PRACTICE | CASES SEPSIS CPD

Disseminated varicella zoster virus infection after vaccination with a live attenuated vaccine

Vinita Dubey MD, Derek MacFadden MD n Cite as: CMAJ 2019 September 16;191:E1025-7. doi: 10.1503/cmaj.190270

70-year-old man presented to the emergency depart- ment with a 2-week history of rash, which started as a KEY POINTS localized eruption on his forehead and progressed to a • Live attenuated vaccines are capable of causing symptomatic vesicularA rash involving his entire body (Figure 1). Over this same vaccine-derived infection, even weeks following vaccination. period, he noted increasing shortness of breath, tiredness, pain- • Immunocompromised hosts, including those taking low-dose ful swallowing and chills. He did not report recent travel. immunosuppressive medications, are at increased risk for The patient had a past history of hypertension, coronary artery infection with live vaccine strains. disease, congestive heart failure, chronic obstructive pulmonary • Caution is required before using live attenuated vaccines in immunocompromised people; expert consultation may be disease and atrial flutter. Successful cardiac ablation had been required. performed 2 weeks before the onset of the rash. He also had rheu- • Severe and unusual adverse events following vaccination matoid arthritis, treated with methotrexate, 2.5 mg/d (6 d per should be reported to local public health authorities for week) for 3 years, hydroxychloroquine, 200 mg/d and prednisone, surveillance and investigative purposes. 10 mg/d. In the previous month, his prednisone dosage had been tapered from 10 mg/d. He was not receiving any biologic agents. On examination, the patient’s blood pressure was 110/60 mm Hg, multiple vesicular and crusted lesions, disseminated varicella heart rate 86 beats/min and temperature 36.8°C. On examination, his zoster virus (VZV) infection was identified as the most likely cardiorespiratory and abdominal systems were initially within nor- cause. It was then ascertained from the patient and family that mal limits. Dermatologic assessment showed numerous widespread he had received a live attenuated herpes zoster vaccine (Zos- vesicles with erythematous bases across all aspects of his body. His tavax II, Merck) about 1 month before the onset of symptoms. He oropharynx was erythematous, with associated lesions. Ocular also reported a history of chickenpox as a child. examination was within normal limits. With the clinical findings and vaccination history, intravenous On admission, the patient’s hemoglobin concentration was treatment with acyclovir was started, 15 mg/kg every 8 h, and contin- 120 (normal 140–180) g/L, leukocyte count 1.7 (normal 4.0–11.0) ued for the duration of the hospital stay. The patient was placed × 109/L, neutrophil count 1.3 (normal 2.0–7.5) × 109/L, lympho- under airborne isolation. Shortly after admission, he was transferred cyte count 0.3 (1.5–4.0) × 109/L and platelet count 84 (normal to the intensive care unit for monitoring. Subsequently, leukopenia 150–400) × 109/L. During the course of evaluating this patient, a and thrombocytopenia developed, with evidence of progressive multi­ wide differential diagnosis was considered (Box 1). Given the organ failure with hypotension. Treatment with broad-spectrum

Figure 1: Widespread vesicular and crusting lesions with surrounding erythema in a patient with disseminated vaccine strain zoster.

