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Ann Thorac Surg 2009;87:423-426. doi:10.1016/j.athoracsur.2008.11.004
© 2009 The Society of Thoracic Surgeons
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Original Articles: General Thoracic

Herpes Zoster After Lung Transplantation: Incidence, Timing, and Outcome

Leonardo Fuks, MD, David Shitrit, MD, Benjamin D. Fox, MD, Anat Amital, MD, Yael Raviv, MD, Ilana Bakal, RN, Mordechai R. Kramer, MD*

Pulmonary Institute, Rabin Medical Center, Beilinson Campus, Petah Tiqwa, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Accepted for publication November 3, 2008.

* Address correspondence to Dr Kramer, Pulmonary Institute, Rabin Medical Center, Beilinson Campus, Petah Tiqwa, 49100, Israel (Email: kremerm{at}clalit.org.il).


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 References
 
Background: Although herpes zoster is a common complication of lung transplantation, the epidemiologic data are limited. The aims of the present study were to determine the incidence and clinical manifestations of herpes zoster in a large cohort of lung transplant recipients and to identify risk factors associated with its development.

Methods: The files of all adult patients who underwent lung transplantation at a major tertiary medical center from January 2001 to December 2007 were reviewed. Data were extracted on background, transplant-related, and posttransplantation factors. The occurrence and clinical characteristics of all episodes of herpes zoster were recorded.

Results: Of the 198 lung transplant recipients, 23 had a herpes zoster infection, of whom 18 had herpes in a single dermatome. Disseminated cutaneous infection was documented in 4 cases (17%) and visceral involvement in 1. The median duration of follow-up was 34 months (range, 1 to 85 months). There were no recurrent infections. Postherpetic neuralgia was detected in 26% of cases. Antiviral prophylaxis, primarily for cytomegalovirus, was effective (during treatment) against herpes zoster. The incidence of herpes zoster was higher in patients treated with rabbit antithymocyte globulin.

Conclusions: The occurrence of herpes zoster peaks between 12 and 36 months after lung transplantation. Additional immunosuppression may increase the risk. Further studies on preventive strategies against herpes zoster in this population are warranted.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Comment
 References
 
Varicella zoster virus (VZV), a very common pathogen, is a member of the herpes family of viruses. It causes chickenpox, usually in childhood. Primary VZV infection is rare in immunocompetent adults, in whom it leads to much more severe disease with high mortality.

After clinical presentation and apparent resolution of the primary infection, the virus becomes latent and can be reactivated, causing a painful vesicular skin rash in a dermatome distribution, termed herpes zoster. The morbidity is significant. The most common complication is postherpetic neuralgia, which is associated with persistent pain for more than 30 days after acute secondary infection [1]. The incidence of VZV reactivation is higher in older persons and individuals with cellular immunosuppression, especially patients with human immunodeficiency virus infection or malignancy and organ transplant recipients [1].

The epidemiologic data on the incidence and clinical consequences of herpes zoster infection after organ transplantation are limited. Its estimated rate of occurrence in solid-organ transplant recipients varies widely, between 3% and 25%, depending on the organ transplanted, type of immunosuppression, and type of antiviral prophylaxis. In the two systematic studies of VZV infection after lung transplantation, the reported incidence was 15% [2] and 12% [3]. The risk factors identified were use of induction therapy and prolonged use of antiviral agents other than cytomegalovirus (CMV) prophylaxis [2]. The time of onset of herpes zoster after transplantation ranged from 100 days to 8 months [4].

The morbidity and mortality of herpes zoster infections may be particularly high in lung transplant recipients because of the high doses of immunosuppressive drugs they receive and their higher-than-normal rate of other herpesvirus infections [5, 6]. The aims of the present study were to determine the incidence and clinical manifestations of herpes zoster in a large cohort of lung transplant recipients and to identify risk factors associated with its development.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 References
 
Patients
The files of all patients older than 18 years of age who underwent lung transplantation at a major tertiary-care medical center between January 2001 and December 2007 were reviewed. Data were extracted on patient age and sex, date of transplantation, underlying disease, pretransplant VZV serostatus, CMV serostatus, induction and maintenance immunosuppressive regimen, diagnosis of diabetes mellitus before transplantation, occurrence of acute rejection, antiviral therapy, presence of bronchiolitis obliterans syndrome, occurrence and characteristics of posttransplant viral infections, and date and cause of death, if applicable. For all events of herpes zoster, we documented onset of the infection, localization, antiviral treatment, need for hospitalization, and postherpetic neuralgia.

