Curr Infect Dis Rep (2014) 16:419 DOI 10.1007/s11908-014-0419-8
TRANSPLANT AND ONCOLOGY (M ISON, SECTION EDITOR)
Emerging Cytomegalovirus Management Strategies After Solid Organ Transplantation: Challenges and Opportunities E. Beam & V. Dioverti & R. R. Razonable
# Springer Science+Business Media New York 2014
Abstract Cytomegalovirus (CMV) remains as one of the most common pathogens after solid organ transplantation (SOT). During the past year, management guidelines were updated, and numerous studies were published—all collectively emphasizing the ongoing efforts to improve management of CMV after SOT. Improvement in laboratory diagnostics was aided by the WHO international calibration standard for nucleic acid testing, which allows for meaningful comparison of viral load values among laboratories. The potential translation of methods for assessing CMV-specific cellular immunity could provide tools for CMV risk assessment and management. Efforts continue to optimize antiviral strategies for CMV disease prevention and treatment. CMV vaccines continue to be tested in various stages of clinical trials. Novel anti-CMV drugs are being developed, including agents that have been used as compassionate therapy for treatment of drug-resistant CMV. In this article, the authors review recent developments on CMVand discuss their implications in CMV management after transplantation. Keywords Cytomegalovirus . Prophylaxis . Transplantation . Viral load . Valganciclovir . Outcomes
there remain ongoing efforts in basic, clinical, and translational research to optimize the diagnosis, treatment, and prevention of CMV after solid organ transplantation (SOT). Diagnostic strategies have improved during the past year with the introduction and utilization of an international calibration standard for CMV nucleic acid testing (NAT), which now allows for comparison of viral load reports across centers. The optimal prevention strategy remains debated, and it is likely that the best prevention approach will vary depending on factors related to host (i.e., risk of disease based on immune status), the virus (i.e., amount of viral burden), and the logistics of providing care (i.e., ability to test and monitor patients). New antiviral agents are continually being developed for CMV management, and there is also an ongoing effort in CMV vaccine development. To provide an overview of all the recent developments in the field, the authors have evaluated publications on CMV in SOT recipients during the past year, using the PubMed database, and discuss them in the context of the current standard for CMV diagnosis, prevention, and treatment.
Epidemiology, Clinical Impact, and Risk Factors Introduction Since the birth of clinical transplantation, cytomegalovirus (CMV) has been its single most common infectious complication. Despite remarkable improvements in its management,
This article is part of the Topical Collection on Transplant and Oncology E. Beam : V. Dioverti : R. R. Razonable (*) Division of Infectious Diseases, Department of Medicine, and the William J von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA e-mail: [email protected]
CMV is a ubiquitous herpes infection with an overall 50 % seroprevalence in the United States [1], although this could be as high as 90 % in elderly and in developing countries [2]. Primary CMV infection in the immunocompetent host is generally asymptomatic or presents as a mild illness, with symptoms of mononucleosis-like illness. In immunocompromised hosts, such as SOT recipients, CMV can present as a primary infection in CMV-naïve transplant recipients or as a secondary infection (reactivation or reinfection) in CMVseropositive individuals. In SOT recipients, CMV infection may occur as an asymptomatic illness that is indicated only by viral DNA or antigen
419, Page 2 of 10
Curr Infect Dis Rep (2014) 16:419
detection in the blood (i.e., viremia), but without clinical symptoms. Asymptomatic CMV infection is detected most often in SOT recipients undergoing routine CMV surveillance. When CMV infection is accompanied by clinical symptoms (and often, laboratory abnormalities), it is called CMV disease, which can be categorized into CMV syndrome or tissue-invasive disease. CMV syndrome presenting as a flulike febrile illness with cytopenias and malaise is the most common form of CMV disease. Less commonly, CMV can involve various organs (termed tissue-invasive disease), with the gastrointestinal tract as the organ most commonly involved. CMV may also involve the allograft, manifesting as carditis in heart recipients, pneumonitis in lung recipients, pancreatitis in pancreas recipients, nephritis in kidney recipients, and hepatitis in liver recipients. Indeed, any organ may be involved, including less common conditions, myelitis and polyradiculopathy [3, 4], cholecystitis