CMV IN SOLID ORGAN TRANSPLANTATION
Every year, more than 100,000 people are added to the growing, global community of solid organ transplant (SOT) recipients.1 With demand for organs vastly exceeding supply, each organ is a precious opportunity to improve a life.2 However, with opportunity comes risk. Cytomegalovirus (CMV) viremia occurs in 16%-56% of transplant patients (median = 30%), and CMV disease is a significant risk factor for graft loss, morbidity, and mortality.3,4
16%-56% VIREMIA incidence3
Presentation: From Viremia to Disease
CMV initially manifests as viremia, which can be asymptomatic. When not successfully treated, viremia can advance to CMV disease.5 Accumulated study findings suggest that CMV viremia predicts the development of CMV disease, which leads to greatly increased rates of morbidity and mortality.4,6 In one prospective, randomized trial of 296 renal transplant recipients, CMV disease occurred in 4.1% or 12.7% depending on the CMV prevention strategy utilized.7
CMV disease can present as CMV syndrome or tissue-invasive CMV. CMV syndrome typically manifests as flu-like illness, fever, and malaise. Tissue-invasive CMV, also called "end-organ" CMV, is typically associated with specific organ involvement (gastrointestinal, pneumonitis, hepatitis, nephritis, myocarditis, retinitis, etc.).4,8
In a recent study of 59 renal and 35 liver recipients in donor positive, recipient negative (D+/R-) transplants, there was a strong association between the degree of CMV viral load and the occurrence of severe CMV disease (p<0.001) and mortality (p<0.001).9
4.1% or 12.7%
Rate of CMV diseasein renal transplant patients after antiviral therapy7
Risk Factors for Developing CMV Viremia and Disease
In solid organ transplants, the number one risk factor for developing CMV viremia is donor and recipient serostatus. When the donor is positive for CMV (D+) and the recipient is negative (R-), risk of transmission is at its highest.5 There is an intermediate risk level for recipient seropositive (R+) transplants, and a lower risk when both recipient and donor are seronegative (D-/R-).4
Additional risk factors for viremia beyond serostatus include blood transfusions, types of immunosuppression, increased corticosteroid administration, younger age, and underlying organ disease.10 CMV viremia risk also varies with the organ transplanted. Lung, small-bowel, pancreas, and combined kidney-pancreas transplant recipients are at highest risk, with liver and heart recipients at intermediate risk, and recipients of kidney transplants at lowest risk.11
CMV has been associated with additional infections, including bacteremia, invasive fungal disease, and Epstein–Barr virus-associated posttransplant lymphoproliferative disease.5
Many of the risk factors for progression to CMV disease are general concerns or challenges related to SOT, including immunosuppressive protocol, use of lymphocyte-depleting agents, cold ischemia time, comorbidities, and lymphopenia. Coinfections with other herpes viruses have also been suggested as risk factors.5
Late-onset CMV, or CMV that occurs after the discontinuation of prophylaxis, can be a significant complication in SOT. Risk factors for late-onset CMV can be similar to development of viremia, but also included are shorter courses of prophylaxis, higher levels of immunosuppression, allograft rejection, and type of transplanted organ.4
The Persistent Challenge of Refractory/Resistant CMV
Viremia rates refuse to go down? CMV that is refractory or resistant to treatment can lead to high morbidity and mortality rates, particularly in D+/R- transplants.12
The risk of resistance can depend on the transplanted organ and immunosuppression regimen, and has been reported to be in the range of 5%-10% in D+/R- transplants.13
16%-56% CMV Viremia rate IN SOT3
resistant CMV rate in D+/R- transplants13
Defining the Problem
Definitions for resistant and refractory CMV can vary between clinical practice and published literature. Clinical trials have historically used the following definitions12:
Antiviral drug resistance Viral genetic alteration—assessed by genotyping—that decreases susceptibility to one or more antiviral drugs.
Refractory CMV CMV viremia that increasesa after at least 2 weeks of appropriately dosed antiviral therapy.
aMore than 1 log10 increase in CMV DNA levels in blood or serum and determined by log10 change from the peak viral load within the first week to the peak viral load at ≥2 weeks as measured in the same laboratory with the same assay.
