In a cohort of adults in Olmsted County, Minnesota, with an initial HZ episode from January 1, 1996, through December 31, 2001, the population-based recurrence rate of HZ was 6.2% after 8 years of follow-up. For many people, HZ is not a once-in-a-lifetime event, demonstrating that having HZ does not ensure protection against future HZ episodes. Indeed, after adjustment for age and sex, the rate of recurrent episodes was similar to the incidence rate of HZ episodes in the same population,17
suggesting that the risk of having another episode of HZ in people with a history of HZ is about the same as the risk of having a first HZ episode in the general population. Laboratory confirmation in 24.8% of cases helps confirm that the recurrences were indeed HZ. Our findings may have implications for HZ recurrence prevention by zoster vaccination.
As anticipated, recurrences were more common among people who were immunocompromised at the time of the index HZ episode, but most recurrences were in people who were immunocompetent at the time of the initial episode.
It is possible that some of the people with recurrences may have become immunocompromised between the time of the initial episode and the first recurrence, a possibility that deserves further evaluation in future studies. Zoster-associated pain lasting for 30 or more days at the index episode was a strong predictor of recurrence. Longer-lasting zoster-related pain has been shown to be associated with greater severity of the initial HZ rash and intensity of pain.16,26
Recurrence could be more common in people with more severe initial HZ, making longer-lasting pain only a proxy measure in our analysis. The medical record data did not provide sufficient detail to assess initial HZ severity so that a definitive answer is not possible from this study. It is also possible that people with milder initial episodes of HZ chose not to seek medical care for any recurrence, leading to underestimation of the number of recurrences.
Our recurrence rates of 5.7% for immunocompetent people and 6.2% overall after 8 years are higher than many of the rates published in the literature. In 1980, Epstein10
reported that, of 400 persons with HZ, 5 (1.3%) had an HZ recurrence over an unspecified period of time. In the classic
paper by Hope-Simpson,11
192 HZ cases were identified during 16 years, of which 8 (4.2%) had a second episode and 1 (0.5%) had a third episode. In the same population as our study but during an earlier time period (1945-1959), Ragozzino et al12
identified 590 persons with a first episode of HZ during the study period, including 31 (5.3%) with a recurrent episode. In 1995, Donahue et al13
used 2 years of insurance claims data follow-up to identify 4 confirmed and 4 possible recurrences among 1075 patients with an initial episode of HZ. Recurrence rates in the insured population studied were reported as 1.5% during a 2-year period when the “possible” cases were included. This claims database study had no confirmation of diagnosis and a very short follow-up period. In an Icelandic study, 457 patients with HZ were noted to have 4 recurrences (0.9%) during a 5-year study period.15
An additional 19 (4.7%) of 403 patients for whom retrospective data were available reported a history of typical HZ before the study period. In a retrospective survey of 1071 persons of advanced age, 235 (21.9%) self-reported having had HZ, including 32 (13.6%) of 235 with at least 1 self-reported recurrence.14
The Shingles Prevention Study, a large clinical trial of the efficacy and safety of a zoster vaccine, was not designed to study recurrence but did report 3 laboratory-confirmed HZ recurrences in 3 years of follow-up among 1308 cases of HZ in immunocompetent people.16
Overall, published data on HZ recurrences are scarce and often based on anecdotal reports of small numbers of cases collected using different methods over varying durations of follow-up. Studies that include only 1 to 2 years of follow-up may underestimate the average yearly recurrence rates over a lifetime. A reliable estimate of HZ recurrence requires several years of follow-up. In our study, few recurrences occurred in the first 12 to 18 months after the index case, except in those who were immunocompromised. Our 2-year recurrence rate (2.0%) is similar to that reported by Donahue et al13
but is poorly predictive of the 8-year recurrence rate.
