ABSTRACT type-6 and -8) are also important in this

ABSTRACT 

Cytomegalovirus (CMV) infection remains one of the
most common infections in patients receiving solid organ transplantation (SOT).
In these patients, CMV is an important cause of morbidity and mortality due to
the development of invasive disease or the immunomodulatory effect of the virus
on the host immune system. Other herpes viruses (herpes simplex,
varicella-zoster, Epstein-Barr, herpesvirus type-6 and -8) are also important
in this setting. During the last few years, new data and consensus documents on
the management of these infections have been generated. In this chapter we provide
practical  recommendations to guide
clinicians on the prevention and treatment of these common viruses.

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PREVENTION AND
TREATMENT OF CYTOMEGALOVIRUS (CMV) INFECTION.

 

DESCRIPTION OF THE PATHOGEN. 

CMV
is a double-stranded DNA virus of the Herpesviridae
family that has the capacity to produce primary infection or reactivation in SOT
 recipients. 

DEFINITIONS

–      
Infection or
replication: Isolation of the virus or the detection of viral
proteins (antigenemia) or CMV DNA/mRNA in any body liquid or tissue. In the SOT
literature, latent infection is considered a separate entity.

–      
Antigenemia: Direct
detection of the CMV pp65 antigen in peripheral blood leukocytes, mainly
neutrophils.

–      
DNAemia: Detection of
CMV DNA in plasma or whole blood.

–      
CMV disease: Evidence of
symptoms or signs coupled with the detection of CMV infection in blood or
tissue.

–      
 “Viral syndrome”: presence of
fever and/or malaise associated with the presence of leukopenia,
thrombocytopenia or an increase in transaminases.  This is considered a type of CMV disease.

–      
Universal
prophylaxis: Administration of an effective antiviral drug to
prevent the development of CMV replication and/or disease in at-risk patients.

–      
Preemptive
therapy: Regular monitoring for CMV replication followed by initiation of antiviral
treatment in patients displaying asymptomatic CMV replication in order to
prevent progression to CMV disease .

 

 

DIAGNOSIS. 

Although
antigenemia is still used, a quantitative real-time nucleic acid amplification
based assay or polymerase chain reaction (PCR) is recommended for the diagnosis
and monitoring of CMV infection after transplantation. Viral loads can be
determined in both plasma and whole blood samples, but the same type of sample
should be used when comparing viral loads or following a given patient. There
are also differences between viral loads obtained in different centers, thus
making an international standard reference necessary. There is a direct
association between viral load values and the likelihood that an individual
will develop active disease. Moreover, the rate of increase of viral loads is
also a predictor of developing disease. Due to the variability of the results
among laboratories, a single test should be used for monitoring patients over
time. Laboratories should establish their own cutoffs and audit clinical
outcomes to verify the trigger points used for treatment.

Viral resistance depends on the existence of mutations
in the CMV genome. Plasma or whole blood is the sample of choice. Genotypic
assays (PCR amplification) are available for clinical use. Two genomic regions
must be studied: UL97 kinase gene involved in the initial phosphorylation of
ganciclovir (codons 400-670) and the UL54 polymerase gene (codons 300-1000). Common
UL97 and UL54 mutations are shown in  Table 1. A web-based search tool, www.informatik.uni-ulm.de/ni/staff/HKestler/hcmv/, has been developed
that links the sequence to a database containing all published UL97 and UL54
mutations and corresponding antiviral drug susceptibility phenotypes. If
mutations only appear in the UL97 gene, viruses are resistant only to
ganciclovir. UL54 mutations typically added to pre-existing UL97 mutations, may
 increase the level of ganciclovir
resistance and commonly confer varying levels of cross-resistance to other CMV
antivirals such as foscarnet or cidofovir. In the future, next-generation
sequencing (NGS) technologies may enable the detection of far smaller viral
subpopulations and may therefore improve the detection of drug resistance
emergence.

