Correspondence

Varicella Vaccine in Recipients of Hematopoietic-Cell Transplants

N Engl J Med 2002; 347:1624-1625November 14, 2002

Article

To the Editor:

Hata et al. (July 4 issue)1 report that inactivated varicella vaccine given before and after hematopoietic-cell transplantation reduces the risk of zoster. The primary end point of their study was the development of zoster within 12 months after transplantation. We believe, however, that the follow-up is too short to support a definite conclusion concerning the effect of vaccination. Offidani et al.2 reported that the actuarial probability of varicella–zoster virus infection in 164 recipients of autologous hematopoietic-cell transplants was 10 percent at one year, 17 percent at two years, and 24 percent at three years. In the study by Hata et al., the incidence of zoster was increasing during the 12 months after transplantation.

Masahiro Kami
Song-Wong Kim
Yoichi Takaue
National Cancer Center Hospital, Tokyo 104-0045, Japan
mkami@ncc.go.jp

2 References

1
Hata A, Asanuma H, Rinki M, et al. Use of an inactivated varicella vaccine in recipients of hematopoietic-cell transplants. N Engl J Med 2002;347:26-34
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2
Offidani M, Corvatta L, Olivieri A, et al. A predictive model of varicella-zoster virus infection after autologous peripheral blood progenitor cell transplantation. Clin Infect Dis 2001;32:1414-1422
CrossRef | Web of Science | Medline

To the Editor:

Herpes zoster after hematopoietic-cell transplantation results in considerable morbidity.1,2 Acyclovir is virtually 100 percent effective in preventing reactivation of herpes simplex virus3 and varicella–zoster virus4 early after hematopoietic-cell transplantation, during the period of the greatest immunosuppression, when complications from infections are higher. The protection lasts as long as acyclovir therapy is continued. Therefore, routine prophylaxis with acyclovir for a variable period of time after hematopoietic-cell transplantation has become standard practice.

Thus, the fact that recipients of hematopoietic-cell transplants enrolled in the study by Hata et al. did not receive prophylactic acyclovir may be controversial. How many of the patients in whom zoster developed — especially within the first three to four months, when they would otherwise have been protected by acyclovir — had clinically significant sequelae (cutaneous or visceral dissemination, postherpetic neuralgia, secondary opportunistic infections, or death) related to reactivation of the virus?

Since zoster that is clinically mild can occur after the discontinuation of acyclovir in these patients, it is possible that the researchers could have achieved their objective by administering acyclovir prophylactically to all patients for three months and comparing the incidence of late zoster in vaccinated patients with that in unvaccinated patients. This approach would have allowed the researchers to avoid exposing immunocompromised patients to unnecessary risk. Presumably, patients were warned about the risks associated with infection as well as about the alternative of using prophylactic acyclovir with near-certain protection against reactivation of the virus.

Jayesh Mehta, M.D.
Northwestern University, Chicago, IL 60611
j-mehta@northwestern.edu

4 References

1
Locksley RM, Flournoy N, Sullivan KM, Meyers JD. Infection with varicella-zoster virus after marrow transplantation. J Infect Dis 1985;152:1172-1181
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2
Schuchter LM, Wingard JR, Piantadosi S, Burns WH, Santos GW, Saral R. Herpes zoster infection after autologous bone marrow transplantation. Blood 1989;74:1424-1427
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3
Wade JC, Newton B, Flournoy N, Meyers JD. Oral acyclovir for prevention of herpes simplex virus reactivation after marrow transplantation. Ann Intern Med 1984;100:823-828
Web of Science | Medline

4
Perren TJ, Powles RL, Easton D, Stolle K, Selby PJ. Prevention of herpes zoster in patients by long-term oral acyclovir after allogeneic bone marrow transplantation. Am J Med 1988;85:99-101
Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: In response to Kami and colleagues: Figure 2 of our article depicts cumulative episodes of zoster. It does not show an increasing frequency over time. We designed our study on the basis of our experience that most cases of zoster occur within 12 months after transplantation for relapsed lymphoma or leukemia,1,2 which is consistent with reports from other centers indicating that approximately 80 percent of recurrences of varicella–zoster virus are diagnosed during this interval. Offidani et al. had found that 65 percent of cases of zoster developed during the first 12 months in their more heterogeneous population of transplant recipients. Identifying the period of peak frequency differs from determining the actuarial risk of zoster in the first 12 months, which was 10 percent in their cohort and 33 percent in our unvaccinated group. Recipients of hematopoietic-cell transplants do remain at some risk for later zoster. However, the enhanced reconstitution of immunity to varicella–zoster virus in vaccinees at 12 months and the correlation between virus-specific CD4 T-cell responses and reduced risk of zoster suggest the possibility of longer-term protection. Vaccine regimens also have the advantage that booster doses can be given.

With regard to acyclovir prophylaxis, we challenge Dr. Mehta's position that this approach is standard practice and that our study design raises ethical questions. The guidelines of the Centers for Disease Control and Prevention for preventing opportunistic infections in recipients of hematopoietic-cell transplants state that long-term prophylaxis to prevent recurrent varicella–zoster virus infection (e.g., during the first six months after hematopoietic-cell transplantation) “is not routinely recommended” and suggest instead that this approach “could be considered for those patients with severe, long-term immunodeficiency.”3 Antiviral prophylaxis is not a recommended or uniform practice because zoster can occur during the administration of acyclovir or after it is discontinued, resulting in no overall decrease in the rate of reactivation of the virus.4,5 Perren et al.5 concluded only that oral acyclovir may be of value in selected patients. Finally, all decisions about the administration of antiviral agents to participants in our study were made solely by their attending physicians, and as we reported, some patients were given acyclovir prophylaxis. The hypothesis that a regimen of inactivated varicella vaccine might be combined effectively with an initial short course of acyclovir prophylaxis is of interest and could be pursued in future clinical investigations.

Ann M. Arvin, M.D.
Karl G. Blume, M.D.
Stanford University School of Medicine, Stanford, CA 94305
aarvin@stanford.edu

5 References

1
Wilson A, Sharp M, Koropchak CM, Ting SF, Arvin AM. Subclinical varicella-zoster virus viremia, herpes zoster, and T lymphocyte immunity to varicella-zoster viral antigens after bone marrow transplantation. J Infect Dis 1992;165:119-126
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2
Redman RL, Nader S, Zerboni L, et al. Early reconstitution of immunity and decreased severity of herpes zoster in bone marrow transplant recipients immunized with inactivated varicella vaccine. J Infect Dis 1997;176:578-585
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3
Guidelines for preventing opportunistic infections among hematopoietic stem-cell transplant recipients. MMWR Morb Mortal Wkly Rep 2000;49:1-125
Medline

4
Ljungman P, Lonnqvist B, Ringden O, Skinhoj P, Gahrton G. A randomized trial of oral versus intravenous acyclovir for treatment of herpes zoster in bone marrow transplant recipients. Bone Marrow Transplant 1989;4:613-615
Web of Science | Medline

5
Perren TJ, Powles RL, Easton D, Stolle K, Selby PJ. Prevention of herpes zoster in patients by long-term oral acyclovir after allogeneic bone marrow transplantation. Am J Med 1988;85:99-101
Web of Science | Medline

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