- Email: [email protected]
Incidence and Clinical Characteristics of Herpes Zoster After Lung Transplantation
Incidence and Clinical Characteristics of Herpes Zoster After Lung Transplantation Oriol Manuel, MD,a Deepali Kumar, MD,a Lianne G. Singer, MD,b Isabel Cobos, RN,a and Atul Humar, MDa Background: Solid-organ transplant recipients are at high risk for the development of herpes zoster. Epidemiologic data in lung transplant recipients are lacking. We determined the incidence and clinical characteristics of herpes zoster, and the risk factors for developing herpes zoster, after lung transplantation. Methods: We retrospectively reviewed all adult (⬎18 years old) lung transplants performed at our institution between January 2001 and December 2005. Clinical characteristics of herpes zoster and potential risk factors associated with herpes zoster were assessed. Results: Two hundred thirty-nine lung transplant recipients were included in the analysis. Median time of follow-up was 722 days (range 18 to 1,943 days). Thirty-five episodes of herpes zoster occurred in 29 patients, with a calculated incidence of 55.1 cases per 1,000 person-years of follow-up. The cumulative probability of herpes zoster was 5.8% at 1 year, 18.1% at 3 years and 20.2% at 5 years post-transplant. Only 2 of the 35 (5.7%) patients had disseminated cutaneous infection and none had visceral involvement. Recurrence of herpes zoster was seen in 13.8% of patients. Post-herpetic neuralgia was detected in 20% of cases. Anti-viral prophylaxis, primarily for cytomegalovirus (CMV), was protective against herpes zoster. No significant epidemiologic risk factors associated with herpes zoster could be identified. Conclusions: Herpes zoster is a common complication after lung transplantation with a peak incidence at between 1 and 4 years post-transplant. Preventive strategies would be beneficial for this population. J Heart Lung Transplant 2008;27:11– 6. Copyright © 2008 by the International Society for Heart and Lung Transplantation.
Varicella zoster virus (VZV) belongs to the herpesvirus family and evidence of past infection is almost universal in adults in Europe and North America. Most cases of primary VZV infection (i.e., chickenpox) occur during childhood. Re-activation of VZV results in herpes zoster (HZ) and is characterized by the onset of painful vesicles usually following a dermatomal distribution.1,2 The incidence of re-activation is increased in the elderly and in those with cellular immunosuppression, especially in patients with human immunodeficiency virus (HIV) infection or malignancy and in organ transplant
From the aDepartment of Transplant Infectious Diseases, University of Alberta, Edmonton, Alberta, and the bToronto Lung Transplant Program, University of Toronto, Toronto, Ontario, Canada. Submitted March 2, 2007; revised July 17, 2007; accepted September 24, 2007. Supported by the Transplantation Society-Roche Research Fellowship in Transplant Infectious Disease (to O.M.). Reprint requests: Oriol Manuel, MD, Provincial Laboratory for Public Health, Microbiology, 8440 112th Street, WMC 2B4.57, Edmonton, AB T6G 2J2, Canada. Telephone: 780-407-1643. Fax: 780-4071601. E-mail: [email protected] Copyright © 2008 by the International Society for Heart and Lung Transplantation. 1053-2498/08/$–see front matter. doi:10.1016/ j.healun.2007.09.028
recipients.1 Immediate complications of VZV re-activation, especially in immunosuppressed patients, include disseminated cutaneous disease and visceral involvement (e.g., pneumonitis and hepatitis). In addition, post-herpetic neuralgia may be a significant cause of morbidity.3 There are limited epidemiologic data regarding the incidence and clinical consequences of HZ after organ transplantation. The rate of HZ in solid-organ transplant recipients has been estimated at between 3% and 25%.4 The reported incidence varies depending on the organ transplanted, the type of immunosuppression, and the type of anti-viral prophylaxis. Risk factors associated with an increased risk of HZ include the use of induction therapy as well as the use of anti-viral agents other than prolonged cytomegalovirus (CMV) prophylaxis.5 Significantly less is known about HZ in lung transplant recipients. A recent study has shown an incidence of 1.7% of HZ that required hospitalization after lung or heart-lung transplantation.6 Because lung transplant recipients are generally on high doses of continuous immunosuppression and appear to have a high incidence of other herpesvirus infections, such as CMV and Epstein-Barr virus (EBV)-related post-transplant lymphoproliferative disorder, it is possible that VZV may be more problematic in these patients.7 11
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The primary aim of the study was to characterize the incidence and clinical manifestations of HZ in a large cohort of lung transplant recipients, and to identify risk factors associated with the development of HZ in this population. METHODS Patients We retrospectively reviewed all adult (ⱖ18 years old) lung transplants performed at our institution between January 2001 and December 2005. Patients with multiple-organ transplantation, and patients with a follow-up of ⬍14 days, due to early death, were excluded from the analysis. Study follow-up finished on September 30, 2006. The study was approved by the local institutional review board. Data were extracted from the Organ Transplant Tracking Record database. Localized HZ was defined as a characteristic vesicular eruption following a dermatome, with or without microbiologic confirmation. Cutaneous dissemination was defined as a characteristic vesicular eruption in two or more non-contiguous dermatomes. Visceral involvement was defined as compatible clinical signs and symptoms with biopsy confirmation of tissue invasion. Post-herpetic neuralgia was defined by pain in the area of eruption persisting for ⬎30 days after the onset of the rash. Data regarding the onset of HZ, localization, anti-viral treatment, need for hospitalization and post-herpetic neuralgia were collected for each episode of HZ. The following characteristics were also collected for all patients: age; gender; date of transplant; underlying disease; pre-transplant VZV serostatus; CMV serostatus; EBV serostatus; induction and maintenance immunosuppressive regimen; diagnosis of diabetes mellitus prior to transplant; need for dialysis or extracorporeal membrane oxygenation (ECMO) just after transplant; acute rejection; CMV infection or disease; all anti-viral therapy; bronchiolitis obliterans syndrome (BOS) and invasive fungal infection; date of death; and cause of death. The definition of infectious diseases, including CMV infection and disease, appearing after transplantation followed the published American Society of Transplantation recommendations for screening, monitoring and reporting of infectious complications in immunosuppression trials in recipients of organ transplantation.8 Acute rejection was diagnosed on the basis of a transbronchial biopsy that demonstrated characteristic perivascular lymphocytic infiltrates using criteria defined by the International Society for Heart and Lung Transplantation (ISHLT).9 For patients in whom a biopsy could not be performed, a clinical diagnosis of rejection was allowed. A clinical diagnosis for BOS was
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made using the ISHLT algorithm based on forced expiratory volume in 1 second (FEV1).10 BOS Grade ⱖ2 was considered as a positive end-point. Immunosuppressive Regimen During the entire study period, the baseline immunosuppressive protocols were essentially uniform and consisted of cyclosporine, prednisone and azathioprine. Basiliximab induction (20 mg intravenously [IV], given at Day 0 and Day 4) was used as a calcineurin inhibitor (CNI)-sparing agent to allow for delayed CNI introduction for patients with cardiopulmonary complications in the operating room or for patients with renal dysfunction. During the study period, some patients also participated in a randomized, placebo-controlled trial of basiliximab for induction. Cyclosporine-targeted trough levels were 250 to 350 mg/liter for the first 3 months, and 200 to 250 mg/liter at the end of the first year. Azathioprine was used at a dose of 1.5 to 2.0 mg/kg/day (except in patients with cystic fibrosis colonized by Burkholderia cepacia, in whom the dose was 1.0 mg/kg/day). Azathioprine was replaced by mycophenolate mofetil (MMF), and cyclosporine for tacrolimus, in cases of intolerance, contraindication or recurrent or refractory acute rejection. Methylprednisolone 500 mg IV was used for the first 3 days, which was then replaced by prednisone 0.5 mg/kg/day, tapered by 5 mg/week until reaching 0.25 mg/kg/day, and then tapered more slowly over the first 1 to 2 years to a dose of 0.15 mg/kg every second day. Anti-viral Prophylaxis A relatively uniform anti-viral strategy was in place during the study period, primarily aimed at preventing CMV. In CMV donor (D) seropositive/recipient (R) seronegative (D⫹/R⫺) patients, CMV prophylaxis consisted of 2 weeks of ganciclovir (5 mg/kg IV twice daily), followed by 12 weeks of ganciclovir (5 mg/kg IV once daily) or valganciclovir 900 mg/day. In R⫹ patients, ganciclovir (5 mg/kg IV twice daily) was given for 14 days after transplantation, followed by ganciclovir (1 g orally three times per week) or valganciclovir (900 mg once daily) for 12 additional weeks. In D⫺/R⫺ patients, 3 months of acyclovir (400 mg orally three times daily) was used for herpes prophylaxis. Statistical Analysis Categorical variables were compared using a chi-square or a Fisher’s exact test. Continuous variables were compared using the Mann-Whitney U-test. Incidence of HZ was calculated using the Kaplan-Meier method. All analyses were performed using SPSS software (SPSS 15.0, Chicago, IL) and p ⬍ 0.05 was considered statistically significant.