with biliary obstruction [5], and cholangitis [6]. In addition, there are numerous indirect effects of CMV, which are partly attributed to its immunomodulatory properties (Table 1). One indirect effect is the increased predisposition to bacterial coinfections. In a study of a small cohort of liver recipients, the majority (n=13 [81 %]) of the 16 patients with CMV infection had concomitant bacterial infection [7]. CMV has been implicated in adversely affecting allograft and patient survival, although the data have been conflicting due to differences in patient population, use of CMV prevention, and measured outcomes. Indeed, studies have come to varying conclusions in terms of the effects of CMV on long-term outcomes after SOT [8]. In an Australian study of pediatric kidney recipients, allograft outcome and patient survival were not influenced by donor and recipient CMV serostatus [9]. A Spanish retrospective study of 104 kidney and 58 liver recipients reported no significant association between CMV and mortality, allograft dysfunction, or graft loss [10]. On the other hand, in the study of 609 kidney and kidney/pancreas recipients, a negative impact of CMV disease on allograft survival was observed [11]. Likewise, a large French retrospective study of 1,279 kidney recipients showed an independent association between a positive donor CMV serology and graft loss [12].
Table 1 Indirect effects of cytomegalovirus Acute allograft rejection Chronic allograft rejection and dysfunction (nephropathy, coronary vasculopathy, bronchiolitis obliterans) Immunosenescence Mortality
Note. HHV, human herpesvirus
Fungal infections Reactivation of other herpes virus (HHV-6, HHV-7)
Bacterial infections Posttransplant lymphoproliferative disease (due to Ebstein Barr virus)
The incidence of CMV disease has been reduced after SOT with the use of antiviral prophylaxis. However, CMV disease still occurs as late-onset disease, especially in patients who are CMV-seronegative prior to transplantation. In a recent cohort study of 428 liver and kidney recipients, CMV disease occurred in 31.3 % of liver and 19.2 % of kidney D+/R−during the first year after transplantation, and almost all occurred after discontinuation of prophylaxis [13]. In another study of kidney and liver recipients, 25 (44 %) of 57 CMV D+/R−recipients developed late-onset CMV infection and disease despite antiviral prophylaxis [10]. These studies confirm previous observations that, in some CMV D+/R−SOT recipients, antiviral prophylaxis has only delayed the onset of clinical illness to the first 3–6 months after completion of prophylaxis. The risk of CMV infection depends on the donor and recipient CMV serologic status (with highest incidence and severity of disease in D+/R−SOT recipients), the type of solid organ transplanted (highest among lung, intestinal, and composite tissue transplant), degree of overall immunosuppression (highest with lymphocyte-depleting drugs), and preventative strategy used against CMV (expectedly higher rates of CMV infection with preemptive therapy, as compared with prophylaxis). In a prospective study of 609 kidney and kidney/pancreas recipients, a total of 108 (17.7 %) episodes of CMV viremia were observed, and the risk factors identified were D+/R−mismatch, donor age>50 years, and higher tacrolimus and mycophenolate blood levels [11]. In another retrospective study of pancreas–kidney and pancreas-afterkidney recipients, the risk factors for CMV infection and disease were CMV D+/R−, preceding non-CMV infection, and duration of antiviral prophylaxis [14]. The degree of immunosuppression used, including antirejection therapy and induction, and maintenance immunosuppression is directly correlated to the risk of CMV. In a cohort of kidney recipients, with an overall rate of 14.2 % of CMV disease, higher rates of CMV disease were observed with the use of induction immunosuppression (e.g., antithymocyte globulin) [15]. Use of T-cell-depleting therapy significantly raises the risk of CMV infection and disease, and in kidney recipients, a fourfold greater risk was reported with thymoglobulin induction [16]. On the other hand, use of mammalian target of rapamycin (mTOR) is associated with lower CMV disease rates. In a multicenter study of lung recipients, overall CMV events were significantly lower among those receiving sirolimus, when compared with azathioprine, even after adjustment for prophylaxis and CMV serostatus [17]. Likewise, in heart recipients, everolimus was associated with a lower risk of CMV infection, as compared with azathioprine or mycophenolate mofetil [18]. Everolimustreated renal recipients have higher CMV-specific CD8+ Tcell responses, as compared with cyclosporine- or mycophenolate-treated patients, likely accounting for the lower incidence of CMV disease during mTOR use [19].
