Copyright C Blackwell Munksgaard 2002American Journal of Transplantation 2002; 2: 880–882

Blackwell Munksgaard ISSN 1600-6135

Case Report

Varicella Infection Following Varicella Vaccination ina Liver Transplant Recipient

Josh Levitsky, Helen S. Te, Thomas W. Faustand Stanley M. Cohen

Center for Liver Diseases, Section of Gastroenterology,

University of Chicago Hospitals, Chicago, IL, USA

*Corresponding author: Stanley M. Cohen,

mcohen@medicine.bsd.uchicago.edu

Varicella infection may result in significant morbidityand mortality in patients who have received an ortho-topic liver transplant (OLT). It is unclear if vaccinatingthese patients against varicella-zoster virus (VZV) in-fection is safe or effective. We report on a liver trans-plant recipient with no prior history of VZV infectionwho was given the varicella vaccine after an indirectVZV exposure. The patient was subsequently hospital-ized twice for treatment of cutaneous varicella infec-tion. We will discuss VZV infection, particularly in re-lation to liver transplantation, and review the prophy-laxis and management of VZV infection after OLT.

Key words: Varicella-Zoster virus, vaccine, orthotopicliver transplant

Received 21 December 2001, revised and accepted forpublication 23 April 2002

Case Report

A 60-year-old Caucasian female underwent an orthotopicliver transplant (OLT) for cryptogenic cirrhosis in September2000 at another institution. Her postoperative course wasuncomplicated with no episodes of infection or rejection. Herimmunosuppressant medications were tapered after OLT andmaintained at the following doses: tacrolimus 6mg twicedaily, sirolimus 10mg daily, and prednisone 10mg daily. Inthe middle of July 2001, her granddaughter was exposed toa friend with chickenpox. At the end of July, the patient andher granddaughter were briefly present in the same room butdid not have direct contact. Because she was concernedabout this encounter and had never had chickenpox as achild, the patient was given the varicella vaccine (VARIVAX,Merck & Co. Inc., Whitehouse Station, NJ) by her internist onAugust 3, 2001. She did not develop any lesions at the siteof injection. A varicella-zoster virus (VZV) IgG titer was notdetermined before vaccination

Three weeks later, she developed small blisters on her abdo-

880

men, shoulders, and back and reported low-grade fevers andfatigue. From August 30 to September 6, she was treated atanother institution with intravenous acyclovir (800mg every8h) for a presumed diagnosis of cutaneous varicella infec-tion. She was discharged with a 5-day course of oral acyclo-vir (five 400mg tablets daily) and had complete resolution ofthe rash by the end of treatment. Two days after completingthe oral acyclovir course, she developed a patchy, pruriticerythematous rash on her legs and abdomen. Clear vesicleseventually erupted in a multidermatomal distribution on theerythematous regions on her legs and abdomen. She wasadmitted to our hospital. Except for low-grade fevers and pru-ritis, she denied other symptoms, including headache,cough, dyspnea, abdominal pain, or any neurologic com-plaints. Her physical examination was only remarkable for thevesicular rash (see Figure 1). Laboratory examination revealeda normal complete blood count, chemistry, and liver function

Figure1: Vesicular, erythematous rash of chicken pox on the leftleg.

Varicella Infection

panel. Trough levels of tacrolimus and sirolimus were 11.6ng/mL and 7.6ng/mL, respectively. A chest radiograph showedno focal infiltrates.

The patient was started immediately on intravenous acyclovir.Both VZV IgM and IgG titers were negative. A direct fluo-rescent antibody test sent from scrapings of the vesicle basewas positive for VZV. The rapid shell vial test was positive forVZV, but the virus was unable to be cultured. After 6days ofintravenous acyclovir therapy (800mg every 8h), over 90%of the vesicular lesions had crusted over and her pruritis re-solved. The tacrolimus dose was decreased to 4mg twicedaily and the sirolimus and prednisone doses were main-tained at the usual doses. She was discharged with a 3-weekcourse of oral acyclovir therapy (five 800mg tablets daily).After 3weeks, she was maintained on acyclovir (two 400mgtablets daily) for prophylaxis. Over the past 5months, she hasremained clinically well and has not developed recurrence ofvesicles or liver function test abnormalities.

Discussion

Varicella-zoster virus, the causative agent of chicken pox orvaricella, is a highly contagious DNA virus that causes ap-proximately 4 million infections, 9000 hospitalizations, and100 deaths in the United States annually (1). It initially infectsthe conjunctivae and/or mucosa of the upper respiratorytract, which later causes a diffuse, pruritic vesicular rash oftenaccompanied by fever and malaise (2). Systemic compli-cations, such as pneumonia, encephalitis, cerebellar ataxia,and hepatitis, are rare. Patients at high risk for these compli-cations include pregnant females in the third trimester, theelderly, patients with HIV/AIDS, and other immunosup-pressed individuals (3).

Liver transplant recipients are among those at high risk ofdeveloping systemic complications from VZV infection be-cause of the degree of immunosuppression. Varicella-zostervirus hepatitis may be seen as early as 3days after OLT andis almost always the result of reactivation of latent VZV ratherthan primary VZV infection. Liver biopsies are characterizedby multiple foci of coagulative necrosis, lobular architecturaldistortion, and characteristic intranuclear inclusion bodies inthe surrounding, normal hepatocytes (4). Early diagnosis andtreatment with intravenous acyclovir are crucial for graft sur-vival and to control disseminated infection.

