Management of cytomegalovirus infection in solid organ transplant recipients: SET/GESITRA-SEIMC/REIPI recommendations

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Abstract

Cytomegalovirus (CMV) infection remains a major complication of solid organ transplantation. Because of management of CMV is variable among transplant centers, in 2011 the Spanish Transplantation Infection Study Group (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) developed consensus guidelines for the prevention and treatment of CMV infection in solid organ transplant recipients. Since then, new publications have clarified or questioned the aspects covered in the previous document. For that reason, a panel of experts revised the evidence on CMV management, including immunological monitoring, diagnostics, prevention, vaccines, indirect effects, treatment, drug resistance, immunotherapy, investigational drugs, and pediatric issues. This document summarizes the recommendations.

Introduction

Cytomegalovirus (CMV) infection remains common 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.

In 2005, the first consensus document on the prophylaxis and treatment of CMV infection in SOT conducted by the Study Group on Infection in Transplantation (GESITRA) of the Spanish Society of Clinical Microbiology and Infectious Diseases (SEIMC) was published [1]. Later, in 2011, the same group published an updated version of these guidelines [2]. Given the recent progress made regarding CMV infection in SOT, these guidelines have recently been updated by a panel of experts from the GESITRA-SEIMC group of the Spanish Network for Research in Infectious Diseases (REIPI) and the Spanish Society of Transplantation (SET). Some of these experts participated in the late International Consensus Guidelines on the management of cytomegalovirus in solid organ transplantation [3].

To develop the recommendations included in the consensus document, the expert panel conducted a systematic review of the literature and established the quality of the evidence using the Grading of Recommendations Assessment, Development and Evaluation system (GRADE) (http://www.gradeworkinggroup.org), which includes an assessment of the strength of the recommendation (e.g., strong, weak) and the quality of evidence (e.g., high, moderate, low, very low) (Table 1) [4], [5], [6], [7].

Section snippets

Diagnostics

  • Methods based on quantitative CMV DNA amplification are the methods of choice for diagnosis, guiding preemptive therapy and monitoring response to therapy (strong, high).

  • Plasma and whole blood samples are both acceptable for measuring CMV load. Individual patients should always be monitored using the same type of sample (strong, high).

  • Laboratories should recalibrate their assay and report values as international units per milliliter (IU/mL) using the World Health Organization (WHO)

Definitions

For the purposes of this document, the following definitions accepted by GESITRA-SEIMC, REIPI and SET are provided.

  • Infection or replication: Isolation of the virus or the detection of viral proteins (antigenemia) or CMV DNA/mRNA in any body liquid or tissue.

  • Viremia: Isolation of CMV from the blood culture of a patient.

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

  • DNAemia: Detection of CMV DNA in plasma, whole blood or leukocyte samples.

What is the “gold standard” for diagnosing CMV infection?

Determination of the CMV serostatus of both donor and recipient is necessary before transplantation, since it conditions the risk of active CMV infection and posttransplant disease. For this reason, a serological method based on the detection of anti-CMV IgG must be used [8].

In the posttransplant period, viral load testing is essential for the diagnosis and monitoring of CMV infection and disease; thus both quantitative nucleic acid amplification testing (QNAT) and antigenemia testing are

When should universal prophylaxis or preemptive therapy be recommended in solid organ transplant recipients?

Two major strategies have been employed to prevent CMV infection in order to reduce CMV disease and potentially prevent some of the “indirect effects” of CMV replication: universal prophylaxis and preemptive therapy [32]. The selection of either strategy depends on the intended goal in each specific risk group (Table 5). Both have proven to be effective in the prevention of CMV, with a 58–80% reduction in the incidence of CMV disease [33], [34], [35]. Recent results of a multinational survey

What methods can be used to monitor CMV-specific cell-mediated response?