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RESULTS Characteristics of Study Population A total of 265 lung transplants were performed during the study period. Fifteen patients were excluded due to survival of ⬍14 days. Ten patients received a heart and lung transplant and one patient received a lung and liver transplant, and therefore these patients were excluded. Thus, 239 lung transplant recipients were included in the study. Baseline characteristics are shown in Table 1. Median follow-up was 722 days (range 18 to 1,943 days). No patient was lost to follow-up for any reason other than death. Based on donor and recipient CMV serostatus, 185 patients (77.4%) received ganciclovir- or valganciclovir-based anti-viral prophylaxis for the first 3 months post-transplant. The remaining 54 patients (22.6%) received oral acyclovir for the first 3 months post-transplant. An additional 19 patients had their duration of anti-viral prophylaxis extended to between 6 months and 1 year post-transplant because they were EBV D⫹/R⫺. Pretransplant VZV serology was available for 184 patients, of whom 10 were seronegative. Mean age for these VZV seronegative patients was 35 years. VZV vaccination with live-attenuated varicella vaccine (Varivax) was provided for 5 of these patients pre-transplant. Immunosuppression use was relatively uniform (see Table 1). Incidence of Herpes Zoster There were 35 episodes of HZ occurring in 29 patients during the study period (Table 2). All cases of HZ, except 1, were diagnosed solely on clinical grounds. The crude incidence of HZ was 29 of 239 (12.1%). The cumulative incidence of HZ (censoring for early deaths) was 5.8% at 1 year, 18.1% at 3 years and 20.2% at 5 years (Figure 1). The calculated incidence per 1,000 personyears of follow-up was 55.1 cases. Mean time to first episode of HZ from transplantation was 486 ⫾ 285 days. Twelve of 29 (41.4%) cases occurred in the first year post-transplant and 16 (55.1%) occurred between 1 and 3 years post-transplant. There were no cases of HZ while patients received either ganciclovir, valganciclovir or acyclovir prophylaxis. The earliest onset of HZ was observed approximately 1 month after discontinuation of anti-viral prophylaxis (123 days after transplant).
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Table 1. Patients’ Baseline Clinical Characteristics (n ⫽ 239) Characteristic Age (years; mean ⫾ SD) Gender (M/F) Type of transplant (single/double lung) Underlying disease Pulmonary fibrosis Cystic fibrosis Emphysema ␣1-anti-trypsin deficiency Sarcoidosis Primary pulmonary hypertension Other Re-transplant Diabetes mellitus pre-transplant Induction immunosuppression None Basiliximab/daclizumab Baseline immunosuppression Cyclosporine/azathioprine/prednisone Cyclosporine/MMF/prednisone Tacrolimus/azathioprine/prednisone Tacrolimus/MMF/prednisone Other Immunosuppression at last follow-up Cyclosporine/azathioprine/prednisone Cyclosporine/MMF/prednisone Tacrolimus/azathioprine/prednisone Tacrolimus/MMF/prednisone Other VZV serology Negative Positive Unknown CMV serostatus D⫺/R⫺ D⫺/R⫹ D⫹/R⫹ D⫹/R⫺ CMV infection CMV disease Rejection episodes 0 1 2 ⱖ3 Anti-thymocyte globulin for rejection Death at last follow-up
N (%) 48.3 ⫾ 14.1 136/103 16/223 61 (25%) 55 (23%) 49 (20%) 16 (7%) 10 (4%) 6 (3%) 42 (18%) 7 (3%) 57 (24%) 151 (63%) 88 (37%) 204 (85%) 13 (5%) 11 (4%) 5 (2%) 6 (3%) 67 (28%) 23 (10%) 56 (23%) 55 (23%) 38 (16%) 10 (4%) 174 (73%) 55 (23%) 54 (23%) 73 (30%) 69 (29%) 43 (18%) 86 (36%) 37 (15%) 98 (41%) 69 (29%) 44 (18%) 28 (12%) 21 (9%) 82 (34%)
VZV, varicella zoster virus; MMF, mycophenolate mofetil; CMV, cytomegalovirus.