Since its approval for use in 1995, the varicella vaccine hasbeen found to be very effective in healthy patients, success-fully seroconverting 97% of children after one dose and 99%of adults after two doses (1, 5). The most common adversereactions to the vaccine are injection site reactions, fever, anda generalized maculopapular rash (6). Severe reactions (en-cephalitis, ataxia, and erythema multiforme) are extremelyrare. Given the high morbidity and mortality associated withVZV infection after OLT, the vaccine is an important consider-ation before OLT. The vaccine has been safely administered

881American Journal of Transplantation 2002; 2: 880–882

to children before OLT (7). Although it has not been studiedin adult liver transplant candidates, the vaccine could begiven to adult patients before OLT who are VZV IgG negativeas long as they are clinically stable and will not be trans-planted in the immediate postimmunization period. However,because it is a live attenuated vaccine, the vaccine is contra-indicated by the Center for Disease Control (CDC) in patientswith immunodeficiency, such as liver transplant recipients (1).

If a liver transplant recipient has direct contact with a patientwho has varicella or with a patient who develops varicellawithin 24–48h after the contact occurred, the most appropri-ate first step is to immediately determine VZV IgG titers.Whether or not they have a prior clinical history of varicella,most adults born and raised in the United States have beenexposed to VZV and will likely have positive VZV IgG titers.It is reasonable to wait for the titer results because passiveimmunization with VZIG is still effective when given within72–96h of exposure (8). If the titers are positive, the patientis considered immune and requires no further therapy. Thereis no evidence that VZIG prophylaxis in these patients isbeneficial. If the titers are negative, VZIG prophylaxis is indi-cated. Addition of oral acyclovir prophylaxis in direct exposuresituations is controversial and requires further study beforedefinitive recommendations can be made.

The varicella vaccine was contraindicated in the liver trans-plant patient presented in this case report for a number ofreasons. First, vaccine administration in liver transplant recipi-ents is currently not recommended by the CDC. Second, theindirect nature of the contact was not an indication for anyform of intervention against VZV. Finally, active immunizationwith the varicella vaccine has no role in prophylaxis andshould only be given outside of exposure situations whenindicated.

In this case, the onset of the rash exactly 3weeks after vac-cine administration strongly suggests that the vaccine viruscaused the cutaneous varicella infection. Because of inad-equate T-cell immunity from liver transplantation and im-munosuppression, the vaccine virus likely first replicated atthe site of injection and then proliferated in peripheral bloodlymphocytes. After 3weeks, hematogenous infection led tothe disseminated rash. The rash returned almost immediatelyafter withdrawal of oral acyclovir therapy, likely because ofinsufficient dosing (400mg) and duration (5days) of treat-ment. Higher antiviral doses and longer courses of treatmentare typically required to eliminate the viremic phase and pre-vent further dissemination.

It is also possible that reactivation of latent VZV in the settingof immunosuppression was responsible for the rash. How-ever, VZV reactivation occurring 3weeks after live vaccine ad-ministration would be entirely coincidental and therefore lesslikely to be the cause of this patient’s illness. The only wayto completely distinguish vaccine-induced varicella from VZVreactivation is to compare the genotype of the virus from cul-ture with the genotype of the vaccine virus. Culturing varicella

Levitsky et al.

is often difficult and was unsuccessful in this case. Conse-quently, genotyping could not be performed.

In summary, liver transplant recipients indirectly exposed toVZV require only reassurance and close monitoring, not ac-tive or passive immunization. For direct exposures, patientswho are VZV IgG negative should be given VZIG prophylaxiswithin 96h of initial contact. Although it is advisable to vacci-nate VZV IgG negative liver transplant candidates before OLT,this is contraindicated by the CDC with regards to vaccinatingliver transplant recipients. However, when taking into accountthe potential for severe graft dysfunction associated with VZVin liver transplant recipients, should the CDC reconsider thevaccine for VZV IgG negative liver transplant recipients? Simi-lar to our patient, liver transplant recipients do not seroconvertas successfully as healthy individuals when given vacci-nations and are at higher risk of developing complicationsfrom live vaccination. Perhaps the vaccine could be adminis-tered once immunosuppressive medications have beentapered to low levels, as patients would be more likely toseroconvert and less likely to develop a serious adverse reac-tion. Until further research on vaccine safety and efficacyafter OLT is performed, the varicella vaccine should not beadministered after OLT.

882 American Journal of Transplantation 2002; 2: 880–882

References

1. Center for Disease Control. Website on Varicella-Zoster Virus: http://

www.cdc.gov/ncidod/srp/varicella.htm.

2. LaRussa P. Clinical Manifestations of Varicella. In: Arvin AM, GershonAA. Varicella-Zooster Virus: Virology and Clinical Management. Cam-bridge: Cambridge University Press, 2000: 206–207.

3. McGregor RS, Zitelli BJ, Urbach AH, Malatack JJ, Gartner JC. Varicellain pediatric orthotopic liver transplant recipients. Pediatrics 1989; 83(2): 256–261.

4. Starzl TE, Demetris AJ. Infectious Problems in Liver Transplantation.In:Liver Transplantation: A 31-year Perspective, 1st edn. Chicago: Year-book Medical Publishers, 1990: 104–105.

5. Arvin AM. Varicella vaccine- the first six years. NEJM 2001; 344 (13):1007–1009.

6. White CJ. Varicella-Zoster virus vaccine. Clin Inf Dis 1997; 24: 753–763.

7. Innocenti L, Losurdo G, Palumbo M et al. Varicella vaccine in childrenrequiring renal or hepatic transplantation. Transplantation 1995; 60(9): 1055–1056.

8. Kusne S, Pappo O, Manez R et al. Varicella-Zoster-Virus hepatitis anda suggested management plan for prevention of VZV infection in adultliver transplant recipients. Transplantation 1995; 60 (6): 619–621.