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

ABSTRACT  Cytomegalovirus (CMV) infection remains one of themost common infections in patients receiving solid organ transplantation (SOT).In these patients, CMV is an important cause of morbidity and mortality due tothe development of invasive disease or the immunomodulatory effect of the viruson the host immune system. Other herpes viruses (herpes simplex,varicella-zoster, Epstein-Barr, herpesvirus type-6 and -8) are also importantin this setting. During the last few years, new data and consensus documents onthe management of these infections have been generated. In this chapter we providepractical  recommendations to guideclinicians on the prevention and treatment of these common viruses.  PREVENTION ANDTREATMENT OF CYTOMEGALOVIRUS (CMV) INFECTION.

 DESCRIPTION OF THE PATHOGEN.  CMVis a double-stranded DNA virus of the Herpesviridaefamily that has the capacity to produce primary infection or reactivation in SOT recipients.  DEFINITIONS-      Infection orreplication: Isolation of the virus or the detection of viralproteins (antigenemia) or CMV DNA/mRNA in any body liquid or tissue. In the SOTliterature, latent infection is considered a separate entity.

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–      Antigenemia: Directdetection of the CMV pp65 antigen in peripheral blood leukocytes, mainlyneutrophils. –      DNAemia: Detection ofCMV DNA in plasma or whole blood.-      CMV disease: Evidence ofsymptoms or signs coupled with the detection of CMV infection in blood ortissue.-       “Viral syndrome”: presence offever and/or malaise associated with the presence of leukopenia,thrombocytopenia or an increase in transaminases.  This is considered a type of CMV disease.-      Universalprophylaxis: Administration of an effective antiviral drug toprevent the development of CMV replication and/or disease in at-risk patients.-      Preemptivetherapy: Regular monitoring for CMV replication followed by initiation of antiviraltreatment in patients displaying asymptomatic CMV replication in order toprevent progression to CMV disease .

  DIAGNOSIS.  Althoughantigenemia is still used, a quantitative real-time nucleic acid amplificationbased assay or polymerase chain reaction (PCR) is recommended for the diagnosisand monitoring of CMV infection after transplantation. Viral loads can bedetermined in both plasma and whole blood samples, but the same type of sampleshould be used when comparing viral loads or following a given patient. Thereare also differences between viral loads obtained in different centers, thusmaking an international standard reference necessary.

There is a directassociation between viral load values and the likelihood that an individualwill develop active disease. Moreover, the rate of increase of viral loads isalso a predictor of developing disease. Due to the variability of the resultsamong laboratories, a single test should be used for monitoring patients overtime. Laboratories should establish their own cutoffs and audit clinicaloutcomes to verify the trigger points used for treatment.Viral resistance depends on the existence of mutationsin the CMV genome. Plasma or whole blood is the sample of choice.

Genotypicassays (PCR amplification) are available for clinical use. Two genomic regionsmust be studied: UL97 kinase gene involved in the initial phosphorylation ofganciclovir (codons 400-670) and the UL54 polymerase gene (codons 300-1000). CommonUL97 and UL54 mutations are shown in  Table 1. A web-based search tool, www.informatik.

uni-ulm.de/ni/staff/HKestler/hcmv/, has been developedthat links the sequence to a database containing all published UL97 and UL54mutations and corresponding antiviral drug susceptibility phenotypes. Ifmutations only appear in the UL97 gene, viruses are resistant only toganciclovir. UL54 mutations typically added to pre-existing UL97 mutations, may increase the level of ganciclovirresistance and commonly confer varying levels of cross-resistance to other CMVantivirals such as foscarnet or cidofovir. In the future, next-generationsequencing (NGS) technologies may enable the detection of far smaller viralsubpopulations and may therefore improve the detection of drug resistanceemergence.   IMMUNOLOGICALMONITORINGTestingfor anti-CMV IgG antibodies should be performed before transplantation indonors and recipients for the purposes of risk-stratification. In recipient -negative(R-) patients, testing should be repeated at the time of transplantation.

