Cytomegalovirus

Cytomegalovirus is the most common infectious complication in solid-organ transplant recipients. Despite the frequency of the problem, no commonly accepted approach to Cytomegalovirus prophylaxis and treatment exists. Because cytomegalovirus may lead to the modulation of the immune system sometimes causing opportunistic superinfections, allograft injury, acute rejection, chronic rejection, and development of posttransplant lymphoproliferative disease, transplant coordinators require knowledge of the disease, diagnostic methods, and treatment and prophylaxis strategies. This case study reviews a high-risk cytomegalovirus transplant recipient after living-related kidney transplantation. In addition to a review of the pathophysiology of the disease process, patient, family, and nursing staff education, and cultural and psychosocial aspects of cytomegalovirus, prophylaxis, diagnosis, treatment strategies as well as role of the transplant coordinator, will be discussed. (Progress in Transplantation. 2005;15:157-160)

Cytomegalovirus (CMV) is a latent herpes virus that infects approximately 15% of adolescents and 50% of adults in the United States. The virus is transmitted through close physical contact, sexual intercourse, and blood transfusions.1 CMV rarely causes disease in the immunocompetent, but frequently reactivates in a compromised host, such as a solid-organ transplant recipient. When CMV primarily infects a previously uninfected recipient or a latent virus reactivates in the recipient, replication can occur in nearly any organ. In addition to the direct impact of the virus, CMV also leads to the modulation of the immune system, which can lead to opportunistic superinfections, allograft injury, acute rejection, chronic rejection, and development of posttransplant lymphoproliferative disease.2

CMV is the most common infectious complication in solid-organ transplant recipients. Despite the frequency of the problem, no commonly accepted approach to CMV prophylaxis and treatment exists.3 Patients who are CMV negative at the time of transplantation and receive a CMV-positive organ are considered to possess the highest risk of developing CMV disease (Table 1).5 The following case review will outline a young woman's clinical course of CMV after kidney transplantation. The role of the transplant coordinator, cultural aspects of the patient care, and the psychosocial issues surrounding CMV after transplantation will be discussed.

Case Presentation

A young, African American, chronic hemodialysis patient received a living donor kidney transplant from an HLA-identical sibling. The transplant recipient had no antibodies to CMV at the time of transplantation, whereas the donor was CMV positive. The patient received antithymocyte globulin 75 mg per protocol as induction therapy and then on postoperative days 1 and 2. The posttransplant immunosuppression therapy included tacrolimus 3 mg twice a day, mycophenolate mofetil 1000 mg twice a day, and prednisone 20 mg every day. The patient was discharged, taking 900 mg of valganciclovir each day for 12 weeks, which is the transplant program's protocol for prophylactic therapy for CMV. The patient was discharged home on postoperative day 4 in excellent condition.

By posttransplant day 90, the patient's immunosuppression included the following: prednisone 10 mg every day. tacrolimus 4 mg twice a day (with levels averaging 8.0), and mycophenolate mofetil 500 mg twice a day. The dose of mycophenolate mofetil was decreased to 500 mg twice a day because of a white blood cell count of 3.0 k/uL.

On posttransplant day 119, the patient was admitted to the inpatient transplant service, complaining of abdominal pain and nausea and experiencing malaise. At that time, the patient's white blood cell count was 5.8 k/uL and her platelet count was within normal limits. Because her CMV prophylactic regime of valganciclovir had been completed on posttransplant day 94, a high suspicion existed for a primary infection with CMV. An endoscopie gastroduodenoscopy was performed and biopsies were taken of the stomach and duodenum and sent to the laboratory to detect CMV in both locations. A CMV polymerase chain reaction (PCR) was drawn from her blood. Within 1 day, the patient felt better and was released from the hospital. A positive CMV culture from her biopsy was received from the laboratory 1 day after the patient was discharged. The duodenal biopsy revealed erosion with acute inflammation and CMV inclusions, and the stomach biopsy revealed the same. Subsequent to that biopsy result, her CMV viral load (PCR) was also found to be positive (8870 copies/mL).