Clinical Characteristics of Herpes Zoster The clinical characteristics of HZ infection are shown in Table 2. The initial episode of HZ was confined to at least one contiguous dermatome in 28 of 29 (96.6%) cases. Including recurrent episodes, only 2 of 35 (5.7%) cases involved disseminated cutaneous HZ. The first patient was a 32-year-old man who was VZV seronegative before transplant. Despite pre-transplant vaccination, he presented with a generalized vesicular rash 33
months after transplant, without visceral involvement. The second patient was a 47-year-old woman, with unknown pre-transplant VZV serology, who developed disseminated cutaneous zoster involving the upper and lower extremities and torso. The patient had two previous episodes of thoracic zoster. No visceral involvement occurred. Facial zoster was the initial presentation in 3 of 29 (10.3%) patients, but none had
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Table 2. Clinical Characteristics of 29 Patients With Herpes Zoster Characteristic Total number of episodes Time after transplant (to first episode), days (mean ⫾ SD) Immunosuppression at time of first episode Cyclosporine/azathioprine/prednisone Tacrolimus/azathioprine/prednisone Cyclosporine/MMF/prednisone Tacrolimus/MMF/prednisone Other Number of episodes per patient 1 2 3 Localization Facial Thoracic Lumbosacral Disseminated Initial anti-viral treatment None IV acyclovir PO acyclovir Famciclovir Valacyclovir Duration of anti-viral therapy, days (mean ⫾ SD) Post-herpetic neuralgia Post-herpetic neuralgia duration, months (median, range) Admission to hospital
N (%) 35 486 ⫾ 285 9/29 (31%) 6/29 (20.7%) 5/29 (17.2%) 4/29 (13.8%) 5/29 (17.2%) 25 2 2 5/35 (14.2%) 6/35 (17.1%) 22/35 (62.8%) 2/35 (5.7%) 2/35 (5.7%) 2/35 (5.7%) 6/35 (17.1%) 19/35 (54.3%) 6/35 (17.1%) 15.3 ⫾ 15.4 7/35 (20%) 4 (1–9) 5 (17.2%)
ocular involvement. After the initial episode of HZ, recurrence was noted in 4 of 29 patients (13.8%), occurring at a mean of 613 days (range 167 to 1,629) after the first episode. Post-herpetic neuralgia was recorded in 7 of 35 (20%) of the episodes. In terms of anti-viral therapy, oral therapy was used to treat the majority of episodes (Table 2). Famciclovir was the most commonly used drug (54.3%). Two patients did not receive any anti-viral therapy because lesions had spontaneously crusted at the time of initial clinical assessment. Two patients with disseminated disease received initial intravenous therapy with acyclovir and were switched to oral therapy after 4 days in both cases. Five patients (17.2%) required hospital admission for a mean of 4 days (range 2 to 7 days). Incidence of Other Infections Twenty-two patients had an invasive fungal infection during the study period: 3 of 29 (10.3%) in patients with HZ, and 19 of 210 (9.0%) in patients without HZ (p ⫽ 0.82). Median time from transplantation was 303 days (range 15 to 1,461). Aspergillus fumigatus was the most common pathogen isolated (n ⫽ 15), followed by
Aspergillus sp. (n ⫽ 4). In all 3 patients with HZ, fungal infection preceded the development of HZ. CMV infection (including symptomatic disease and asymptomatic viremia) was diagnosed in 86 patients: 10 of 29 (34.5%) in patients with HZ, and 76 of 210 (36.2%) in patients without HZ (p ⫽ 0.86). Thirty-seven of the 86 patients (43.0%) had CMV disease. Median time from transplantation was 171 days (range 43 to 1,326). In patients with CMV and HZ, CMV preceded HZ, with no cases of concomitant viral infection. None of the patients with HZ had significant neutropenia (absolute neutrophil count ⬍1,000 cells/l) at the time of symptom onset. Risk Factors for HZ Infection Risk factors were assessed for their association with HZ and are shown in Table 3. No factor was found to be significantly associated with an increased risk of HZ. Specifically, HZ was not associated with any particular immunosuppression regimen. For example, the use of MMF instead of azathioprine or the use of tacrolimus instead of cyclosporine were not risk factors for HZ. Induction antibody therapy with basiliximab did not increase the risk of HZ. The use of either pulse steroids or rabbit anti-thymocyte globulin (RATG) for the treatment of acute rejection was not associated with HZ. In fact, there was a trend toward a lower incidence of HZ in patients who had received RATG for treatment of acute rejection (0 of 21 [0%] for those with RATG treatment compared with 29 of 218 [13.3%] for those without RATG treatment, p ⫽ 0.09). This likely reflects the standard use of anti-viral prophylaxis in patients receiving RATG therapy for acute rejection. Overall, the use of anti-viral prophylaxis (primarily for CMV) was very protective against HZ during anti-viral therapy. The
Figure 1. Cumulative probability of herpes zoster after lung transplantation. The number of patients still followed at 1 year, 3 years and 5 years was 179, 53 and 7, respectively. The cumulative incidence of herpes zoster after lung transplantation was 5.8% at 1 year, 18.1% at 3 years and 20.2% at 5 years.
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Table 3. Risk Factors for Herpes Zostera
Characteristic Gender (M/F) Age ⬎50 years Age, years (mean ⫾ SD) Cystic fibrosis VZV seronegativeb Use of MMF Use of tacrolimus Use of basiliximab/daclizumab Pre-transplant diabetes mellitus Acute rejection Use of anti-thymocyte globulin for acute rejection Acyclovir prophylaxis (CMV D⫺/R⫺) CMV infection CMV disease
Patients with Patients without zoster zoster (n ⫽ 210) (n ⫽ 29) 16/13 120/90 19 (65.5%) 108 (51.4%) 51.2 ⫾ 12.7 47.9 ⫾ 14.3 4 (13.8%) 51 (24.3%) 2/21 (9.5%) 8/163 (4.9%) 11 (37.9%) 74 (35.2%) 16 (55.1%) 109 (51.9%) 11 (37.9%) 77 (36.7%) 10 (34.5%) 47 (22.3%) 19 (65.5%) 122 (58.0%) 0 (0%) 6 (20.7%) 10 (34.5%) 4 (13.8%)
21 (10%) 48 (22.8%) 76 (36.2%) 33 (15.7%)
VZV, varicella zoster virus; MMF, mycophenolate mofetil; CMV, cytomegalovirus. a There were no significant differences between groups. b In 55 patients pre-transplant VZV serology was unknown.
calculated incidence was 0 case per 22,489 patient-days (0 case per 1,000 patient-years) while on prophylaxis vs 29 cases per 169,543 patient-days (62.3 cases per 1,000 patient-years) while not on prophylaxis (p ⬍ 0.001). DISCUSSION This is the largest study evaluating Varicella zoster virus infections in lung transplant recipients. We identified 35 cases of HZ in 29 of 239 lung transplant recipients (crude incidence 12.1%). In lung transplant recipients surviving to 3 years the incidence is 18.1%, and by 5 years the incidence is 20.2%, making this a very common complication after lung transplantation. Compared with epidemiologic studies in the general population our data suggest that the incidence of HZ in lung transplant patients is approximately 30 times higher than in the general population,11 and 5 times higher than in those ⬎60 years of age.12 In our study most cases of HZ were of mild to moderate severity, with only 2 cases of disseminated disease. In addition, most patients were successfully treated with oral therapy as outpatients. No cases were complicated by visceral involvement. Recurrence was noted in a subset of patients (recurrence rate 13.8%). There is limited published literature on the epidemiology of HZ in lung transplant recipients. Gourishankar et al analyzed HZ incidence in 869 solid-organ transplant recipients, the majority of whom had liver and kidney transplants.5 The incidence of HZ in that study was 8.6% and induction antibody therapy was noted as a risk factor. Their study included 53 lung transplant recipients, of whom 8 developed HZ (incidence 15.1%). In contrast to our results, a recent study involving lung