Donorserostatus should also be performed to stratify  the subsequent risk of CMV infection anddisease. CMVspecific cell-mediated assay may also be clinically useful.  The characteristics of different technicsavailable for immunological monitoring are reviewed in table 2. If available, pretransplantCMV-specific cell-mediated immunity has been explored together with serologicaltesting to stratify the risk of CMV infection after transplantation. Thisapproach may be  particularly useful inR+ recipients. The potential utility of monitoring CMV-specific cell-mediatedimmunity has been investigated in various posttransplant clinical scenarios.Overall, a reactive test has  a highnegative predictive values for detecting risk of CMV replication, supportingthe safety of discontinuing prophylaxis in high-risk patients above theprotective threshold. Alternatively, patients with no evidence of protectiveresponse at the end of the prophylaxis period could benefit from the so-called”hybrid approach” (in which preemptive monitoring is initiated after completingprophylaxis).

On the other hand, immune monitoring in intermediate-riskpatients managed preemptively may be useful in guiding the frequency forsurveillance of CMV infection and the thresholds for initiating antiviraltherapy, or in case of treatment failure after appropriate antiviral therapy.However, further clinical trials are required to evaluate protocolizedinterventions based on the posttransplant kinetics of CMV-specific responses.  PREVENTION.Two majorstrategies have been employed to prevent CMV infection: universal prophylaxisand 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 Gancicloviris currently the preferred antiviral. High-dose Valacyclovir is an  alternative option  in renal transplantation.  Late-onsetCMV disease, defined as disease occurring after discontinuation of prophylaxis,has been found in all studies evaluating universal prophylaxis in D+/R- transplantrecipients. A 200-day prophylaxis regimen can be recommended in D+/R- kidneytransplant patients and, by extension, possibly in other high-risk transplantrecipients (e.

g. heart, pancreas). In R+ patients, three-month regimens  are recommended. In lung and intestinaltransplant recipients, the majority of the groups extend prophylaxis over 6 to12 months after transplantation for both D+/R- and R+ patients.

In recipientsreceiving alemtuzumab as induction therapy, monitoring of CD4+ T lymphocyteshas been used to continue prophylaxis (for at least 6 months) until CD4 Tlymphocytes are over 200 cell/mm3.           In a pre-emptive strategy,viral load is typically monitored weekly for the first 12-14 weekspost-transplant. There are no evidence-based recommendations regarding theviral load cutoff for initiating antivirals and the optimal duration ofpreemptive therapy.

It may be preferable to initiate preemptive therapy in any high-riskpatients with a positive viral load. In lower risk patients, it is possible toestablish local cut-off points and eventually delay therapy, consider reducingthe levels of immunosuppressive therapy and repeat a second viral load after ashort interval , since small blips may disappear spontaneously. Treatmentshould be administered for a minimum of 2 weeks. Monitoring of CMV viral loadshould direct the extension of treatment. At least one negative viral loaddetermination (or viral load below a specific threshold) in plasma specimens isrequired in order to withdraw treatment.  Relapseof CMV infection is frequent after a therapy course, although it isgenerally resolved after a new course of treatment. There is no available datasupporting the use of a combined preemptive therapy strategy after  prophylaxis in low-risk transplant recipients. Nevertheless, this strategy, which isknown as a “hybrid strategy”, is commonly used in certain high-risk transplantrecipients (D+/R-, lung, pancreas and small bowel recipients and/or thosereceiving lymphocyte-depleting treatments).

The duration has not beendetermined.Taking into account the low riskof CMV disease reported in the subgroup of D-/R- recipients, the use ofprophylaxis or preemptive therapy have not been recommended. Other measures,such as the use of leuko-depleted or CMV-seronegative blood products, directedat preventing CMV infection acquisition, are recommended. Monitoring of primaryCMV infection may be of interest in patients at a higher risk of severe primaryinfection.Hypogammaglobulinemia(IgG <500 mg/dL) is a risk factor for CMV disease after SOT transplantation.In heart transplant recipients, the administration of non-specific intravenousimmunoglobulins (IVIGs) with the goal of maintaining normal IgG levels wasassociated with a lower risk of CMV infection.

