Objectives: Varicella zoster virus (VZV) is an important pathogen after renal transplant. The aim of this study is to assess the outcome of dis­seminated Varicella zoster virus infection in renal transplant recipients and to determine potential risk factors for mortality.

Materials and Methods: From January 2001 to January 2014, we performed 1614 renal transplants at our institution. Varicella zoster virus infection was diagnosed in 41 patients (2.5%). Median time of diagnosis of Varicella zoster virus was 5 years after transplant (range, 3 mo to 13 y).

Results: Thirty-seven patients (90%) had derma­tomal distribution of Varicella zoster virus, 4 patients (10%) had disseminated Varicella zoster virus infection. After diagnosis of Varicella zoster virus immunsuppressive therapy was reduced and patients received acyclovir. Cutaneous lesions were healed with a scar in 7 cases (17%). Two patients (5%) developed postherpetic neuralgia. Seventy percent of cases were diagnosed within 5 years, and 92% were diagnosed within 10 years after transplant. Mortality due to Varicella zoster virus was 2% (n = 1). Visceral involvement found to be a risk factor for mortality. Profilactic acyclovir or gancyclovir therapy following transplantation reduced Varicella zoster virus infection. However, Varicella zoster virus seropositivity did not influence fatal outcome.

Conclusions: Early initiation of antiviral therapy may prevent development of complication and visceral dissemination of disease. Active immunization should be applied for all seronegative patients before organ transplant.

Key words : Varicella zoster virus, Infection, Transplant

Introduction

Varicella-zoster virus (VZV) is a human, double-stranded DNA herpesvirus. Primary infection presents as acute varicella or chicken pox, a usually benign illness in children acquired from direct contact with a skin lesion or exposure by airborne spread from respiratory droplets. After primary infection, VZV establishes latency in dorsal root ganglia, and can reactivate years or decades later as herpes zoster (HZ) or shingles.^1,2 The risk of shingles increases with altered cell-mediated immune responses, which occur naturally as a result of aging or in immunocompromised patients. In solid-organ transplant recipients, the incidence of reactivation is 10- to 100-fold higher than the general population, ranging from 1% to 12%.^3,4 The typical clinical presentation of zoster is a painful, localized, unilateral, vesicular rash involving ≤ 2 adjacent dermatomes.²

The VZV is an important pathogen after renal transplant. The risk of an individual for development of infection after renal transplant is determined by the relation between the epidemiologic exposure of the individual and the state of immunosuppression that determines the individual’s susceptibility to infection.⁵ Infection with VZV causes 2 clinically different forms of disease: (1) primary disease (varicella or chicken pox), characterized by vesicular lesions on the trunk, head, or extremities; and (2) HZ (shingles), characterized by a painful unilateral vesicular eruption that rarely may be disseminated.⁶

The aim of this study was to assess the outcome of disseminated VZV infection in renal transplant recipients and to determine potential risk factors for mortality.

Materials and Methods

Patients
From January 2001 to January 2014, we performed 1614 renal transplants at our institution. The VZV infection was diagnosed in 41 patients (2.5%). Median time of diagnosis of VZV was 5 years after transplant (range, 3 mo to 13 y).

Data collection
The following information was collected: age, sex, date of transplant, cause of nephropathy, induction therapy, immunosuppressive regimen, treated rejection episodes, pretransplant VZV serologic status, presentation of VZV disease (including fever, cutaneous, gastrointestinal, and neurologic symptoms), complications (including hepatitis, pancreatitis, pneumonitis, neurologic problems, and disseminated intravascular coagulation [DIC]), antiviral and immunoglobulin (Ig) treatment, time from transplant to infection, time from onset of symptoms to treatment, and outcome (death or favorable outcome). The pretransplant VZV serologic status was recorded as seropositive, seronegative, or unknown and was based on laboratory testing for VZV immunoglobulin G (IgG). The diagnosis was made on clinical grounds and/or VZV sero­conversion. The study was approved by the Ethics Committee of Medicine of Baskent University.

Immunosuppressive protocols
The immunosuppressive protocols included anti­proliferative drugs, steroids, tacrolimus, and cyclo­sporine. Steroid dosage at transplant was 0.5 mg/kg/d and was tapered to the maintenance dosage of
0.05 mg/kg/d. Induction treatment was used occasionally (18.4% patients). Rejection episodes were treated with steroids (10 mg/kg) that were given in
3 to 5 boluses.

