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

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