell‐deficient.
(Low, Strong)
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There is no widely applicable viral load threshold for initiation of preemptive therapy, and this value should be assay‐specific, center‐specific, and risk‐specific. (Moderate, Strong)
Future studies are needed to define clinically relevant viral load thresholds in IU/ml for the initiation of preemptive therapy. However, these thresholds will likely remain assay‐specific and risk profile‐dependent.
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The recommended antiviral drugs for preemptive therapy are valganciclovir (900 mg twice daily) and intravenous ganciclovir (5 mg/kg every 12 hours), adjusted based on renal function. (High, Strong)
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The duration of preemptive antiviral therapy should be individualized. (High, Strong)
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CMV QNAT (or pp65 antigenemia) should be performed once weekly to monitor response to preemptive treatment. (High, Strong)
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Antiviral therapy should be continued until CMV DNAemia or antigenemia is no longer detectable or has declined to levels below a predefined threshold. (High, Strong)
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  • When using less sensitive assays, CMV QNAT should be undetectable or below a predefined threshold for at least 2 consecutive weeks in the blood prior to stopping antiviral treatment.
(Moderate, Strong)
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  • The duration may be reduced to a single negative result when using a highly sensitive CMV QNAT assay.
(Moderate, Weak)
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There are data supporting the potential role of CMV‐specific T‐cell immune monitoring to guide the need and the duration of preemptive antiviral therapy. (Low, Weak)

However, further research is needed before this can be adapted widely in clinical practice.

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HSV1‐ or HSV2‐seropositive SOT recipients who are undergoing CMV surveillance, and not actively receiving valganciclovir or intravenous ganciclovir, should receive herpes simplex virustargeted antiviral prophylaxis with acyclovir, valacyclovir, or famciclovir. (High, Strong)

Refer to the HSV guidance for specific recommendations.

