NIEWYDOLNOŚĆ SERCA I PŁUC, TRANSPLANTOLOGIA
Successful use of cidofovir to treat refractory cytomegalovirus infection in heart transplant recipient – a case report

Introduction

Cytomegalovirus (CMV), from the human herpes virus family (HHV), is a common viral pathogen in solid organ recipients, which contributes to high morbidity and mortality in the early postoperative period [1-3]. Apart from the direct impact of CMV infection on the transplanted organ recipient, the virus is also responsible for many indirect effects, such as acute graft rejection, cardiac allograft vasculopathy and increased susceptibility to non-viral infections [1, 4, 5]. The overall incidence of CMV disease in solid organ recipients varies from 30% to 50% of this population [1, 6]. In heart transplant recipients the frequency of CMV infection is 9-35% and CMV disease – 25% [1, 5]. CMV infection is characteristic for the early postoperative period. Since the use of anti-CMV prophylaxis is on the increase, late CMV disease is becoming more common (estimated range from 15% to 38%) [2, 6]. Especially, it is combined with prophylactic antiviral drug administration to the whole population, or only to a selected group of high-risk patients. It is less likely when pre‑emptive therapy is used. Late onset CMV disease usually occurs within 3 months after discontinuation of antiviral drugs [2, 6].

Classically, CMV disease in solid organ recipients is described as presence of documented fever (> 38°C) on 2 out of 4 consecutive days, neutropenia or thrombocytopenia and the detection of CMV in blood. However, patients with delayed-onset CMV disease may have atypical presentation and it may be more severe [6]. CMV infection and disease typically occurs within the time period from the 2nd to the 6th month after organ transplantation. CMV disease that presents after 6 months is described as late CMV disease, and is usually related either to discontinuation of antiviral prophylaxis or to increased immunosuppression due to a rejection episode [2, 6].

Risk factors for CMV disease were widely investigated and some associations were found. The three most important risk factors are CMV serostatus prior to transplantation, therapy of a rejection episode and type of transplanted organ. The other elements to consider are young recipient age, blood transfusions and high degree of HLA (human leukocyte antigens) mismatch. The risk of CMV disease is the highest when the donor/recipient (D/R) serostatus is D+/R-, and the lowest when it is D-/R-. At highest CMV disease risk are recipients of organs such as lung, liver and pancreas. The most endangered are patients who received antilymphocyte antibodies for acute rejection. High degree HLA mismatch is probably linked with increased immunosuppression in such patients. Young age of recipients may reflect CMV serostatus, because young people are more likely to be seronegative than the older [1, 2].

In this case, detection of CMV presence was based on evaluation of CMV phosphoprotein 65 (pp65 CMV antigen) on peripheral blood leukocytes (immunoenzymatic assay). This semiquantitative method is reliable and sufficient for recognition and treatment of CMV infection and disease [2].

Case report

A 19-year-old Caucasian male was admitted to the Department of Cardiosurgery and Transplantation in the Silesian Center for Heart Diseases with end-stage cardiac failure for an urgent heart transplantation. His past medical history is as follows. He presented to the local hospital with fatigue and dyspnoea increasing for six months. He had no past medical history during adolescence and he had been regularly practising football. The diagnosis of dilated cardiomyopathy was made and, because of its rapid progress, he was presented as a candidate for heart transplantation. There was no family history of cardiomyopathy or any hereditary disease.

He successfully underwent heart transplantation and during the postoperative period his status was gradually improving. As a result of insufficient own heart rhythm, the patient had a pacemaker (DDDR type) implanted. In the course of routine endomyocardial biopsies an acute rejection (ISHLT grade 3A) was detected, but no worsening in graft function was observed. After recognition of this rejection episode as steroid-resistant, rabbit antithymocyte immunoglobulin was initiated, with satisfactory effect. The immunosuppression therapy consisted of tacrolimus, steroid and mycophenolate mofetil which was switched to everolimus in the 3rd week after surgery due to the occurrence of steroid-resistant rejection.

