Multiple Sclerosis and Related Disorders (2013) 2, 391–394
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/msard
Varicella vaccination after fingolimod: A case report Joseph R. Bergern Department of Neurology, University of Kentucky College of Medicine, Kentucky Clinic L-445, 740 S. Limestone St., Lexington, KY 40536-0284, USA Received 20 January 2013; received in revised form 5 March 2013; accepted 7 March 2013
1.
KEYWORDS
Abstract
Fingolimod; Multiple sclerosis; Varicella zoster virus; Shingles; Varicella zoster vaccine; Immunosuppression
A 36 year old woman with relapsing remitting multiple sclerosis and a childhood history of varicella (chickenpox) received 5 days of fingolimod (Gilenya®) before the drug was stopped upon discovery that she was varicella zoster virus (VZV) seronegative. Despite medical advice to the contrary, she was vaccinated with attenuated zoster virus vaccine (Zostavax®) the day after discontinuing fingolimod. Although the vaccination was uncomplicated by rash or systemic illness, her 3 year old daughter developed varicella 14 days following the vaccination. The patient developed recurrent thoracic herpes zoster 8 and 10.5 months following the vaccination while receiving fingolimod. Both episodes resolved during acyclovir therapy. This case report suggests that the immunomodulation that attends the administration of fingolimod may increase the risk of viral shedding following vaccination with attenuated VZV and reduce the efficacy of vaccination. & 2013 Elsevier B.V. All rights reserved.
Introduction
A possible association of fingolimod and serious herpes infections was suggested in the seminal TRANSFORMS study in which 2 patients died from herpes infection, one from herpes simplex virus encephalitis and the other with disseminated varicella zoster virus (VZV) infection (Cohen et al., 2010). However, in that study, the overall incidence of herpes infections was 2.8% in the placebo group, 2.1% in the 0.5 mg fingolimod dose and 5.5% in the 1.25 mg dose (Cohen et al, 2010). In the extension study of TRANSFORMS, only 1 patient (1%) in the treatment arms of low and high n
Tel.: +1 859 218 5039; fax: +1 859 323 5943. E-mail address: [email protected]
2211-0348/$ - see front matter & 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.msard.2013.03.002
dose fingolimod (0.5 mg or 1.25 mg) experienced herpes infections in the 13–24 months after the switch from intramuscular interferon-β (Avonex®); whereas none had before the switch. In the FREEDOMS study (Kappos et al., 2010) comparing two doses of fingolimod to placebo, overall herpes infections rates 8.7% for 0.5 mg fingolimod, 5.8% for 1.25 mg fingolimod and 7.9% for the placebo arm. Similar numbers for herpes virus infection in overall and VZV infections were derived from an all group analysis (Duquette et al., 2011). For any herpes infection, the frequency was 8.1% (95/1176) for fingolimod 0.5 mg and 9.4% (122/1302) for fingolimod 1.25 mg and for VZV the rate was 1.8% (21/1176) for fingolimod 0.5 mg and 2.6% (34/ 1302) for fingolimod 1.25 mg (Duquette et al., 2011). Therefore, the frequency of overall herpes virus infections
392
J.R. Berger
and VZV specifically were not significantly different with fingolimod when compared to either placebo or IFN-β. Nonetheless, the recommendation before initiating the drug is to assess VZV antibody status and to vaccinate seronegative patients with attenuated varicella virus vaccine (Zostavax®) regardless of a prior history of varicella (chickenpox). We encountered a VZV seronegative patient with a prior history of varicella (chickenpox) who was started on fingolimod before the VZV serological results were available. The drug was discontinued after 5 days and, against medical advice, she received Zostavax® the day after its discontinuation. Two weeks later, her daughter developed varicella and in the subsequent year, the patient has had two episodes of thoracic shingles.
2.