 

 

IMMUNOLOGICAL
MONITORING

Testing
for anti-CMV IgG antibodies should be performed before transplantation in
donors and recipients for the purposes of risk-stratification. In recipient -negative
(R-) patients, testing should be repeated at the time of transplantation. Donor
serostatus should also be performed to stratify  the subsequent risk of CMV infection and
disease.

CMV
specific cell-mediated assay may also be clinically useful.  The characteristics of different technics
available for immunological monitoring are reviewed in table 2. If available, pretransplant
CMV-specific cell-mediated immunity has been explored together with serological
testing to stratify the risk of CMV infection after transplantation. This
approach may be  particularly useful in
R+ recipients. The potential utility of monitoring CMV-specific cell-mediated
immunity has been investigated in various posttransplant clinical scenarios.
Overall, a reactive test has  a high
negative predictive values for detecting risk of CMV replication, supporting
the safety of discontinuing prophylaxis in high-risk patients above the
protective threshold. Alternatively, patients with no evidence of protective
response at the end of the prophylaxis period could benefit from the so-called
“hybrid approach” (in which preemptive monitoring is initiated after completing
prophylaxis). On the other hand, immune monitoring in intermediate-risk
patients managed preemptively may be useful in guiding the frequency for
surveillance of CMV infection and the thresholds for initiating antiviral
therapy, or in case of treatment failure after appropriate antiviral therapy.
However, further clinical trials are required to evaluate protocolized
interventions based on the posttransplant kinetics of CMV-specific responses.

 

PREVENTION.

Two major
strategies have been employed to prevent CMV infection: universal prophylaxis
and preemptive therapy. Both are effective in the prevention of CMV. Universal prophylaxis may be preferable in  scenarios of aggressive viral dynamics
(lymphocyte-depleting therapy, potent immunosuppression, D+/R- setting). Oral valganciclovir or intravenous Ganciclovir
is currently the preferred antiviral. High-dose Valacyclovir is an  alternative option  in renal transplantation.  

Late-onset
CMV disease, defined as disease occurring after discontinuation of prophylaxis,
has been found in all studies evaluating universal prophylaxis in D+/R- transplant
recipients. A 200-day prophylaxis regimen can be recommended in D+/R- kidney
transplant patients and, by extension, possibly in other high-risk transplant
recipients (e.g. heart, pancreas). In R+ patients, three-month regimens  are recommended. In lung and intestinal
transplant recipients, the majority of the groups extend prophylaxis over 6 to
12 months after transplantation for both D+/R- and R+ patients. In recipients
receiving alemtuzumab as induction therapy, monitoring of CD4+ T lymphocytes
has been used to continue prophylaxis (for at least 6 months) until CD4 T
lymphocytes are over 200 cell/mm3.

          In a pre-emptive strategy,
viral load is typically monitored weekly for the first 12-14 weeks
post-transplant. There are no evidence-based recommendations regarding the
viral load cutoff for initiating antivirals and the optimal duration of
preemptive therapy. It may be preferable to initiate preemptive therapy in any high-risk
patients with a positive viral load. In lower risk patients, it is possible to
establish local cut-off points and eventually delay therapy, consider reducing
the levels of immunosuppressive therapy and repeat a second viral load after a
short interval , since small blips may disappear spontaneously. Treatment
should be administered for a minimum of 2 weeks. Monitoring of CMV viral load
should direct the extension of treatment. At least one negative viral load
determination (or viral load below a specific threshold) in plasma specimens is
required in order to withdraw treatment.  Relapse
of CMV infection is frequent after a therapy course, although it is
generally resolved after a new course of treatment.

There is no available data
supporting the use of a combined preemptive therapy strategy after  prophylaxis in low-risk transplant recipients.
 Nevertheless, this strategy, which is
known as a “hybrid strategy”, is commonly used in certain high-risk transplant
recipients (D+/R-, lung, pancreas and small bowel recipients and/or those
receiving lymphocyte-depleting treatments). The duration has not been
determined.

Taking into account the low risk
of CMV disease reported in the subgroup of D-/R- recipients, the use of
prophylaxis or preemptive therapy have not been recommended. Other measures,
such as the use of leuko-depleted or CMV-seronegative blood products, directed
at preventing CMV infection acquisition, are recommended. Monitoring of primary
CMV infection may be of interest in patients at a higher risk of severe primary
infection.

