The development of sensitive diagnostic testing and effective antiviral and antifungal therapies has done much to decrease the morbidity and mortality due to CMV, invasive fungal infections, and other herpes viruses after HCT. With the publication of evidence-based guidelines by the CDC in 2000, physicians and transplant centers were provided with detailed recommendations for the prevention and treatment of opportunistic infections in HCT. However, to our knowledge, there have been no studies investigating the adoption of these recommendations globally. With this large, multinational survey we had a unique opportunity to perform such a study using a simple, web-based survey tool. With a response rate of 72%, representing 175 programs in 32 different countries, we were able to obtain a detailed view of the strategies utilized both before and after publication of these guidelines.
In accord with the CDC recommendations, approximately one-quarter of programs did not use long term low-dose suppressive acyclovir in VZV seropositive patients (DIII).(7
) However, three-quarters of programs departed from the recommendation by treating for varying durations, with approximately one-fifth of the programs treating for the first year after transplantation. We speculate that this practice was influenced by a randomized, placebo-controlled trial of long term acyclovir for prevention of VZV disease which had been completed and presented in abstract form at international meetings, but was not published at the time the guidelines were written. In the most recent guidelines this has been upgraded to a BI level recommendation.(10
) We observed statistically significant regional variation in the treatment strategy utilized for VZV+/HSV− patients. For example, in Europe, 90% of centers treated for some duration of time, varying from 1–4 months, but no centers treated for as long as one year. In contrast, one-third of North American centers did not offer any prophylaxis and one-third treated for the entire first year (Table S1
). Again, this division likely reflects evidence-based transitions of practice prior to their inclusion in the published guidelines.
A majority of centers utilized low-dose acyclovir prophylaxis to HSV+ patients after HCT, which is consistent with CDC recommendations (AI). However, given the proven efficacy, excellent safety profile, and the low cost of acyclovir prophylaxis, it was surprising that there were 10 programs that did not appear to be using any strategy for HSV disease prevention. There was significant regional variation in the duration of acyclovir prophylaxis. The CDC guidelines recommend continuation of acyclovir until engraftment or resolution of mucositis, whichever is longer (BIII), while recommending against treatment for longer than 1 month (DIII).(7
) In our study we found that a similar number of programs were in accord with this recommendation as departed from it by treating HSV+/VZV- patients for much longer durations. Approximately one-quarter of programs treated for at least 6 months or discontinuation of immunosuppression, and about one-eighth treated for one year. This practice is encouraged by evidence that long-term suppressive therapy with low-dose acyclovir (800 mg twice daily or 500mg twice daily of valacyclovir) reduces the incidence of HSV disease and the development of acyclovir resistant HSV.(11
All but two of the participating programs placed all patients at risk for post-transplant CMV disease on a CMV disease prevention program for the first 100 days post-transplant, with high-dose acyclovir, prophylactic ganciclovir, or surveillance with preemptive therapy (AI). Surveillance with preemptive ganciclovir or foscarnet therapy was used by 90.8% of centers in at least some patients, compared to 31.4% of programs using high-dose acyclovir and 27.6% using ganciclovir prophylaxis. There were no significant differences in the use of these strategies across all regions. However, there was considerable regional variation in the duration of prophylaxis and the duration of treatment after detection with surveillance. Approximately one-quarter of programs indicated that their center used both a strategy of ganciclovir prophylaxis and surveillance with preemptive therapy during the same time period. This could be interpreted as a center policy allowing physicians to choose between two equally recommended strategies. However, it is also possible that the survey questions were misinterpreted - a limitation common to all survey studies.
There were no significant differences in treatment practices by center size as determined by the number of transplants performed annually, comparing those centers that perform more than fifty allogeneic transplants per year to those that perform less than fifty per year. Moreover, with a few exceptions, no differences in practices existed between those centers that treated primarily pediatric patients, those that treated primarily adult patients, and those that treated both. The most interesting exception was the increased use of high-dose acyclovir prophylaxis in patients at risk for CMV disease in one-half of centers that treated primarily pediatric patients compared with only one-quarter of those that treated primarily adults and those that treated both. It is possible that this prophylactic strategy is used less commonly in centers that treat adults because of the weight-based dosing of the parenteral acyclovir formulation, which could be deemed prohibitively expensive for adult patients at some centers.
While most programs reported center strategies that were consistent with the recommendations for prevention of CMV reactivation in the first 100 days after HCT, many fewer programs continue to monitor for CMV after day 100, with 30% of programs reporting that they do not routinely use either prophylaxis or surveillance with preemptive therapy for high-risk patients after day 100. However the most recent guidelines have increased the rating to a BII level based on a non-randomized study where patients at high risk for CMV disease continued to undergo surveillance for 26 weeks after HCT. (12
) In this study, twenty-seven percent of patients required preemptive treatment after day 100, however, there were no cases of CMV disease. It is likely that an updated query would find a greater number of programs continuing their CMV prevention programs beyond day 100. The variation in frequency of surveillance testing observed in this study is indicative of the paucity of clear evidence to guide providers in these decisions. (10
All but 12 of the 175 participating programs used some method of decreasing the risk of CMV transmission via blood products, an AI level recommendation, by using either blood products from CMV seronegative donors, leukoreduced blood products, or both.
This survey-based study is, to our knowledge, the first to compare center-specific practices for the prevention of herpes virus infections after HCT in a large number of programs from 32 different countries. Because of the high response rate, and the diversity of the participating programs, we were also able to make comparisons by patient age population and by center size. However, the large number of comparisons performed increases the probability of finding statistically significant differences when there is no true difference. This statistical problem places a limit on the inferences that should be made about these, primarily descriptive, data. Another limitation of this study is that the survey asked the respondents about the prevention strategies used by their centers a few years in the past, thus their answers are potentially subject to recall bias. Also, while the survey reflects institutional practices actual adherence to these stated practices was unknown. As with many survey studies, it is also possible that, despite careful attention to design of the questions, misinterpretation by the respondents could have affected the accuracy of our findings. Finally, prevention strategies in specific transplant risk groups could not be performed.
In conclusion, in this large, multinational survey, center-specific practices regarding prevention and treatment of herpes virus infections were examined. Most, but not all, responding centers reported provision of HSV, VZV and CMV prevention and treatment regimens prior to the publication of the CDC guidelines in 2000. While several programs reported switching from a CMV antigen based surveillance method to PCR-based detection, overall, very few centers reported significant changes in their prevention and treatment strategies between 1999 and 2003. Additionally, with the exception of increased use of high-dose acyclovir for CMV prophylaxis at centers that treated primarily pediatric patients, there were no differences in center strategies based on patient age or the number of transplants performed annually. There is an ongoing need for high-quality clinical studies to clarify many of these questions as reflected in the significant regional differences observed in the following areas: (1) duration of antiviral prophylaxis for HSV and VZV seropositive patients, (2) duration of antiviral prophylaxis for patients at risk of CMV disease, (3) selection of patients to undergo CMV surveillance testing, (4) duration of preemptive therapy, (5) and strategies for prevention of late CMV disease.