Case report
This 36 year old woman was diagnosed with MS at age 29 in 2005. Continued disease progression clinically and by MRI criteria was evident during treatment with interferon β1b (Betaseron®) and glatiramir acetate (Copaxone®) and she was advanced to natalizumab (Tysabri®) 300 mg intravenous infusion monthly in October 2009. After a total of 23 total infusions of natalizumab, the drug was discontinued on September 21, 2011, as her disease remained active on natalizumab despite being natalizumab neutralizing antibody negative. On October 13, 2011, her lymphocyte count was 3370 cells/cu mm. On November 3, 2011, fingolimod (Gilenya®) was initiated, but discontinued after 5 days when it was realized that her VZV antibody was negative despite a childhood history of chickenpox. Although advised to wait at 4–6 weeks before VZV vaccination, she received it one day later on November 9, 2011. She experienced no ill effects following the vaccination; however, on November 23, when her lymphocyte count was 1550 cells/cu mm, her 3 year old daughter developed chickenpox. Her daughter did not attend a preschool nor was she exposed to anyone with chickenpox. On December 8, 2011, fingolimod was reinitiated. On January 23, 2012, she developed influenza and had an MS relapse requiring 5 days of intravenous methylprednisolone. She had not been previously vaccinated for influenza. At that time, her lymphocyte count was 190 cells/cu mm. On March 25, she developed a urinary tract infection and was found to have leukopenia (300 WBCs/cu mm) and thrombocytopenia (98,000 platelets/cu mm). These were ascribed to sepsis and returned to baseline values by March 30 (WBCs 7400/cu mm and platelets 224,000 cells/cu mm) with cephalosporin treatment. On May 10, her CD4/8 ratio was 0.2 (normal 0.9–3.7) and CD4 10% (normal 30–60%); unfortunately, an absolute CD4 lymphocyte count was not available nor could it be calculated; her absolute white blood cell count at the time was 5000 cells/cu mm. On July 9, she developed shingles in a left T8-11 distribution that resolved in association with course of acyclovir 800 mg five times for 2 weeks. On September 28, she had recurrent shingles that involved the lower thoracic dermatomes bilaterally. She was retreated with acyclovir and recovered within 10 days. On February 27, 2013, repeat varicella antibody testing, performed 16 months after Zostavax administration and
following 2 bouts of zoster, was again negative. An immunoglobulin assay was normal with the exception of a slightly diminished IgG of 629 mg/dl (normal 720–1589 mg/dl).
3.
Discussion
Recent case reports (Gross et al., 2012; Ratchford et al., 2012) continue to raise concerns about a possible association between fingolimod and serious herpes infection. One patient developed zoster cranial polyneuritis with a high VZV copy number in the CSF 42 months after the initiation of fingolimod 0.5 mg daily (Gross et al., 2012). Another patient developed encephalopathy and brainstem infarction attributed to VZV encephalitis and vasculopathy three months after the initiation of fingolimod when his absolute lymphocyte count was 190 cells/uL (Ratchford et al., 2012). The patient described appears to have transmitted VZV to her daughter after inoculation following a very short course of fingolimod. Furthermore, during the first year of fingolimod treatment, she has had 2 discrete episodes of recurrent herpes zoster. These observations suggests the possibility that zoster vaccine efficacy is attenuated in patients who had received fingolimod immediately prior to vaccination, even a short course, and that VZV control may be diminished during treatment with fingolimod leading to recurrent zoster in some patients. A blunted immune response to vaccination to varicella would not be surprising in the setting of the administration of immunosuppressive drugs as it has been observed with influenza and pneumococcal vaccinations (Agarwal et al., 2011). It is unlikely that either her influenza infection or the corticosteroid administration for the MS relapse occurring on its heels contributed to her bouts of shingles as there was a 6 month hiatus between them and the first onset of zoster. The zoster vaccine is a live-attenuated virus (Oka/Merck strain) that is extremely safe and highly immunogenic (Gershon, 2001). It reduces the risk of developing zoster by 51.3% (95% CI = 44.2–57.6) (Oxman et al., 2005). It has been proposed that vaccinated individuals may shed the attenuated virus increasing the herd immunity following vaccination efforts; however, early studies by the manufacturer failed to confirm transmission of the vaccine virus in contacts (Harpaz et al., 2008). While transmission of the live attenuated varicella virus to contacts is infrequent (Diaz et al., 1991), it has been described (LaRussa et al., 1997; Salzman et al., 1997). The incubation period from time of exposure to VZV to the clinical expression of varicella is typically 14–15 days (Gelb, 1985), precisely the time from our patient's vaccination to the development of her daughter's varicella. and transmission may occur in the absence of the rash (Moore and Hopkins, 1991). As our patient's 3 year old daughter had not been otherwise exposed to VZV, it is likely that the source of her viral infection was her mother's inoculation two weeks earlier. Although our patient had been advised to wait 4–6 weeks from time of discontinuing the fingolimod, zoster vaccination was administered the day after she had received 5 days of fingolimod. Zoster vaccine should not be administered to persons with primary or acquired immunodeficiency (Harpaz et al., 2008). It is quite possible that the immunological compromise attending fingolimod administration favored
Varicella vaccination after fingolimod VZV shedding, although the patient suffered no ill effects at the time of inoculation. Although disseminated and persistent varicella infection has been reported in immunosuppressed individuals who have been vaccinated with varicella, our patient seemed to tolerate the vaccination without complication. Furthermore, her MS did not worsen following the vaccination. While on fingolimod, the patient experienced separate episodes of thoracic herpes zoster 8 and 10.5 months following zoster inoculation. Both recurrences resolved within 10 days of acyclovir administration. Although the zoster vaccine is not totally effective in preventing episodes of herpes zoster and recurrent herpes zoster has been described in immunocompetent individuals, recurrent herpes zoster is rare in vaccinated immunocompetent individuals. Among immunocompetent adults vaccinated after a recent episode of herpes zoster, the rate of recurrent herpes zoster was only 0.99 per 1000 patient years (Tseng et al., 2012). This case report must be interpreted cautiously. Viral cultures were not obtained from her daughter or from the patient's lesions during the recurrent episodes of zoster. Transmission of the varicella Oka vaccine to non-vaccinated individuals has been documented on rarely. Furthermore, the multidermatomal nature of her second episode of shingles is unusual as well, though the symptoms and lesion appearance strongly suggested recurrent zoster. Despite a history of childhood varicella, she was VZV antibody negative and remained VZV antibody negative after Zostavax and two bouts of shingles. There was no evidence of a primary immunodeficiency either clinically or by laboratory examination suggesting that fingolimod may have blunted the humoral response to immunization and recrudescent infection. Cell mediated immunity is fundamental to viral reactivation and clinical expression of the disease; the incidence of herpes zoster is substantially increased with hematological and solid tumors (Rusthoven et al., 1988), HIV infection (McNulty et al., 1997), hematopoietic stem cell (Arvin, 2000), and organ transplantation (Gourishankar et al., 2004), as well as with other conditions affecting cell mediated immunity. Whether fingolimod which inhibits the egress of naive and central memory T cells, but not effector memory cells (Mehling et al., 2008) truly predisposes to increases the risk of and aggressiveness of VZV remains uncertain. Current data suggests that there is be no relationship between the degree of lymphopenia associated with fingolimod and the occurrence of all herpes infections (Francis et al., 2010) Vigilance for unusual complications of VZV during treatment with fingolimod is warranted.