Hypogammaglobulinemia
(IgG <500 mg/dL) is a risk factor for CMV disease after SOT transplantation. In heart transplant recipients, the administration of non-specific intravenous immunoglobulins (IVIGs) with the goal of maintaining normal IgG levels was associated with a lower risk of CMV infection. In heart, lung and intestinal recipients at high-risk for CMV disease (D+R-), some centers add specific anti-CMV IVIG to prevent CMV infection. The best dosing regimen has not been established. A recommendation regarding the use of CMV vaccine in SOT recipients cannot be made as no vaccine has been approved for use in a clinical setting.       TREATMENT Intravenous ganciclovir and oral valganciclovir are the antiviral drugs of choice for treating CMV infection and disease. Intravenous ganciclovir (5 mg/kg/12h) should be used in patients with severe CMV disease or when valganciclovir is poorly tolerated or not well absorbed. It is important to administer the appropriate doses of intravenous ganciclovir or oral valganciclovir adjusted for renal function, as inadequate dosing can cause clinical failure or viral resistance. Oral valganciclovir (900 mg/12h) is effective in patients with mild to moderate CMV disease. It can also be used in sequential therapy in patients treated with intravenous ganciclovir, once clinical improvement is documented. The optimum duration of treatment, should  be guided by weekly virological monitoring (treat until viral load negative or below a certain threshold) and clinical response. The minimum duration of treatment is two weeks. Following initial treatment secondary prophylaxis is commonly used for a period of 1-3 months although evidence for this is lacking. The treatment of a recurrence should generally be  the same used during the first episode. The evidence to support the use of specific anti-CMV immunoglobulins in cases of life-threatening CMV disease, particularly severe pneumonitis is lacking, although it is often used. Resistance to antiviral drugs should be suspected in the presence of progressive or stable viral loads or if clinical symptoms persist despite adequate antiviral treatment for 2 weeks, especially in the presence of risk factors (D+/R- serostatus, serious invasive disease and/or high viral load, intermittent low-level viral replication during therapy or suboptimal drug levels and prolonged antiviral drug exposure, and lung transplantation). If genotypic tests demonstrate the existence of a high-level resistance mutation in the UL97 gene or the UL54 gene (table 1), foscarnet is indicated. Increasing the dose of ganciclovir up to 10 mg/kg/12h might be useful for other mutations in the UL97 gene and can be considered for patients with non-severe CMV disease, or in those whom the use of foscarnet should be avoided (nephrotoxicity). Maribavir has been successfully used in salvage therapy in patients with refractory/resistant CMV infection and is currently in phase 3 trial for this indication. Brincidofovir and letermovir are also promising drugs that need clinical development in this indication. Switching immunosuppression from calcineurin inhibitors to an mTOR inhibitor-based regimen has proposed as an adjunctive therapy but is unproven.  Leflunomide should be considered unproven therapy for this indication.  Adoptive immunotherapy can be useful for the rescue of case refractory to conventional treatment and who do not develop a satisfactory immune response. However, clinical experience is very limited, and the technique can only be used in the setting of research projects or rescue strategies. General approach. The top recommendations for the management of CMV infection are provided in table 3.                 PREVENTION AND TREATMENT OF OTHER HERPES VIRUSES.   DESCRIPTION OF THE PATHOGENS.  Herpes simplex virus (HSV), varicella-zoster virus (VZV), human herpesvirus type-6 (HHV-6) and -8 (HHV-8) virus belong to the Herpesviridae family and have the capacity to produce primary infection or reactivation in the recipients of a solid organ transplant. Epstein-Barr virus is reviewed in a specific chapter. Human hersvirus-7 is generally not of significant  clinical impact.   HERPES SIMPLEX VIRUS.   