Cytomegalovirus after allogeneic haematopoietic stem cell transplantation : complications in the era of CMV-specific antiviral treatment

Abstract

Since the start of treatment with allogeneic haematopoietic stem cell transplantation (SCT), cytomegalovirus (CMV) has been one of the most feared complications. With the help of different CMV-protective strategies, the frequency of CMV-disease before day 100 after SCT has decreased to 4-6%. The cost is an over-treatment with antiviral compounds and the development of new types of problems. These studies were undertaken to describe how the modern treatment modalities have changed the pattern of CMV-related complications after SCT.

In a study of 584 consecutive allogeneic SCT patients, the overall probability for CMVdisease was 8.9%, and the risk for death in CMV-disease 5.7%. The risk varied depending on CMV-serologies in donors and recipients. Unrelated or mismatched family donors and recipient CMV-seropositivity were risk factors for both CMV-disease and CMV-related death. In the models excluding low-risk patients, the use of preemptive CMV-strategy was a protective factor against CMV-disease and CMV-related death. Transplant related mortality (TRM) and overall mortality were also significantly reduced with the preemptive treatment strategy against CMV. Analyzing data on 262 consecutive patients, transplanted with HLA-identical sibling donors and surviving more than three months after SCT, the use of preemptive treatment strategy against CMV was the only factor that significantly decreased the risk for extensive chronic GVHD. The antiviral treatment that was actually given on the basis of preemptive strategy was significantly associated to a decreased risk for moderate to severe chronic GVHD.

In a study on 21 patients treated with allogeneic SCT due to malignant disease, a persistent HHV-6 infection and a higher HHV-6 viral load significantly increased the risk for an impaired recovery of the CMV-specific lymphocyte proliferation, and for the need of several courses with preemptive antiviral treatment against CMV, as did acute GVHD grades II-IV. Unfortunately the number of cases was too small for an adequate multivariate risk factor analysis.

CMV-retinitis (CMVR) has previously been a rare complication after SCT. In a European multicentre study on 30 patients developing CMVR after SCT, it was shown that 1.2% of all patients transplanted at the participating centres after 1996 developed CMVR, and that the complication had become almost four times more common during that period. Three cases of CMVR were seen after autologous SCT, the rest after allogeneic SCT, in whom fourteen were performed with alternative donors and nine with T-cell depleted grafts. 23/27 allogeneic SCT patients (85%) were on immunosuppressive treatment at time for the diagnoses, 18/23 (78%) on regimens containing corticosteroids. CMVR was a late occurring complication, with the median time of diagnosis being 145 days after SCT, (range 19-537). Its clinical features were the same as in AIDS-patients, and the outcome was poor, with 18/25 evaluable patients (72%) ending up with decreased vision.

A risk factor analysis for development of CMVR was performed in 27 allogeneic SCTpatients transplanted after 1990 at twelve European centres and the Fred Hutchinson Cancer Centre in Seattle, Washington. The risk factors found were CMV-negative donor and CMVpositive recipient, and antiviral prophylaxis against CMV after SCT.

In conclusion, these studies have shown that the preemptive treatment strategy against CMV has decreased the risk for CMV-disease and CMV-related death after SCT, as well as the risk for extensive chronic GVHD. A persistent HHV-6 infection and a high HHV-6 viral load have been identified as new possible risk factors for an impaired recovery of the CMV-specific immunity. CMVR has become four times more common after 1996, and risk factors for its development were CMV-negative donor, CMV-positive recipient, and the use of antiviral CMV-prophylaxis.