Curr Infect Dis Rep (2014) 16:419
Page 3 of 10, 419
Diagnostic and Immunologic Monitoring The methods for the detection of CMV and its immune response are listed in Table 2. Tests for detecting active CMV infection are viral culture, antigen testing, and NAT. The use of viral culture to demonstrate CMV viremia is virtually nonexistent, due to poor sensitivity and long turnaround time, and this has been replaced by NAT and pp65 antigenemia. However, viral culture is still performed for detecting CMV in other body fluids and tissues not optimized for NAT. Both pp65 antigenemia and quantitative NAT (QNAT) are the mainstays for diagnosis of CMV infection. The choice of test varies on the basis of advantages and disadvantages (Table 3). While pp65 antigenemia testing was initially utilized by many centers, its use is declining in favor of QNAT [20]. Until recently, QNAT was not standardized, and there were wide variations in viral loads reported in a multicenter study across laboratories in America and Europe [20]. This limited the generation of viral thresholds for diagnosis, risk stratification, preemptive therapy, and duration of treatment [21]. In November 2010, the World Health Organization released an international calibration standard for CMV QNAT [20]. Initial studies have indicated improvement in viral load reporting, and there is now better agreement among different methods of QNAT [21, 22•]. In one study, there was high interlaboratory agreement and precision of viral load results among WHO standard-optimized QNAT at five different laboratories [22•]. In one of the first studies that assessed the clinical application of standardized QNAT, SOT recipients with lower pretreatment viral loads (i.e.,
TRANSPLANT AND ONCOLOGY (M ISON, SECTION EDITOR)
Emerging Cytomegalovirus Management Strategies After Solid Organ Transplantation: Challenges and Opportunities E. Beam & V. Dioverti & R. R. Razonable
# Springer Science+Business Media New York 2014
Abstract Cytomegalovirus (CMV) remains as one of the most common pathogens after solid organ transplantation (SOT). During the past year, management guidelines were updated, and numerous studies were published—all collectively emphasizing the ongoing efforts to improve management of CMV after SOT. Improvement in laboratory diagnostics was aided by the WHO international calibration standard for nucleic acid testing, which allows for meaningful comparison of viral load values among laboratories. The potential translation of methods for assessing CMV-specific cellular immunity could provide tools for CMV risk assessment and management. Efforts continue to optimize antiviral strategies for CMV disease prevention and treatment. CMV vaccines continue to be tested in various stages of clinical trials. Novel anti-CMV drugs are being developed, including agents that have been used as compassionate therapy for treatment of drug-resistant CMV. In this article, the authors review recent developments on CMVand discuss their implications in CMV management after transplantation. Keywords Cytomegalovirus . Prophylaxis . Transplantation . Viral load . Valganciclovir . Outcomes
there remain ongoing efforts in basic, clinical, and translational research to optimize the diagnosis, treatment, and prevention of CMV after solid organ transplantation (SOT). Diagnostic strategies have improved during the past year with the introduction and utilization of an international calibration standard for CMV nucleic acid testing (NAT), which now allows for comparison of viral load reports across centers. The optimal prevention strategy remains debated, and it is likely that the best prevention approach will vary depending on factors related to host (i.e., risk of disease based on immune status), the virus (i.e., amount of viral burden), and the logistics of providing care (i.e., ability to test and monitor patients). New antiviral agents are continually being developed for CMV management, and there is also an ongoing effort in CMV vaccine development. To provide an overview of all the recent developments in the field, the authors have evaluated publications on CMV in SOT recipients during the past year, using the PubMed database, and discuss them in the context of the current standard for CMV diagnosis, prevention, and treatment.
