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In reply—Risk of Disseminated Varicella Zoster in Immunosuppressed Patients Receiving Zoster Vaccination

      We thank Dr Bubb for his interest in our study and appreciate the opportunity to respond to his questions and concerns. Specifically, concern was raised about our conclusion that our findings “support the current recommendations for zoster vaccination in that patients should withhold their immunosuppressants for 4 weeks before immunization,”
      • Cheetham T.C.
      • Marcy S.M.
      • Tseng H.-F.
      • et al.
      Risk of herpes zoster and disseminated varicella zoster in patients taking immunosuppressant drugs at the time of zoster vaccination.
      even though we found no cases of disseminated varicella zoster among 4826 vaccinated individuals who were taking immunosuppressant medication. Additional concerns centered on our findings related to herpes zoster, specifically that (1) our data revealing a higher risk of herpes zoster in immunosuppressed patients who stopped immunosuppressive therapy argue that it would be prudent to vaccinate immunosuppressed patients as soon as possible, (2) the data do not support withholding immunosuppressant therapy for a minimum of 4 weeks before vaccination compared with any other arbitrarily chosen interval, and (3) vaccination is unlikely to be the cause of the increased risk of zoster during the 42 days postvaccination in the current vs remote immunosuppressant users.
      Dr Bubb brings up good points, and we should have been clearer in our concluding remarks about withholding immunosuppressants. Current guidelines state that high-dose corticosteroids should be withheld for 4 weeks before administering the zoster vaccine, but the vaccine can be given to individuals taking low-dose corticosteroids without stopping therapy.
      • Rubin L.G.
      • Levin M.J.
      • Ljungman P.
      • et al.
      2013 IDSA clinical practice guideline for vaccination of the immunocompromised host.
      • Harpaz R.
      • Ortega-Sanchez I.R.
      • Seward J.F.
      Prevention of herpes zoster: recommendations of the Advisory Committee on Immunization Practices (ACIP).
      The results from our investigation suggest that there is a low risk of disseminated herpes zoster associated with the zoster vaccine when given to patients currently using immunosuppressant medications. However, it should be kept in mind that most of the patients in this study were receiving low-dose corticosteroids; too few patients were taking high-dose corticosteroids (n=550) at the time of vaccination to determine any associations or draw any inferences. Therefore, our results regarding disseminated varicella zoster support the recommendation to vaccinate patients taking low-dose corticosteroids without stopping therapy, but there is insufficient evidence to recommend vaccinating patients taking high-dose corticosteroids without stopping treatment. We recognize that our concluding statement could have been better stated.
      According to Dr Bubb, the data confirm that “immunosuppression increases the risk of herpes zoster even after stopping immunosuppressive therapy” and suggest that “it would be prudent to vaccinate immunosuppressed patients as soon as possible to minimize the time-dependent risk of herpes zoster.” The rate of herpes zoster for the remote immunosuppressant user group in our study was 15 cases per 1000 person-years, which is indeed higher than the rate of herpes zoster in nonimmunocompromised individuals (range, 6.0-8.6 cases per 1000 person-years among adults 60-79 years of age)
      • Yawn B.P.
      • Saddier P.
      • Wollan P.C.
      • St Sauver J.L.
      • Kurland M.J.
      • Sy L.S.
      A population-based study of the incidence and complication rates of herpes zoster before zoster vaccine introduction.
      but is in fact consistent with rates of herpes zoster reported in patients with immune-mediated diseases, which range from as low as 6.4 to as high as 32.5 cases per 1000 patient-years.
      • Smitten A.L.
      • Choi H.K.
      • Hochberg M.C.
      • et al.
      The risk of herpes zoster in patients with rheumatoid arthritis in the United States and the United Kingdom.