Conflict of interest Dr. Berger serves on PML Adjudication Committees for Millenium, Johnson and Johnson, and Amgen; has served on scientific advisory boards or as a consultant for Amgen, Bayer, BiogenIdec, Eisai, Genzyme, GlaxoSmithKline, Genentech, Novartis, and Pfizer; has received speaking fees from CMSC, AAN, Bayer and BiogenIdec; serves as an associate editor of the Journal of Neurovirology and serves on the editorial boards of ISRN Education, MS and Related Disorders, Neuroscience, and World Journal of
393 Rheumatology; and receives research support from the PML Consortium.
References Agarwal N, Ollington K, Kaneshiro M, Frenck R, Melmed GY. Are immunosuppressive medications associated with decreased responses to routine immunizations? A systematic review Vaccine 2011;30:1413–24. Arvin AM. Varicella-zoster virus: pathogenesis, immunity, and clinical management in hematopoietic cell transplant recipients. Biology of Blood and Marrow Transplantation 2000;6:219–30. Cohen JA, Barkhof F, Comi G, Hartung HP, Khatri BO, Montalban X, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. New England Journal of Medicine 2010;362:402–15. Diaz PS, Au D, Smith S, Amylon M, Link M, Arvin AM. Lack of transmission of the live attenuated varicella vaccine virus to immunocompromised children after immunization of their siblings. Pediatrics 1991;87:166–70. Duquette P, Kappos L, Cohen JA, Francis G, Collins W, ZhangAuberson L, et al. Long-tem safety of fingolimod in relapsing MS: phase 2 and 3 analyses. In: Proceedings of the 24th annual meeting of the consortium of multiple sclerosis centers. Montreal, Quebec; 2011. Francis G, Kappos L, O'Connor P, Collins W, Zhang-Auberson L, de Vera A, et al. Lymphocytes and fingolimod—temporal pattern and relationship with infections. In: Proceedings of the 26th Congress of the European Committee for the treatment and research in multiple sclerosis. Gothenberg, Sweden; 2010. Gelb LD. Varicella-zoster virus. In: Fields BN, Knipe DM, Chanock RM, Melnick JL, Roizman B, Shope RE, editors. Fields virology. New York: Raven Press; 1985. p. 591–627. Gershon AA. Live-attenuated varicella vaccine. Infectious Disease Clinics of North America 2001;15:65–81. Gourishankar S, McDermid JC, Jhangri GS, Preiksaitis JK. Herpes zoster infection following solid organ transplantation: incidence, risk factors and outcomes in the current immunosuppressive era. American Journal of Transplantation 2004;4:108–15. Gross CM, Baumgartner A, Rauer S, Stich O. Multiple sclerosis rebound following herpes zoster infection and suspension of fingolimod. Neurology 2012;79:2006–7. Harpaz R, Ortega-Sanchez IR, Seward JF. Prevention of herpes zoster: recommendations of the Advisory Committee on immunization practices. Morbidity and Mortality Weekly Report 2008;57:1–30. Kappos L, Radue EW, O’Connor P, Polman C, Hohlfeld R, Calabresi P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. New England Journal of Medicine 2010;362:387–401. LaRussa P, Steinberg S, Meurice F, Gershon A. Transmission of vaccine strain varicella-zoster virus from a healthy adult with vaccine-associated rash to susceptible household contacts. Journal of Infectious Diseases 1997;176:1072–5. McNulty A, Li Y, Radtke U, Kaldor J, Rohrsheim R, Cooper DA, et al. Herpes zoster and the stage and prognosis of HIV-1 infection. Genitourinary Medicine 1997;73:467–70. Mehling M, Brinkmann V, Antel J, Bar-Or A, Goebels N, Vedrine C, et al. FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis. Neurology 2008;71:1261–7. Moore DA, Hopkins RS. Assessment of a school exclusion policy during a chickenpox outbreak. American Journal of Epidemiology 1991;133:1161–7. Oxman MN, Levin MJ, Johnson GR, Schmader KE, Straus SE, Gelb LD, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. New England Journal of Medicine 2005;352:2271–84.
394 Ratchford JN, Costello K, Reich DS, Calabresi PA. Varicella-zoster virus encephalitis and vasculopathy in a patient treated with fingolimod. Neurology 2012;79:2002–4. Rusthoven JJ, Ahlgren P, Elhakim T, Pinfold P, Reid J, Stewart L, et al. Varicella-zoster infection in adult cancer patients. A population study. Archives of Internal Medicine 1988;148:1561–6. Salzman MB, Sharrar RG, Steinberg S, LaRussa P. Transmission of varicella-vaccine virus from a healthy 12-month-old child to his pregnant mother. Journal of Pediatrics 1997;131:151–4.
