Cytomegalovirus in Solid Organ Transplantation (장기이식 환자에서 CMV 감염 진료 지침)

Cytomegalovirus in Solid Organ Transplantation
(장기이식 환자에서 CMV 감염 진료 지침)


CMV infection
Presence of CMV replication regardless of symptoms
CMV replication is detected (1) nucleic acid testing (NAT), (2) antigen testing and (3) culture. Depending on the method used, CMV infection can be termed as CMV DNAemia or RNAemia (NAT), CMV antigenemia (viral antigen testing) and CMV viremia (culture).

CMV disease
CMV infection accompanied by clinical signs and symptoms.
CMV disease is categorized into 
(1) CMV syndrome, which manifests as fever and/or malaise, leukopenia or thrombocytopenia, and 
(2) tissue-invasive CMV disease (e.g. gastrointestinal disease; pneumonitis; hepatitis; nephritis;myocarditis;pancreatitis; retinitis, others). 
CMV infection without any clinical manifestations should be labeled “asymptomatic CMV infection.”


Risk Factors of CMV disease

(1) primary CMV infection occurs in an SOT recipient with no preexisting CMV-specific immunity, such as the CMV donorseropositive, recipient-seronegative (D+R–) patient

(2) Overall state of immunosuppression as determined by the immunosuppressive protocol (e.g. type of drug, dose, timing, duration), host factors (e.g. age, comorbidity, leukopenia and lymphopenia, genetic factors) and others (e.g. cold ischemia time, critical illness, stress)

(3) Use of lymphocyte-depleting agents such as antilymphocyte antibodies is associated with CMV disease, particularly when these are used for rejection therapy

(4) Lung and small intestinal recipients are considered at highest risk among SOT recipients. (in part due to the amount of lymphoid tissue in transplanted organs and the intensity of immunosuppression.)
(5) Coinfections with human herpes virus (HHV)-6 and HHV-7 have been suggested as
risk factors

CMV D–/R– SOT recipients have the lowest risk of CMV disease, and they should receive CMV-negative blood or leuko-depleted blood products. The use of mTOR inhibitors (everolimus, sirolimus) is associated with a lower risk of CMV disease

Laboratory Diagnosis

(1) histopathology

presence of tissue-invasive CMV disease
invasive procedure to obtain tissue for diagnosis
may be needed when CMV disease is suspected but CMV testing in the blood is negative, such as in some cases of gastrointestinal CMV disease

(2) culture

Viral culture is highly specific for the diagnosis of CMV infection. However, its use is limited by its modest sensitivity and slow turn-around time. Tissue culture may take weeks before the virus can be detected. Viral culture is needed when phenotypic antiviral drug resistance testing is requested, although genotypic assays are the method of choice for detecting drug resistance.

(3) serology

CMV serology to detect CMV-IgM and IgG antibodies has a limited utility for diagnosis of CMV disease after transplantation. Because of immunosuppression, SOT recipients may have delayed or impaired ability to mount an antibody response to CMV infection.

Serologic assays to detect CMV-IgM and IgG antibodies should not be used for the diagnosis of CMV disease

(4) antigenemia

semiquantitative assay that detects pp65 antigen in CMV-infected peripheral blood leukocytes. The CMV antigenemia assay is useful to guide preemptive therapy, for rapid and sensitive diagnosis of CMV disease, and to guide treatment responses. The main disadvantage is the need to process the clinical sample within few hours, and since the test relies on leukocytes, it has limited utility in leukopenic patients.

(5) molecular assays that detect and quantify CMV nucleic acid (NAT)

Molecular tests that detect CMV DNA or RNA are the preferred methods for the diagnosis of CMV after SOT. detection of CMV RNA is indicative of active CMV replication. In contrast, detection of CMV DNA may or may not reflect CMV replication since a highly sensitive NAT may amplify latent viral DNA. Hence, quantitative NAT (QNAT) assays have been developed to potentially differentiate active viral replication (typically associated with high viral load) from latent virus (low-level CMV DNAemia if using highly sensitive tests. Higher CMV load values are generally associated with tissue-invasive disease, while lower values are seen with asymptomatic CMV infection, and intermediate-range viral loads are seen with CMV syndrome. the faster the rise in CMV load, the higher is the risk of CMV disease.