      • Wolfe F.
      • Michaud K.
      • Chakravarty E.F.
      Rates and predictors of herpes zoster in patients with rheumatoid arthritis and non-inflammatory musculoskeletal disorders.
      • Gupta G.
      • Lautenbach E.
      • Lewis J.D.
      Incidence and risk factors for herpes zoster among patients with inflammatory bowel disease.
      • Borba E.F.
      • Ribeiro A.C.
      • Martin P.
      • Costa L.P.
      • Guedes L.K.
      • Bonfá E.
      Incidence, risk factors, and outcome of Herpes zoster in systemic lupus erythematosus.
      • Chakravarty E.F.
      • Michaud K.
      • Katz R.
      • Wolfe F.
      Increased incidence of herpes zoster among patients with systemic lupus erythematosus.
      Regarding the choice of the 4-week interval for withholding therapy, the evidence supporting the recommendation to withhold immunosuppressants for 4 weeks before administering a live virus vaccine has never been strong. These recommendations, however, are not arbitrary but reflect the opinion of experts and are in part based on knowledge of the time it takes for the hypothalamic-pituitary-adrenal axis to recover from prolonged immunosuppression with corticosteroids. In our study, patients were classified as remote users if the immunosuppressant was stopped a minimum of 4 weeks before vaccination and as current users if the immunosuppressant was continued into this time frame. With lower rates of herpes zoster in the remote user group, our study results provide some evidence to support the recommendation to withhold immunosuppressants for 4 weeks before vaccination. Because most of the patients in this study were taking low-dose corticosteroids, the question then becomes whether low-dose corticosteroids should be stopped before vaccination. We do not believe that the results from this study, by themselves, support stopping low-dose corticosteroids before vaccination.
      Our finding that the risk of herpes zoster was increased in the 42 days following vaccination in the current vs remote exposure group is complex because several factors are potentially at work. The study was designed to include a cohort of patients who, at baseline, have a higher risk of herpes zoster; the only observable difference between the comparison groups was current vs remote use of immunosuppressants. As stated in the “Discussion” section of our article, it is unlikely that the herpes zoster experienced by these patients was caused by the vaccine virus strain. In this regard, we agree with Dr Bubb that vaccination is unlikely to be the cause of the increased risk of zoster during the 42 days postvaccination in the current immunosuppressant users. However, there are several potential explanations for our findings: (1) administration of the vaccine could possibly trigger herpes zoster in response to the antigen load in some immunosuppressed patients, (2) current immunosuppressant use could delay the immune response to the zoster vaccine, leading to a higher risk of herpes zoster in a population already at risk (ie, as an indicator of immune response, peak antibody levels after zoster vaccination in elderly individuals without immune-mediated diseases is 21 days
      • Weinberg A.
      • Zhang J.H.
      • Oxman M.N.
      • et al.
      US Department of Veterans Affairs (VA) Cooperative Studies Program Shingles Prevention Study Investigators
      Varicella-zoster virus-specific immune responses to herpes zoster in elderly participants in a trial of a clinically effective zoster vaccine.
      but is likely longer in patients receiving immunosuppressants), (3) current immunosuppressant use by itself could increase the risk of herpes zoster, and (4) current use of immunosuppressants could indicate a population that is fundamentally different from remote users in ways that are not captured using an observational design.
      In conclusion, we agree that patients with certain immune-mediated diseases are at a higher risk of herpes zoster, and therefore, measures should be undertaken to maximize immunization of these individuals with the zoster vaccine in a safe and effective manner.