Localized herpes zoster was defined as a characteristic vesicular eruption in a dermatome configuration, with or without microbiologic confirmation. Cutaneous dissemination was defined as a characteristic vesicular eruption in two or more noncontiguous dermatomes. Visceral involvement was defined as compatible clinical signs on biopsy study or radiologic evidence of visceral organ involvement. Postherpetic neuralgia was defined as pain in the area of eruption persisting for more than 30 days.

Posttransplant infectious diseases, including CMV infection, were defined according to the American Society of Transplantation recommendations for the screening, monitoring, and reporting of infectious complications in immunosuppression trials in recipients of organ transplants [7]. Acute rejection was diagnosed by transbronchial biopsy findings of a characteristic perivascular lymphocytic infiltrate, according to the criteria of the International Society for Heart and Lung Transplantation [8]. For patients in whom a biopsy could not be performed, rejection was diagnosed clinically. Bronchiolitis obliterans syndrome was diagnosed clinically using the International Society for Heart and Lung Transplantation algorithm, which is based on forced expiratory volume in 1 second [9].

The study was approved by the local institutional review board, and the requirement for patient consent was waived.

Immunosuppressive Regimen
All lung transplant recipients at our center receive initial immunosuppression according to the following protocol: intravenous (IV) methylprednisolone 500 mg intraoperatively, before graft reperfusion; three doses of IV methylprednisolone 125 mg every 8 hours postoperatively, followed by standard prednisone oral taper; mycophenolate mofetil 1 g twice daily; and tacrolimus titrated to whole blood trough levels of 15 to 20 ng/mL for 2 weeks. The patients are subsequently maintained on a triple regimen: oral prednisone, 0.25 mg/kg per day for the first 6 to 9 months, then 7.5 mg every day to 1 year; tacrolimus titrated to whole blood levels of 8 to 12 ng/mL; and mycophenolate mofetil 0.5 g three times a day. Induction therapy is not routine, except in cases of repeated transplantation. Rejection episodes are treated with IV methylprednisolone 1 g/day for 3 days, after which the prednisone is tapered down.

Every patient also receives trimethoprim-sulfamethoxazole prophylaxis against Pneumocystis carinii infection, one tablet (960 mg) three times weekly, and itraconazole 200 mg two times a day for 6 to 12 months against fungal infection.

Antiviral Prophylaxis
A relatively uniform antiviral strategy was used in the department during the study period, aimed primarily at preventing CMV infection. If the serologic study was positive for CMV in the recipient or the recipient and the donor, IV ganciclovir was added to the protocol at 5 mg/kg twice a day for 5 days, followed by valganciclovir for 6 months. If the serology findings were negative for CMV in the recipient but positive in the donor, treatment with valganciclovir was extended to 12 months.


   Results
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 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 References
 
Study Group
Our file review identified 198 adult patients who underwent lung transplantation during the study period, of whom 23 had a posttransplantation episode of herpes zoster. The baseline features of the 23 patients with herpes zoster are shown in Table 1. Nine patients (39%) were older than 60 years. The median duration of follow-up was 34 months (range, 1 to 85 months). No patient was lost to follow-up.


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  		Table 1 Clinical Characteristics of 23 Patients With Herpes Zoster After Lung Transplantation
 
Incidence of Herpes Zoster
The crude incidence of posttransplantation herpes zoster was 11.6% (23 of 198). The characteristics of the infections are shown in Table 2. All cases were diagnosed solely on clinical grounds. Twenty-two patients (95.5%) were CMV immunoglobulin G (IgG) positive, of whom 19 (86%) had an IgG-positive donor and 3 (14%) had an IgG-negative donor. The sole CMV IgG-negative transplant recipient received a lung from an IgG-negative donor.


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  		Table 2 Clinical Characteristics of 23 Cases of Herpes Zoster
 
The mean time to infection after transplantation was 22.3 ± 12.2 months (range, 8 to 54 months). The earliest case occurred 5 months after antiviral prophylaxis was discontinued (240 days after transplantation). Six (26%) cases occurred in the first year after transplantation and 15 (65%), between 2 and 3 years after transplantation. There were no cases of herpes zoster while the patients were being treated with ganciclovir or valganciclovir. There were no recurrences of herpes zoster during the study period.