QNAT is useful for guiding preemptive therapy, for rapid and sensitive diagnosis of CMV infection, and to guide treatment responses

The major drawback to QNAT is the lack of (until recently) an international reference standard. Accordingly, the viral load results of one assay cannot be directly extrapolated as equal that of another assay. An up to a 3-log10 variation among different CMV QNAT has been demonstrated, due to differences in assay platform, samples, calibrator standards, gene target, extraction techniques, among others.

In 2011, the WHO released the first International Reference Standard for the quantification of CMV nucleic acid, and laboratory and commercially developed CMV QNAT assays should now be calibrated to this standard.
--> CMV QNAT assays should be calibrated based on the WHO International Reference Standard.

CMV QNAT or pp65 antigenemia should be performed once weekly for monitoring the response of CMV disease to antiviral treatment, should be performed once weekly to predict risk of CMV disease, if preemptive therapy is used for CMV prevention.


Prevention of CMV Disease

The two major strategies for CMV prevention

(1) Antiviral prophylaxis (Universal Anti-CMV Prophylaxis)
  - administration of antiviral drug to all “at-risk” patients for a defined period after SOT
  - advantage of preventing reactivation of other herpes viruses, and has been associated with a lower incidence of indirect CMV effects.
  - antiviral prophylaxis is associated with late-onset CMV disease, particularly among CMV D+/R– patients

Antiviral drugs for CMV prophylaxis are valganciclovir and oral or intravenous ganciclovir.
In general, antiviral prophylaxis should be started as early as possible, and within the first 10 days after transplantation
CMV-specific antiviral prophylaxis is not recommended for CMV D–/R– SOT recipients as long as they receive CMV-negative blood or leuko-depleted blood products.

(2) Preemptive therapy (Pre-Emptive Anti-CMV Therapy)
  - administration of antiviral drug only to asymptomatic patientswith evidence of early CMV replication in order to prevent CMV disease.
  - SOT recipients are monitored at regular intervals (usually once weekly) for evidence of early CMV replication using a laboratory assay such as CMV QNAT or pp65 antigenemia.
  - lower drug costs and adverse toxicities
  - difficult approach for patients who reside at considerable distance from the transplant center.
  - Due to a lack of QNAT standardization, there is currently no widely acceptable viral load threshold that can guide preemptive therapy.

There is debate as to the optimal method for monitoring (pp65 antigenemia or QNAT), the viral load threshold to guide antiviral therapy, the duration of antiviral therapy, and the duration of laboratory monitoring.

However, due to the current lack of standardized assays and reporting (as discussed earlier), site-specific and assay-specific viral load threshold values for initiation of preemptive therapy should be locally validated prior to institution of a preemptive protocol.

The recommended monitoring frequency is once weekly for 12 weeks after transplantation

Once pp65 and QNAT is positive above a defined threshold, treatment with oral valganciclovir (900-mg twice daily) or intravenous ganciclovir (5-mg/kg twice daily) should be initiated.

Antiviral therapy should be continued until CMV DNAemia or antigenemia is no longer detectable. Many authorities recommend treating until two consecutive negative weekly pp65 antigenemia or QNAT testing has been attained.

Laboratory monitoring for CMV by QNAT or pp65 antigenemia is recommended once weekly during antiviral therapy.

* 두 가지 치료에 대한 비교 연구
only few randomized trials directly comparing preemptive therapy versus antiviral prophylaxis. mainly in kidney recipients
--> demonstrate that both are similarly effective for CMV disease prevention. However, long-term graft survival was significantly higher with antiviral prophylaxis.