In heart, lung and intestinalrecipients at high-risk for CMV disease (D+R-), some centers add specificanti-CMV IVIG to prevent CMV infection. The best dosing regimen has not beenestablished. A recommendation regarding theuse of CMV vaccine in SOT recipients cannot be made as no vaccine has beenapproved for use in a clinical setting.    TREATMENT Intravenousganciclovir and oral valganciclovir are the antiviral drugs of choice fortreating CMV infection and disease. Intravenous ganciclovir (5 mg/kg/12h) shouldbe used in patients with severe CMV disease or when valganciclovir is poorlytolerated or not well absorbed.

It is important to administer the appropriatedoses of intravenous ganciclovir or oral valganciclovir adjusted for renalfunction, as inadequate dosing can cause clinical failure or viral resistance.Oral valganciclovir (900 mg/12h) is effective in patients with mild to moderateCMV disease. It can also be used in sequential therapy in patients treated withintravenous ganciclovir, once clinical improvement is documented.Theoptimum duration of treatment, should  beguided by weekly virological monitoring (treat until viral load negative orbelow a certain threshold) and clinical response. The minimum duration oftreatment is two weeks.

Following initial treatment secondary prophylaxis iscommonly 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.Theevidence to support the use of specific anti-CMV immunoglobulins in cases oflife-threatening CMV disease, particularly severe pneumonitis is lacking,although it is often used. Resistance to antiviral drugs should be suspected in the presence ofprogressive or stable viral loads or if clinical symptoms persist despite adequateantiviral 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 druglevels and prolonged antiviral drug exposure, and lung transplantation). If genotypictests demonstrate the existence of a high-level resistance mutation in the UL97gene or the UL54 gene (table 1), foscarnet is indicated. Increasing the dose ofganciclovir up to 10 mg/kg/12h might be useful for other mutations in the UL97gene and can be considered for patients with non-severe CMV disease, or inthose whom the use of foscarnet should be avoided (nephrotoxicity). Maribavir hasbeen successfully used in salvage therapy in patients with refractory/resistantCMV infection and is currently in phase 3 trial for this indication. Brincidofovirand letermovir are also promising drugs that need clinical development in thisindication.

Switching immunosuppression from calcineurin inhibitors to an mTORinhibitor-based regimen has proposed as an adjunctive therapy but isunproven.  Leflunomide should beconsidered unproven therapy for this indication.  Adoptive immunotherapy can beuseful for the rescue of case refractory to conventional treatment and who donot develop a satisfactory immune response. However, clinical experience isvery limited, and the technique can only be used in the setting of researchprojects or rescue strategies.Generalapproach.

The top recommendations for the management of CMV infection are providedin table 3.        PREVENTION ANDTREATMENT OF OTHER HERPES VIRUSES. DESCRIPTION OF THE PATHOGENS.

  Herpessimplex virus (HSV), varicella-zoster virus (VZV), human herpesvirus type-6(HHV-6) and -8 (HHV-8) virus belong to the Herpesviridaefamily and have the capacity to produce primary infection or reactivation inthe recipients of a solid organ transplant. Epstein-Barr virus is reviewed in aspecific chapter. Human hersvirus-7 is generally not of significant  clinical impact.  HERPES SIMPLEX VIRUS. DiagnosisPretransplantIgG serostatus of recipients is necessary for posttransplant riskstratification. Transplant patients can have atypical mucocutaneous lesions andvisceral or disseminated disease.