Epidemiology, Clinical Impact, and Risk Factors Introduction Since the birth of clinical transplantation, cytomegalovirus (CMV) has been its single most common infectious complication. Despite remarkable improvements in its management,
This article is part of the Topical Collection on Transplant and Oncology E. Beam : V. Dioverti : R. R. Razonable (*) Division of Infectious Diseases, Department of Medicine, and the William J von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA e-mail: [email protected]
CMV is a ubiquitous herpes infection with an overall 50 % seroprevalence in the United States [1], although this could be as high as 90 % in elderly and in developing countries [2]. Primary CMV infection in the immunocompetent host is generally asymptomatic or presents as a mild illness, with symptoms of mononucleosis-like illness. In immunocompromised hosts, such as SOT recipients, CMV can present as a primary infection in CMV-naïve transplant recipients or as a secondary infection (reactivation or reinfection) in CMVseropositive individuals. In SOT recipients, CMV infection may occur as an asymptomatic illness that is indicated only by viral DNA or antigen
419, Page 2 of 10
Curr Infect Dis Rep (2014) 16:419
detection in the blood (i.e., viremia), but without clinical symptoms. Asymptomatic CMV infection is detected most often in SOT recipients undergoing routine CMV surveillance. When CMV infection is accompanied by clinical symptoms (and often, laboratory abnormalities), it is called CMV disease, which can be categorized into CMV syndrome or tissue-invasive disease. CMV syndrome presenting as a flulike febrile illness with cytopenias and malaise is the most common form of CMV disease. Less commonly, CMV can involve various organs (termed tissue-invasive disease), with the gastrointestinal tract as the organ most commonly involved. CMV may also involve the allograft, manifesting as carditis in heart recipients, pneumonitis in lung recipients, pancreatitis in pancreas recipients, nephritis in kidney recipients, and hepatitis in liver recipients. Indeed, any organ may be involved, including less common conditions, myelitis and polyradiculopathy [3, 4], cholecystitis with biliary obstruction [5], and cholangitis [6]. In addition, there are numerous indirect effects of CMV, which are partly attributed to its immunomodulatory properties (Table 1). One indirect effect is the increased predisposition to bacterial coinfections. In a study of a small cohort of liver recipients, the majority (n=13 [81 %]) of the 16 patients with CMV infection had concomitant bacterial infection [7]. CMV has been implicated in adversely affecting allograft and patient survival, although the data have been conflicting due to differences in patient population, use of CMV prevention, and measured outcomes. Indeed, studies have come to varying conclusions in terms of the effects of CMV on long-term outcomes after SOT [8]. In an Australian study of pediatric kidney recipients, allograft outcome and patient survival were not influenced by donor and recipient CMV serostatus [9]. A Spanish retrospective study of 104 kidney and 58 liver recipients reported no significant association between CMV and mortality, allograft dysfunction, or graft loss [10]. On the other hand, in the study of 609 kidney and kidney/pancreas recipients, a negative impact of CMV disease on allograft survival was observed [11]. Likewise, a large French retrospective study of 1,279 kidney recipients showed an independent association between a positive donor CMV serology and graft loss [12].