* Preemptive therapy 의 치료 알고리즘

Treatment of CMV Disease

The antiviral drugs for treating CMV disease are intravenous ganciclovir and valganciclovir. 
--> Intravenous ganciclovir (5 mg/kg every 12 h) or oral valganciclovir (900 mg twice daily)

Oral ganciclovir should NOT be used for treatment of CMV disease because its poor oral bioavailability will lead to insufficient systemic levels.
And, may lead to emergence of ganciclovir resistance.
The duration of antiviral therapy should be individualized based on resolution of clinical symptoms and virologic clearance. Generally, SOT recipients with CMV disease should bemonitored once weekly using pp65 antigenemia or QNAT to assess virologic response. Therefore, patients with CMV disease should remain on full therapeutic dose of antiviral therapy until CMV DNAemia or antigenemia has declined to undetectable levels or negative threshold value for a given test.


* CMV 치료의 목표

Treatment of CMV disease should be continued until the following criteria are met :
--> 모두 and 관계
(1) Resolution of clinical symptoms
(2) Virologic clearance belowa threshold negative value (test specific) based on laboratory monitoring with CMV QNAT or pp65 antigenemia once a week
(3) Minimum 2 weeks of antiviral treatment.

Transplant recipients with CMVdisease treated initially with intravenous ganciclovir may be switched to oral valganciclovir once there is adequate clinical and virologic control.

Ganciclovir Resistant CMV

The initial phosphorylation of ganciclovir is carried out by a kinase encoded by CMV gene UL97. Subsequent phosphorylation by cellular enzymes leads to the active ganciclovir-triphosphate, which competitively inhibits CMV DNA polymerase encoded by the viral gene UL54. Therefore, mutations in UL97 and less commonly in UL54 can confer ganciclovir resistance.

Combined mutations (UL97 and UL54) often have high-level resistance to ganciclovir. Isolated UL54 mutation (in the absence of UL97 mutation) is rare.

Foscarnet is often the first line for the treatment of UL97-mutant ganciclovir-resistant CMV. The major problem with foscarnet in transplant patients is significant nephrotoxicity.

Cidofovir is another alternative for the treatment. Cidofovir is highly nephrotoxic. Generally, ganciclovir-resistant CMV isolates with UL97 mutations remains susceptible to foscarnet and cidofovir.

Since ganciclovir, foscarnet and cidofovir act by competitively inhibiting UL54-encoded CMV DNA polymerase, mutations in the UL54 may result in resistance to any or all of these drugs depending on the site of themutation. Treatment should therefore be guided by genotypic assays

The incidence of ganciclovir-resistant CMV remains low. It was 1.9% in SOT patients who received 3 months of oral ganciclovir prophylaxis and 0% in patients who received 3 months of valganciclovir prophylaxis.
Risk factors for resistance include prolonged low-dose oral prophylaxis, D+/R–serostatus, increased intensity of immunosuppression and lung transplantation.

* Gaciclovir 내성을 의심해야 하는 상황

Resistance should be suspected if (1) the patient has received prolonged antiviral therapy, either as antiviral prophylaxis or preemptive therapy, (2) the viral load fails to decline or it increases despite 2 weeks of adequate dose antiviral therapy and (3) patients have other risk factors for resistance.
Genetic resistance testing should be very helpful in managing resistant CMV.
Genotypic testing for resistance should be performed, and this is preferred over phenotypic resistance testing.

Immunosuppression should be cautiously reduced in patients with drug-resistant CMV disease. Switch to sirolimus-containing regimen may be an option due to the reportedly lower risk of CMV disease in patients receiving mTOR inhibitors.
Options for the empiric treatment of drug-resistant CMV disease include increasing the dose of intravenous ganciclovir (up to 10-mg/kg two times a day) or full-dose foscarnet.

Reference : 
The AST Infectious Diseases Community of Practice. 
The American Society of Transplantation Infectious Disease Guidelines 3rd Edition. Am J Transplant 2013;13


2018. 7. 15 - SJH


Designed by JB FACTORY