Laboratory confirmation may be necessary. PCRtesting of mucocutaneous, lesions, bronchoalveolar lavage and other clinicalsamples (plasma, cerebrospinal fluid) is the diagnostic test of choice. Theclinical significance of finding HSV DNA in the blood of patients without disseminateddisease has not been well established. Also, a positive BAL PCR may be eitherdue to mucutaneous contamination during sampling or due to HSV pneumonitis. Tissuehistopathology with immunocytochemistry for HSV can be helpful.    PreventionHSVprophylaxis is generally indicated for HSV-1 or -2 seropositive recepients notreceiving CMV prophylaxis ((val)ganciclovir prevents HSV replication). Someexperts also recommend prophylaxis in HSV seronegative to prevent the infectiontransmitted from organs or blood transfusions, however, this is a rareoccurrence.

 A low-dose acyclovir regimen(< 1gr/day) is effective  (200 mgthree or four times a day, 400 mg two times a day) for prophylaxis.Valacyclovir (two times a day) or Famciclovir can also be used. Antiviralprophylaxis should continue for at least a month. Resumption of prophylaxis maybe considered for patients being treated with T cell depleting agents. In patientswith severe clinical recurrences (?2), suppressive antiviral therapy may beindicated and may occasionally be required for very prolonged durations. All recepients(not only seronegative) should avoid contact with persons with active lesions.

Condomsdo not completely protect against HSV transmission. HSV-2 seronegativetransplant recipients should consider having their partner tested for HSV-2. Inserodiscordant couples, daily antiviral therapy taken by the seropositivepartner can prevent HSV-2 transmission to the seronegative partner.

Theefficacy of postexposure prophylaxis is unknown.   Treatment.Disseminated,visceral, or extensive mucocutaneous HSV disease should be treated withintravenous acyclovir at a dose of 5–10 mg/kg every 8 h for a minimum of 2weeks (3 weeks in case of encephalitis).  Non- severe mucocutaneous disease can betreated with oral acyclovir, valacyclovir or famciclovir fora minimum of oneweek. Overall treatment durations are determined by clinical response.

HSVkeratitis can be treated with systemic or topical agents (trifluridinesolution, vidarabine ointment or topical ganciclovir gel). Resistancemust be considered in patients whose lesions are not responding clinically toappropriate doses of systemic therapy. Genotypic testing for known resistancemutations is available in some settings. Intravenous Foscarnet or Cidofovir arerecommended, but both are associated with significant renal toxicity.

Topicalagents (imiquimod, cidofovir, trifluridine) can be used for resistant anogenitaldisease. Generalapproach.  The toprecommendations for the management of HSV infection are provided in table 4. VARICELLAZOSTER VIRUS DiagnosisAllrecipients should undergo serologic testing to determineposttransplantrisk. In general, both primary varicella and herpes zoster have typicalclinical presentations that allow for a presumptive clinical diagnosis.Nevertheless, transplant recipients can have atypical presentations ormulti-organ involvement with delayed or absent rash. Definitive laboratorytesting is indicated for atypical cases and visceral disease.

PCR is the methodof choice (vesicle fluid, serum, spinal fluid, and other tissues).  Prevention.Antiviraltherapy.  Antiviralprophylaxis for VZV is not needed during periods of CMV prophylaxis.

Herpessimplex (HSV) prophylaxis may also be effective against VZV during the periodimmediately posttransplant. Pretransplant vaccination. Seronegative potential transplantpatients should receive varicella vaccination with the live attenuatedvaccine at least 4 weeks before transplant. Posttransplantvaccination. The live vaccine poses a risk of disseminated infectioninimmunosuppressed patients and therefore is contraindicated forposttransplant recipients .

Postexposureprophylaxis. Options for postexposure prophylaxis include passiveimmunoprophylaxis and/or antiviral therapy. VZV inmmunoglobulins are recommendedin susceptible (seronegative) patients exposed to VZV and should be given assoon as possible but within at least 10 days of exposure. Antiviral therapy shouldbe considered as adjunctive therapy or in patients who were unable to receiveimmunoprophylaxis before 10 days after their exposure.

