Varicella in Pediatric Liver Transplant Patients: A Retrospective Analysis of Treatment and Outcome

Background: Varicella is a common childhood disease that can cause morbidity and mortality among immunosuppressed patients. There have been few previous studies monitoring the course of pediatric liver transplant patients with acute varicella. The aim of this study was to evaluate the treatment, outcomes, and complications of pediatric liver transplant patients admitted with acute varicella infection.

Cited Here...: A retrospective chart review was carried out based on discharge diagnoses of orthotopic liver transplant and varicella among pediatric patients (age range, birth-18 years) admitted to the UCLA Medical Center between 1985 and 2001.

Cited Here...: Five hundred fifty-six pediatric patients received liver transplantations between 1985 and 2001. Twenty-two of these patients were admitted to the UCLA Medical Center with varicella (11 females, 11 males). No patients were treated on an outpatient basis. Mean age of the patients was 6 years (range, 1-16 years). None of these patients received the varicella vaccine before hospitalization. On admission, 5 of 22 patients (23%) had received varicella zoster immunoglobulin within 96 hours of exposure. The mean length of hospitalization was 6 days (range, 2-11 days). All immunosuppression dosages were reduced during the admissions. None of the patients had been treated with high-dose corticosteroids for acute rejection before the onset of the varicella infection. Patients were treated until defervescence with intravenous acyclovir and until their varicella lesions crusted. Patients were discharged with oral acyclovir to complete a 10-day course (including the intravenous treatment). No patients had complications from the varicella infection. A complication of an elevated serum creatinine for one patient was noted with the intravenous acyclovir treatment. This patient had associated headache and nausea that resolved when the creatinine level returned to normal.

Conclusions: There were no complications or dissemination of varicella infection among our pediatric liver transplant patients. Further prospective randomized trials are required to evaluate the management of pediatric liver transplant patients infected with varicella.

Varicella (chickenpox) continues to be a common childhood disease. The varicella zoster virus is the cause of both varicella as a primary infection and herpes zoster as a reactivation infection usually during adulthood (¹). Varicella zoster viral infections occur throughout the world and occur equally among both sexes. In the absence of immunization, almost all persons acquire varicella over the course of a lifetime; an estimated 4 million cases occur each year in the United States (²). Varicella is highly contagious, with a 90% secondary attack rate in susceptible household contacts (²). Its transmission is via the respiratory tract and the skin, and its incubation period is 10 to 21 days after virus inoculation.

There are no standardized guidelines for treatment of varicella among liver transplant recipients. The first suggestion that acyclovir may be a useful agent in the treatment of established herpes infections in the immunocompromised appeared in 1979 (³). By 1984, intravenous acyclovir was added to the routine management of chickenpox among pediatric renal transplant recipients, coinciding with the addition of cyclosporine to the maintenance immunosuppression regimen (⁴). In 1997, Kashtan et al. (⁴), at the University of Minnesota, reported a standardized method of treatment among their pediatric renal transplant recipients. Since 1984, their method has been to discontinue azathioprine, to continue prednisone (and cyclosporine in those patients receiving it for maintenance immunosuppression), and to administer intravenous acyclovir until fever and new crops of vesicles have ceased and all vesicles are crusted over.

In March of 1995, the United States Food and Drug Administration licensed a live virus varicella vaccine (Varivax; Merck & Co, Inc., West Point, PA) to prevent the infection (⁵). Children 12 months to 12 years of age require one dose; persons more than 12 years of age require two doses separated by 4 to 8 weeks (⁶). The dilemma that this vaccine poses for children who are awaiting or have received a liver transplant, however, is that it contains a live attenuated OKA (Oka, Japan) strain of the varicella zoster virus (⁷). Live vaccines are to be avoided among liver transplant recipients, as recommended by the American Academy of Pediatrics. Ideally, all children who are expected to receive a liver transplant should be given the varicella zoster vaccine, but the onset of illness usually is not predictable. The Liver Transplant Program of the UCLA Medical Center recommends considering administration of the varicella vaccine at 9 months of age (earlier than the recommended age of 12 months), especially if it seems likely that the child already may be listed for transplantation at the time the vaccination is usually given (⁸). In 2000, Kanra et al. (⁹) conducted a study among 114 9-month-old healthy infants to evaluate the safety and immunogenicity of the live attenuated varicella vaccine. Their study showed that the vaccine was safe and immunogenic among this age group, thus supporting the early use of this vaccine when necessary. If the varicella vaccine is given early, checking for an immune antibody response is important and consideration can be given to repeating the dose if the immune level is still negative after the initial vaccination (⁸).

Current recommendations for pediatric liver transplant patients who have been exposed to varicella include the administration of varicella zoster immune globulin within 72 to 96 hours of exposure among those patients with no documented history of varicella pretransplantation or no demonstrable serum antibody, regardless of immunosuppressive dosages (¹⁰). It is also recommended that if clinical varicella develops, intravenous acyclovir at doses of 500 mg per meter square per dose every 8 hours should be started within 24 hours of eruption of the skin rash and should be continued for 7 to 10 days (¹¹). No large studies have been carried out to offer alternative approaches to the management of varicella among pediatric liver transplant patients. The purpose of this study was to present the results of our experience in treating these patients among the largest population of pediatric liver transplant recipients in the United States.