J.R. Berger Tseng HF, Chi M, Smith N, Marcy SM, Sy LS, Jacobsen SJ. Herpes zoster vaccine and the incidence of recurrent herpes zoster in an immunocompetent elderly population. Journal of Infectious Diseases 2012;206:190–6.
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/msard
Varicella vaccination after fingolimod: A case report Joseph R. Bergern Department of Neurology, University of Kentucky College of Medicine, Kentucky Clinic L-445, 740 S. Limestone St., Lexington, KY 40536-0284, USA Received 20 January 2013; received in revised form 5 March 2013; accepted 7 March 2013
1.
KEYWORDS
Abstract
Fingolimod; Multiple sclerosis; Varicella zoster virus; Shingles; Varicella zoster vaccine; Immunosuppression
A 36 year old woman with relapsing remitting multiple sclerosis and a childhood history of varicella (chickenpox) received 5 days of fingolimod (Gilenya®) before the drug was stopped upon discovery that she was varicella zoster virus (VZV) seronegative. Despite medical advice to the contrary, she was vaccinated with attenuated zoster virus vaccine (Zostavax®) the day after discontinuing fingolimod. Although the vaccination was uncomplicated by rash or systemic illness, her 3 year old daughter developed varicella 14 days following the vaccination. The patient developed recurrent thoracic herpes zoster 8 and 10.5 months following the vaccination while receiving fingolimod. Both episodes resolved during acyclovir therapy. This case report suggests that the immunomodulation that attends the administration of fingolimod may increase the risk of viral shedding following vaccination with attenuated VZV and reduce the efficacy of vaccination. & 2013 Elsevier B.V. All rights reserved.
Introduction
A possible association of fingolimod and serious herpes infections was suggested in the seminal TRANSFORMS study in which 2 patients died from herpes infection, one from herpes simplex virus encephalitis and the other with disseminated varicella zoster virus (VZV) infection (Cohen et al., 2010). However, in that study, the overall incidence of herpes infections was 2.8% in the placebo group, 2.1% in the 0.5 mg fingolimod dose and 5.5% in the 1.25 mg dose (Cohen et al, 2010). In the extension study of TRANSFORMS, only 1 patient (1%) in the treatment arms of low and high n
Tel.: +1 859 218 5039; fax: +1 859 323 5943. E-mail address: [email protected]
2211-0348/$ - see front matter & 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.msard.2013.03.002
dose fingolimod (0.5 mg or 1.25 mg) experienced herpes infections in the 13–24 months after the switch from intramuscular interferon-β (Avonex®); whereas none had before the switch. In the FREEDOMS study (Kappos et al., 2010) comparing two doses of fingolimod to placebo, overall herpes infections rates 8.7% for 0.5 mg fingolimod, 5.8% for 1.25 mg fingolimod and 7.9% for the placebo arm. Similar numbers for herpes virus infection in overall and VZV infections were derived from an all group analysis (Duquette et al., 2011). For any herpes infection, the frequency was 8.1% (95/1176) for fingolimod 0.5 mg and 9.4% (122/1302) for fingolimod 1.25 mg and for VZV the rate was 1.8% (21/1176) for fingolimod 0.5 mg and 2.6% (34/ 1302) for fingolimod 1.25 mg (Duquette et al., 2011). Therefore, the frequency of overall herpes virus infections
392
J.R. Berger
and VZV specifically were not significantly different with fingolimod when compared to either placebo or IFN-β. Nonetheless, the recommendation before initiating the drug is to assess VZV antibody status and to vaccinate seronegative patients with attenuated varicella virus vaccine (Zostavax®) regardless of a prior history of varicella (chickenpox). We encountered a VZV seronegative patient with a prior history of varicella (chickenpox) who was started on fingolimod before the VZV serological results were available. The drug was discontinued after 5 days and, against medical advice, she received Zostavax® the day after its discontinuation. Two weeks later, her daughter developed varicella and in the subsequent year, the patient has had two episodes of thoracic shingles.
