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Postexposure Prophylaxis Against Varicella Zoster Virus Infection Among Hematopoietic Stem Cell Transplant Recipients
Biology of Blood and Marrow Transplantation 12:1096-1097 (2006) 䊚 2006 American Society for Blood and Marrow Transplantation 1083-8791/06/1210-0001$32.00/0 doi:10.1016/j.bbmt.2006.06.005
LETTER
TO THE
EDITOR
Postexposure Prophylaxis Against Varicella Zoster Virus Infection Among Hematopoietic Stem Cell Transplant Recipients A comprehensive approach is essential to minimize the morbidity caused by varicella zoster virus (VZV) among hematopoietic stem cell transplant (HSCT) recipients. However, prophylactic regimens to prevent VZV infection among HSCT recipients are controversial and vary widely [1]. Recently published guidelines from a National Institutes of Health working group on criteria for clinical trials in chronic graft-versus-host disease (GVHD) included the recommendation that “if VZV-seronegative patients with chronic GVHD are exposed to varicella (primary or postvaccination illness), VZV Ig should be given within 96 hours” [2]. We question this recommendation for 3 reasons: First, VZV Ig may be suboptimal; second, supplies of VZV Ig are limited; and third, the recommendation does not include an approach for VZV-seropositive patients. VZV Ig is only partially effective as postexposure prophylaxis. In studies, 25%– 45% of contacts treated with VZV Ig (including immunocompetent persons) developed clinically apparent varicella [3,4]. In contrast, acyclovir has reasonable efficacy as postexposure prophylaxis. In a nonrandomized study, varicella developed in 16% of seronegative immunocompetent children treated with acyclovir, compared with 100% of untreated controls [5]. Although no data are available on acyclovir as postexposure prophylaxis in HSCT recipients, extensive clinical experience indicates that acyclovir and valacyclovir are highly effective at preventing VZV reactivation in these patients [6-10]. After exposure to VZV disease (ie, varicella or zoster), patients who are not known to be VZV seropositive should undergo VZV antibody testing. VZV-seronegative HSCT recipients at Memorial Sloan-Kettering Cancer Center (MSKCC) and Fred Hutchinson Cancer Research Center (FHCRC) are offered valacyclovir or acyclovir in addition to VZV Ig. Based on institutional experience and extrapolation from the treatment of VZV disease, we use valacyclovir 1 g po tid for patients weighing ⬎ 40 kg or 500 mg po tid for those weighing ⬍ 40 kg on postexposure days 3–22. An alternative is acyclovir 1096
600 mg/m2 po qid; valacyclovir is not recommended for children under age 12 years. Because VZV Ig can prolong the VZV incubation period [11], valacyclovir (or acyclovir) is administered on postexposure days 3–28 in patients who are also receiving VZV Ig. VZVseronegative patients who are receiving acyclovir at lower doses (eg, for HSV prophylaxis) receive the higher dose on postexposure days 3–22 (or days 3–28 if VZV Ig was administered). Patients receiving standard induction or maintenance doses of gancyclovir, foscarnet, or cidofovir do not require a change in therapy after VZV exposure, because these agents are active against VZV. Postexposure prophylaxis against VZV infection for patients who were VZV seropositive before HSCT remains highly controversial. At least 57 immunocompromised patients with possible reinfection have been reported [12]. Given that seropositive HSCT recipients may be at risk for reinfection, we offer all immunocompromised HSCT recipients postexposure prophylaxis. A particularly compelling point in favor of postexposure prophylaxis is the potential for falsepositive VZV antibody results, especially in patients who have received immune globulin and other blood products. Commercially available VZV antibody tests also vary markedly in sensitivity and specificity [13] and have not been adequately evaluated in immunocompromised patients. However, seropositive HSCT recipients at MSKCC and FHCRC do not routinely receive VZV Ig postexposure prophylaxis. The low risk of reinfection, the limited efficacy of VZV Ig, and lack of a VZV Ig dose–response relationship argue against its routine use. Instead, seropositive patients are routinely offered postexposure prophylaxis with valacyclovir or acyclovir if ⬍ 6 months after an autologous HSCT or ⬍ 12 months after an allogeneic HSCT, are receiving immunosuppressive therapy, have active GVHD, or are otherwise immunodeficient (eg, CD4 count ⬍ 200/L, recent opportunistic infection). The single exception is seropositive patients who have previously experienced an episode of VZV disease after HSCT, who appear to be at no risk for VZV reinfection [11].