METHODS

We reviewed the charts of all children between the ages of birth and 18 years discharged with the diagnoses of orthotopic liver transplant and varicella from UCLA Medical Center (including Mattel Children's Hospital at UCLA Medical Center, established in 1998). This review included 22 charts from 1985 through 2001.

RESULTS

Between 1985 and 2001, 556 pediatric patients received liver transplantations. During that time, 22 patients were diagnosed with varicella and subsequently were admitted. No patients were treated on an outpatient basis. There was an equal number of male and female patients: 11 females and 11 males. The mean age was 6 years, with a range of 1 to 16 years. The mean length of hospitalization was 6 days, with a range of 2 to 11 days. None of these patients had received the varicella zoster vaccine before their liver transplantation.

Five of the 22 patients (23%) had received varicella zoster immunoglobulin within 96 hours of an exposure. Table 1 summarizes the prehospitalization immunosuppression regimens. Eight of 22 patients were treated with cyclosporine (average dose, 8 mg/kg daily) and low-dose prednisone (range, 0.05-0.3 mg/kg daily); 7 of 22 patients were treated with tacrolimus (average dose, 0.07 mg/kg daily) and-low dose prednisone; 5 of 22 patients were treated with cyclosporine (average dose, 7.2 mg/kg daily), azathioprine (average dose 0.7 mg/kg daily), and low-dose prednisone; and 2 of the patients were treated with tacrolimus (average dose, 0.04 mg/kg daily), mycophenolate mofetil (average dose, 20 mg/kg daily), and low-dose prednisone. During hospitalization for all of the patients, prednisone was held and cyclosporine and tacrolimus dosages were decreased by 25% to 50%. Azathioprine and mycophenolate mofetil were also held for those patients who received these medications as part of their maintenance immunosuppression. None of the patients had been treated with high-dose corticosteroids for acute rejection before the onset of the varicella infection.

Table 1

All of these patients were treated with intravenous acyclovir (recommended dosage) until they defervesced and their varicella lesions crusted. None of these patients received antibiotics as part of their treatment. On discharge from the hospital, the intravenous acyclovir was discontinued and the patients were started on oral acyclovir. For patients weighing fewer than 40 kg, 20 mg/kg four times daily of oral acyclovir was prescribed. For those patients weighing more than 40 kg, 800 mg four times daily was prescribed. A 10-day course of acyclovir (intravenous plus oral) was completed. All immunosuppressive medications were then restarted at their preadmission dosages.

Complications from the acyclovir treatment included one patient in whom an elevated serum creatinine of 1.7 mg/dL developed (normal for patient was 0.3 mg/dL), with nausea and a headache. The intravenous acyclovir was held for 18 hours while the patient continued to receive intravenous hydration. A normalization of the serum creatinine was noted at 0.7 mg/dL, and the patient's nausea and headache resolved. The intravenous acyclovir was then restarted at a lower dose, and the patient's serum creatinine level returned to the baseline of 0.3 mg/dL.

There were no complications from the varicella zoster infections among our patients. There was a 0% frequency of disseminated varicella zoster infection noted from 1985 through 2001.

DISCUSSION

Immunosuppressed patients, such as those who have received orthotopic liver transplants and who have not been immunized with the varicella vaccine, are at risk of complications associated with the varicella zoster virus. The most common complication of varicella is acute bacterial skin infections, most commonly caused by Staphylococcus aureus or Streptococcus pyogenes (group A beta-hemolytic streptococci) (²). Life-threatening complications that have been reported from disseminated disease include pneumonitis, encephalitis, and hepatitis (^11-15).

All of the patients included in our study had their immunosuppression dosages decreased, and they had all been receiving low-dose maintenance prednisone. None of our patients had been treated with high-dose corticosteroids for acute rejection before the onset of the varicella infection. This suggests that pediatric liver transplant patients who are on lower doses of maintenance immunosuppression may have a lower risk of experiencing complications from the varicella virus.

Currently, one method of treatment for varicella among liver transplant patients is used: hospitalization and intravenous acyclovir until the patient has defervesced and the varicella lesions have crusted. Immunosuppression dosages are altered variably. No alternative treatment methods have been reported or suggested. Acyclovir, an acyclic purine nucleoside analog, is a highly potent inhibitor of varicella zoster viruses and herpes simplex and has very low toxicity for the normal host cells (¹⁶). However, renal insufficiency occasionally has been associated with intravenous acyclovir use. Other side effects include headache, lightheadedness, skin rash, and abdominal pain with vomiting and diarrhea. Bone marrow suppression also can be seen. Changes in renal tubular function previously have been described during acyclovir therapy and may be especially frequent in patients who are inadequately hydrated (^17-19). The concomitant administration of potentially nephrotoxic medications such as tacrolimus and cyclosporine may have a synergistic effect on renal function. Pediatric liver transplant patients often have underlying renal disease or damage, making them more susceptible to the renal insufficiency seen with acyclovir.

Further investigation with the use of prospective randomized trials is required to evaluate the management of pediatric liver transplant patients infected with the varicella zoster virus.