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TREATMENT

CMV disease should be treated with intravenous ganciclovir (5 mg/kg every 12 hours) or oral valganciclovir (900 mg twice daily), adjusted based on renal function. (High, Strong)
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Intravenous ganciclovir is the recommended initial treatment for severe or life‐threatening CMV disease, (High, Strong)
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  • those with very high viral load,
(Moderate, Strong)
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  • and those with questionable gastrointestinal absorption.
(Moderate, Strong)
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Oral valganciclovir and intravenous ganciclovir are equally effective initial therapy for mild‐to‐moderate CMV disease. (High, Strong)
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Because of the risk of nephrotoxicity, foscarnet and cidofovir are considered second‐line alternative drugs for SOT recipients unable to tolerate valganciclovir or intravenous ganciclovir. (Moderate, Strong)
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Until clinical trials demonstrate its efficacy and safety in the SOT population, letermovir is not recommended for treatment of CMV disease after SOT. (Low, Strong)
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Antiviral treatment of CMV disease should be continued until the following criteria are met
  • Resolution of clinical symptoms, AND
  • Virologic clearance below a threshold negative value (test specific; see text) based on laboratory monitoring with CMV QNAT or pp65 antigenemia once a week, AND
  • Minimum 2 weeks of antiviral treatment
(High, Strong)
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Transplant recipients with CMV disease treated initially with intravenous ganciclovir may be switched to oral valganciclovir once there is adequate clinical and virologic control, based on the clinical assessment of the treating provider. (High, Strong)
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Acyclovir, valacyclovir, and oral ganciclovir (no longer commercially available in the United States) should NOT be used for treating CMV disease. (High, Strong)
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The addition of IVIg or CMV‐Ig to antiviral treatment of CMV disease may be considered for patients with life‐threatening disease, CMV pneumonitis and possibly other severe forms of disease, drug‐resistant virus, and those with hypogammaglobulinemia. (Low, Weak)
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CMV QNAT (or pp65 antigenemia) should be performed once weekly to assess virologic response to treatment. (High, Strong)
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Only one type of CMV QNAT assay and one sample type (plasma or whole blood) should be used to assess virologic response over the course of CMV disease. (High, Strong)
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CMV QNAT should decline to a level below a predefined threshold or to undetectable level prior to stopping antiviral treatment of CMV disease. (High, Strong)
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  • When using less sensitive assays, CMV QNAT should be undetectable or below the predefined threshold for at least two consecutive weeks in the blood prior to stopping antiviral treatment.
(Moderate, Strong)
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The duration may be reduced to a single negative result when using a highly sensitive CMV QNAT assay. (Moderate, Weak)
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Complete blood count (with differential) and serum creatinine should be monitored once weekly to assess for potential drug toxicity. (High, Strong)
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Antiviral drug dosing should not be adjusted down due to leukopenia or pancytopenia. (High, Strong)
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Antiviral drug dosing should be adjusted based on renal function. (High, Strong)
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Serum ganciclovir level monitoring (therapeutic drug monitoring) is not recommended for routine clinical use. (Moderate, Strong)
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After completion of full‐dose antiviral treatment, secondary prophylaxis intended to prevent CMV relapse is not recommended as a routine practice for all patients, (Moderate, Strong)
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  • but may be considered in subsets of high‐risk patients.
(Low, Weak)
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Patients should have clinical and virologic follow‐up after discontinuation of antiviral treatment to assess the risk of CMV relapse. (Moderate, Strong)
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Lymphopenia may be used to assess the risk of CMV relapse. (Low, Weak)
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CMV‐specific (and nonspecific) T‐cell immune monitoring may be used to determine a patient's risk of CMV relapse. (Low, Weak)
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The approach to preventing CMV relapse in high‐risk T cell-deficient patients is not known, but approaches such as secondary prophylaxis (Low, Weak)
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  • and further reduction in immunosuppression to allow for T‐cell immune reconstitution, if feasible, are suggested.
(Low, Weak)
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If feasible, cautious reduction in immunosuppression should be considered in SOT patients presenting with CMV disease, especially if moderate to severe. (Moderate, Strong)
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Reduction in immunosuppression may not be feasible in patients with recent rejection or at heightened risk of rejection episodes. (, )
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Reduction in immunosuppression should be strongly considered in SOT patients with severe lymphopenia and those with deficient nonspecific or CMV‐specific T‐cell function. (Low, Weak)
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REFRACTORY AND RESISTANT CMV

Patients who develop refractory CMV infection or disease after prolonged antiviral drug exposures and those failing to respond after at least two weeks of appropriately dosed antiviral treatment should be suspected of having drug‐resistant virus. (Moderate, Strong)
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Genotypic assays to detect UL97 mutation should be performed among patients suspected to have resistance to ganciclovir, and UL54 mutation analysis should be performed among patients suspected to have resistance to ganciclovir, foscarnet, and cidofovir, and this is preferred over phenotypic resistance testing. (, Strong)
(moderate to high)
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Genotypic assay to detect mutations in UL56 and less commonly in UL51/UL89 should be performed when resistance to letermovir is suspected. (Low, Strong)
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Cautious reduction in immunosuppression is recommended for patients with refractory or resistant CMV infection and disease. (Moderate, Strong)
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A switch to sirolimus‐containing regimen may be an option due to the reportedly lower risk of CMV disease in patients receiving mTOR inhibitors. (Moderate, Weak)
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Options for empiric treatment of suspected resistant CMV disease include high‐dose intravenous ganciclovir (up to 10 mg/kg q 12 hours, renally adjusted) or foscarnet. (, Weak)
(low to moderate)
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  • Definitive antiviral treatment should be guided by results of genotypic testing.
(, Strong)
(moderate to high)
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Other therapeutic options are cidofovir (weak, low), participation clinical trials (eg, maribavir treatment of refractory and resistant CMV), (Low, Strong)
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  • and off‐label letermovir.
(Very Low, Weak)
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CMV immunoglobulin or IVIg may be used as an adjunct to antiviral drugs in transplant recipients with resistant CMV disease. (Low, Weak)
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If available, adoptive transfer of CMV‐specific T cells may be considered for the treatment of refractory and resistant CMV, (Low, Weak)

but this will need to be investigated further in controlled clinical trials.