This patient’s serostatus was perioperatively negative, regarding cytomegalovirus, hepatitis B virus, hepatitis C virus, human immunodeficiency virus, Epstein-Barr virus and toxoplasmosis. The donor was CMV-seropositive, but the recipient received no antiviral therapy in the postoperative period. After heart transplantation the presence of CMV infection was observed, by detection of pp65 antigen on peripheral blood leukocytes. The maximal value of CMV-positive cells was 127 pp65 positive leukocytes per 200 000 cells, 1 month after surgery. The values of pp65-positive cells during the observation period are shown in Fig. 1.

In the Silesian Center for Heart Diseases the following protocol of CMV prophylaxis in patients after heart transplantation is carried out. To prevent CMV disease routine screening of pp65 CMV antigen on peripheral blood leukocytes is performed from the 25th day after heart transplantation. Antiviral therapy is administered to heart recipients who either develop evidence of CMV infection, confirmed by pp65 CMV antigen presence on peripheral blood leukocytes, or who are without any clinical symptoms of CMV disease, but with a high value of pp65 CMV positive cells (above 20 pp65 positive leukocytes/200 000 examined cells).

In this case during the in-patient stay neither signs of CMV disease nor deterioration in graft function were observed, but because of the high value of pp65 CMV positive cells, intravenous ganciclovir was used for 3 weeks in standard doses (10 mg/kg/24 h). Additionally, the patient received two doses of anti-CMV immunoglobulin (IgG-CMV, Cytotect) at the beginning of the antiviral therapy. At discharge from hospital the patient was still CMV-positive, without any clinical signs of CMV disease; therefore he received oral valganciclovir (1.8 g/24 h) therapy. Out-patient control appointments were arranged for every 2 weeks.

During follow-up, the patient complained about nausea, abdominal pain, dyspepsia and diarrhea, which was associated with valganciclovir side effects.

In the 2nd month after heart transplantation no evidence of CMV infection was found (pp65 CMV antigen test was negative), which resulted in reduction in valganciclovir dose to 900 mg/24 h and termination of this therapy was planned in one month time. Unfortunately, 4 weeks later the number of CMV-infected leukocytes was high and valganciclovir in a dose of 900 mg/24 h was continued. From the 3rd to the 6th month after surgery the patient’s condition remained stable and complaint-free, with good exercise tolerance. All routinely performed endomyocardial biopsies were negative (ISHLT grade 0).

In the 7th month after heart transplantation, he was admitted to the hospital with signs of CMV gastrointestinal disease (nausea, abdominal pain, dyspepsia and diarrhea). The number of CMV infected leukocytes (detected by the presence of pp65 antigen) was elevated. He was successfully treated with ganciclovir intravenously with anti-CMV immunoglobulin and discharged after 2 weeks. Valganciclovir 1.8 g/24 h was prescribed. Seven days later he presented in the Silesian Center for Heart Diseases with worsening of gastrointestinal symptoms, but no fever. In blood results neutropenia, thrombocytopenia and high serum creatinine, but low number of pp65 CMV positive peripheral blood leukocytes, were remarkable. Again, intravenous ganciclovir and anti-CMV immunoglobulin were administered. After a few days he underwent a cardiac arrest in the mechanism of electromechanical dissociation and was reanimated with only slight neurological defects. He was transferred to the intensive care unit, where a tendency to severe hypotonia, resistant to drugs was observed. During this period the patient remained apyrexial. Blood culture and other body tissue cultures were negative. Acute phase proteins were highly elevated, whereas platelet count, white cell count with neutrophil count and creatinine were within the normal range. At this stage the working diagnosis of atypical CMV disease was made.

