Breakthrough Varicella in a Cancer Patient with Persistent VaricellaAntibody after One Varicella Vaccination*

Masaki Yamada, MD, Natalie Kamberos, MD, and Charles Grose, MD

A boy with Hodgkin disease contracted breakthrough varicella from his father, who had chickenpox. The boy hadreceived a single varicella vaccination and was seropositive by enzyme-linked immunosorbent assay before beingdiagnosed with breakthrough varicella. Seropositivity after a single varicella vaccination does not guarantee com-plete protection in an immunocompromised child. (J Pediatr 2013;163:1511-3).

From the Divisions of Infectious Diseases/Virology and Hematology/Oncology,Children’s Hospital, University of Iowa, Iowa City, IA

Supported by the National Institutes of Health (AI89716). The authors declare no

This report describes an exception to the guidelines formanaging varicella zoster virus (VZV) infection inimmunocompromised children, as provided in the

2012 Report of the Committee on Infectious Diseases.1 Theguidelines do not recommend any intervention for childrenidentified as seropositive for varicella antibody when exposedto varicella. The presence of detectable anti-VZV antibody haslong been considered by infectious disease and hematology-oncology services as the best indicator of protection againstvaricella in their immunocompromised patients. That hasalso been our policy at the Children’sHospital at the Universityof Iowa for more than 20 years. Here we report a case of break-through varicella in a cancer patient with a positive screen forvaricella antibody titer and suggest an alternative approach.

Diagnosis of VZV Infection

VZV IgG antibody was detected by enzyme-linked immuno-sorbent assay (ELISA) with the VIDAS Immunoassay Kit(bioM_erieux, Durham, North Carolina). For diagnosis ofVZV infection, DNA was extracted from the peripheral whiteblood cells and purified using the DNeasy Blood and TissueKit (Qiagen, Valencia, California). VZV DNA was amplifiedwith primers within ORF62, and the polymerase chain reac-tion products were subjected to pyrosequencing at theUniversity of Iowa’s DNA core facility. To distinguish awild-type VZV strain from the vaccine strain, single nucleo-tide polymorphisms within ORF62 were analyzed with refer-ence to 2 European/North American strains (VZVDumas andVZV 32), as well as the Japanese parental and vaccine strains(pOka and vOka), as described previously.2 Varivax (Merck,West Point, Pennsylvania) is derived from the vOka strain.Sequences taken from the complete VZV genomes shown inthe Figure have been published previously.3,4

Case Report

A 12 year-old boy with stage IIA Hodgkin disease developedvesicular lesions on his trunk and left shoulder (Figure,

ELISA Enzyme-linked immunosorbent assay

IV Intravenous

VZV Varicella zoster virus

day 0). He had been diagnosed with Hodgkin disease 3months before the current episode. As for all new cancerpatients, we obtained a history, which revealed a singlevaricella vaccination at age 1 and confirmed a positiveVZV-IgG antibody titer of >0.90 units (VIDAS Kit;negative, <0.60; equivocal, 0.60-0.90; positive, >0.90),before administering chemotherapy or any blood products.Within 3 months, the patient had completed 4 cycles ofchemotherapy, as well as radiation therapy.The boy’s father, who is the sole caregiver, had contracted

varicella 9 days before the boy’s rash was evident. The fatherhad no history of varicella or vaccination. The father was givena prescription for oral acyclovir after diagnosis. When the fa-ther’s varicella diagnosis was reported to the child’s physician,the child was given a single infusion of intravenous (IV)immunoglobulin (400 mg/kg), owing to the close exposureto a family member (Figure, A). Nevertheless, the childpresented with varicella 4 days later. Considering that VZVis transmissible for 2 days before the onset of rash, theincubation period between father and son was at least 11 days.The patient was admitted and given IV acyclovir (45mg/kg/

day). His lesions quickly crusted and he was discharged onoral acyclovir after completing a 5-day course of IV acyclovir.On day 8, however, he developed new vesicles on histrunk, and subsequently was readmitted and restarted on IVacyclovir (Figure, A). He was discharged with a prescriptionfor oral valacyclovir (1000-mg tablet every 8 hours) for1 month. His symptoms resolved without a recurrence ofvaricella.A VZV-specific polymerase chain reaction amplification

test performed on a peripheral blood sample obtained onday 8 was positive for ORF62 sequences resembling thosefound in wild-type VZV DNA and negative for those foundin vaccine VZV DNA (Figure, B).

conflicts of interest.