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and heart-lung transplant recipients showed a 1.7% incidence of HZ, with a high rate of disseminated disease and mortality.6 Our contrasting results can be explained by the fact that Carby et al6 included only hospitalized patients with microbiologically confirmed HZ (either by serology or molecular testing). The majority of patients in our cohort were diagnosed and treated as outpatients. Two recent studies in liver transplant recipients reported HZ incidence rates of 12% and 1.2%, respectively.13,14 Morbidity due to post-herpetic neuralgia may be higher in organ transplant recipients compared with the general population. Rates of post-herpetic neuralgia reported in the previously noted studies in transplant recipients varied between 30% and 40%.5,13 We found an incidence of post-herpetic neuralgia of 20%. However, we cannot exclude the possibility that the incidence might be underreported, due to the retrospective nature of our study. In the general population, the incidence of post-herpetic neuralgia varies between 1.8% and 17% and is dependent on the age of the patient and whether anti-viral therapy was given or not.15,16 Previous studies in adult transplant recipients also have shown low rates of disseminated VZV infection, and a lack of VZV infection-related deaths.5,13,14 In pediatric transplantation, VZV infection has been historically associated with severe disease and a high mortality rate.17,18 However, recent studies have shown a low incidence of visceral involvement with VZV infection after pediatric organ transplantation (0% to 8.6%).19,20 We identified no specific risk factors associated with HZ. In particular, the use of MMF was not associated with a higher incidence of HZ. In a large, randomized trial with 650 heart transplant recipients, there was a trend toward a higher incidence of HZ in patients receiving MMF compared with those receiving azathioprine (14.5% vs 9.5%, respectively; p ⫽ NS).21 In addition, some studies in adult and pediatric renal transplant recipients have suggested that MMF may be a risk factor for disseminated VZV infection.22,23 However, this observation was not confirmed in other series.24 In the study by Gourishankar et al, MMF was associated with HZ in liver recipients, but not in lung transplant recipients. The use of anti-lymphocyte induction therapy has been identified previously as a risk factor for HZ. Because none of the patients in our study received anti-lymphocyte induction we could not assess this possibility. However, RATG, when used for treatment of acute rejection, was not associated with subsequent HZ, likely due to the use of anti-viral prophylaxis. In fact, we observed that anti-viral prophylaxis, primarily for CMV, was very effective in preventing HZ while patients were on therapy. Due to the high incidence of HZ after organ transplantation, preventive strategies should be further eval-
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uated. Current recommendations suggest pre-transplant serology and vaccination of VZV-seronegative patients with the live attenuated Oka strain vaccine.25 However, despite vaccination in five seronegative patients, we still observed two cases of VZV infection post-transplant in these patients: one case of thoracic zoster 4 months after transplant, and one case of disseminated VZV infection 33 months after transplant. Potential approaches to prevention in seropositive patients include pre-transplant vaccination with the live attenuated zoster vaccine (Zostavax). In a large, randomized trial in adults ⬎60 of age, the zoster vaccine showed a reduction of 51% and 66% in the incidence of HZ and post-herpetic neuralgia, respectively.10 A heat-inactivated vaccine has been evaluated in autologous hematopoietic stem cell recipients.26 The vaccine was given 30 days before transplant and 30, 60 and 90 days after transplant and demonstrated a significant reduction in the incidence of HZ, from 33% to 13% at 12 months. Our study had several limitations. First, it was a retrospective study. Therefore, although the quality of the information collected in the database was generally good and constant during the study period, data on duration of post-herpetic neuralgia may occasionally have been incomplete. It is also possible that some cases of HZ were missed because of underreporting. Therefore, this is a conservative estimate and the actual incidence of HZ in lung transplant recipients may be greater. However, at our institute it is common practice for lung transplant recipients to continue lifelong follow-up with us from the time of their transplant. Finally, because the majority of cases were diagnosed without microbiologic confirmation, a misdiagnosis with herpes simplex virus infection cannot be excluded. In summary, HZ is a common complication in lung transplant recipients, and its onset may occur years after transplantation. Although the majority of cases were managed on an outpatient basis, and no mortality was attributable to HZ, post-herpetic neuralgia is a prominent complication in this population. No risk factors for developing HZ were clearly identified. REFERENCES 1. Gnann JW Jr, Whitley RJ. Herpes zoster. N Engl J Med 2002;347: 340 – 6. 2. Dworkin RH, Johnson RW, Breuer J, et al. Recommendations for the management of herpes zoster. Clin Infect Dis 2007;44(suppl 1):S1–26. 3. Kost RG, Strauss SE. Postherpetic neuralgia—pathogenesis, treatment, and prevention. N Engl J Med 1996;335:32– 42. 4. Gnann JW. Herpes simplex and varicella-zoster virus infection after hemopoietic stem cell or solid organ transplantation. In: Transplant infections, 2nd ed. Lippincott-Raven; 2003:350 – 66. 5. Gourishankar S, McDermid JC, Jhangri GS, Preiksaitis JK. Herpes zoster infection following solid organ transplantation: incidence, risk factors and outcomes in the current immunosuppressive era. Am J Transplant 2004;4:108 –15.
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6. Carby M, Jones A, Burke M, Hall A, Banner N. Varicella infection after heart and lung transplantation: a single-center experience. J Heart Lung Transplant 2007;26:399 – 402. 7. Zamora MR. Cytomegalovirus and lung transplantation. Am J Transplant 2004;4:1219 –26. 8. Humar A, Michaels M. American Society of Transplantation recommendations for screening, monitoring and reporting of infectious complications in immunosuppression trials in recipients of organ transplantation. Am J Transplant 2006;6: 262–74. 9. Yousem SA, Berry GJ, Cagle PT, et al. Revision of the 1990 working formulation for the classification of pulmonary allograft rejection: lung rejection study group. J Heart Lung Transplant 1996;15:1–15. 10. Cooper JD, Billingham M, Egan T, et al. A working formulation for the standardization of nomenclature and for clinical staging of chronic dysfunction in lung allografts. J Heart Lung Transplant 1993;12:713– 6. 11. Donahue JG, Choo PW, Manson J, Platt R. The incidence of herpes zoster. Arch Intern Med 1995;155:1605–9. 12. Oxman MN, Levin MJ, Johnson GR, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 2005;352:2271– 84. 13. Herrero JI, Quiroga J, Sangro B, et al. Herpes zoster after liver transplantation: incidence, risk factors, and complications. Liver Transplant 2004;10:1140 –3. 14. Levitsky J, Kalil A, Meza JL, Hurst GE, Freifeld A. Herpes zoster infection after liver transplantation: a case– control study. Liver Transplant 2005;11:320 –5. 15. Helgason S, Petursson G, Gudmundsson S, Sigurdsson JA. Prevalence of postherpetic neuralgia after a first episode of herpes zoster: prospective study with long term follow up. BMJ 2000; 321:794 – 6. 16. Jung BF, Johnson RW, Griffin DRJ, Dworkin RH. Risk factors for postherpetic neuralgia in patients with herpes zoster. Neurology 2004;62:1545–51. 17. Lynfield R, Herrin JT, Rubin RH. Varicella in pediatric renal transplant recipients. Pediatrics 1992;90:216 –20. 18. Feldhoff CM, Balfour HH Jr, Simmons RL, et al. Varicella in children with renal transplants. J Pediatr 1981;98:25–31. 19. Pandya A, Wasfy S, Hebert D, Allen UD. Varicella-zoster infection in pediatric solid-organ transplant recipients: a hospital-based study in the prevaricella vaccine era. Pediatr Transplant 2001;5: 153–9. 20. Levitsky J, Kalil AC, Meza JL, et al. Chicken pox after pediatric liver transplantation. Liver Transplant 2005;11:1563– 6. 21. Eisen H, Kobashigawa J, Keogh A, et al. Three-year results of a randomized, double-blind, controlled trial of mycophenolate mofetil versus azathioprine in cardiac transplant recipients. J Heart Lung Transplant 2005;24:517–25. 22. Lauzurica R, Bayes B, Frias C, et al. Disseminated varicella infection in adult renal allograft recipients: role of mycophenolate mofetil. Transplant Proc 2003;35:1758 –9. 23. Rothwell WS, Gloor JM, Morgenstern BZ, Milliner DS. Disseminated varicella infection in pediatric renal transplant recipients treated with mycophenolate mofetil. Transplantation 1999;68: 158 – 61. 24. Fehr T, Bossart W, Wahl C, Binswanger U. Disseminated varicella infection in adult renal allograft recipients: four cases and a review of the literature. Transplantation 2002;73:608 –11. 25. Herpes simplex virus (HSV)-1 and -2, and varicella zoster virus (VZV). Am J Transplant 2004;4(suppl 10):69 –71. 26. Hata A, Asanuma H, Rinki M, et al. Use of an inactivated varicella vaccine in recipients of hematopoietic-cell transplants. N Engl J Med 2002;347:26 –34.