Immune control of CMV infection in SOT recipients involves both innate and adaptive mechanisms that operate in a coordinated manner. Functional CMV-specific CD8+ and CD4+ T cells play a crucial role in limiting CMV replication and in preventing the development of CMV viremia and CMV end-organ disease [145]. Although over 70% of the virus proteome is targeted by CD8+ and CD4+ T cells, the cellular responses against pp65- and immediate-early (IE)-1 antigens appears to be the most important for

When should CMV vaccines be recommended?

CMV vaccine research has focused on a limited number of viral proteins that dominate cellular or humoral immune response. Published phase-2 clinical trials with CMV vaccines have focused on healthy females, HSCT recipients and SOT recipients [193], [194], [195], [196], [197].

In SOT recipients, two phase-2 clinical trials have been published. The Towne strain, a live-attenuated whole virus vaccine, was compared with placebo in renal transplant recipients. Patients who were seropositive at the

In what scenarios can the development of indirect effects influence the general recommendations for prevention? What modifications to prophylactic management are recommended?

In addition to the direct effects caused by invasive organ infection, CMV produces a series of indirect effects independently of the presence of high levels of viremia which result from the interaction of the virus with the host immune system. Diverse indirect effects have been described so far, including acute and chronic graft rejection, atherosclerosis, diabetes mellitus after transplantation, posttransplant lymphoproliferative disease and increased opportunistic infections. The association

Which antiviral drug should be used?

Intravenous ganciclovir and oral valganciclovir are the antiviral drugs of choice for treating CMV infection and disease [126], [243]. The VICTOR trial comparing three weeks of oral valganciclovir (900 mg every 12 h) to intravenous ganciclovir (5 mg/kg/12 h) for the treatment of SOT recipients (74% renal transplant recipients) with mild to moderate CMV disease demonstrated similar efficacy and safety [121]. Moreover, during long-term follow-up at 1 year, there were no significant differences in

What does the treatment involve?

Adoptive therapy involves the administration of specific T cells (CD4+ and CD8+) to treat refractory infections caused by a given microorganism, in this case, CMV. Such procedures have generally been performed in individuals receiving hematopoietic stem cells from seropositive donors [269]. The main risk associated with this therapy is graft-versus-host disease (GVHD) [269], [270]. Application in SOT is usually limited by the lack of an HLA-matched donor. However, the recent successful use of

Specific recommendations in the pediatric population: What particular characteristics are of clinical significance?

Pediatric SOT recipients have some particular characteristics that make them especially susceptible to CMV infection and are therefore considered high-risk patients. However, the impact of the infection has been significantly reduced due to the development of effective prevention strategies, with CMV disease rates of 4.5% and 15% in kidney and liver transplant patients, respectively [281], [282]. In pediatric lung transplant recipients, however, CMV infection continues to be a risk factor for

What drugs could have clinical use in the near future?

There are three drugs that could become a reality in the management of CMV infection in the near future, namely, letermovir, brincidofovir and maribavir. Their main characteristics are shown in Table 8.

What do they add? What is their setting?

The new drugs have their chance in playing a role in different settings attending to the results obtained in initial studies as shown in Table 9.

Future directions

A new phase II, dose-ranging study to assess the safety and anti-CMV activity of maribavir versus valganciclovir for treatment of CMV infections in

Financial support

This document has been financed by the Spanish Society of Transplantation (SET) that has received an unrestricted grant for Roche Farma. It has been also supported by the Plan Nacional de I + D + i and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Economía y Competitividad, Spanish Network for Research in Infectious Diseases (REIPI RD12/0015) and co-financed by European Development Regional Fund “A way to achieve Europe” ERDF.

Financial disclosures

Torre-Cisneros J has received from Roche Pharma research grants and honoraria for participating in several conferences. Aguado JM has been a consultant to and on the speakers' bureau for Astellas Pharma, Pfizer, Gilead Sciences, Merck Sharp and Dohme (MSD) and Roche Pharma. Castón JJ has received honoraria for talks on behalf on Pfizer, Astellas and Novartis. Almenar L has no conflict of interest. Alonso A has no conflict of interest. Cantisán S has received an unrestricted research grant from

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