In clinical practice, the suspicion of drug-resistant CMV infection is often based on suboptimal responses to antiviral agents, whether or not it is confirmed by laboratory testing and the identification of a known mutation by genotyping.12
Risk Factors for Refractory/Resistant CMV
There are many factors which can contribute to resistant CMV in solid organ transplants. One of the most widely accepted is subtherapeutic drug levels.12,14,15 The highest risk group for drug-resistant CMV infection in SOT is D+/R-. Other factors include the type of organ transplanted, lower doses or longer duration of prophylaxis, peak CMV viral loads, and intensity and type of immunosuppression.12
REFRACTORY/RESISTANT CMV IS A THREAT TO SURVIVAL
Refractory/resistant CMV corresponds with significant clinical challenges: protracted disease course, organ dysfunction, recurrences, and an increased mortality rate.14 To make matters even more complex, second-line treatments for CMV often have significant toxicities. In one retrospective study of 39 transplant recipients from 2016, 51% of patients treated with a second-line antiviral experienced renal dysfunction.14
subtherapeutic drug levelsincrease risk of refractory/resistant CMV12
Refractory/resistant CMVINCREASES MORTALITY RATE14
16%-56% CMV Viremia rate IN SOT3
Incidence of Neutropenia18 in CMV patients who were treated with an antiviral18
The Compounding Harm of Neutropenia
CMV is just one front in the battle against posttransplant infection, but it is not an isolated fight. Because CMV plays a role in influencing the production of various cytokines and T-cell responses, CMV makes it more difficult for the body to fight off additional infections.16 This is compounded by the neutropenia caused by antiviral treatment, leaving the recipient more vulnerable to coinfection, which may ultimately lead to worse outcomes.8,17
In a recent retrospective study of 82 CMV patients who were treated with an antiviral, 55% experienced neutropenia.18 In kidney recipients, neutropenia has been associated with an increased risk of allograft loss and death.19
The Menacing Risk of Graft Loss
With its tendency to invade the donated organ, CMV represents a threat to graft survival. CMV infection is an important contributor to acute and chronic allograft injury, including chronic allograft nephropathy (or tubulointerstitial fibrosis in kidney recipients), bronchiolitis obliterans (lung recipients), and coronary vasculopathy (heart recipients).5
The rate of graft loss after CMV replication varies by organ, with one prospective multicenter study showing rates of 1.4% in heart (n=97), 5.5% in kidney (n=917), 7.6% in liver (n=237), and 11% in lung (n=163). All of these rates are significantly higher than in patients who did not experience CMV replication.20
Additionally, overall graft survival is negatively associated with incidents of neutropenia. In order to alleviate concerns around neutropenia, some physicians choose to adjust immunosuppression after neutropenia occurs.21 A reduction in immunosuppression may have a negative impact on graft survival.19,22
a bidirectional relationship between CMV and allograft rejection
Allograft rejection creates a proinflammatory environment that can reactivate CMV. CMV upregulates antigens, which increases alloreactivity of the transplanted organ, facilitating allograft rejection.8
CMV ALLOGRAFT REJECTION
ANTIVIRAL DOSE ADJUSTMENT Refractory/ resistant viremia Increased viral load CMV disease Threat of renal dysfunction
The Precarious Threat of Renal Dysfunction
Kidneys are at an increased risk after SOT, with chronic kidney disease prevalence rates in non-renal organ recipients historically ranging from 10% to 90%. This wide range is primarily due to lack of consensus criteria of chronic kidney disease in this population.23 Some of the danger lies in immunosuppressive protocols, which are an integral part of transplantation but are often nephrotoxic.24,25 To further complicate management, prophylaxis against or treatment for CMV has been associated with nephrotoxicity, requiring dose adjustment for renal dysfunction.4,14 This creates the difficult balancing act of managing CMV with renal dysfunction.
A dangerous cycle that increases the risk of resistance
The nephrotoxicity balancing act is a tricky one. Decreases in antiviral dosing to avoid nephrotoxicity may increase the chances of resistance, in turn making CMV infection more difficult to treat successfully.15
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- Transplantation. World Health Organization. Accessed August 10, 2020. https://www.who.int/transplantation/gkt/statistics/en/
- Organ Donation Statistics. organdonor.gov. Accessed August 10, 2020. https://www.organdonor.gov/statistics-stories/statistics.html
- Stycyzynski J. Who Is the Patient at Risk of CMV Recurrence: A Review of the Current Scientific Evidence with a Focus on Hematopoietic Cell Transplantation. Infect Dis Ther. 2018;7(1):1-16.
- Kotton CN, Kumar D, Caliendo AM, et al. The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation. Transplantation. 2018;102(6):900-931.
- Razonable RR, Humar A. Cytomegalovirus in Solid Organ Transplant. J Transplant. 2013;13(Suppl 4):93-106.