1097
Letter to the Editor
A final approach not mentioned in the guidelines is the postexposure management of VZV-susceptible household members or close contacts of HSCT recipients. Considering the inordinately high risk of transmission from household and other close contacts, we recommend an aggressive treatment strategy to avoid VZV disease in this group. If a VZV-susceptible household member or close contact of an HSCT recipient is exposed to VZV, then the contact should undergo VZV vaccination. A study of immunocompetent children vaccinated within 3 days of exposure found a protective efficacy of VZV vaccine as postexposure prophylaxis of approximately 90% [14]. If ineligible for vaccine, the exposed contact should receive valacylcovir or acyclovir. If VZV Ig becomes readily available in the future at a reasonable cost, it may be reasonable to administer VZV Ig, in addition to valacyclovir or acyclovir, to the exposed contact, because this combination would likely offer greater protection than either agent alone. Contact between the exposed person and the HSCT recipient should be minimized to the greatest extent possible on postexposure days 10 –21 (or days 10 –28 if VZV Ig was administered) after exposure. If the contact is vaccinated, then vaccine-strain varicella could potentially be transmitted to the HSCT recipient. This risk appears to be small, and VZV disease transmitted from vaccine recipients is generally mild [15]. This comprehensive approach to preventing postexposure VZV disease is used routinely at our institutions. Although randomized trials are lacking, the excellent safety record of these agents and the high risk for morbidity and mortality from VZV disease among HSCT recipients support the use of an aggressive strategy for postexposure prophylaxis.
4. Orenstein WA, Heymann DL, Ellis RJ, et al. Prophylaxis of varicella in high-risk children: dose-response effect of zoster immune globulin. J Pediatr. 1981;98:368-373. 5. Suga S, Yoshikawa T, Ozaki T, et al. Effect of oral acyclovir against primary and secondary viraemia in incubation period of varicella. Arch Dis Child. 1993;69:639-642. 6. Kanda Y, Mineishi S, Saito T, et al. Long-term low-dose acyclovir against varicella-zoster virus reactivation after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2001;28:689-692. 7. Ljungman P, Wilczek H, Gahrton G, et al. Long-term acyclovir prophylaxis in bone marrow transplant recipients and lymphocyte proliferation responses to herpes virus antigens in vitro. Bone Marrow Transplant. 1986;1:185-192. 8. Lundgren G, Wilczek H, Lonnqvist B, et al. Acyclovir prophylaxis in bone marrow transplant recipients. Scand J Infect Dis Suppl. 1985;47:137-144. 9. Steer CB, Szer J, Sasadeusz J, et al. Varicella-zoster infection after allogeneic bone marrow transplantation: incidence, risk factors and prevention with low-dose aciclovir and ganciclovir. Bone Marrow Transplant. 2000;25:657-664. 10. Boeckh M, Kim HW, Flowers ME, et al. Long-term acyclovir for prevention of varicella zoster virus disease after allogeneic hematopoietic cell transplantation: a randomized double-blind placebo-controlled study. Blood. 2006;107:1800-1805. 11. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. MMWR. 2000;49: 1-128. 12. Weinstock DM, Boeckh M, Boulad F, et al. Postexposure prophylaxis against varicella-zoster virus infection among recipients of hematopoietic stem cell transplant: unresolved issues. Infect Control Hosp Epidemiol. 2004;25:603-608. 13. Weinstock DM, Rogers M, Lim S, et al. Seroconversion rates in health care workers using a latex agglutination assay after varicella virus vaccination. Infect Control Hosp Epidemiol. 1999; 20:504-507. 14. Arbeter AM, Starr SE, Plotkin SA. Varicella vaccine studies in healthy children and adults. Pediatrics. 1986;78:748-756. 15. Sharrar RG, LaRussa P, Galea SA, et al. The postmarketing safety profile of varicella vaccine. Vaccine. 2000;19:916-923.
REFERENCES 1. Brandt L, Broadbent V. A survey of recommendations given to patients going home after bone marrow transplant. Arch Dis Child. 1994;71:529-531. 2. Couriel D, Carpenter PA, Cutler C, et al. Ancillary therapy and supportive care of chronic graft-versus-host disease: national institutes of health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: V. Ancillary Therapy and Supportive Care Working Group Report. Biol Blood Marrow Transplant. 2006;12:375-396. 3. Zaia JA, Levin MJ, Preblud SR, et al. Evaluation of varicellazoster immune globulin: protection of immunosuppressed children after household exposure to varicella. J Infect Dis. 1983; 147:737-743.