      References

        • Cheetham T.C.
        • Marcy S.M.
        • Tseng H.-F.
        • et al.
        Risk of herpes zoster and disseminated varicella zoster in patients taking immunosuppressant drugs at the time of zoster vaccination.
        Mayo Clin Proc. 2015; 90: 865-873
        • Rubin L.G.
        • Levin M.J.
        • Ljungman P.
        • et al.
        2013 IDSA clinical practice guideline for vaccination of the immunocompromised host.
        Clin Infect Dis. 2014; 58 ([published correction appears in Clin Infect Dis. 2014;59(1):144]): 309-318
        • Harpaz R.
        • Ortega-Sanchez I.R.
        • Seward J.F.
        Prevention of herpes zoster: recommendations of the Advisory Committee on Immunization Practices (ACIP).
        MMWR Recomm Rep. 2008; 57: 1-30
        • Yawn B.P.
        • Saddier P.
        • Wollan P.C.
        • St Sauver J.L.
        • Kurland M.J.
        • Sy L.S.
        A population-based study of the incidence and complication rates of herpes zoster before zoster vaccine introduction.
        Mayo Clin Proc. 2007; 82 ([published correction appears in Mayo Clin Proc. 2008;83(2):255]): 1341-1349
        • Smitten A.L.
        • Choi H.K.
        • Hochberg M.C.
        • et al.
        The risk of herpes zoster in patients with rheumatoid arthritis in the United States and the United Kingdom.
        Arthritis Rheum. 2007; 57: 1431-1438
        • Wolfe F.
        • Michaud K.
        • Chakravarty E.F.
        Rates and predictors of herpes zoster in patients with rheumatoid arthritis and non-inflammatory musculoskeletal disorders.
        Rheumatology (Oxford). 2006; 45: 1370-1375
        • Gupta G.
        • Lautenbach E.
        • Lewis J.D.
        Incidence and risk factors for herpes zoster among patients with inflammatory bowel disease.
        Clin Gastroenterol Hepatol. 2006; 4: 1483-1490
        • Borba E.F.
        • Ribeiro A.C.
        • Martin P.
        • Costa L.P.
        • Guedes L.K.
        • Bonfá E.
        Incidence, risk factors, and outcome of Herpes zoster in systemic lupus erythematosus.
        J Clin Rheumatol. 2010; 16: 119-122
        • Chakravarty E.F.
        • Michaud K.
        • Katz R.
        • Wolfe F.
        Increased incidence of herpes zoster among patients with systemic lupus erythematosus.
        Lupus. 2013; 22: 238-244
        • Weinberg A.
        • Zhang J.H.
        • Oxman M.N.
        • et al.
        • US Department of Veterans Affairs (VA) Cooperative Studies Program Shingles Prevention Study Investigators
        Varicella-zoster virus-specific immune responses to herpes zoster in elderly participants in a trial of a clinically effective zoster vaccine.
        J Infect Dis. 2009; 200: 1068-1077

      Linked Article

      • Risk of Disseminated Varicella Zoster in Immunosuppressed Patients Receiving Zoster Vaccination
        Mayo Clinic ProceedingsVol. 90Issue 11
        • Preview
          The report by Cheetham et al1 in the July 2015 issue of Mayo Clinic Proceedings uniquely addresses the risk of disseminated varicella zoster in patients taking immunosuppressant drugs at the time of zoster vaccination. For those of us providing care to immunosuppressed patients, 2 key questions are (1) whether immunosuppression reduces the efficacy of vaccination and (2) whether there are any risks specifically related to the use of a live attenuated vaccine. The first question is not addressed in the study by Cheetham et al, but the fact that there were no cases of disseminated zoster in this study's 4826 immunosuppressed patients who were vaccinated provides reassuring evidence that the risk of dissemination is low in this population.
        • Full-Text
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      • Risk of Disseminated Disease in Immunosuppressed Patients Receiving Live Zoster Vaccine
        Mayo Clinic ProceedingsVol. 91Issue 7
        • Preview
          I read with interest the letter by Bubb1 and the reply by Cheetham et al2 in the November 2015 issue of Mayo Clinic Proceedings regarding the risk of disseminated disease in immunosuppressed patients receiving live zoster vaccine. Although the vaccine has been found to be highly effective and there is a paucity of cases of vaccine-related infections, the following report serves to highlight the need for caution when immunizing highly immunosuppressed patients.
        • Full-Text
        • PDF