Varicella zoster virus (VZV) belongs to the herpesvirus family and evidence of past infection is almost universal in adults in Europe and North America. Most cases of primary VZV infection (i.e., chickenpox) occur during childhood. Re-activation of VZV results in herpes zoster (HZ) and is characterized by the onset of painful vesicles usually following a dermatomal distribution.1,2 The incidence of re-activation is increased in the elderly and in those with cellular immunosuppression, especially in patients with human immunodeficiency virus (HIV) infection or malignancy and in organ transplant
From the aDepartment of Transplant Infectious Diseases, University of Alberta, Edmonton, Alberta, and the bToronto Lung Transplant Program, University of Toronto, Toronto, Ontario, Canada. Submitted March 2, 2007; revised July 17, 2007; accepted September 24, 2007. Supported by the Transplantation Society-Roche Research Fellowship in Transplant Infectious Disease (to O.M.). Reprint requests: Oriol Manuel, MD, Provincial Laboratory for Public Health, Microbiology, 8440 112th Street, WMC 2B4.57, Edmonton, AB T6G 2J2, Canada. Telephone: 780-407-1643. Fax: 780-4071601. E-mail: [email protected] Copyright © 2008 by the International Society for Heart and Lung Transplantation. 1053-2498/08/$–see front matter. doi:10.1016/ j.healun.2007.09.028
recipients.1 Immediate complications of VZV re-activation, especially in immunosuppressed patients, include disseminated cutaneous disease and visceral involvement (e.g., pneumonitis and hepatitis). In addition, post-herpetic neuralgia may be a significant cause of morbidity.3 There are limited epidemiologic data regarding the incidence and clinical consequences of HZ after organ transplantation. The rate of HZ in solid-organ transplant recipients has been estimated at between 3% and 25%.4 The reported incidence varies depending on the organ transplanted, the type of immunosuppression, and the type of anti-viral prophylaxis. Risk factors associated with an increased risk of HZ include the use of induction therapy as well as the use of anti-viral agents other than prolonged cytomegalovirus (CMV) prophylaxis.5 Significantly less is known about HZ in lung transplant recipients. A recent study has shown an incidence of 1.7% of HZ that required hospitalization after lung or heart-lung transplantation.6 Because lung transplant recipients are generally on high doses of continuous immunosuppression and appear to have a high incidence of other herpesvirus infections, such as CMV and Epstein-Barr virus (EBV)-related post-transplant lymphoproliferative disorder, it is possible that VZV may be more problematic in these patients.7 11
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The primary aim of the study was to characterize the incidence and clinical manifestations of HZ in a large cohort of lung transplant recipients, and to identify risk factors associated with the development of HZ in this population. METHODS Patients We retrospectively reviewed all adult (ⱖ18 years old) lung transplants performed at our institution between January 2001 and December 2005. Patients with multiple-organ transplantation, and patients with a follow-up of ⬍14 days, due to early death, were excluded from the analysis. Study follow-up finished on September 30, 2006. The study was approved by the local institutional review board. Data were extracted from the Organ Transplant Tracking Record database. Localized HZ was defined as a characteristic vesicular eruption following a dermatome, with or without microbiologic confirmation. Cutaneous dissemination was defined as a characteristic vesicular eruption in two or more non-contiguous dermatomes. Visceral involvement was defined as compatible clinical signs and symptoms with biopsy confirmation of tissue invasion. Post-herpetic neuralgia was defined by pain in the area of eruption persisting for ⬎30 days after the onset of the rash. Data regarding the onset of HZ, localization, anti-viral treatment, need for hospitalization and post-herpetic neuralgia were collected for each episode of HZ. The following characteristics were also collected for all patients: age; gender; date of transplant; underlying disease; pre-transplant VZV serostatus; CMV serostatus; EBV serostatus; induction and maintenance immunosuppressive regimen; diagnosis of diabetes mellitus prior to transplant; need for dialysis or extracorporeal membrane oxygenation (ECMO) just after transplant; acute rejection; CMV infection or disease; all anti-viral therapy; bronchiolitis obliterans syndrome (BOS) and invasive fungal infection; date of death; and cause of death. The definition of infectious diseases, including CMV infection and disease, appearing after transplantation followed the published American Society of Transplantation recommendations for screening, monitoring and reporting of infectious complications in immunosuppression trials in recipients of organ transplantation.8 Acute rejection was diagnosed on the basis of a transbronchial biopsy that demonstrated characteristic perivascular lymphocytic infiltrates using criteria defined by the International Society for Heart and Lung Transplantation (ISHLT).9 For patients in whom a biopsy could not be performed, a clinical diagnosis of rejection was allowed. A clinical diagnosis for BOS was
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made using the ISHLT algorithm based on forced expiratory volume in 1 second (FEV1).10 BOS Grade ⱖ2 was considered as a positive end-point. Immunosuppressive Regimen During the entire study period, the baseline immunosuppressive protocols were essentially uniform and consisted of cyclosporine, prednisone and azathioprine. Basiliximab induction (20 mg intravenously [IV], given at Day 0 and Day 4) was used as a calcineurin inhibitor (CNI)-sparing agent to allow for delayed CNI introduction for patients with cardiopulmonary complications in the operating room or for patients with renal dysfunction. During the study period, some patients also participated in a randomized, placebo-controlled trial of basiliximab for induction. Cyclosporine-targeted trough levels were 250 to 350 mg/liter for the first 3 months, and 200 to 250 mg/liter at the end of the first year. Azathioprine was used at a dose of 1.5 to 2.0 mg/kg/day (except in patients with cystic fibrosis colonized by Burkholderia cepacia, in whom the dose was 1.0 mg/kg/day). Azathioprine was replaced by mycophenolate mofetil (MMF), and cyclosporine for tacrolimus, in cases of intolerance, contraindication or recurrent or refractory acute rejection. Methylprednisolone 500 mg IV was used for the first 3 days, which was then replaced by prednisone 0.5 mg/kg/day, tapered by 5 mg/week until reaching 0.25 mg/kg/day, and then tapered more slowly over the first 1 to 2 years to a dose of 0.15 mg/kg every second day. Anti-viral Prophylaxis A relatively uniform anti-viral strategy was in place during the study period, primarily aimed at preventing CMV. In CMV donor (D) seropositive/recipient (R) seronegative (D⫹/R⫺) patients, CMV prophylaxis consisted of 2 weeks of ganciclovir (5 mg/kg IV twice daily), followed by 12 weeks of ganciclovir (5 mg/kg IV once daily) or valganciclovir 900 mg/day. In R⫹ patients, ganciclovir (5 mg/kg IV twice daily) was given for 14 days after transplantation, followed by ganciclovir (1 g orally three times per week) or valganciclovir (900 mg once daily) for 12 additional weeks. In D⫺/R⫺ patients, 3 months of acyclovir (400 mg orally three times daily) was used for herpes prophylaxis. Statistical Analysis Categorical variables were compared using a chi-square or a Fisher’s exact test. Continuous variables were compared using the Mann-Whitney U-test. Incidence of HZ was calculated using the Kaplan-Meier method. All analyses were performed using SPSS software (SPSS 15.0, Chicago, IL) and p ⬍ 0.05 was considered statistically significant.