David M. Weinstock1,2 1
Division of Infectious Diseases and 2Division of Bone Marrow Transplantation, Memorial Sloan-Kettering Cancer Center, New York, New York
Michael Boeckh Program in Infectious Diseases, Fred Hutchinson Cancer Research Center, Seattle, Washington
Kent A. Sepkowitz Division of Infectious Diseases, Memorial Sloan-Kettering Cancer Center, New York, New York
LETTER
TO THE
EDITOR
Postexposure Prophylaxis Against Varicella Zoster Virus Infection Among Hematopoietic Stem Cell Transplant Recipients A comprehensive approach is essential to minimize the morbidity caused by varicella zoster virus (VZV) among hematopoietic stem cell transplant (HSCT) recipients. However, prophylactic regimens to prevent VZV infection among HSCT recipients are controversial and vary widely [1]. Recently published guidelines from a National Institutes of Health working group on criteria for clinical trials in chronic graft-versus-host disease (GVHD) included the recommendation that “if VZV-seronegative patients with chronic GVHD are exposed to varicella (primary or postvaccination illness), VZV Ig should be given within 96 hours” [2]. We question this recommendation for 3 reasons: First, VZV Ig may be suboptimal; second, supplies of VZV Ig are limited; and third, the recommendation does not include an approach for VZV-seropositive patients. VZV Ig is only partially effective as postexposure prophylaxis. In studies, 25%– 45% of contacts treated with VZV Ig (including immunocompetent persons) developed clinically apparent varicella [3,4]. In contrast, acyclovir has reasonable efficacy as postexposure prophylaxis. In a nonrandomized study, varicella developed in 16% of seronegative immunocompetent children treated with acyclovir, compared with 100% of untreated controls [5]. Although no data are available on acyclovir as postexposure prophylaxis in HSCT recipients, extensive clinical experience indicates that acyclovir and valacyclovir are highly effective at preventing VZV reactivation in these patients [6-10]. After exposure to VZV disease (ie, varicella or zoster), patients who are not known to be VZV seropositive should undergo VZV antibody testing. VZV-seronegative HSCT recipients at Memorial Sloan-Kettering Cancer Center (MSKCC) and Fred Hutchinson Cancer Research Center (FHCRC) are offered valacyclovir or acyclovir in addition to VZV Ig. Based on institutional experience and extrapolation from the treatment of VZV disease, we use valacyclovir 1 g po tid for patients weighing ⬎ 40 kg or 500 mg po tid for those weighing ⬍ 40 kg on postexposure days 3–22. An alternative is acyclovir 1096
600 mg/m2 po qid; valacyclovir is not recommended for children under age 12 years. Because VZV Ig can prolong the VZV incubation period [11], valacyclovir (or acyclovir) is administered on postexposure days 3–28 in patients who are also receiving VZV Ig. VZVseronegative patients who are receiving acyclovir at lower doses (eg, for HSV prophylaxis) receive the higher dose on postexposure days 3–22 (or days 3–28 if VZV Ig was administered). Patients receiving standard induction or maintenance doses of gancyclovir, foscarnet, or cidofovir do not require a change in therapy after VZV exposure, because these agents are active against VZV. Postexposure prophylaxis against VZV infection for patients who were VZV seropositive before HSCT remains highly controversial. At least 57 immunocompromised patients with possible reinfection have been reported [12]. Given that seropositive HSCT recipients may be at risk for reinfection, we offer all immunocompromised HSCT recipients postexposure prophylaxis. A particularly compelling point in favor of postexposure prophylaxis is the potential for falsepositive VZV antibody results, especially in patients who have received immune globulin and other blood products. Commercially available VZV antibody tests also vary markedly in sensitivity and specificity [13] and have not been adequately evaluated in immunocompromised patients. However, seropositive HSCT recipients at MSKCC and FHCRC do not routinely receive VZV Ig postexposure prophylaxis. The low risk of reinfection, the limited efficacy of VZV Ig, and lack of a VZV Ig dose–response relationship argue against its routine use. Instead, seropositive patients are routinely offered postexposure prophylaxis with valacyclovir or acyclovir if ⬍ 6 months after an autologous HSCT or ⬍ 12 months after an allogeneic HSCT, are receiving immunosuppressive therapy, have active GVHD, or are otherwise immunodeficient (eg, CD4 count ⬍ 200/L, recent opportunistic infection). The single exception is seropositive patients who have previously experienced an episode of VZV disease after HSCT, who appear to be at no risk for VZV reinfection [11].
