Definitions of Cytomegalovirus Infection and Disease in Transplant Patients for Use in Clinical Trials.
Karolinska University Hospital1, Karolinska Institutet2, University of Washington3, Fred Hutchinson Cancer Research Center4, University of Basel5, Medical Products Agency6, University of Copenhagen7, Durham University8, Center for Drug Evaluation and Research9, Mayo Clinic10, University of California, Berkeley11, University College London12
TL;DR: The main changes compared to previous definitions are the introduction of a "probable disease" category and to incorporate quantitative nucleic acid testing in some end-organ disease categories.
Abstract: Cytomegalovirus (CMV) infection and disease are important causes of morbidity and mortality in transplant recipients. For the purpose of developing consistent reporting of CMV outcomes in clinical trials, definitions of CMV infection and disease were developed and most recently published in 2002. Since then, there have been major developments in its diagnosis and management. Therefore, the CMV Drug Development Forum consisting of scientists, clinicians, regulators, and industry representatives has produced an updated version incorporating recent knowledge with the aim to support clinical research and drug development. The main changes compared to previous definitions are the introduction of a "probable disease" category and to incorporate quantitative nucleic acid testing in some end-organ disease categories. As the field evolves, the need for updates of these definitions is clear, and collaborative efforts between scientists, regulators, and industry can provide a platform for this work.
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TL;DR: Highlights include advances in molecular and immunologic diagnostics, improved understanding of diagnostic thresholds, optimized methods of prevention, advances in the use of novel antiviral therapies and certain immunosuppressive agents, and more savvy approaches to treatment resistant/refractory disease.
Abstract: Cytomegalovirus (CMV) remains one of the most common infections after solid organ transplantation, resulting in significant morbidity, graft loss, and occasional mortality. Management of CMV varies considerably among transplant centers. A panel of experts on CMV and solid organ transplant was convened by The Infectious Diseases Section of The Transplantation Society to develop evidence and expert opinion-based consensus guidelines on CMV management including diagnostics, immunology, prevention, treatment, drug resistance, and pediatric issues.
1,351 citations
TL;DR: There is an increasing use of CMV‐specific cell‐mediated immune assays to stratify the risk ofCMV infection after solid organ transplantation, but their role in optimizing CMV prevention and treatment efforts has yet to be demonstrated.
Abstract: Cytomegalovirus (CMV) is one of the most common opportunistic infections that affect the outcome of solid organ transplantation. This updated guideline from the American Society of Transplantation Infectious Diseases Community of Practice provides evidence-based and expert recommendations for screening, diagnosis, prevention, and treatment of CMV in solid organ transplant recipients. CMV serology to detect immunoglobulin G remains as the standard method for pretransplant screening of donors and transplant candidates. Antiviral prophylaxis and preemptive therapy are the mainstays of CMV prevention. The lack of a widely applicable viral load threshold for diagnosis and preemptive therapy is highlighted, as a result of variability of CMV nucleic acid testing, even in the contemporary era when calibrators are standardized. Valganciclovir and intravenous ganciclovir remain as drugs of choice for CMV management. Strategies for managing drug-resistant CMV infection are presented. There is an increasing use of CMV-specific cell-mediated immune assays to stratify the risk of CMV infection after solid organ transplantation, but their role in optimizing CMV prevention and treatment efforts has yet to be demonstrated. Specific issues related to pediatric transplant recipients are discussed.
351 citations
TL;DR: This Review summarises the reviewed literature and the recommendations of the ECIL 7 for management of cytomegalovirus in patients with haematological malignancies and covers diagnosis, preventive strategies such as prophylaxis and pre-emptive therapy, and management.
Abstract: Summary Cytomegalovirus is one of the most important infections to occur after allogeneic haematopoietic stem cell transplantation (HSCT), and an increasing number of reports indicate that cytomegalovirus is also a potentially important pathogen in patients treated with recently introduced drugs for hematological malignancies. Expert recommendations have been produced by the 2017 European Conference on Infections in Leukaemia (ECIL 7) after a review of the literature on the diagnosis and management of cytomegalovirus in patients after HSCT and in patients receiving other types of therapy for haematological malignancies. These recommendations cover diagnosis, preventive strategies such as prophylaxis and pre-emptive therapy, and management of cytomegalovirus disease. Antiviral drugs including maribavir and letermovir are in development and prospective clinical trials have recently been completed. However, management of patients with resistant or refractory cytomegalovirus infection or cytomegalovirus disease is a challenge. In this Review we summarise the reviewed literature and the recommendations of the ECIL 7 for management of cytomegalovirus in patients with haematological malignancies.
242 citations
TL;DR: A review of immune responses to HCMV and countermeasures deployed by the virus, the establishment of latency and reactivation from it, exogenous reinfection with additional strains, pathogenesis, development of end organ disease, indirect effects of infection, immune correlates of control of replication, current treatment strategies and the evaluation of novel vaccine candidates can be found in this article.