Because of no improvement, the decision of cidofovir administration was made. This patient received 3 courses of this medication, strictly according to the producer’s advice (275 mg/24 h intravenously, every 2 weeks), simultaneously with renal protection (prehydration and probenecid). There was deterioration in renal function observed, but the patient did not require hemofiltration or dialysis and renal function improved. There were no other side effects observed. The patient got gradually better, despite high markers of CMV infection, and was eventually discharged after 10 weeks of hospital stay. As supportive therapy he received valganciclovir 1.8 g/24 h and five courses of cidofovir infusion in two-week intervals. The number of pp65 CMV positive peripheral blood leukocytes gradually dropped and eventually the patient became CMV-negative in the 15th month after heart transplantation. At present, this 21-year-old patient feels very well and has good exercise tolerance. His immunosuppression regimen consists of tacrolimus 14 mg/24 h (Advagraf); he receives no antiviral drugs.

Discussion

We presented a case of refractory CMV disease in an immunocompromised host after heart transplantation, which was atypical because of the prolongation in time and because of the lack of characteristic signs and symptoms in the late phase of the disease. The late relapse occurred > 6 months after surgery and was not related to the treatment of rejection. The patient was afebrile for the whole time and experienced a single episode of leucopenia and thrombocytopenia. The number of pp65 CMV antigen positive blood peripheral leukocytes was irrelevant to signs and symptoms of the disease. Despite the lack of stringent diagnostic criteria for CMV disease, it is likely that his condition was due to CMV infection, because his illness resolved with anti-CMV therapy. Although the patient was on maintenance valganciclovir therapy, there were still signs of CMV infection, which may suggest that his CMV strain was at least partially resistant to ganciclovir. Eventually, the initiation of cidofovir therapy resulted in health improvement and finally in elimination of CMV from blood. Antiviral therapy consisted of ganciclovir/valganciclovir, anti-CMV immunoglobulin and finally cidofovir.

Cidofovir, together with foscarnet, is a second-line drug, useful for treatment of CMV diseases caused by ganciclovir-resistant CMV strains [2, 7]. Cidofovir is an acyclic nucleoside phosphonate. It is a broad-spectrum antiviral agent with potency against both herpesviruses and other DNA viruses, such as smallpox virus. Host kinases convert cidofovir to the active diphosphoryl form, and cidofovir diphosphate acts as a competitive inhibitor of the viral DNA polymerase, causing premature chain termination in viral DNA synthesis. This drug is available only as an intravenous formulation; its oral bioavailability is less than 5%. The major limitation of cidofovir (apart from uveitis) is severe renal toxicity; therefore it remains a second-line therapy. Primarily, cidofovir received US marketing approval for treatment of retinitis in AIDS patients. In transplantation, it is used in second-line pre‑emptive strategies in allogeneic stem cell transplant recipients [8]. The clinical data regarding its use in solid organ transplant patients are poor and no data from randomized clinical trials are available to support the use of cidofovir in solid organ transplant recipients.

In recent years some studies have investigated factors contributing to drug-resistance CMV strains [7, 9]. In solid organ transplant recipients, the incidence of ganciclovir-resistant CMV is approximately 5-10% and is often linked to progressive or fatal CMV disease [7]. The routine administration of antiviral prophylaxis in organ recipients may have led to the emergence of drug-resistant CMV strains. Other reasons may be severe immunosuppression, prolonged antiviral therapy (especially after introduction of orally administered antiviral agents), and subtherapeutic drug concentration, caused for example by patient non-compliance [2, 7]. The beneficial early effects of heart transplant immunosuppressive treatment with proliferation signaling inhibitors (or mTOR inhibitors) – everolimus and sirolimus – is thought to be, at least partially, a result of suppression of CMV replication [10]. Surprisingly, the everolimus introduction in the described case seemed not to have any positive influence on the course of infection.

Conclusions

Case reports about late and atypical CMV disease, as well as clinical experiences with the use of cidofovir in CMV disease in patients after heart transplantation, are rare in medical literature [6, 11]. This matter raises an interesting question concerning a possible change in the epidemiology of CMV disease in solid organ recipients together with evolution of the definition of CMV disease. Therefore the diagnosis of CMV disease should be taken into consideration at any time after transplantation. Moreover, different antiviral strategies against CMV-resistant strains need to be more widely investigated.

References

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