1097
Letter to the Editor
A final approach not mentioned in the guidelines is the postexposure management of VZV-susceptible household members or close contacts of HSCT recipients. Considering the inordinately high risk of transmission from household and other close contacts, we recommend an aggressive treatment strategy to avoid VZV disease in this group. If a VZV-susceptible household member or close contact of an HSCT recipient is exposed to VZV, then the contact should undergo VZV vaccination. A study of immunocompetent children vaccinated within 3 days of exposure found a protective efficacy of VZV vaccine as postexposure prophylaxis of approximately 90% [14]. If ineligible for vaccine, the exposed contact should receive valacylcovir or acyclovir. If VZV Ig becomes readily available in the future at a reasonable cost, it may be reasonable to administer VZV Ig, in addition to valacyclovir or acyclovir, to the exposed contact, because this combination would likely offer greater protection than either agent alone. Contact between the exposed person and the HSCT recipient should be minimized to the greatest extent possible on postexposure days 10 –21 (or days 10 –28 if VZV Ig was administered) after exposure. If the contact is vaccinated, then vaccine-strain varicella could potentially be transmitted to the HSCT recipient. This risk appears to be small, and VZV disease transmitted from vaccine recipients is generally mild [15]. This comprehensive approach to preventing postexposure VZV disease is used routinely at our institutions. Although randomized trials are lacking, the excellent safety record of these agents and the high risk for morbidity and mortality from VZV disease among HSCT recipients support the use of an aggressive strategy for postexposure prophylaxis.
4. Orenstein WA, Heymann DL, Ellis RJ, et al. Prophylaxis of varicella in high-risk children: dose-response effect of zoster immune globulin. J Pediatr. 1981;98:368-373. 5. Suga S, Yoshikawa T, Ozaki T, et al. Effect of oral acyclovir against primary and secondary viraemia in incubation period of varicella. Arch Dis Child. 1993;69:639-642. 6. Kanda Y, Mineishi S, Saito T, et al. Long-term low-dose acyclovir against varicella-zoster virus reactivation after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2001;28:689-692. 7. Ljungman P, Wilczek H, Gahrton G, et al. Long-term acyclovir prophylaxis in bone marrow transplant recipients and lymphocyte proliferation responses to herpes virus antigens in vitro. Bone Marrow Transplant. 1986;1:185-192. 8. Lundgren G, Wilczek H, Lonnqvist B, et al. Acyclovir prophylaxis in bone marrow transplant recipients. Scand J Infect Dis Suppl. 1985;47:137-144. 9. Steer CB, Szer J, Sasadeusz J, et al. Varicella-zoster infection after allogeneic bone marrow transplantation: incidence, risk factors and prevention with low-dose aciclovir and ganciclovir. Bone Marrow Transplant. 2000;25:657-664. 10. Boeckh M, Kim HW, Flowers ME, et al. Long-term acyclovir for prevention of varicella zoster virus disease after allogeneic hematopoietic cell transplantation: a randomized double-blind placebo-controlled study. Blood. 2006;107:1800-1805. 11. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. MMWR. 2000;49: 1-128. 12. Weinstock DM, Boeckh M, Boulad F, et al. Postexposure prophylaxis against varicella-zoster virus infection among recipients of hematopoietic stem cell transplant: unresolved issues. Infect Control Hosp Epidemiol. 2004;25:603-608. 13. Weinstock DM, Rogers M, Lim S, et al. Seroconversion rates in health care workers using a latex agglutination assay after varicella virus vaccination. Infect Control Hosp Epidemiol. 1999; 20:504-507. 14. Arbeter AM, Starr SE, Plotkin SA. Varicella vaccine studies in healthy children and adults. Pediatrics. 1986;78:748-756. 15. Sharrar RG, LaRussa P, Galea SA, et al. The postmarketing safety profile of varicella vaccine. Vaccine. 2000;19:916-923.
REFERENCES 1. Brandt L, Broadbent V. A survey of recommendations given to patients going home after bone marrow transplant. Arch Dis Child. 1994;71:529-531. 2. Couriel D, Carpenter PA, Cutler C, et al. Ancillary therapy and supportive care of chronic graft-versus-host disease: national institutes of health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: V. Ancillary Therapy and Supportive Care Working Group Report. Biol Blood Marrow Transplant. 2006;12:375-396. 3. Zaia JA, Levin MJ, Preblud SR, et al. Evaluation of varicellazoster immune globulin: protection of immunosuppressed children after household exposure to varicella. J Infect Dis. 1983; 147:737-743.
David M. Weinstock1,2 1
Division of Infectious Diseases and 2Division of Bone Marrow Transplantation, Memorial Sloan-Kettering Cancer Center, New York, New York
Michael Boeckh Program in Infectious Diseases, Fred Hutchinson Cancer Research Center, Seattle, Washington
Kent A. Sepkowitz Division of Infectious Diseases, Memorial Sloan-Kettering Cancer Center, New York, New York