© 2019 Joule Inc. or its licensors CMAJ | SEPTEMBER 16, 2019 | VOLUME 191 | ISSUE 37 E1025 PRACTICE E1026 noncontiguous dermatomesandcanresultin centralnervous neuropathic pain.Disseminated zosterofteninvolvesmultiple that doesnotcrossthemidline andisoftenassociatedwith ulopapular vesicularrashoccurring along1or2 dermatomes ter, commonlyknownasshingles, typicallymanifestsasamac- dorsal root ganglia and may reactivate later in life. Herpes zos- live attenuatedvirus.The virus typically remainsdormantin the through exposuretowild-typevirusorvaccinationwith receipt oftheliveattenuatedherpeszostervirusvaccine. infection resultinginmultiorganfailureanddeath,following This isacasereportofdisseminatedvaccine(Oka)strainVZV Discussion they wereathighriskforcomplicationsofVZVinfection. members werecontactedandevaluatedtodeterminewhether lowing vaccinationandinvestigation.Closecontactsfamily local publichealthauthorityforreportingofanadverseeventfol- lesions anddilatedcardiomyopathy.Thecasewasreferredtothe ure from disseminated VZV infection, with pulmonary and colonic the Oka (vaccine) strain. Autopsy findings included multiorgan fail- the NationalMicrobiologyLaboratoryconfirmedpresenceof the firstdayafteradmission,andposthumousviralgenotypingby at thetimeofinitialpresentationconfirmedpresenceVZVon subsequently culturedfrom1of2 bloodspecimens. measures and initiation of a palliative approach. sion totheintensivecareunit,followingwithdrawalofsupportive antibiotics wasstarted.Thepatientdiedonthefifthdayafteradmis- Varicella zostervirusinfectionisacquiredeithernaturally Polymerase chainreactiontestingofalesionalswabobtained • • • • Noninfectious • • • • • • Bacterial • • • • • • Viral Infectious Box 1:Differentialdiagnosisfordiffusevesicularrash Erythema multiforme Eczema vaccinatum Delayed hypersensitivity(e.g.,poisonivy) Severe idiosyncraticreactions(e.g.,toxicepidermalnecrolysis) Ecthyma gangrenosum Secondary syphilis Rickettsial infections Folliculitis Impetigo Disseminated neisserialinfections Enteroviruses (includinghand,footandmouthdisease) Parvovirus B19 Measles HIV Varicella zostervirus(chickenpoxordisseminatedzoster) Herpes simplexvirus(disseminatedherpesoreczemaherpeticum) CMAJ | SEPTEMBER 16,2019 Klebsiella spp. 1 was was commonly inpeoplewithcompromisedimmunesystems. system, pulmonaryandhepaticinvolvement.Itoccursmore publicly fundthevaccineforadults65–70yearsofage. immunization programs.” analysis, as well as on the feasibility and acceptability of zoster zoster vaccinecharacteristics,diseasemodellingandeconomic tions onthe“basisofepidemiologyvaricellazostervirus, competent adultsaged60– mittee recommendedthatlivezostervaccinebeofferedtoimmuno- ing medications.” high dosecorticosteroids,chemotherapyorotherimmunesuppress - hematopoietic stemcelltransplantation(HSCT),orinthosereceiving “HIV infection(regardlessofCD4countorviralload),post-organ or groups, NACIdidnotrecommendlivezostervaccineforthosewith there wasinsufficientevidenceofsafetyandefficacyincertain largely on the fact that most Canadians have had varicella, testing beforeorafterzoster vaccination. Thispracticeisbased immunosuppressive medications. dations regardingpatientswho werereceivingmultiplelow-dose 14 days ormore. 14 days ormoreofprednisone oritsequivalentforanadult 20 mg/d postherpetic neuralgia. both havebeen shown to reduce the incidenceof herpes zosterand 6-mercaptopurine (≤ (≤ methotrexate were definedaslow-doseprednisone(< 20 mg/d), (NACI) considersbothvaccinestobesafeandimmunogenic. cmaj.ca/lookup/suppl/doi:10.1503/cmaj.190270/-/DC1). of these vaccines is presented in Appendix 1 (available at www. GlaxoSmithKline) was authorized for use in Canada. A comparison since 2008.In2017,arecombinantsubunitzostervaccine(Shingrix, zoster vaccine(ZostavaxII)hasbeenauthorizedforuseinCanada toms, mostimportantlypostherpeticneuralgia.Aliveattenuated prevent shinglesandreducethedurationseverityofsymp- ormore.Thepurposeofthevaccinesisto for adultsaged50 years vaccine strainisconsideredsusceptibletotheantiviralacyclovir. spread disseminationofVZVinfectionwithavaccinestrain.TheOka Regardless ofthediagnosticclassification,thispatienthadwide- followingvaccinationwithalivevirusvaccine. about 1 month would nothavebeeninformativegiventhathissymptomsbegan was notperformedduringthepatient’shospitalstayandlikely to differentiatefromprimary varicella.Varicellaserologictesting nated zoster,althoughthissyndromecansometimesbechallenging tion, thepresentationinourpatientcouldbeconsideredasdissemi- vaccine couldbeconsideredundercertaincircumstances. 