Diagnosis Pretransplant IgG serostatus of recipients is necessary for posttransplant risk stratification. Transplant patients can have atypical mucocutaneous lesions and visceral or disseminated disease. Laboratory confirmation may be necessary. PCR testing of mucocutaneous, lesions, bronchoalveolar lavage and other clinical samples (plasma, cerebrospinal fluid) is the diagnostic test of choice. The clinical significance of finding HSV DNA in the blood of patients without disseminated disease has not been well established. Also, a positive BAL PCR may be either due to mucutaneous contamination during sampling or due to HSV pneumonitis. Tissue histopathology with immunocytochemistry for HSV can be helpful.       Prevention HSV prophylaxis is generally indicated for HSV-1 or -2 seropositive recepients not receiving CMV prophylaxis ((val)ganciclovir prevents HSV replication). Some experts also recommend prophylaxis in HSV seronegative to prevent the infection transmitted from organs or blood transfusions, however, this is a rare occurrence.  A low-dose acyclovir regimen (< 1gr/day) is effective  (200 mg three or four times a day, 400 mg two times a day) for prophylaxis. Valacyclovir (two times a day) or Famciclovir can also be used. Antiviral prophylaxis should continue for at least a month. Resumption of prophylaxis may be considered for patients being treated with T cell depleting agents. In patients with severe clinical recurrences (?2), suppressive antiviral therapy may be indicated and may occasionally be required for very prolonged durations. All recepients (not only seronegative) should avoid contact with persons with active lesions. Condoms do not completely protect against HSV transmission. HSV-2 seronegative transplant recipients should consider having their partner tested for HSV-2. In serodiscordant couples, daily antiviral therapy taken by the seropositive partner can prevent HSV-2 transmission to the seronegative partner. The efficacy of postexposure prophylaxis is unknown.     Treatment. Disseminated, visceral, or extensive mucocutaneous HSV disease should be treated with intravenous acyclovir at a dose of 5–10 mg/kg every 8 h for a minimum of 2 weeks (3 weeks in case of encephalitis).  Non- severe mucocutaneous disease can be treated with oral acyclovir, valacyclovir or famciclovir fora minimum of one week. Overall treatment durations are determined by clinical response. HSV keratitis can be treated with systemic or topical agents (trifluridine solution, vidarabine ointment or topical ganciclovir gel). Resistance must be considered in patients whose lesions are not responding clinically to appropriate doses of systemic therapy. Genotypic testing for known resistance mutations is available in some settings. Intravenous Foscarnet or Cidofovir are recommended, but both are associated with significant renal toxicity. Topical agents (imiquimod, cidofovir, trifluridine) can be used for resistant anogenital disease. General approach.  The top recommendations for the management of HSV infection are provided in table 4.   VARICELLA ZOSTER VIRUS   Diagnosis All recipients should undergo serologic testing to determine posttransplant risk. In general, both primary varicella and herpes zoster have typical clinical presentations that allow for a presumptive clinical diagnosis. Nevertheless, transplant recipients can have atypical presentations or multi-organ involvement with delayed or absent rash. Definitive laboratory testing is indicated for atypical cases and visceral disease. PCR is the method of choice (vesicle fluid, serum, spinal fluid, and other tissues).   Prevention. Antiviral therapy.  Antiviral prophylaxis for VZV is not needed during periods of CMV prophylaxis. Herpes simplex (HSV) prophylaxis may also be effective against VZV during the period immediately posttransplant. Pretransplant vaccination. Seronegative potential transplant patients should receive varicella vaccination with the live attenuated vaccine at least 4 weeks before transplant. Posttransplant vaccination. The live vaccine poses a risk of disseminated infection in immunosuppressed patients and therefore is contraindicated for posttransplant recipients . Postexposure prophylaxis. Options for postexposure prophylaxis include passive immunoprophylaxis and/or antiviral therapy. VZV inmmunoglobulins are recommended in susceptible (seronegative) patients exposed to VZV and should be given as soon as possible but within at least 10 days of exposure. Antiviral therapy should be considered as adjunctive therapy or in patients who were unable to receive immunoprophylaxis before 10 days after their exposure. Acyclovir or valacyclovir or famciclovir can be used for a 7-14 day course.   