- Cytomegalovirus in Transplantation: Developing Drugs to Treat or Prevent Disease. US Dept of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). May 2020:1-30. Accessed August 12, 2020. https://www.fda.gov/media/112942/download
- Witzke O, Hauser IA, Bartels M, Wolf G, Wolters H, Nitschke M. Valganciclovir Prophylaxis Versus Preemptive Therapy in Cytomegalovirus-Positive Renal Allograft Recipients: 1-Year Results of a Randomized Clinical Trial. Transplantation. 2012;93(1):61-68.
- Ramanan P, Razonable R. Cytomegalovirus Infections in Solid Organ Transplantation: A Review. Infect Chemother. 2013;45(3):260-271.
- McBride JM, Sheinson D, Jiang J, et al. Correlation of Cytomegalovirus (CMV) Disease Severity and Mortality With CMV Viral Burden in CMV Seropositive Donor and CMV-Seronegative Solid Organ Transplant Recipients. Open Forum Infect Dis. 2019;6(2):1-8.
- Gorensek MJ, Carey WM, Vogt D, Goormastic M. A Multivariate Analysis of Risk Factors for Cytomegalovirus Infection in Liver-Transplant Recipients. Gastroenterology. 1990;98(5 Pt 1):1326-1332.
- Snydman DR, Limaye A, Potena L, Zamora M. Update and review: State-of-the-art management of cytomegalovirus infection and disease following thoracic organ transplantation. Transplant Proc. 2011;43(3 Suppl):S1-S17.
- Chemaly RF, Chou S, Einsele H, et al. Definitions of Resistant and Refractory Cytomegalovirus Infection and Disease in Transplant Recipients for Use in Clinical Trials. Clin Infect Dis. 2019;68(8):1420-1426.
- Lurain NS, Chou S. Antiviral Drug Resistance of Human Cytomegalovirus. Clin Microbiol Rev. 2010;23(4):689-712.
- Avery RK, Arav-Boger R, Marr KA, et al. Outcomes in Transplant Recipients Treated With Foscarnet for Ganciclovir-Resistant or Refractory Cytomegalovirus Infection. Transplantation. 2016;100(10):e74-e80.
- Drew WL. Cytomegalovirus Resistance Testing: Pitfalls and Problems for the Clinician. Clin Infect Dis. 2010;50(5):733-6.
- Solak Y, Biyik Z, Cizmecioglu A, et al. Cytomegalovirus and Aspergillus spp. coinfection in organ transplantation: a case report and review of the literature. CEN Case Rep. 2013;2(1):59-67.
- Mavrakanas TA, Fournier MA, Clairoux S, et al. Neutropenia in kidney and liver transplant recipients: Risk factors and outcomes. Clin Transplant. 2017;31(10):1-7.
- Ritchie BM, Barreto JN, Barreto EF, et al. Relationship of Ganciclovir Therapeutic Drug Monitoring with Clinical Efficacy and Patient Safety. Antimicrob Agents Chemother. 2019;63(3):1-10.
- Hurst FP, Belur P, Nee R, et al. Poor Outcomes Associated With Neutropenia After Kidney Transplantation: Analysis of United States Renal Data System. Transplantation. 2011;91(1):36-40.
- Stern M, Hirsch H, Cusini A, et al. Cytomegalovirus Serology and Replication Remain Associated With Solid Organ Graft Rejection and Graft Loss in the Era of Prophylactic Treatment. Transplantation. 2014;98(9):1013-1018.
- Helou GE, Razonable RR. Safety considerations with current and emerging antiviral therapies for cytomegalovirus infection in transplantation. Expert Opin Drug Saf. 2019;18(11):1017-1030.
- Knoll GA, Macdonald I, Khan A, Van Walraven C. Mycophenolate Mofetil Dose Reduction and the Risk of Acute Rejection after Renal Transplantation. J Am Soc Nephrol. 2003;14(9):2381-2386.
- Bloom RD, Reese PP. Chronic Kidney Disease after Nonrenal Solid-Organ Transplantation. J Am Soc Nephrol. 2007;18(12):3031-3041.
- Duncan MD, Wilkes, DS. Transplant-related Immunosuppression: A Review of Immunosuppression and Pulmonary Infections. Proc Am Thorac Soc. 2005;2(5):449-455.
- Martin MF. Nephrotoxic Effects of Immunosuppression. Mayo Clin Proc. 1994;69(2):191-192.