Unlike other studies, our cohort came from a community-based population with a well-established infrastructure to report administrative diagnoses and allow access to medical records for in-depth review. The ability to obtain follow-up information across all health care facilities within the county is likely to have ensured a high degree of completeness of recurrence identification. Twenty-six (<25%; 9 of them immunocompromised) of our cases had laboratory confirmation of their HZ. This is higher than was anticipated and may be reflective of physicians' desire to confirm that HZ recurrences occur within months to years of the initial HZ episode. The use of a standardized HZ definition requiring both a dermatomal vesicular rash and pain or dysesthesia to confirm the diagnosis of HZ was important for optimizing the specificity of the HZ diagnosis for both the initial and recurrent HZ episodes, with laboratory confirmation a bonus. The specificity of a clinical diagnosis has been confirmed in studies that range from the small (111 patients [specificity 87%]18
) to the very large (>38,000 patients [specificity of 94.0% for the “suspected” cases and >99.0% for the “clinically definite” cases]).19
By collecting data on recurrences in both immunocompetent and immunocompromised people, we were able to assess the role played by immune status in the risk of HZ recurrence. Our study did not include assessment of the immune status at the time of the recurrence, a factor that should be assessed in future studies. Although the Kaplan-Meier curves clearly demonstrate the higher rates of recurrence among immunocompromised people (about 2.4 times higher), the overall numbers show that most episodes of recurrent HZ occur in immunocompetent people (85.7%, 90/105). Thus, more than 85% of recurrent cases occur in those eligible to receive a live virus vaccine, such as the currently available zoster vaccine.
If the concept of boosting by exposure to the varicella zoster virus is true, the initial reactivation or HZ episode would be expected to boost immunity and delay a recurrence, with recurrences becoming increasingly more common during the follow-up period. However, the number of recurrences appeared to flatten out over time rather than increase. This lack of apparent boosting effect appears consistent with the lack of a marked increase in the overall HZ rate after introduction of the varicella vaccine for children in the United States and Canada.17,27
The childhood vaccine should decrease the boosting effect of exposure of adults to children with chickenpox and potentially result in a marked increase in the temporal trend of HZ cases. This effect has not been confirmed.17,27
An alternative explanation for our results could be an innate (possibly genetic) predisposition for HZ, which has received some attention in studies of HZ in families.28
This is an area that clearly requires further study.
Although this study on HZ recurrence is the largest to date, it has some limitations. Diagnosis of HZ for both the index and recurrent episodes was based on clinical data, and only a modest proportion of cases were confirmed by laboratory testing. Such is the current standard of care, with HZ considered a clinical diagnosis and laboratory confirmation only used in unusual, unclear, or confusing cases. As a result, HZ could have been overdiagnosed. Conversely, the recurrence rate could be underestimated because not all people with an HZ recurrence may seek care, such as those with a very mild initial case. Also excluded were all possible recurrences that were only included in the differential diagnosis of unexplained pain. All of these factors likely led to an underestimation of the number of recurrences. Interestingly, when reviewing in detail the medical records of the 1669 confirmed index HZ cases in the initial incidence cohort, we identified 93 persons who had an HZ episode 2 to 50 years before their index episode, despite the absence of an HZ code in the administrative database. This finding suggests that a proportion of HZ cases who seek medical attention may not be coded as such, which may also underestimate the true incidence and recurrence rates. This study was conducted in Olmsted County, Minnesota, where racial diversity is limited among the adult population. This limited racial diversity prevented assessment of possible racial/ethnic differences in HZ recurrence, information that is currently unavailable in the literature. Health care systems are the largest employers in Olmsted County, Minnesota. As a result, our population may have been more aware of possible HZ and more likely to seek health care for it than the general population. The impact of heightened awareness among people who have already had an episode of HZ is unknown but may have been an advantage in this study, in which it was desirable to identify as many cases as possible. Finally, although longer than in most previous studies, the follow-up for recurrence in this study was only slightly longer than 7 years on average. Our results need to be repeated in a larger study sample with longer-term follow-up.