Table 1 Indirect effects of cytomegalovirus Acute allograft rejection Chronic allograft rejection and dysfunction (nephropathy, coronary vasculopathy, bronchiolitis obliterans) Immunosenescence Mortality
Note. HHV, human herpesvirus
Fungal infections Reactivation of other herpes virus (HHV-6, HHV-7)
Bacterial infections Posttransplant lymphoproliferative disease (due to Ebstein Barr virus)
The incidence of CMV disease has been reduced after SOT with the use of antiviral prophylaxis. However, CMV disease still occurs as late-onset disease, especially in patients who are CMV-seronegative prior to transplantation. In a recent cohort study of 428 liver and kidney recipients, CMV disease occurred in 31.3 % of liver and 19.2 % of kidney D+/R−during the first year after transplantation, and almost all occurred after discontinuation of prophylaxis [13]. In another study of kidney and liver recipients, 25 (44 %) of 57 CMV D+/R−recipients developed late-onset CMV infection and disease despite antiviral prophylaxis [10]. These studies confirm previous observations that, in some CMV D+/R−SOT recipients, antiviral prophylaxis has only delayed the onset of clinical illness to the first 3–6 months after completion of prophylaxis. The risk of CMV infection depends on the donor and recipient CMV serologic status (with highest incidence and severity of disease in D+/R−SOT recipients), the type of solid organ transplanted (highest among lung, intestinal, and composite tissue transplant), degree of overall immunosuppression (highest with lymphocyte-depleting drugs), and preventative strategy used against CMV (expectedly higher rates of CMV infection with preemptive therapy, as compared with prophylaxis). In a prospective study of 609 kidney and kidney/pancreas recipients, a total of 108 (17.7 %) episodes of CMV viremia were observed, and the risk factors identified were D+/R−mismatch, donor age>50 years, and higher tacrolimus and mycophenolate blood levels [11]. In another retrospective study of pancreas–kidney and pancreas-afterkidney recipients, the risk factors for CMV infection and disease were CMV D+/R−, preceding non-CMV infection, and duration of antiviral prophylaxis [14]. The degree of immunosuppression used, including antirejection therapy and induction, and maintenance immunosuppression is directly correlated to the risk of CMV. In a cohort of kidney recipients, with an overall rate of 14.2 % of CMV disease, higher rates of CMV disease were observed with the use of induction immunosuppression (e.g., antithymocyte globulin) [15]. Use of T-cell-depleting therapy significantly raises the risk of CMV infection and disease, and in kidney recipients, a fourfold greater risk was reported with thymoglobulin induction [16]. On the other hand, use of mammalian target of rapamycin (mTOR) is associated with lower CMV disease rates. In a multicenter study of lung recipients, overall CMV events were significantly lower among those receiving sirolimus, when compared with azathioprine, even after adjustment for prophylaxis and CMV serostatus [17]. Likewise, in heart recipients, everolimus was associated with a lower risk of CMV infection, as compared with azathioprine or mycophenolate mofetil [18]. Everolimustreated renal recipients have higher CMV-specific CD8+ Tcell responses, as compared with cyclosporine- or mycophenolate-treated patients, likely accounting for the lower incidence of CMV disease during mTOR use [19].
Curr Infect Dis Rep (2014) 16:419
Page 3 of 10, 419
Diagnostic and Immunologic Monitoring The methods for the detection of CMV and its immune response are listed in Table 2. Tests for detecting active CMV infection are viral culture, antigen testing, and NAT. The use of viral culture to demonstrate CMV viremia is virtually nonexistent, due to poor sensitivity and long turnaround time, and this has been replaced by NAT and pp65 antigenemia. However, viral culture is still performed for detecting CMV in other body fluids and tissues not optimized for NAT. Both pp65 antigenemia and quantitative NAT (QNAT) are the mainstays for diagnosis of CMV infection. The choice of test varies on the basis of advantages and disadvantages (Table 3). While pp65 antigenemia testing was initially utilized by many centers, its use is declining in favor of QNAT [20]. Until recently, QNAT was not standardized, and there were wide variations in viral loads reported in a multicenter study across laboratories in America and Europe [20]. This limited the generation of viral thresholds for diagnosis, risk stratification, preemptive therapy, and duration of treatment [21]. In November 2010, the World Health Organization released an international calibration standard for CMV QNAT [20]. Initial studies have indicated improvement in viral load reporting, and there is now better agreement among different methods of QNAT [21, 22•]. In one study, there was high interlaboratory agreement and precision of viral load results among WHO standard-optimized QNAT at five different laboratories [22•]. In one of the first studies that assessed the clinical application of standardized QNAT, SOT recipients with lower pretreatment viral loads (i.e.,