Clinical Characteristics and Treatment of Herpes Zoster
At least one contiguous dermatome was involved at the initial presentation in all cases; 4 cases (17.3%) involved more than two dermatomes.

Twenty-two of the herpes zoster episodes (95.5%) were treated with oral acyclovir (Table 2); doses were adjusted according to renal function. In 1 patient with disseminated disease, initial therapy consisted of IV acyclovir which was then switched to the oral route after 4 days. Three patients (13.3%) were hospitalized for a mean of 4 days (range, 2 to 7 days).

The average duration of symptoms was 21 days, except for the postherpetic neuralgia group, whose patients complained about continuous pain for months.

Complications
Postherpetic neuralgia was recorded in six episodes of herpes zoster (26%). Four cases were managed with oral tramadol, one with oral naproxen, and one with intensive palliative pain care and continuous follow-up in a pain clinic. Four patients also received carbamazepine (Tegretol, Novartis) for 3 to 6 months. The response to the analgesic treatment was very individual, and we cannot reach conclusions as to what analgesics were more helpful in this group.

Of the 17 patients without postherpetic neuralgia, 3 did not require any analgesic treatment, 8 were treated with tramadol, and 6 with dipyrone. Three also received Tegretol, concomitantly or at a later period. The response to pain killers was satisfactory in that group, and we could not see an advantage in using one type of treatment over the others.

Outcome
Graft rejection occurred in 7 patients (30.4%), 4 chronic and 3 acute, before onset of the herpes zoster infection. Four of them were receiving additional immunosuppression therapy with azathioprine and rabbit antithymocyte globulin. All were alive at the end of the study period.

Two patients, both with localized (genital and chest) herpes zoster, died during the study period. Neither had chronic or acute lung graft rejection. The cause of death was secondary sepsis 30 days after onset of herpes zoster and metastatic lung cancer 11 months after herpes zoster.


   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
References
 
This is the one of the few studies evaluating VZV infections in a cohort of lung transplant recipients. We identified 23 cases of herpes zoster in 198 patients after lung transplantation, for a crude incidence of 11.6%. This rate is in line with studies showing that herpes zoster is a common complication of solid-organ transplantation [2, 3, 10], especially in immunocompromised patients [11]. Donahue and colleagues [12] reported that the incidence of herpes zoster in lung transplant patients is more than 30 times higher than in the general population.

The mean time to infection after transplantation was 22.3 ± 12.2 months (range, 8 to 54 months). Gnann [13] found that herpes zoster occurred between 3.5 to 8 months after solid-organ transplantation, and Gourishankar and associates [2] reported a mean time to onset of 13.9 months.

Nine of our 23 patients (39%) were older than 60 years. Accordingly, epidemiologic studies in the general population suggested that the rate of herpes zoster is five times higher in this age group [14].

Most of our cases were of mild to moderate severity, and the vast majority of patients (n = 20) were successfully treated with oral acyclovir on an outpatient basis. Three patients required hospitalization, but only one had visceral pulmonary involvement. There were four cases of disseminated cutaneous herpes zoster, all with a good outcome. There were no recurrences.

We found that CMV prophylaxis was effective in preventing herpes zoster. None of our patients acquired the infection during treatment with anti-CMV agents. Other studies have shown that antiviral CMV prophylaxis reduces the mortality associated with herpes zoster [15], but it does not appear to reduce its incidence [16]. The VZV cell-mediated immune response is increased in healthy elderly subjects who are vaccine-immunized. A booster vaccine was found to yield a significant benefit in elderly patients who were already IgG-positive for VZV vaccine [17]. Furthermore, patients after bone marrow transplantation who were seropositive for varicella zoster enjoyed greater protection against the development of herpes zoster when they were immunized with the varicella vaccine [18]: the incidence of herpes zoster dropped from 33% to 13% at 12 months. A new live-attenuated zoster vaccine (Zostavax, Merck & Co, NY) that stimulates a boost in waning immunity in the elderly population has been approved in the United States for prevention of herpes zoster (shingles), and is distinct from the standard varicella vaccine (Varivax, Merck & Co, NY). A large randomized trial demonstrated a reduction in herpes zoster of more than 50% [14]. Because it is a live vaccine, posttransplant recipients should not receive the zoster vaccine. Further data are awaited regarding whether it is efficacious in preventing posttransplant zoster when administered to varicella-seropositive pretransplant candidates not receiving immunosuppressive therapy [19]. Current recommendations suggest pretransplant serology and vaccination of VZV-seronegative patients with the live attenuated Oka strain vaccine [20].