2.
Case report
This 36 year old woman was diagnosed with MS at age 29 in 2005. Continued disease progression clinically and by MRI criteria was evident during treatment with interferon β1b (Betaseron®) and glatiramir acetate (Copaxone®) and she was advanced to natalizumab (Tysabri®) 300 mg intravenous infusion monthly in October 2009. After a total of 23 total infusions of natalizumab, the drug was discontinued on September 21, 2011, as her disease remained active on natalizumab despite being natalizumab neutralizing antibody negative. On October 13, 2011, her lymphocyte count was 3370 cells/cu mm. On November 3, 2011, fingolimod (Gilenya®) was initiated, but discontinued after 5 days when it was realized that her VZV antibody was negative despite a childhood history of chickenpox. Although advised to wait at 4–6 weeks before VZV vaccination, she received it one day later on November 9, 2011. She experienced no ill effects following the vaccination; however, on November 23, when her lymphocyte count was 1550 cells/cu mm, her 3 year old daughter developed chickenpox. Her daughter did not attend a preschool nor was she exposed to anyone with chickenpox. On December 8, 2011, fingolimod was reinitiated. On January 23, 2012, she developed influenza and had an MS relapse requiring 5 days of intravenous methylprednisolone. She had not been previously vaccinated for influenza. At that time, her lymphocyte count was 190 cells/cu mm. On March 25, she developed a urinary tract infection and was found to have leukopenia (300 WBCs/cu mm) and thrombocytopenia (98,000 platelets/cu mm). These were ascribed to sepsis and returned to baseline values by March 30 (WBCs 7400/cu mm and platelets 224,000 cells/cu mm) with cephalosporin treatment. On May 10, her CD4/8 ratio was 0.2 (normal 0.9–3.7) and CD4 10% (normal 30–60%); unfortunately, an absolute CD4 lymphocyte count was not available nor could it be calculated; her absolute white blood cell count at the time was 5000 cells/cu mm. On July 9, she developed shingles in a left T8-11 distribution that resolved in association with course of acyclovir 800 mg five times for 2 weeks. On September 28, she had recurrent shingles that involved the lower thoracic dermatomes bilaterally. She was retreated with acyclovir and recovered within 10 days. On February 27, 2013, repeat varicella antibody testing, performed 16 months after Zostavax administration and
following 2 bouts of zoster, was again negative. An immunoglobulin assay was normal with the exception of a slightly diminished IgG of 629 mg/dl (normal 720–1589 mg/dl).
3.
Discussion
Recent case reports (Gross et al., 2012; Ratchford et al., 2012) continue to raise concerns about a possible association between fingolimod and serious herpes infection. One patient developed zoster cranial polyneuritis with a high VZV copy number in the CSF 42 months after the initiation of fingolimod 0.5 mg daily (Gross et al., 2012). Another patient developed encephalopathy and brainstem infarction attributed to VZV encephalitis and vasculopathy three months after the initiation of fingolimod when his absolute lymphocyte count was 190 cells/uL (Ratchford et al., 2012). The patient described appears to have transmitted VZV to her daughter after inoculation following a very short course of fingolimod. Furthermore, during the first year of fingolimod treatment, she has had 2 discrete episodes of recurrent herpes zoster. These observations suggests the possibility that zoster vaccine efficacy is attenuated in patients who had received fingolimod immediately prior to vaccination, even a short course, and that VZV control may be diminished during treatment with fingolimod leading to recurrent zoster in some patients. A blunted immune response to vaccination to varicella would not be surprising in the setting of the administration of immunosuppressive drugs as it has been observed with influenza and pneumococcal vaccinations (Agarwal et al., 2011). It is unlikely that either her influenza infection or the corticosteroid administration for the MS relapse occurring on its heels contributed to her bouts of shingles as there was a 6 month hiatus between them and the first onset of zoster. The zoster vaccine is a live-attenuated virus (Oka/Merck strain) that is extremely safe and highly immunogenic (Gershon, 2001). It reduces the risk of developing zoster by 51.3% (95% CI = 44.2–57.6) (Oxman et al., 2005). It has been proposed that vaccinated individuals may shed the attenuated virus increasing the herd immunity following vaccination efforts; however, early studies by the manufacturer failed to confirm transmission of the vaccine virus in contacts (Harpaz et al., 2008). While transmission of the live attenuated varicella virus to contacts is infrequent (Diaz et al., 1991), it has been described (LaRussa et al., 1997; Salzman et al., 1997). The incubation period from time of exposure to VZV to the clinical expression of varicella is typically 14–15 days (Gelb, 1985), precisely the time from our patient's vaccination to the development of her daughter's varicella. and transmission may occur in the absence of the rash (Moore and Hopkins, 1991). As our patient's 3 year old daughter had not been otherwise exposed to VZV, it is likely that the source of her viral infection was her mother's inoculation two weeks earlier. Although our patient had been advised to wait 4–6 weeks from time of discontinuing the fingolimod, zoster vaccination was administered the day after she had received 5 days of fingolimod. Zoster vaccine should not be administered to persons with primary or acquired immunodeficiency (Harpaz et al., 2008). It is quite possible that the immunological compromise attending fingolimod administration favored
Varicella vaccination after fingolimod VZV shedding, although the patient suffered no ill effects at the time of inoculation. Although disseminated and persistent varicella infection has been reported in immunosuppressed individuals who have been vaccinated with varicella, our patient seemed to tolerate the vaccination without complication. Furthermore, her MS did not worsen following the vaccination. While on fingolimod, the patient experienced separate episodes of thoracic herpes zoster 8 and 10.5 months following zoster inoculation. Both recurrences resolved within 10 days of acyclovir administration. Although the zoster vaccine is not totally effective in preventing episodes of herpes zoster and recurrent herpes zoster has been described in immunocompetent individuals, recurrent herpes zoster is rare in vaccinated immunocompetent individuals. Among immunocompetent adults vaccinated after a recent episode of herpes zoster, the rate of recurrent herpes zoster was only 0.99 per 1000 patient years (Tseng et al., 2012). This case report must be interpreted cautiously. Viral cultures were not obtained from her daughter or from the patient's lesions during the recurrent episodes of zoster. Transmission of the varicella Oka vaccine to non-vaccinated individuals has been documented on rarely. Furthermore, the multidermatomal nature of her second episode of shingles is unusual as well, though the symptoms and lesion appearance strongly suggested recurrent zoster. Despite a history of childhood varicella, she was VZV antibody negative and remained VZV antibody negative after Zostavax and two bouts of shingles. There was no evidence of a primary immunodeficiency either clinically or by laboratory examination suggesting that fingolimod may have blunted the humoral response to immunization and recrudescent infection. Cell mediated immunity is fundamental to viral reactivation and clinical expression of the disease; the incidence of herpes zoster is substantially increased with hematological and solid tumors (Rusthoven et al., 1988), HIV infection (McNulty et al., 1997), hematopoietic stem cell (Arvin, 2000), and organ transplantation (Gourishankar et al., 2004), as well as with other conditions affecting cell mediated immunity. Whether fingolimod which inhibits the egress of naive and central memory T cells, but not effector memory cells (Mehling et al., 2008) truly predisposes to increases the risk of and aggressiveness of VZV remains uncertain. Current data suggests that there is be no relationship between the degree of lymphopenia associated with fingolimod and the occurrence of all herpes infections (Francis et al., 2010) Vigilance for unusual complications of VZV during treatment with fingolimod is warranted.
