This study demonstrates a high incidence of HZ in a large multi-center cohort of VA SOT recipients. The overall incidence in this cohort was 22.2 per 1000 patient-years, with African American subjects and heart transplant recipients demonstrating the highest incidence of post-transplant HZ. In a time-dependent model, African Americans, older transplant recipients and those with prior organ rejection also appeared to have higher rates of HZ. Subjects remained at risk throughout the entire post-transplant follow-up period.
To the best of our knowledge, this study is the largest multi-center cohort of SOT recipients to date to assess the incidence of HZ. These data provide important information on long-term risk of HZ following SOT, afford the first assessment of risk in other non-white populations, and present further evidence for an increased risk of HZ in SOT recipients. Other published studies evaluating HZ incidence in this transplant population have been limited to single centers, short follow-up periods, and or a specific type of transplant (kidney, liver, lung, and heart). Corresponding to these varied populations and study methods, the reported incidence of rates of HZ have varied from 1.5% to 16.2% (9
). Our data are in accordance with the two largest studies published to date (9
), which indicate incidence rates anywhere from 2–5 times those seen in the general population (35
The age-related increase in HZ in older transplant recipients seen in our study is similar in magnitude to that seen in the immunocompetent population, and is likely a reflection of ongoing decline in varicella zoster virus-specific T-cell immunity, in addition to transplant-related immunosuppression (37
). These findings are of particular public health importance. Patients aged 60 years and older represent the fastest growing population with end-stage renal disease worldwide (39
). Furthermore, the number of new registrants for kidney transplants between the ages of 50 and 64 years has doubled and those aged 65 years and older has nearly tripled (39
Most studies evaluating HZ incidence in SOT have focused primarily on white recipients. While large databases, such as the United Organ Network for Organ Sharing and the Scientific Registry for Transplant Recipients, would be useful for calculating population based incidence rates, they do not currently collect information on HZ. Our cohort’s racial and ethnic distribution are more consistent with current US census data (41
), and provide a longitudinal assessment of HZ incidence in SOT recipients in the US. In addition to assessing incidence in a more heterogeneous population then has previously been possible, the availability of follow-up data reveals important new information on the long-term rate of HZ following SOT.
This is the first study to demonstrate a higher incidence of HZ in African American SOT recipients. The increased incidence seen in African Americans in our study could be caused in part by higher rates of organ rejection in African Americans (42
), differences in immunosuppressive regimens (45
) or metabolism (47
), or as yet undetermined racial variations in viral immune response, as seen in other viral infections (51
). The limited but conflicting findings in regards to racial differences in HZ incidence seen in other non-transplant populations (54
), also suggest that these findings warrant confirmation in future studies.
Differences in health care utilization could also be a reflection of racial variations in HZ incidence, as African Americans are known to access VA services at higher rates than Whites (55
). In addition, the overall incidence rates in our study are most likely an underestimation, as incident cases are expected to be missed in those who sought care at non-VA facilities. Finally, our finding that service connection, a reflection of VA healthcare use, was associated with an increased incidence of HZ is consistent with this hypothesis as improved access would be associated with a higher event capture. These data in African Americans may therefore be a more accurate assessment of HZ risk in SOT, and the rates described in this population will be important to consider in planning future prospective trials.
Heart transplant recipients had a high rate of HZ in our cohort, which is consistent with prior studies (10
), and may be a reflection on differences in immunosuppression (59
). In contrast, liver transplants are relatively resistant to rejection compared to other organs and generally require less immunosuppression (60
). The lower incidence of HZ seen in liver transplant recipients in our cohort and in other studies (10
), provides further evidence that intensity of immunosuppression may be important in determining risk of HZ. We can only hypothesize about the decline in HZ incidence in those patients transplanted in more recent years. The decreased incidence seen in latter cohorts is likely in part a result of shorter follow-up and the increasing use of antiviral prophylaxis for CMV, which has been shown to further limit risk of HZ in the first 1–2 years following transplantation (9
). Improvements in immunosuppressive regimens, prevention of rejection, and other alterations in antiviral prophylaxis may also play a role in this decline, but will need to be assessed in future studies.
The high penetrance of HZ seen in this study indicates a need for future prevention studies. Current American Society of Transplantation guidelines do not recommend antiviral prophylaxis (62
), and to date no formal studies of HZ prevention in SOT have been published. Because daily acyclovir is safe and has been shown to prevent the development of HZ in other immunosuppressed populations (63
), prospective studies are needed to assess long-term antiviral drug prophylaxis after organ transplantation. Additionally, while the currently available HZ vaccine is contraindicated in SOT recipients (66
), future studies are needed to address the safety and efficacy of the live-attenuated virus vaccine in the pre-transplant period. Ongoing studies using a heat-killed HZ vaccine in immunosuppressed populations may provide another option for future prevention (67
Determining the incidence rate of HZ in SOT recipients is complicated by the diverse demographics of the population, data ascertainment from primarily outpatient records, and the inherent costs of long-term follow-up studies. The VA healthcare system database provided an efficient way to assess the incidence of HZ in large multi-center population of transplant recipients over a 10-year period. However, this analysis has strengths and limitations imposed by these data. It is probable that these data underestimate the true incidence rate in this population, as incident and recurrent cases of HZ in subjects who sought alternate clinical care outside of the VA system were not captured (68
). In addition, although rates of post-herpetic neuralgia are similar to rates in other post-transplant populations (9
), higher rates reported by others suggest that we may also underestimate the frequency of this complication (10
). Because of our use of ICD-9 coding, we could not assess invasive HZ complications or dissemination, both of which may be higher in SOT recipients (69
). Furthermore, data on bacterial super-infection need to be assessed in future prospective studies. Most importantly, we could not address critical treatment-related risk factors, such as immunosuppressive regimen and concomitant antiviral therapy, as other studies have done (10
). However, our data are strengthened by the size and multi-center nature of the cohort, the length of long-term follow-up, and the racial and ethnic diversity of the VA population. Furthermore, since our incidence rates are likely conservative, they could be useful for developing appropriately powered clinical trials in HZ prevention.
In summary, in this cohort of VA SOT recipients, we found that HZ was a common infectious complication in the post-transplant period. African Americans, subjects receiving heart transplants, and older transplant recipients appeared to have the highest incidence rates of HZ. In addition, in time-dependent analyses, African Americans, subjects who developed organ rejection and older transplant recipients appeared to have higher rates of HZ. The rates of HZ seen during long-term follow-up of this multi-center cohort confirm findings from other large retrospective studies, and provide additional support for future studies in HZ prevention.