2018, vaccinationofimmunocompromisedpeoplewithlivezoster and complicationsofzosterinimmunocompromisedhosts,before promised people.However,inlightofthehighburdenreactivation inhibitors onacase-by-casebasis. low-dose immunosuppressiontherapyortumournecrosisfactor report, livezostervaccinecouldbeconsideredforthosereceiving | VOLUME 191 0.4 mg/kg perweek),azathioprine(≤ 0.4 mg/kg In addition,NACIdoesnotrecommend routineserologic The Canadian National Advisory Committee on Immunization The CanadianNationalAdvisoryCommitteeonImmunization There are2licensedherpeszostervaccinesavailableinCanada Given thehistoryofalocalizederuptionfollowedbydissemina- Live virusvaccinesaretypicallycontraindicatedinimmunocom- | ISSUE 37 5 However, at the time of the case in the present However,atthetimeofcaseinpresent 5 High-dosecorticosteroidsweredefinedas 1.5 mg/kg perday). 1.5 mg/kg 3 In2014,theCanadianImmunizationCom- 3 In 2016, Ontario was the first province to In2016,Ontariowasthefirstprovinceto 65 years ormorewithoutcontraindica- 65 years 5 Low-dose immunosuppressives Low-doseimmunosuppressives 5 Therewerenorecommen- 3.0 mg/kg perday)and 3.0 mg/kg 4 5 2 Since Since 3 They They PRACTICE ​ ​ ​ ​ ​ / ​ ac­­ www​. /docs/ E1027 BMJ Case Case BMJ www.canada. Available: immunization ac­­­cessed 2019 Sept. 3). Available: accessed 2019 June 24). cessed 2019 June 24). www.canada.ca/content ac­­ www.canada.ca/en/public . 3 Risk of herpes zoster and dissemi- Live zoster vaccination in an immu- Available: Herpes zoster vaccine live: a 10 year Herpes zoster vaccine live: a 10 year Available: 3890- et al. et al. , et al. 36: K Fatal disseminated varicella zoster infection , HF, E 2018; et al. canada.ca/en/public-health/services/publications/ Tseng accessed 2019 June 24). J, accessed 2019 June 24). Brown Macartney , SM, M Vaccine PL, Brown -use-herpes-zoster-vaccines-eng.pdf ( Available: www.health.gov.on.ca/en/pro/programs/ J, ISSUE 37 ISSUE : : Marcy | Tong TC, KE, Woodward Buxton E, ED, Available . . recommendations​ Costa healthy-living/update-use-herpes-zoster​-vaccine​.html ( Rep 2016;2016:bcr2015212688. Alexander following zoster vaccination in an immunocompromised patient. following zoster vaccination in an immunocompromised shingles_hcp_qa_en.pdf ( Committee on Immuniza- An Advisory Committee Statement (ACS) National Advisory tion (NACI): Update on the use of herpes zoster vaccine. Ottawa: Public Health Agency of Canada; 2014. ;35:7231-9. review of post-marketing safety experience. Vaccine 2017 Cheetham drugs at the time nated varicella zoster in patients taking immunosuppressant of zoster vaccination. Mayo Clin Proc 2015;90:865-73. System (CAEFISS).Canadian Adverse Events Following Immunization Surveillance July 16. Ottawa: Public Health Agency of Canada; modified 2019 Ottawa: Canada. (AEFI) in immunization following events adverse Reporting . Public Health Agency of Canada; modified 2013 Oct. 3 ca/en/public-health/services/immunization/reporting-adverse-events-following -immunization/form.html ( Publicly funded shingles (herpes zoster) immunization program: information forprogram: information zoster) immunization (herpes funded shingles Publicly and Long-Term Care;health care providers. Toronto: Ontario Ministry of Health 2019 nocompromised patient leading to death secondary to disseminated varicellanocompromised patient leading to death secondary zoster virus infection. ​-adverse-events canada​.ca/en/public-health/services/immunization/canadian ( -following-immunization-surveillance-system-caefiss.html Willis dam/phac​-aspc​/documents/services/publications/healthy-living/updated - Herpes zoster (shingles) vaccine: Canadian immunization guide. Canadian Canadian immunization guide. Canadian Herpes zoster (shingles) vaccine: professionals. Ottawa: Public Health Agency immunization guide for health Aug. 30. of Canada; modified 2018 -health/services/publications/healthy-living/canadian-immunization-guide (ACS) National Advisory Committee on Immuniza- An Advisory Committee Statement on the use of herpes zoster vaccines. Ottawa:tion (NACI): updated recommendations . 2018 Public Health Agency of Canada; Infect Chemother 2015;47:155-66. Kang JH. Febrile illness with skin rashes. ( -part-4​-active​-vaccines/page-8-herpes-zoster-(shingles)-vaccine.html cessed 2019 June 24). In conclusion, disseminated VZV infection is a rare but potentially is a rare VZV infection disseminated In conclusion, Competing interests: None declared. This article has been peer reviewed. The authors have obtained consent from the patient’s next of kin. Affiliations: Toronto Public Health (Dubey); Dalla Lana School of Pub- lic Health (Dubey) and Division of Infectious Disease (MacFadden), University of Toronto, Toronto, Ont. Contributors: Both authors contributed to the conception and for it revised critically manuscript, the drafted work, the of design beto version the of approval final gave content, intellectual important published and agreed to be accountable for all aspects of the work. Acknowledgements: The authors thank Janice Vandezande for completing the follow-up of the public health investigation, and - their thought for Gold Wayne Abirami Vijenthira and Lindsay Melvin, ful review of this case. Correspondence to: Vinita Dubey, [email protected] . . . . . 6. 9. 8. 1. 7 4 5 VOLUME 191 VOLUME |