Statistical analyses
We used descriptive statistics. Results were presented as median (percentile 25-percentile 75) or number (%). The 2-tailed t test or Mann-Whitney test was used for comparison between groups, depending on the distribution. Patient survival rates were calculated according to Kaplan-Meier method. Statistical analyses were performed using statistical software (SPSS for Windows, Version 18.0, SPSS Inc., Armonk, NY, USA). All tests were 2-tailed, and P ≤ .05 was considered significant.

Results

There were 37 patients (90%) who had dermatomal distribution of VZV and 4 patients (10%) who had disseminated VZV infection (Figure 1). After diagnosis of VZV, immunosuppressive therapy was reduced and patients received acyclovir. Cutaneous lesions were healed with scar in 7 patients (17%). There were 2 patients (5%) who developed post­herpetic neuralgia. Most (70%) patients were diagnosed within 5 years, and 92% patients were diagnosed within 10 years after transplant. Mortality due to VZV occurred in 1 patient (2%). Visceral involvement was a risk factor for mortality. Varicella-zoster virus prevalence is reported between 1% and 12% in the literature; however our center VZV prevalence was reduced to 1% with ganciclovir and acyclovir therapy after transplant. However, VZV seropositive status did not affect fatal outcome (Table 1).

Serologic information about previous immuni­zation status was available in 30 patients; 5 patients had VZV IgG prior to admission, and 11 patients were not immune to VZV. Symptoms at presentation and visceral complications occurred equally in both groups. There was no difference in mortality between patients with primary varicella and patients with reactivating VZV (not significant).

Discussion

The VZV infection is a rare but potentially serious complication in renal transplant recipients. Lethal outcomes of VZV infection have been reported. Our results demonstrated a low prevalence of VZV infection in renal transplant recipients (3.51%) compared with other studies that reported a prevalence of 3% to 10%.^3,4 Previous studies showed that female sex was a risk factor for developing HZ in liver transplant recipients, but 63% renal transplant patients who developed VZV infection were male.³

The frequency and intensity of VZV infection is associated with the intensity of immunosuppression. Introduction of mycophenolate mofetil to immuno­suppressive protocols improved graft survival.⁷ However, an increased incidence of different viral infections was reported. According to our results, introduction of mycophenolate mofetil to immuno­suppressive protocols resulted in higher incidence and severity of VZV disease.

Early therapy of choice is oral acyclovir and reduction of mycophenolate mofetil dose. We believe that the dosage adjustment and finding an upper limit of the therapeutic range of mycophenolic acid, above which the risk of different viral infections is increased, should be determined for mycophenolate mofetil therapy at least in patients who received increased immunosuppression early after transplant.⁸

There were 70% patients who were exposed to intensive immunosuppressive treatment before VZV infection; they had an induction drug, steroid bolus therapy for treatment of acute rejection, or a high calcineurin inhibitor concentration. This is consistent with previous observations that intensive immuno­suppression is a risk factor for development of VZV infection. There were 4 cases (10%) of disseminated HZ recorded, which is a higher proportion than observed in other studies. A mortality rate of 34% was described in patients with disseminated HZ. We have 1 mortality due to disseminated VZV infection, and this low number was probably due to fast recognition of the infection and initiation of antiviral therapy.

Risk factors for mortality included a longer time between transplant and VZV infection. This may reflect a longer duration of time under immuno­suppression, and possibly a follow-up less rigid than early after transplant. Primary varicella potentially has a fatal outcome in immuno­compromised patients. In cases with VZV reactivation, physicians can be wrongfully reassured by the previous immune status of the patient. Although limited by publication bias, this study emphasizes the possible fatal outcome in patients who have disseminated reactivation, which places these patients at risk of mortality equal to patients who present with acute varicella.

We reported a low rate of postherpetic neuralgia (5%) in our patients but a high rate of cutaneous scarring (17%). Other authors reported postherpetic neuralgia in 42.7% solid-organ recipients.⁹ Active immunization for VZV-seronegative patients before transplant should be performed. High-dose acyclovir therapy and reduction of immunosuppression are primary treatment for VZV infection. Timely initiation of therapy may prevent development of complications and the visceral form of disease. Based on our experience with the development of chicken pox, we suggest active immunization for all seronegative patients before organ transplant.

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