On posttransplant day 122, the patient was notified of this result and readmitted to the inpatient transplant service for placement of a peripherally inserted central catheter and to facilitate the start of intravenous ganciclovir therapy to treat CMV. The patient received ganciclovir 275 mg (5 mg/kg) intravenously every 12 hours, which was the dose adjusted for her creatinine clearance at that time. Her dose of the immunosuppressant agent mychophenolate mofetil was lowered to 250 mg twice a day, then held for a period of 1 month because of a low white blood cell count. Prophylactically, she was also placed on oral esomeprazole for gastric acid inhibition because of the risk for ulcers with CMV disease. Weekly monitoring of laboratory values included a basic metabolic panel and complete blood cell count; a serum CMV PCR was performed every other week.

The CMV PCR became negative by the end of the 3-week course of ganciclovir, the therapy was discontinued, and the patient's central catheter was removed. CMV PCRs were checked every other week for 4 weeks, then monthly, and then at her annual appointment once therapy was complete to ensure the virus did not reactivate. No oral antiviral agents were given after the completion of her intravenous ganciclovir, but these CMV PCRs were monitored as noted. All CMV PCRs after completion of CMV therapy were negative.

Discussion

Pathophysiology of the Disease Process

It is important that transplant coordinators working with transplant recipients are aware of their patient's viral serology status. The importance of beginning prophylactic therapy immediately after transplantation cannot be minimized to avoid infection in the early posttransplant period. Options for preventing CMV disease included either universal prophylaxis, in which all at-risk patients receive prophylaxis for a fixed period, or preemptive therapy, in which CMV viral loads are monitored at regular intervals and therapy is initiated when the viral load increases above a particular threshold, typically between 1000 and 5000 copies/mL for kidney transplant recipients.3 Acyclovir, valacyclovir, ganciclovir, and valganciclovir can be used for CMV prophylaxis. Valacyclovir, ganciclovir, and valganciclovir are approved by the Food and Drug Administration for the indication of CMV disease in kidney transplant recipients.6 Table 2 reviews the pharmacologie agents available for the prevention and treatment of CMV.

CMV-negative patients who receive an organ from a CMV-positive donor are at highest risk for CMV disease. Antithymocyte globulin, a T-cell depleting, polyclonal agent and potent immunosuppressant, places patients at an increased risk for infectious diseases such as CMV.2 The transplant coordinator should be watchful of the signs and symptoms of CMV disease, as well as facilitate initiation of treatment for CMV disease if it is found in these high-risk patients. Transplant coordinators should teach their atrisk patients to report any signs and symptoms of CMV, such as myalgias, arthralagias, headache, fever, and malaise, and remain vigilant to detect leukopenia, and thrombocytopenia in laboratory results.7

Traditionally, CMV infection is divided into 2 categories: (1) CMV syndrome, characterized by fever, leukopenia, and an increase in a CMV antigen titer, and (2) CMV disease, characterized by pneumonitis, hepatitis, or gastrointestinal disease. Diagnosis of disease in tissue is achieved through microscopic detection of inclusion bodies, special CMV staining, and electron microscopy.2 Both CMV disease and syndrome can also be diagnosed with a blood CMV PCR or antigenemia assay; these assays are quantitative in nature, so typically the higher the level the higher the likelihood of disease. Although Piiparinen and colleagues8 reported that CMV PCR is equal in detecting viral load to the antigenemia assay, Mengelle and colleagues10 reported that quantitative PCR is more sensitive, less laborious, and more rapid than the antigenemia assay. Table 3 presents a review of the various CMV diagnostic testing techniques. The transplant coordinator should be familiar with his or her institution's preference of diagnostic method.