10. 11.

lethal complication of vaccination with the live attenuated zoster vac- with the live attenuated of vaccination lethal complication immunocom - administration in considering live vaccine cine. When consultation be taken, and expert caution should promised patients, immu- adverse events following Severe and unusual may be required. for inves- public health authorities be reported to local nization should Canada’s vaccine safety surveillance system. tigation and inclusion in References 2 3

​ 3 10 .ca/ Local Local 3 11 Another 8 .canada​ Recombinant 3

2 9 SEPTEMBER 16, 2019 SEPTEMBER | CMAJ The authors of a review of post- 10 6,7 In our case, however, disseminated vaccine-strain infection infection In our case, however, disseminated vaccine-strain Balancing the risks of vaccination with the increased risk of increased risk of Balancing the risks of vaccination with the There have been few previous reports of death from dissemi- There have been few In 2018, NACI updated the herpes zoster vaccine recommendations updated the herpes In 2018, NACI Adverse events should be reported if there is a temporal associ- beginning about 4 weeks after vaccination and resulting in multi- our knowledge, there organ failure and death was confirmed. To - with live attenu reports of death associated have been no other ated zoster vaccine in Canada. herpes zoster is crucial for each patient. Our case highlights the Our case highlights the herpes zoster is crucial for each patient. a vaccination his- importance of inquiring about and recording and considering tory in potentially relevant patient encounters in the differential diag- an adverse event following vaccination to the local pub- nosis. Such adverse events should be reported or territory. lic health authority in the patient’s province nated VZV infection related to the live attenuated zoster vaccine in to the live attenuated zoster vaccine nated VZV infection related immunocompromised people. and provided a preferential recommendation for the recombinant zos- recombinant the for recommendation preferential a provided and Zostavax II. attenuated vaccine, Shingrix, over the live ter vaccine, review of over 14 000 patients who received zoster vaccination a small increasedwhile taking immunosuppressant drugs showed risk of herpes zoster for up to 42 days after vaccination but sug- due to reactivation of gested that the increased risk was likely virus. latent zoster virus rather than vaccine-derived - have a specific indication for use in immuno zoster vaccine does not areas the results of studies in these populations compromised people, live that it will be a safer alternative to the still pending. It is expected - contain whole virus particles capable of caus vaccine since it does not the Guidance from NACI now states that ing symptomatic disease. - (not the live zoster vaccine) may be con recombinant zoster vaccine adults 50 years of age or more. sidered in immunocompromised even if they do not recall this, and zoster vaccination is likely is likely zoster vaccination this, and not recall if they do even susceptible to VZV. adults who are safe in healthy marketing safety of the live zoster vaccine concluded that the concluded that the marketing safety of the live zoster vaccine what had been previ- safety profile was good and concordant with clinical trials. ously found in postlicensure studies and reporting forms are available, or the reporting form from the reporting forms are available, or the reporting form from the Public Health Agency of Canada can be used (www​ content/dam/phac​-aspc​/documents/services/immunization​/ adverse-events-following​-immunization-reporting-declaration -manifestations-cliniques-inhabituelles-suite-immunisation​-eng​.pdf). Not all adverse events following vaccination need to be reported. Well-known, expected events such as injection site pain or fever do not need to be reported unless they are more severe than expected. ation with the vaccine and there is no other clear cause for the event. However, a causal association between the vaccination and Severe event. the report to required not is event adverse the events that should be reported include life-threatening events, death, hospital admission, disability and congenital malforma- tions. Adverse events that are unusual or unexpected should also be reported. Reporting adverse events following vaccination ensures the events can be investigated by public health and reported in Canada’s passive vaccine safety surveillance system. However, a recommendation still remains that the live vaccine may beremains that the live vaccine recommendation still However, a recombinantwhom in populations for immunocompetent considered unavailable or inaccessible. contraindicated, vaccine is