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RESULTS Characteristics of Study Population A total of 265 lung transplants were performed during the study period. Fifteen patients were excluded due to survival of ⬍14 days. Ten patients received a heart and lung transplant and one patient received a lung and liver transplant, and therefore these patients were excluded. Thus, 239 lung transplant recipients were included in the study. Baseline characteristics are shown in Table 1. Median follow-up was 722 days (range 18 to 1,943 days). No patient was lost to follow-up for any reason other than death. Based on donor and recipient CMV serostatus, 185 patients (77.4%) received ganciclovir- or valganciclovir-based anti-viral prophylaxis for the first 3 months post-transplant. The remaining 54 patients (22.6%) received oral acyclovir for the first 3 months post-transplant. An additional 19 patients had their duration of anti-viral prophylaxis extended to between 6 months and 1 year post-transplant because they were EBV D⫹/R⫺. Pretransplant VZV serology was available for 184 patients, of whom 10 were seronegative. Mean age for these VZV seronegative patients was 35 years. VZV vaccination with live-attenuated varicella vaccine (Varivax) was provided for 5 of these patients pre-transplant. Immunosuppression use was relatively uniform (see Table 1). Incidence of Herpes Zoster There were 35 episodes of HZ occurring in 29 patients during the study period (Table 2). All cases of HZ, except 1, were diagnosed solely on clinical grounds. The crude incidence of HZ was 29 of 239 (12.1%). The cumulative incidence of HZ (censoring for early deaths) was 5.8% at 1 year, 18.1% at 3 years and 20.2% at 5 years (Figure 1). The calculated incidence per 1,000 personyears of follow-up was 55.1 cases. Mean time to first episode of HZ from transplantation was 486 ⫾ 285 days. Twelve of 29 (41.4%) cases occurred in the first year post-transplant and 16 (55.1%) occurred between 1 and 3 years post-transplant. There were no cases of HZ while patients received either ganciclovir, valganciclovir or acyclovir prophylaxis. The earliest onset of HZ was observed approximately 1 month after discontinuation of anti-viral prophylaxis (123 days after transplant).
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Table 1. Patients’ Baseline Clinical Characteristics (n ⫽ 239) Characteristic Age (years; mean ⫾ SD) Gender (M/F) Type of transplant (single/double lung) Underlying disease Pulmonary fibrosis Cystic fibrosis Emphysema ␣1-anti-trypsin deficiency Sarcoidosis Primary pulmonary hypertension Other Re-transplant Diabetes mellitus pre-transplant Induction immunosuppression None Basiliximab/daclizumab Baseline immunosuppression Cyclosporine/azathioprine/prednisone Cyclosporine/MMF/prednisone Tacrolimus/azathioprine/prednisone Tacrolimus/MMF/prednisone Other Immunosuppression at last follow-up Cyclosporine/azathioprine/prednisone Cyclosporine/MMF/prednisone Tacrolimus/azathioprine/prednisone Tacrolimus/MMF/prednisone Other VZV serology Negative Positive Unknown CMV serostatus D⫺/R⫺ D⫺/R⫹ D⫹/R⫹ D⫹/R⫺ CMV infection CMV disease Rejection episodes 0 1 2 ⱖ3 Anti-thymocyte globulin for rejection Death at last follow-up
N (%) 48.3 ⫾ 14.1 136/103 16/223 61 (25%) 55 (23%) 49 (20%) 16 (7%) 10 (4%) 6 (3%) 42 (18%) 7 (3%) 57 (24%) 151 (63%) 88 (37%) 204 (85%) 13 (5%) 11 (4%) 5 (2%) 6 (3%) 67 (28%) 23 (10%) 56 (23%) 55 (23%) 38 (16%) 10 (4%) 174 (73%) 55 (23%) 54 (23%) 73 (30%) 69 (29%) 43 (18%) 86 (36%) 37 (15%) 98 (41%) 69 (29%) 44 (18%) 28 (12%) 21 (9%) 82 (34%)
VZV, varicella zoster virus; MMF, mycophenolate mofetil; CMV, cytomegalovirus.
Clinical Characteristics of Herpes Zoster The clinical characteristics of HZ infection are shown in Table 2. The initial episode of HZ was confined to at least one contiguous dermatome in 28 of 29 (96.6%) cases. Including recurrent episodes, only 2 of 35 (5.7%) cases involved disseminated cutaneous HZ. The first patient was a 32-year-old man who was VZV seronegative before transplant. Despite pre-transplant vaccination, he presented with a generalized vesicular rash 33
months after transplant, without visceral involvement. The second patient was a 47-year-old woman, with unknown pre-transplant VZV serology, who developed disseminated cutaneous zoster involving the upper and lower extremities and torso. The patient had two previous episodes of thoracic zoster. No visceral involvement occurred. Facial zoster was the initial presentation in 3 of 29 (10.3%) patients, but none had
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Table 2. Clinical Characteristics of 29 Patients With Herpes Zoster Characteristic Total number of episodes Time after transplant (to first episode), days (mean ⫾ SD) Immunosuppression at time of first episode Cyclosporine/azathioprine/prednisone Tacrolimus/azathioprine/prednisone Cyclosporine/MMF/prednisone Tacrolimus/MMF/prednisone Other Number of episodes per patient 1 2 3 Localization Facial Thoracic Lumbosacral Disseminated Initial anti-viral treatment None IV acyclovir PO acyclovir Famciclovir Valacyclovir Duration of anti-viral therapy, days (mean ⫾ SD) Post-herpetic neuralgia Post-herpetic neuralgia duration, months (median, range) Admission to hospital
N (%) 35 486 ⫾ 285 9/29 (31%) 6/29 (20.7%) 5/29 (17.2%) 4/29 (13.8%) 5/29 (17.2%) 25 2 2 5/35 (14.2%) 6/35 (17.1%) 22/35 (62.8%) 2/35 (5.7%) 2/35 (5.7%) 2/35 (5.7%) 6/35 (17.1%) 19/35 (54.3%) 6/35 (17.1%) 15.3 ⫾ 15.4 7/35 (20%) 4 (1–9) 5 (17.2%)
ocular involvement. After the initial episode of HZ, recurrence was noted in 4 of 29 patients (13.8%), occurring at a mean of 613 days (range 167 to 1,629) after the first episode. Post-herpetic neuralgia was recorded in 7 of 35 (20%) of the episodes. In terms of anti-viral therapy, oral therapy was used to treat the majority of episodes (Table 2). Famciclovir was the most commonly used drug (54.3%). Two patients did not receive any anti-viral therapy because lesions had spontaneously crusted at the time of initial clinical assessment. Two patients with disseminated disease received initial intravenous therapy with acyclovir and were switched to oral therapy after 4 days in both cases. Five patients (17.2%) required hospital admission for a mean of 4 days (range 2 to 7 days). Incidence of Other Infections Twenty-two patients had an invasive fungal infection during the study period: 3 of 29 (10.3%) in patients with HZ, and 19 of 210 (9.0%) in patients without HZ (p ⫽ 0.82). Median time from transplantation was 303 days (range 15 to 1,461). Aspergillus fumigatus was the most common pathogen isolated (n ⫽ 15), followed by