As previously mentioned, CMV disease must be treated aggressively to avoid further complications. In the case of CMV gastric and duodenal involvement, avoidance of progression of disease to ulcers must be a priority. A low threshold for performing endoscopie studies should be afforded any high-risk patient with gastrointestinal complaints. CMV disease in the gastrointestinal tract has been reported to lead to large-volume intestinal bleeding and death.9 Because CMV is associated with an increased risk of rejection and other opportunistic infections, early detection, treatment, and close monitoring of follow-up blood testing for disease is essential.11

Patient, Family, and Nursing Staff Education

It is valuable for the transplant coordinator working with transplant patients to have an understanding of the pathophysiology and natural history of CMV disease. Recognizing that onset of CMV disease is most likely to occur 4 to 6 weeks after transplantation or anytime after the discontinuation of CMV prophylaxis therapy is key. One reason for this is so they may educate the patient, family, and other members of the healthcare team about the disease process. It is imperative that patients and family members are given understandable information about this disease process and treatment. Having an understanding of the rationale for treatment may increase the likelihood of adherence to the medication regime and follow-up care. When a patient understands the risks of becoming infected with CMV and understands the associated immunomediated risk factors, adherence to the strategy may improve.

Nursing staff education is a component of the transplant coordinator role. Transplantation requires that nurses have a specialty knowledge of immunosuppressive agents, infectious diseases, and rejection. A transplant coordinator's role includes education of nursing staff and other healthcare providers about signs and symptoms the disease, treatment, administration of treatment, and the laboratory findings that are necessary to diagnose and treat the disease.

Cultural and Psychosocial Issues

There continues to be a national shortage of available organs for patients with end-stage renal disease on the kidney transplant list. Patients wishing to pursue a transplantation often find a loved one who is willing to donate an organ. Most transplant centers feel that a mismatch of CMV status is not a reason to withhold transplantation. The benefits and costs of transplantation far outweigh the risk of CMV and continued time on dialysis. Overall, the field of transplantation, laden with psychosocial, ethical, and cultural issues, presents many dilemmas, particularly when an issue like transmission of infection from donor to recipient arises. In this case, a sibling gives an organ to his sister, but the sister develops an active infection because of a pathogen given to her in her sibling's kidney. This phenomenon requires astute educational and informational sessions be provided by the transplant coordinator working with both clients in this circumstance. While one sibling may deal with the feeling of guilt and fear, the other sibling deals with the illness management and treatment and uncertainty about the effect this may have on overall health status and kidney function. The recipient must engage in the daily administration of infusions of intravenous ganciclovir. The transplant coordinator's role in providing education regarding the prevalence of CMV in the population at large and answering the questions of both donor and recipient is of utmost importance to allay fears and reduce feelings of guilt and shame.

The patient and her donor sibling were both of African American descent, a population that has been less served by the organ allocation system.12 A literature review did not find reasons for religious obstacles or that the majority of blacks are disinterested in transplantation. The literature also failed to show a religious teaching against transplantation. Often, religious myths and misperceptions, distrust of the medical community, and racism have been cited as reasons for blacks to refuse or not pursue transplantation.13,14 A literature search is unrevealing of cultural and social impacts of CMV and its relationship to kidney transplantation. When illness arises as a direct response to a healthcare intervention, the transplant coordinator should acknowledge this phenomenon and take steps to allay mistrust through therapeutic communication techniques and education. In this case, open discussions about CMV disease with the patient and donor were conducted while providing emotional support and reassurance.

Summary

This case review focuses on the prevention and treatment strategies currently in practice to prevent and treat CMV infection in transplant recipients, as well as the role of the transplant coordinator caring for these patients. Few studies are available in the current literature regarding psychosocial implications and cultural issues for the donor and recipient involved in a transmission of CMV disease. In order for CMV dis ease to be managed appropriately and in a timely manner, the transplant coordinator working with transplant recipients requires reliable knowledge of institutional protocols for initial prophylaxis, identification of patients at risk, early detection and diagnosis of disease, and effective therapy for control of disease. In April 2003, Schnitzler et al15 reported that CMVseropositive donors compared to seronegative donors were associated with significantly higher incidence of CMV disease, graft loss, and costs when transplanted into seronegative recipients. Tailored management of antiviral therapy and immunosuppression are needed. As CMV disease continues to challenge the transplant community, the transplant coordinator requires a current knowledge with respect to the multiple facets of CMV at the local transplant center.