Conflict of interest Dr. Berger serves on PML Adjudication Committees for Millenium, Johnson and Johnson, and Amgen; has served on scientific advisory boards or as a consultant for Amgen, Bayer, BiogenIdec, Eisai, Genzyme, GlaxoSmithKline, Genentech, Novartis, and Pfizer; has received speaking fees from CMSC, AAN, Bayer and BiogenIdec; serves as an associate editor of the Journal of Neurovirology and serves on the editorial boards of ISRN Education, MS and Related Disorders, Neuroscience, and World Journal of
393 Rheumatology; and receives research support from the PML Consortium.
References Agarwal N, Ollington K, Kaneshiro M, Frenck R, Melmed GY. Are immunosuppressive medications associated with decreased responses to routine immunizations? A systematic review Vaccine 2011;30:1413–24. Arvin AM. Varicella-zoster virus: pathogenesis, immunity, and clinical management in hematopoietic cell transplant recipients. Biology of Blood and Marrow Transplantation 2000;6:219–30. Cohen JA, Barkhof F, Comi G, Hartung HP, Khatri BO, Montalban X, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. New England Journal of Medicine 2010;362:402–15. Diaz PS, Au D, Smith S, Amylon M, Link M, Arvin AM. Lack of transmission of the live attenuated varicella vaccine virus to immunocompromised children after immunization of their siblings. Pediatrics 1991;87:166–70. Duquette P, Kappos L, Cohen JA, Francis G, Collins W, ZhangAuberson L, et al. Long-tem safety of fingolimod in relapsing MS: phase 2 and 3 analyses. In: Proceedings of the 24th annual meeting of the consortium of multiple sclerosis centers. Montreal, Quebec; 2011. Francis G, Kappos L, O'Connor P, Collins W, Zhang-Auberson L, de Vera A, et al. Lymphocytes and fingolimod—temporal pattern and relationship with infections. In: Proceedings of the 26th Congress of the European Committee for the treatment and research in multiple sclerosis. Gothenberg, Sweden; 2010. Gelb LD. Varicella-zoster virus. In: Fields BN, Knipe DM, Chanock RM, Melnick JL, Roizman B, Shope RE, editors. Fields virology. New York: Raven Press; 1985. p. 591–627. Gershon AA. Live-attenuated varicella vaccine. Infectious Disease Clinics of North America 2001;15:65–81. Gourishankar S, McDermid JC, Jhangri GS, Preiksaitis JK. Herpes zoster infection following solid organ transplantation: incidence, risk factors and outcomes in the current immunosuppressive era. American Journal of Transplantation 2004;4:108–15. Gross CM, Baumgartner A, Rauer S, Stich O. Multiple sclerosis rebound following herpes zoster infection and suspension of fingolimod. Neurology 2012;79:2006–7. Harpaz R, Ortega-Sanchez IR, Seward JF. Prevention of herpes zoster: recommendations of the Advisory Committee on immunization practices. Morbidity and Mortality Weekly Report 2008;57:1–30. Kappos L, Radue EW, O’Connor P, Polman C, Hohlfeld R, Calabresi P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. New England Journal of Medicine 2010;362:387–401. LaRussa P, Steinberg S, Meurice F, Gershon A. Transmission of vaccine strain varicella-zoster virus from a healthy adult with vaccine-associated rash to susceptible household contacts. Journal of Infectious Diseases 1997;176:1072–5. McNulty A, Li Y, Radtke U, Kaldor J, Rohrsheim R, Cooper DA, et al. Herpes zoster and the stage and prognosis of HIV-1 infection. Genitourinary Medicine 1997;73:467–70. Mehling M, Brinkmann V, Antel J, Bar-Or A, Goebels N, Vedrine C, et al. FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis. Neurology 2008;71:1261–7. Moore DA, Hopkins RS. Assessment of a school exclusion policy during a chickenpox outbreak. American Journal of Epidemiology 1991;133:1161–7. Oxman MN, Levin MJ, Johnson GR, Schmader KE, Straus SE, Gelb LD, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. New England Journal of Medicine 2005;352:2271–84.
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