Aspergillus sp. (n ⫽ 4). In all 3 patients with HZ, fungal infection preceded the development of HZ. CMV infection (including symptomatic disease and asymptomatic viremia) was diagnosed in 86 patients: 10 of 29 (34.5%) in patients with HZ, and 76 of 210 (36.2%) in patients without HZ (p ⫽ 0.86). Thirty-seven of the 86 patients (43.0%) had CMV disease. Median time from transplantation was 171 days (range 43 to 1,326). In patients with CMV and HZ, CMV preceded HZ, with no cases of concomitant viral infection. None of the patients with HZ had significant neutropenia (absolute neutrophil count ⬍1,000 cells/l) at the time of symptom onset. Risk Factors for HZ Infection Risk factors were assessed for their association with HZ and are shown in Table 3. No factor was found to be significantly associated with an increased risk of HZ. Specifically, HZ was not associated with any particular immunosuppression regimen. For example, the use of MMF instead of azathioprine or the use of tacrolimus instead of cyclosporine were not risk factors for HZ. Induction antibody therapy with basiliximab did not increase the risk of HZ. The use of either pulse steroids or rabbit anti-thymocyte globulin (RATG) for the treatment of acute rejection was not associated with HZ. In fact, there was a trend toward a lower incidence of HZ in patients who had received RATG for treatment of acute rejection (0 of 21 [0%] for those with RATG treatment compared with 29 of 218 [13.3%] for those without RATG treatment, p ⫽ 0.09). This likely reflects the standard use of anti-viral prophylaxis in patients receiving RATG therapy for acute rejection. Overall, the use of anti-viral prophylaxis (primarily for CMV) was very protective against HZ during anti-viral therapy. The
Figure 1. Cumulative probability of herpes zoster after lung transplantation. The number of patients still followed at 1 year, 3 years and 5 years was 179, 53 and 7, respectively. The cumulative incidence of herpes zoster after lung transplantation was 5.8% at 1 year, 18.1% at 3 years and 20.2% at 5 years.
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Table 3. Risk Factors for Herpes Zostera
Characteristic Gender (M/F) Age ⬎50 years Age, years (mean ⫾ SD) Cystic fibrosis VZV seronegativeb Use of MMF Use of tacrolimus Use of basiliximab/daclizumab Pre-transplant diabetes mellitus Acute rejection Use of anti-thymocyte globulin for acute rejection Acyclovir prophylaxis (CMV D⫺/R⫺) CMV infection CMV disease
Patients with Patients without zoster zoster (n ⫽ 210) (n ⫽ 29) 16/13 120/90 19 (65.5%) 108 (51.4%) 51.2 ⫾ 12.7 47.9 ⫾ 14.3 4 (13.8%) 51 (24.3%) 2/21 (9.5%) 8/163 (4.9%) 11 (37.9%) 74 (35.2%) 16 (55.1%) 109 (51.9%) 11 (37.9%) 77 (36.7%) 10 (34.5%) 47 (22.3%) 19 (65.5%) 122 (58.0%) 0 (0%) 6 (20.7%) 10 (34.5%) 4 (13.8%)
21 (10%) 48 (22.8%) 76 (36.2%) 33 (15.7%)
VZV, varicella zoster virus; MMF, mycophenolate mofetil; CMV, cytomegalovirus. a There were no significant differences between groups. b In 55 patients pre-transplant VZV serology was unknown.
calculated incidence was 0 case per 22,489 patient-days (0 case per 1,000 patient-years) while on prophylaxis vs 29 cases per 169,543 patient-days (62.3 cases per 1,000 patient-years) while not on prophylaxis (p ⬍ 0.001). DISCUSSION This is the largest study evaluating Varicella zoster virus infections in lung transplant recipients. We identified 35 cases of HZ in 29 of 239 lung transplant recipients (crude incidence 12.1%). In lung transplant recipients surviving to 3 years the incidence is 18.1%, and by 5 years the incidence is 20.2%, making this a very common complication after lung transplantation. Compared with epidemiologic studies in the general population our data suggest that the incidence of HZ in lung transplant patients is approximately 30 times higher than in the general population,11 and 5 times higher than in those ⬎60 years of age.12 In our study most cases of HZ were of mild to moderate severity, with only 2 cases of disseminated disease. In addition, most patients were successfully treated with oral therapy as outpatients. No cases were complicated by visceral involvement. Recurrence was noted in a subset of patients (recurrence rate 13.8%). There is limited published literature on the epidemiology of HZ in lung transplant recipients. Gourishankar et al analyzed HZ incidence in 869 solid-organ transplant recipients, the majority of whom had liver and kidney transplants.5 The incidence of HZ in that study was 8.6% and induction antibody therapy was noted as a risk factor. Their study included 53 lung transplant recipients, of whom 8 developed HZ (incidence 15.1%). In contrast to our results, a recent study involving lung
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and heart-lung transplant recipients showed a 1.7% incidence of HZ, with a high rate of disseminated disease and mortality.6 Our contrasting results can be explained by the fact that Carby et al6 included only hospitalized patients with microbiologically confirmed HZ (either by serology or molecular testing). The majority of patients in our cohort were diagnosed and treated as outpatients. Two recent studies in liver transplant recipients reported HZ incidence rates of 12% and 1.2%, respectively.13,14 Morbidity due to post-herpetic neuralgia may be higher in organ transplant recipients compared with the general population. Rates of post-herpetic neuralgia reported in the previously noted studies in transplant recipients varied between 30% and 40%.5,13 We found an incidence of post-herpetic neuralgia of 20%. However, we cannot exclude the possibility that the incidence might be underreported, due to the retrospective nature of our study. In the general population, the incidence of post-herpetic neuralgia varies between 1.8% and 17% and is dependent on the age of the patient and whether anti-viral therapy was given or not.15,16 Previous studies in adult transplant recipients also have shown low rates of disseminated VZV infection, and a lack of VZV infection-related deaths.5,13,14 In pediatric transplantation, VZV infection has been historically associated with severe disease and a high mortality rate.17,18 However, recent studies have shown a low incidence of visceral involvement with VZV infection after pediatric organ transplantation (0% to 8.6%).19,20 We identified no specific risk factors associated with HZ. In particular, the use of MMF was not associated with a higher incidence of HZ. In a large, randomized trial with 650 heart transplant recipients, there was a trend toward a higher incidence of HZ in patients receiving MMF compared with those receiving azathioprine (14.5% vs 9.5%, respectively; p ⫽ NS).21 In addition, some studies in adult and pediatric renal transplant recipients have suggested that MMF may be a risk factor for disseminated VZV infection.22,23 However, this observation was not confirmed in other series.24 In the study by Gourishankar et al, MMF was associated with HZ in liver recipients, but not in lung transplant recipients. The use of anti-lymphocyte induction therapy has been identified previously as a risk factor for HZ. Because none of the patients in our study received anti-lymphocyte induction we could not assess this possibility. However, RATG, when used for treatment of acute rejection, was not associated with subsequent HZ, likely due to the use of anti-viral prophylaxis. In fact, we observed that anti-viral prophylaxis, primarily for CMV, was very effective in preventing HZ while patients were on therapy. Due to the high incidence of HZ after organ transplantation, preventive strategies should be further eval-