Acyclovir orvalacyclovir or famciclovir can be used for a 7-14 day course. Treatment.Varicella. Patientsshould be treated with intravenous acyclovir, initiated early,especially within 24-hours of rash onset.

Herpeszoster. Patients with disseminated or organ invasive disease shouldbe treated with IV acyclovir. Localized nonsevere HZ can be treated with oralvalacyclovir or famciclovir, with the exception of herpes zoster ophthalmicusor oticus. Generalapproach. The top recommendations for the management of HZV infection are providedin table 5.HUMAN HERPESVIRUS 6  DiagnosisRoutinemonitoring for HHV-6 is not recommended based on the current evidence or lowrate of disease and subclinical infections. Diagnostic testing should belimited to symptomatic HHV-6 disease, in order to guide treatment. Quantitativereal-time PCR is preferred for the detection of HHV-6 viremia.

It candistinguish between HHV-6A, HHV-6B but they may not always differentiate activefrom latent infection depending on the sample type or assay used. It is alsoimportant to consider the potential detection of chromosamally integrated HHV-6in blood samples, characterized by persistent HHV-6 viral loads typically ofover a million copies per mL of whole blood, which may be misinterpreted as activeinfection leading to unnecessary treatment. Qualitative or quantitative HHV-6PCR of the cerebrospinal fluid is useful to diagnose HHV-6 encephalitis inpatients with the appropriate clinical signs. Immunohistochemistry to detectviral antigens in biopsy specimens is appropriate in cases of organ disease, althoughit can be detected in the absence of symptoms.

 PreventionSpecificantiviral prophylaxis or pre-emptive therapy for HHV-6 infection is notrecommended.  Antiviral prophylaxis forCMV does appear to reduce the incidence of HHV-6 viremia.  TreatmentTreatment ofasymptomatic viral reactivation is not recommended. Ganciclovir, foscarnet andcidofovir 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 isimportant for severe disease.Generalapproach.

The top recommendations for the management of HHV-6 infection areprovided in table 6. HUMAN HERPESVIRUS 8 DiagnosisPre-transplantserological screening is not routinely indicated, although it may beconsidered, in geographic regions with high rates of infection. QuantitativePCR is the method of choice to detect viremia, which is associated with thedevelopment of Kaposi sarcoma.

PCR may be an option to monitor for risk ofdisease 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 forthe presence of HHV-8 in biopsy or fluid samples using immunohistochemistry, insitu hybridization or PCR is also valuable.

 PreventionThe efficacyof antiviral prophylaxis in HHV-8 seropositive recipients or in patientsreceiving an organ from a seropositive donor is unknown. Avoidance of over-immunosuppressionin high-risk individuals and in those with detectable HHV-8 viremia isadvisable. Use of immunosuppression regimens containing sirolimus rather thancalcineurin inhibitors may be indicated. In high-riskpatients, monitoring of HHV-8 viral load after transplantation may be a usefulto determine the risk of disease. However, the frequency and duration ofmonitoring or the level of clinically relevant HHV-8 replication has yet to bedetermined.  Moreover, once HHV-8 isdetected, current data are insufficient to define a beneficial preemptivestrategy with antivirals (ganciclovir, foscarnet, cidofovir),  TreatmentAnindividualized reduction or cessation of immunosuppression (kidney transplant)is the first line therapy for the treatment of Kaposi sarcoma. Patientsreceiving a calcineurin inhibitor based regimen should be switched to a mTORinhibitor based regimen.

  Sirolimus hasantitumor properties and can block HHV-8 replication. Patients whose tumorlesions do not regress may require intralesional chemotherapy, surgicalexcision or radiation therapy or other local treatment for isolated lesions, orsystemic chemotherapy for visceral or severe disease, using liposomaldoxorubicin, paclitaxel, or other agents. The benefits of antiviral therapy with(ganciclovir, foscarnet, cidofovir) have been suggested but are unproven.Generalapproach. The top recommendations for the management of HHV-8 infection areprovided in table 7.

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