0022-3476/$ - see front matter. Copyright ª 2013 The Authors.

All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2013.06.043

*This is an open-access article distributed under the terms of the Creative Commons Attribution-

NonCommercial-No Derivative Works License, which permits non-commercial use, distribution,

and reproduction in any medium, provided the original author and source are credited.

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Figure. A, Clinical and virological data from the patient. B,Molecular diagnosis for VZV infection was performed on day8, because of the unanticipated recurrence of the vesicularexanthem after the first hospitalization. Because of the largenumber of single nucleotide polymorphisms within VZVORF62, a segment of ORF62 was amplified from the VZV-infected white blood cells, and its sequence was comparedwith published sequences of European/North American VZVstrains (Dumas and 32), as well as with the Japanese/AsianOka strains. The patient’s VZV strain (1202) was not a vaccinestrain. IVIG, IV immunoglobulin; PO, oral.

THE JOURNAL OF PEDIATRICS � www.jpeds.com Vol. 163, No. 5

Discussion

Varicella is the disease caused by primary infection withVZV.5 Generally, protective immunity after wild-type vari-cella is life-long, although some exceptions have been pub-lished.6 Protection after varicella vaccination, especially aftera single varicella vaccination, is not life-long.7 Breakthroughvaricella in otherwise healthy vaccine recipients has becomean increasing problem in the early 21st century in the US,and universal vaccination with 2 doses of varicella vaccinewas recommended in 2006.1 This recommendation wasbased on the presumption that breakthrough varicella likelyoccurred in children who had lost serologic evidence of im-munity many years after their single vaccination, althoughprimary vaccine failure is another possibility.8 A large sur-vey of the effectiveness of single-dose vaccination, the Cen-ters for Disease Control and Prevention cited an important

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analysis that controlled for the effects of age of vaccination,age of breakthrough varicella, and year of infection andfound a 2.6-fold greater risk for moderate to severe break-through varicella in children who had received a single vari-cella vaccine >5 years earlier compared with children whohad been vaccinated <5 years before exposure to wild-typevaricella.9 Our case fits into that risk group, and illustratesthe need for a second varicella vaccination, especially as acatch-up vaccination in older children and adolescents toprevent breakthrough varicella.1 Finally, there may havebeen a predisposition to breakthrough varicella in ourcase because of an unrecognized decline in cell-mediatedimmunity secondary to the anticancer therapies5; however,we did not evaluate VZV cell-mediated immunity in thispatient.A previous report described 9 children with leukemia who

contracted a second bout of wild-type varicella despite a pos-itive VZV ELISA titer (using the Diamedix VZV Test Kit;Miami, Florida) at the time of cancer diagnosis.10 Of note,most of these second cases also had household exposures towild-type varicella. The authors proposed the wider use ofprophylactic acyclovir.In summary, our case report suggests that immunocom-

promised children with a multiday household exposure towild-type varicella may need prophylaxis with either a Vari-ZIG injection (Cangene, Winnipeg, Manitoba, Canada) ororal acyclovir if they have had only a single varicella vaccina-tion, regardless of the presence or absence of detectable anti-body by the widely used commercial VZV antibody kits. TheVZV fluorescent antibody to membrane antigen test mayprovide more predictable protective titers than ELISA, butis currently available in only a few research laboratories.8 n

Submitted for publication Apr 10, 2013; last revision received May 31, 2013;

accepted Jun 20, 2013.

Reprint requests: Dr Charles Grose, Children’s Hospital, University Hospital,

200 Hawkins Dr, Iowa City, IA 52242. E-mail: charles-grose@uiowa.edu

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