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PEDIATRIC ISSUES

Pretransplant screening

In pediatric SOT candidates <18 months of age who may have passively acquired maternal CMV IgG antibody, CMV QNAT or culture of urine specimen may be performed to determine baseline CMV status. (Moderate, Strong)
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If urine CMV QNAT or culture is positive, the transplant candidate is considered CMV‐infected. (High, Strong)
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If urine CMV QNAT or culture is negative, the assignment of CMV status should be based on the highest‐risk level for the purposes of CMV prevention, and will take into account the CMV status of the donor. (Moderate, Strong)
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  • For donors <18 months age, if the CMV serology is positive, the donor should be assumed as truly seropositive.
(Moderate, Strong)
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Prevention and treatment

Antiviral prophylaxis, preemptive therapy, and hybrid approach are effective for prevention of CMV disease in pediatric SOT patients. (Moderate, Strong)
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Intravenous ganciclovir and oral valganciclovir are recommended for CMV prophylaxis, preemptive treatment of asymptomatic infection, and treatment of established CMV disease. Dosing of valganciclovir in children should be based on body surface area and renal function. (Moderate, Strong)
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There is no single standard recommendation for the optimal duration of antiviral prophylaxis. The duration of intravenous ganciclovir prophylaxis varies from a minimum of 14 days to 3 months. Other centers prolong antiviral prophylaxis to 6 months after transplantation. (Moderate, Weak)
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The risk of postprophylaxis delayed‐onset CMV disease is highest during the first 3 months after cessation of antiviral prophylaxis, and pediatric SOT patients should undergo CMV QNAT surveillance during this at‐risk period. (Moderate, Strong)
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For pediatric patients undergoing the strategy of preemptive therapy, CMV QNAT is recommended once weekly for at least 12 weeks. (High, Strong)
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Oral valganciclovir is recommended for treatment of asymptomatic CMV DNAemia. (Low, Strong)
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Treatment of mild‐to‐moderate CMV disease is with intravenous ganciclovir (Moderate, Strong)
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  • or oral valganciclovir.
(Low, Strong)
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Intravenous ganciclovir is recommended as first‐line therapy for severe CMV disease. (Moderate, Strong)
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CMV‐Ig or intravenous Ig is generally not recommended (Low, Weak)
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  • but may be considered in combination with intravenous ganciclovir for the treatment of CMV disease in young infants and for treatment of more severe forms of CMV disease.
(Low, Weak)
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Intravenous ganciclovir treatment of CMV disease in pediatric SOT recipients may be transitioned to oral valganciclovir in clinically stable patients with declining and well‐controlled viremia and resolved or resolving clinical symptoms. (Low, Strong)
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Recommendation Grading

Overview

Title

Cytomegalovirus In Solid Organ Transplant Recipients

Authoring Organization

Publication Month/Year

March 1, 2019

Document Type

Guideline

External Publication Status

Published

Country of Publication

US

Document Objectives

This updated guideline from the American Society of Transplantation Infectious Diseases Community of Practice provides evidence‐based and expert recommendations for screening, diagnosis, prevention, and treatment of CMV in solid organ transplant recipients.

Target Patient Population

Solid organ transplant recipients

Inclusion Criteria

Female, Male, Adolescent, Adult, Older adult

Health Care Settings

Ambulatory, Hospital, Operating and recovery room, Outpatient

Intended Users

Nurse, nurse practitioner, physician, physician assistant

Scope

Assessment and screening, Diagnosis, Prevention, Treatment

Diseases/Conditions (MeSH)

D014180 - Transplantation, D019737 - Transplants, D016377 - Organ Transplantation, D003587 - Cytomegalovirus, D003586 - Cytomegalovirus Infections

Keywords

transplant, solid organ transplant, cytomegalovirus

Source Citation

 https://doi.org/10.1111/ctr.13512