Abstract: Human cytomegalovirus (HCMV) is a herpesvirus that infects ~60% of adults in developed countries and more than 90% in developing countries. Usually, it is controlled by a vigorous immune response so that infections are asymptomatic or symptoms are mild. However, if the immune system is compromised, HCMV can replicate to high levels and cause serious end organ disease. Substantial progress is being made in understanding the natural history and pathogenesis of HCMV infection and disease in the immunocompromised host. Serial measures of viral load defined the dynamics of HCMV replication and are now used routinely to allow intervention with antiviral drugs in individual patients. They are also used as pharmacodynamic read-outs to evaluate prototype vaccines that may protect against HCMV replication and to define immune correlates of this protection. This novel information is informing the design of randomized controlled trials of new antiviral drugs and vaccines currently under evaluation. In this Review, we discuss immune responses to HCMV and countermeasures deployed by the virus, the establishment of latency and reactivation from it, exogenous reinfection with additional strains, pathogenesis, development of end organ disease, indirect effects of infection, immune correlates of control of replication, current treatment strategies and the evaluation of novel vaccine candidates.
151 citations
TL;DR: Improvement in survival and reduction in complications were substantial after allogeneic transplant, and relapse of cancer remains the largest obstacle to better survival outcomes.
Abstract: Advances in the care of patients having allogeneic hematopoietic cell transplant led to improved outcomes reported a decade ago. However, allogeneic transplant continues to be accompanied by substa...
124 citations
Cites background or methods from "Definitions of Cytomegalovirus Infe..."
...4 μmol/L (≥4 mg/dL) 233 (20) 123 (11) 0....
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...We defined cytomegalovirus (CMV) infection as the presence of viral pp65 antigen (2003 to 2006) or DNA in plasma (after 2006); CMV disease was defined using international criteria (11)....
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...Respiratory failure through day 100 Mechanical ventilation 131 (11) 77 (7) 0....
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...Day-200 nonrelapse mortality, n (%) 181 (16)* 127 (11) 0....
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...88) Gram-negative bacteremia 129 (11) 74 (7) 0....
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References
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TL;DR: This study seeks to update the definitions of CMV on the basis of recent developments in diagnostic techniques, as well as to add to these definitions the concept of indirect effects caused by CMV.
Abstract: Cytomegalovirus (CMV) infection and disease are important causes of morbidity and mortality among transplant recipients. For the purpose of developing consistent reporting of CMV in clinical trials, definitions of CMV infection and disease were developed and published. This study seeks to update the definitions of CMV on the basis of recent developments in diagnostic techniques, as well as to add to these definitions the concept of indirect effects caused by CMV.
1,206 citations
"Definitions of Cytomegalovirus Infe..." refers methods in this paper
...disease were initially developed and published as part of the proceedings of the Fourth International CMV Conference in Paris in 1993 [1], and these were subsequently updated in 1995 [2] and most recently in 2002 [3]....
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TL;DR: A controlled trial of ganciclovir in recipients of bone marrow transplants who had asymptomatic pulmonary CMV infection and sought to identify risk factors for the development of CMV interstitial pneumonia.
Abstract: Background. Cytomegalovirus (CMV)-associated interstitial pneumonia is a major cause of death after allogeneic bone marrow transplantation. We conducted a controlled trial of ganciclovir in recipients of bone marrow transplants who had asymptomatic pulmonary CMV infection. We also sought to identify risk factors for the development of CMV interstitial pneumonia. Methods. After bone marrow transplantation, 104 patients who had no evidence of respiratory disease underwent routine bronchoalveolar lavage on day 35. The 40 patients who had positive cultures for CMV were randomly assigned to either prophylactic ganciclovir or observation alone. Ganciclovir (5 mg per kilogram of body weight intravenously) was given twice daily for two weeks and then five times per week until day 120. Results. Of the 20 culture-positive patients who received prophylactic ganciclovir, 5 (25 percent) died or had CMV pneumonia before day 120, as compared with 14 of the 20 culture-positive control patients (70 percent) who w...
595 citations
University of Alberta1, François Rabelais University2, University of California, San Francisco3, University of Pennsylvania4, University of Michigan5, University of Washington6, Université libre de Bruxelles7, University of Glasgow8, University of Hertfordshire9, Goethe University Frankfurt10, Ghent University11
TL;DR: It is demonstrated that extending valganciclovir prophylaxis (900 mg once daily) to 200 days significantly reduces the incidence of CMV disease and viremia through to 12 months compared with 100 days’ prophYLaxis, without significant additional safety concerns associated with longer treatment.
427 citations
"Definitions of Cytomegalovirus Infe..." refers background in this paper
...The gold standard of CMV end-organ disease for documenting the effects of new agents is difficult to incorporate in current clinical trial designs as it has become increasingly rare [12, 13]....
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TL;DR: Although cytomegalovirus disease occurs in the context of suppressed cell-mediated immunity post-transplantation, humoral immunity has a role in reduction of cytomeGalovirus viraemia.
348 citations
TL;DR: Treatment with oral CMX001 at a dose of 100 mg twice weekly significantly reduced the incidence of CMV events in recipients of hematopoietic-cell transplants.
Abstract: A b s t r ac t Background The use of available antiviral agents for the prevention of cytomegalovirus (CMV) disease is limited by frequent toxic effects and the emergence of resistance. CMX001 has potent in vitro activity against CMV and other double-stranded DNA viruses. We evaluated the safety and anti-CMV activity of CMX001 in patients who had undergone allogeneic hematopoietic-cell transplantation. Methods
320 citations