Postherpetic neuralgia is a severe complication of herpes zoster in transplant recipients. The reported incidence ranged from 20% to 42% [2, 3], in agreement with the 26% reported in our series. Of our 6 patients with postherpetic neuralgia, 5 were symptom-free by the end of the study period. In 1 patient, however, pain persisted long after resolution of the viral disease, and he required continued follow-up in the pain clinic. In the general population, the incidence of postherpetic neuralgia varies between 1.8% and 17%, depending on patient age and receipt of antiviral therapy [21, 22].

All our patients survived the herpes zoster episode. Two patients died of unrelated causes.

It is noteworthy that in 4 patients, the herpes zoster infection developed during or immediately after receipt of rabbit antithymocyte globulin treatment for graft rejection. This finding suggests that augmentation of immunosuppression could raise the risk of herpes zoster.

In summary, herpes zoster is a common late complication of lung transplantation. The use of continuous therapy with acyclovir to prevent herpes zoster in lung transplant recipients warrants further study in a large prospective trial.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 References
 

  1. Kost RG, Stauss SE. Postherpetic neuralgia: pathogenesis, treatment and prevention N Engl J Med 1996;335:32-42.[Medline]
  2. 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;4:108-115.[Medline]
  3. Manuel O, Kumar D, Singer LG, Cobos I, Humar A. Incidence and clinical characteristics of herpes zoster after lung transplantation J Heart Lung Transplant 2008;27:11-16.[Medline]
  4. Gnann JW, Whitley RJ. Herpes zoster N Engl J Med 2002;347:340-346.[Medline]
  5. 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.[Medline]
  6. Zamora MR. Cytomegalovirus and lung transplantation Am J Transplant 2004;4:1219-1226.[Medline]
  7. 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;6:262-274.[Medline]
  8. 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.[Medline]
  9. 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;12:713-716.[Medline]
  10. Herpes simplex and varicella-zoster virus infection after hemopoietic stem cell or solid organ transplantationIn: Gnann JW, editor. Transplant infections. 2nd ed.. Philadelphia: Lippincott-Raven; 2003. pp. 350-372.
  11. Gilden DH, Kleingschmitd-De Masters BK, LaGuardia JJ, Mahalingam R, Cohrs RJ. Neurologic complications of the reactivation of varicella-zoster virus N Engl J Med 2000;342:635-645.[Medline]
  12. Donahue JG, Choo PW, Manson J, Platt R. The incidence of herpes zoster Arch Intern Med 1995;155:1605-1609.[Abstract/Free Full Text]
  13. Other herpesviruses: herpes simplex virus, varicella-zoster virus, human herpes types 6, 7 and 8In: Gnann JW, editor. Transplant infections. 1st ed.. Philadelphia: Lippincott-Raven; 1998. pp. 265-286.
  14. 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;352:2271-2284.[Medline]
  15. Masaoka T, Hiraoka A, Teshima H, Tominaga N. Varicella zoster virus infection in immunocompromised patients J Med Virol 1993;1:82-84.
  16. Hans CS, Miller W, Haake R, Weidsorf D. Varicella zoster infection after bone marrow transplantation: incidence, risk factors and complications Bone Marrow Transplant 1994;13:277-283.[Medline]
  17. Landow K. Acute and chronic herpes zoster Postgrad Med 2000;107:107-118.[Medline]
  18. 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.[Medline]
  19. Avery RK, Michaels M. Update on immunizations in solid organ transplant recipients: what clinicians need to know Am J Transplant 2008;8:9-14.[Medline]
  20. Guidelines for vaccination of solid organ transplant candidates and recipients Am J Transplant 2004;4(Suppl 10):160-163.[Medline]
  21. 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;321:794-796.[Abstract/Free Full Text]
  22. Jung BF, Johnson RW, Griffin DRJ, Dworkin RH. Risk factors for postherpetic neuralgia in patients with herpes zoster Neurology 2004;62:1545-1551.[Abstract/Free Full Text]




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