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uated. Current recommendations suggest pre-transplant serology and vaccination of VZV-seronegative patients with the live attenuated Oka strain vaccine.25 However, despite vaccination in five seronegative patients, we still observed two cases of VZV infection post-transplant in these patients: one case of thoracic zoster 4 months after transplant, and one case of disseminated VZV infection 33 months after transplant. Potential approaches to prevention in seropositive patients include pre-transplant vaccination with the live attenuated zoster vaccine (Zostavax). In a large, randomized trial in adults ⬎60 of age, the zoster vaccine showed a reduction of 51% and 66% in the incidence of HZ and post-herpetic neuralgia, respectively.10 A heat-inactivated vaccine has been evaluated in autologous hematopoietic stem cell recipients.26 The vaccine was given 30 days before transplant and 30, 60 and 90 days after transplant and demonstrated a significant reduction in the incidence of HZ, from 33% to 13% at 12 months. Our study had several limitations. First, it was a retrospective study. Therefore, although the quality of the information collected in the database was generally good and constant during the study period, data on duration of post-herpetic neuralgia may occasionally have been incomplete. It is also possible that some cases of HZ were missed because of underreporting. Therefore, this is a conservative estimate and the actual incidence of HZ in lung transplant recipients may be greater. However, at our institute it is common practice for lung transplant recipients to continue lifelong follow-up with us from the time of their transplant. Finally, because the majority of cases were diagnosed without microbiologic confirmation, a misdiagnosis with herpes simplex virus infection cannot be excluded. In summary, HZ is a common complication in lung transplant recipients, and its onset may occur years after transplantation. Although the majority of cases were managed on an outpatient basis, and no mortality was attributable to HZ, post-herpetic neuralgia is a prominent complication in this population. No risk factors for developing HZ were clearly identified. REFERENCES 1. Gnann JW Jr, Whitley RJ. Herpes zoster. N Engl J Med 2002;347: 340 – 6. 2. Dworkin RH, Johnson RW, Breuer J, et al. Recommendations for the management of herpes zoster. Clin Infect Dis 2007;44(suppl 1):S1–26. 3. Kost RG, Strauss SE. Postherpetic neuralgia—pathogenesis, treatment, and prevention. N Engl J Med 1996;335:32– 42. 4. Gnann JW. Herpes simplex and varicella-zoster virus infection after hemopoietic stem cell or solid organ transplantation. In: Transplant infections, 2nd ed. Lippincott-Raven; 2003:350 – 66. 5. Gourishankar S, McDermid JC, Jhangri GS, Preiksaitis JK. Herpes zoster infection following solid organ transplantation: incidence, risk factors and outcomes in the current immunosuppressive era. Am J Transplant 2004;4:108 –15.
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6. Carby M, Jones A, Burke M, Hall A, Banner N. Varicella infection after heart and lung transplantation: a single-center experience. J Heart Lung Transplant 2007;26:399 – 402. 7. Zamora MR. Cytomegalovirus and lung transplantation. Am J Transplant 2004;4:1219 –26. 8. Humar A, Michaels M. American Society of Transplantation recommendations for screening, monitoring and reporting of infectious complications in immunosuppression trials in recipients of organ transplantation. Am J Transplant 2006;6: 262–74. 9. Yousem SA, Berry GJ, Cagle PT, et al. Revision of the 1990 working formulation for the classification of pulmonary allograft rejection: lung rejection study group. J Heart Lung Transplant 1996;15:1–15. 10. Cooper JD, Billingham M, Egan T, et al. A working formulation for the standardization of nomenclature and for clinical staging of chronic dysfunction in lung allografts. J Heart Lung Transplant 1993;12:713– 6. 11. Donahue JG, Choo PW, Manson J, Platt R. The incidence of herpes zoster. Arch Intern Med 1995;155:1605–9. 12. Oxman MN, Levin MJ, Johnson GR, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 2005;352:2271– 84. 13. Herrero JI, Quiroga J, Sangro B, et al. Herpes zoster after liver transplantation: incidence, risk factors, and complications. Liver Transplant 2004;10:1140 –3. 14. Levitsky J, Kalil A, Meza JL, Hurst GE, Freifeld A. Herpes zoster infection after liver transplantation: a case– control study. Liver Transplant 2005;11:320 –5. 15. Helgason S, Petursson G, Gudmundsson S, Sigurdsson JA. Prevalence of postherpetic neuralgia after a first episode of herpes zoster: prospective study with long term follow up. BMJ 2000; 321:794 – 6. 16. Jung BF, Johnson RW, Griffin DRJ, Dworkin RH. Risk factors for postherpetic neuralgia in patients with herpes zoster. Neurology 2004;62:1545–51. 17. Lynfield R, Herrin JT, Rubin RH. Varicella in pediatric renal transplant recipients. Pediatrics 1992;90:216 –20. 18. Feldhoff CM, Balfour HH Jr, Simmons RL, et al. Varicella in children with renal transplants. J Pediatr 1981;98:25–31. 19. Pandya A, Wasfy S, Hebert D, Allen UD. Varicella-zoster infection in pediatric solid-organ transplant recipients: a hospital-based study in the prevaricella vaccine era. Pediatr Transplant 2001;5: 153–9. 20. Levitsky J, Kalil AC, Meza JL, et al. Chicken pox after pediatric liver transplantation. Liver Transplant 2005;11:1563– 6. 21. Eisen H, Kobashigawa J, Keogh A, et al. Three-year results of a randomized, double-blind, controlled trial of mycophenolate mofetil versus azathioprine in cardiac transplant recipients. J Heart Lung Transplant 2005;24:517–25. 22. Lauzurica R, Bayes B, Frias C, et al. Disseminated varicella infection in adult renal allograft recipients: role of mycophenolate mofetil. Transplant Proc 2003;35:1758 –9. 23. Rothwell WS, Gloor JM, Morgenstern BZ, Milliner DS. Disseminated varicella infection in pediatric renal transplant recipients treated with mycophenolate mofetil. Transplantation 1999;68: 158 – 61. 24. Fehr T, Bossart W, Wahl C, Binswanger U. Disseminated varicella infection in adult renal allograft recipients: four cases and a review of the literature. Transplantation 2002;73:608 –11. 25. Herpes simplex virus (HSV)-1 and -2, and varicella zoster virus (VZV). Am J Transplant 2004;4(suppl 10):69 –71. 26. Hata A, Asanuma H, Rinki M, et al. Use of an inactivated varicella vaccine in recipients of hematopoietic-cell transplants. N Engl J Med 2002;347:26 –34.