Prospective study on CMV-reactivations under preemptive strategy in CMV-seropositive adult liver transplant recipients
Introduction
Cytomegalovirus (CMV) is a significant infectious agent causing morbidity in transplant patients. CMV infection mostly appears within the first 2–3 months after transplantation. In addition to fever, end-organ disease, such as colitis and hepatitis, are the most common clinical symptoms after liver transplantation.1, 2 To prevent CMV infection, most liver centres use prophylaxis for high-risk CMV-seronegative recipients receiving an organ from a seropositive donor (D+/R−) and additionally many centres even use prophylaxis for all seroposive recipients (R+).1, 3 Pre-emptive treatment is mainly used for those at a moderate or low risk of CMV. Both strategies have decreased the incidence of CMV disease.4 Recent international guidelines summarise the advantages and disadvantages of both strategies in solid-organ transplantation.5 However, in Europe, pre-emptive therapy is commonly used, even for the patients at the risk of primary infection, and especially for (R+) liver-transplant patients.6, 7, 8
A major advantage of pre-emptive therapy is that patients who would not develop CMV disease are not exposed to unnecessary antiviral medication. Other advantages include lower drug costs and lower risk of late-onset CMV disease.4, 5 Pre-emptive therapy is based on screening for early evidence of CMV by frequent monitoring of viral load, usually by quantitative polymerase chain reaction (PCR) methods with specific cut-off levels.4, 5, 9 A disadvantage of pre-emptive therapy is that it might result in the onset of clinical illness prior to laboratory detection of CMV. This is especially the case in patients with primary infections, in which the replication kinetics of the virus can be very rapid.10 In CMV-seropositive recipients, however, pre-emptive strategy may be useful.
As the main interest has been focussed on the high-risk patients D+/R−, very little attention has been paid to the management of CMV in R+ patients. Here we report our experience on the prospective follow-up of CMV replication, demonstrated by quantitative PCR monitoring, in 161 CMV-seropositive (R+) adult liver-transplant patients under pre-emptive strategy.
Section snippets
Objectives
A prospective long-term follow-up of CMV-seropositive adult liver-transplant patients under pre-emptive strategy was investigated.
Study design
CMV-seropositive liver recipients, transplanted during the years 2003–2007, were monitored for CMV by real-time quantitative plasma PCR. The patients received ganciclovir/valganciclovir for pre-emptive CMV therapy. A total of 161 patients with follow-up of >4 years were included in the study.
Patients
Altogether 211 adult patients underwent liver transplantation with grafts from deceased donors at the Helsinki University Hospital during 2003–2007. Sixty-eight percent had end-stage chronic liver disease, 19% had acute liver failure, 9% hepatocellular carcinoma and 4% metabolic disease. The basic immunosuppression consisted of calcineurin inhibitors (cyclosporine or tacrolimus), azathioprine/mycophenole mophetil plus steroids tapered out and discontinued as feasible. Rejections were treated
Monitoring of CMV viral load
The patients were frequently monitored for CMV-DNAaemia from the day of transplantation onwards. Plasma samples were obtained at least weekly during the patients’ hospitalisation and thereafter once in 1–2 weeks for up to 3 months, once in 2–4 weeks for up to 6 months and then in most patients monthly or at least at 9 and 12 months postoperatively and in the case of clinical symptoms. In the case of a positive CMV finding, the patients were monitored until CMV-DNAaemia was no more detected. An
Results
In most cases, 98/161 (61%), no evidence of CMV was seen, and just 63/161 (39%) developed CMV-DNAaemia during the post-transplant year with a mean of 49 days (range 7–183 days) after transplantation. Only 25/63 reactivations exceeded 5000 copies/ml considered as cut-off level for pre-emptive treatment (median 21,500, range 5100–813300 copies/ml), and most had self-limiting, low-level CMV-DNAaemia (median 850, range 234–4000 copies/ml) (Fig. 1). There was a tendency of higher viral loads in the
Clinical outcome of the patients
Acute rejections verified by histology were diagnosed in 10/38 (26%) patients with low DNAaemia, in most (7/10) before CMV activation, only in one case during CMV DNAaemia and two thereafter. The patients with high viral loads had more acute rejections 14/25 (56%) which, however, in most (8/14) preceded CMV activation and only in one case did CMV and acute rejection occur concomitantly. However, there was no significant difference compared to those with no CMV-DNAaemia (42/98, 42%).
Four
Discussion
According to the international consensus guidelines both prophylaxis and a pre-emptive strategy are acceptable in liver transplantation.5 In a survey of CMV prevention strategies of 110 liver transplant centres, prophylaxis was preferred over pre-emptive therapy by the majority of centres in the prevention of CMV infection in the high-risk patients3 However, even 54–60% of the liver centres in Canada and USA have been reported to use prophylaxis also for moderate-risk patients (D−/R+) and
Funding
This work was supported by the grants from Sigrid Juselius Foundation (to KH and IL) and from Helsinki University Hospital Funds (to IL).
Conflict of interest
The authors declare no conflict of interest.
Ethical approval
The study was approved by the Ethics Committee of Helsinki University Hospital.
Acknowledgement
The authors thank Stephen Venn for correcting the English text.
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