Treatment. Varicella. Patients should be treated with intravenous acyclovir, initiated early, especially within 24-hours of rash onset. Herpes zoster. Patients with disseminated or organ invasive disease should be treated with IV acyclovir. Localized nonsevere HZ can be treated with oral valacyclovir or famciclovir, with the exception of herpes zoster ophthalmicus or oticus. General approach. The top recommendations for the management of HZV infection are provided in table 5. HUMAN HERPESVIRUS 6   Diagnosis Routine monitoring for HHV-6 is not recommended based on the current evidence or low rate of disease and subclinical infections. Diagnostic testing should be limited to symptomatic HHV-6 disease, in order to guide treatment. Quantitative real-time PCR is preferred for the detection of HHV-6 viremia. It can distinguish between HHV-6A, HHV-6B but they may not always differentiate active from latent infection depending on the sample type or assay used. It is also important to consider the potential detection of chromosamally integrated HHV-6 in blood samples, characterized by persistent HHV-6 viral loads typically of over a million copies per mL of whole blood, which may be misinterpreted as active infection leading to unnecessary treatment. Qualitative or quantitative HHV-6 PCR of the cerebrospinal fluid is useful to diagnose HHV-6 encephalitis in patients with the appropriate clinical signs. Immunohistochemistry to detect viral antigens in biopsy specimens is appropriate in cases of organ disease, although it can be detected in the absence of symptoms.   Prevention Specific antiviral prophylaxis or pre-emptive therapy for HHV-6 infection is not recommended.  Antiviral prophylaxis for CMV does appear to reduce the incidence of HHV-6 viremia.   Treatment Treatment of asymptomatic viral reactivation is not recommended. Ganciclovir, foscarnet and cidofovir can be active against HHV-6. Ganciclovir is the drug of choice. HHV6-A can be resistant to ganciclovir though mutations in U69 and U28 genes. Foscarnet can be used in resistant HHV-6. Reduction in immunosuppression is important for severe disease. General approach. The top recommendations for the management of HHV-6 infection are provided in table 6.   HUMAN HERPESVIRUS 8   Diagnosis Pre-transplant serological screening is not routinely indicated, although it may be considered, in geographic regions with high rates of infection. Quantitative PCR is the method of choice to detect viremia, which is associated with the development of Kaposi sarcoma. PCR may be an option to monitor for risk of disease as a part of a preemptive strategy in selected high-risk individuals. In addition, HHV-8 viral load measurements can be used  to assess response to therapy. Testing for the presence of HHV-8 in biopsy or fluid samples using immunohistochemistry, in situ hybridization or PCR is also valuable.   Prevention The efficacy of antiviral prophylaxis in HHV-8 seropositive recipients or in patients receiving an organ from a seropositive donor is unknown. Avoidance of over-immunosuppression in high-risk individuals and in those with detectable HHV-8 viremia is advisable. Use of immunosuppression regimens containing sirolimus rather than calcineurin inhibitors may be indicated. In high-risk patients, monitoring of HHV-8 viral load after transplantation may be a useful to determine the risk of disease. However, the frequency and duration of monitoring or the level of clinically relevant HHV-8 replication has yet to be determined.  Moreover, once HHV-8 is detected, current data are insufficient to define a beneficial preemptive strategy with antivirals (ganciclovir, foscarnet, cidofovir),   Treatment An individualized reduction or cessation of immunosuppression (kidney transplant) is the first line therapy for the treatment of Kaposi sarcoma. Patients receiving a calcineurin inhibitor based regimen should be switched to a mTOR inhibitor based regimen.  Sirolimus has antitumor properties and can block HHV-8 replication. Patients whose tumor lesions do not regress may require intralesional chemotherapy, surgical excision or radiation therapy or other local treatment for isolated lesions, or systemic chemotherapy for visceral or severe disease, using liposomal doxorubicin, paclitaxel, or other agents. The benefits of antiviral therapy with (ganciclovir, foscarnet, cidofovir) have been suggested but are unproven. General approach. The top recommendations for the management of HHV-8 infection are provided in table 7.

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