Acknowledgment

The author wishes to thank Michael Ison, MS, MD, for his assistance with this manuscript.

References

1. Drew WL. Cytomegalovirus as a sexually transmitted disease. In: Becker Y, Caria C, eds. Molecular Aspects of Human Cytomegalovirus Disease. Heidelberg, Germany: Springer-Verlag; 1993:92-100.

2. Kubak BM, Pegues DA, Holt CD. Infectious complications of kidney transplantation and their management. In: Danovitch GM, ed. Handbook of Kidney Transplantation. Philadelphia, Pa: Lippincott, Williams, & Wilkins; 2001:221-262.

3. Singh N. Preemptive versus universal prophylaxis with ganciclovir for Cytomegalovirus in solid organ transplant recipients. CHn Infect Dis. 2001;32:742-751.

4. Davis CL. The prevention of disease in renal transplantation. Am J Kidney Dis. 1990;16:175.

5. Abbott KC, Hypolite IO, Viola R, et al. Hospitalization for CMV disease in renal transplantation in the United States. Ann Epidemiol. 2002;12:402-409.

6. Ukins ME. Valganciclovir versus intravenous ganciclovir, revisited. Medscape Transplantation. 2003;4(2). Available at: http://www.medscape.com/viewarticle/462041?src=search. Accessed October 2003.

7. Stosor V. Infections in transplant recipients. In: Stuart FP, Abecassis MM, Kaufman DB, eds. Organ Transplantation. 2nd ed. Georgetown, Tex: Landes Bioscience; 2003:399-425.

8. Piiparinen H, Hockerstedt K, Lappalainen M, Suni J, Lautenschlager I. Monitoring of viral load by quantitative plasma PCR during active Cytomegalovirus infection of individual liver transplant patients. J Clin Microbiol. August 2002; 40:2945-2952.

9. Mengelle C, Pasquier C, Rostaing L, et al. Quantitative of human Cytomegalovirus in recipients of solid organ transplant by real-time quantitative PCR and pp65 antigenemia. J Med Virol. 2003;69:225-231.

10. Leung SF, Lee KC, Lam HW. Gastrointestinal Cytomegalovirus infection and extensive colonie ulceration in a renal transplant recipient. Hong Kong Med J. 1998;4:434-436.

11. Becker BN, Becker YT, Leverson GE, Simmons WD, Sollinger HW, Pirsch JD. Reassessing the impact of CMV infection in kidney and kidney pancreas transplantation. Am J Kidney Dis. 2002;39:1088-1095.

12. Foster CE, Philosophe B, Schweitzer EJ, et al. A decade of experience with renal transplantation in African-Americans. Ann Surg. 2002;236:794-805.

13. Siminoff L, Sturm C. African-American reluctance to donate: beliefs and attitudes about organ donation and implications for policy. Kennedy Institute Ethics J. 2000;10:59-74.

14. Davidson MN, Devney P. Attitudinal barriers to organ donation among black Americans. Transplant Proc. 1991;23: 2531-2532.

15. Schnitzler MA, Lowell JA, Hardinger KL, Boxerman SB, Bailey TC, Brennan DC. The association of Cytomegalovirus sero-pairing with outcomes and costs following cadaveric renal transplantation prior to the introduction of oral ganciclovir prophylaxis. Am J Transplant. 2003;3:445-451.

Carol A. Lawson, RN, BSN, CCTC

University of Virginia Health System, Charles O. Strickler Transplant Program, Charlottesville, Va

Copyright North American Transplant Coordinators Organization Jun 2005
Provided by ProQuest Information and Learning Company. All rights Reserved