Since 1960, only 2 U.S. studies, conducted in the Harvard Community Health Plan (HCHP) HMO10
and a small New Hampshire solo practice22
have reported data on the incidence of HZ in U.S. general clinical practice. Using 1990 to 1992 data from automated medical records, a crude annual incidence of HZ episodes of 2.1 per 1,000 person-years was reported in the HCHP analysis10
However, when incidence rates from the HCHP study were age- and sex-adjusted to the 2000 U.S. population (our estimations), the annual incidence of HZ (3.3 per 1,000 person-years) was found to very similar to that observed in the MarketScan analyses (3.2 per 1,000 person-years). A crude HZ incidence rate of 3.3 per 1,000, and age- and sex-adjusted rate (our estimations) of 3.7 per 1,000, were estimated based on patients seen for HZ within the New Hampshire solo practice between 1983 and 1992; although population denominators were defined with less certainty in that analysis.22
The age- and sex-adjusted incidence rates reported for the U.S. are similar to those observed internationally for France (3.2 per 1,000 person-years),20
the Netherlands (3.4 per 1,000 person-years),13
Canada (3.5 per 1,000 person-years),19
and the United Kingdom (U.K.) (3.8 per 1,000 person-years).19
Previous estimates of the annual number of incident cases of HZ within the U.S. have utilized incidence rates similar to the unadjusted rate from the HCHP study.1,5,10
This has resulted in projections of an annual burden of HZ within the U.S. population of approximately 500,000 cases.1,5,10
However, when extrapolated to the general population,30
the age- and sex-adjusted estimates of incidence from recent U.S. studies would translate to nearly 1,000,000 cases of HZ diagnosed in the U.S. each year, suggestive of a higher absolute burden of HZ within the U.S. population than that previously estimated.1,5,10
Consistent with previous studies, the burden of HZ was substantially higher among the elderly than among younger individuals.10,13,19
The incidence of HZ was higher among females than males within all age groups. This finding contrasts with prior U.S. studies, in which a similar incidence of HZ was observed across the sexes,10,32
but is consistent with results from a large U.K. study, utilizing data from 1994 to 2001, which found a 28% higher age standardized incidence of HZ among females compared to males.11
Standardizing data for both sexes in the present analysis to the age distribution of the 2000 U.S. population30
yielded a similar excess incidence for females compared with males of 33%. This figure was only slightly attenuated after controlling for recent care for conditions and treatments which may result in immunosuppression (i.e., cancer, HIV infection, and transplantation).
The reasons underlying gender differences in HZ incidence remain unclear. Given that HZ diagnoses examined in the present study were reflective of health care encounters, the gender differential could be caused in part by differences in care-seeking behavior. It has also been posited that females may have a differing immune response than males to latent viral infection.11
The finding of a higher HZ incidence among females has raised questions concerning the relative magnitude of importance of a purported association between repeated exposure to VZV and a reduced risk of HZ.11,33
Females typically have more direct contact with children than males, including children with varicella.34,35
A strong negative association between repeated exposure to VZV and subsequent HZ would lead one to expect a lower risk of HZ among females than among males, the opposite of the pattern observed in the present analysis. Further studies are needed to better determine the reasons for these gender differences.
There has been little prior investigation of geographic variability in the incidence of HZ within the U.S. In the present study, there was found to be little regional variation between the Northeast, Midwest, South, and West in the frequency of HZ.
The age- and sex-adjusted risk of developing HZ among individuals with recent care for cancer, HIV infection, or transplantation was observed to be significantly higher than among individuals without recent care for these conditions/treatments. Although aggregated incidence rates with respect to these conditions/treatments are reported in this study, it should be noted that there is likely to be considerable variation in the level of immunosuppression, and subsequent risk of HZ, within and across patient groups with evidence of recent care for cancer, HIV, or transplantation.
Overall, 9% of HZ patients had evidence of recent care for cancer, HIV infection, or transplantation, supporting the notion that the vast majority of patients developing HZ may not have a recent history of an immunosuppressive comorbid condition that would constitute an obvious risk factor for HZ. This finding is consistent with results observed previously in the HCHP study in which 11% of HZ patients were found to have had a diagnosis code for cancer or HIV within the 6 months prior to an HZ diagnosis.21
This study has several potential limitations. First, consistent with other population-based studies of HZ,10,11,32
disease incidence in the present analysis was based upon the observation of a health care encounter for HZ. It is possible that some individuals developing HZ may not seek medical care; however, the frequency with which this may occur is unknown.
Second, incident cases were identified based on the appearance of an ICD-9 diagnosis code for HZ on a health care claim. Thus, the validity of the results depends upon the accuracy of a physician-assigned diagnosis of HZ and the resultant diagnostic coding generated by a given encounter. Although misclassification between HZ and herpes simplex virus has been reported in the literature,36–38
the routine clinical diagnosis of HZ is generally regarded as reliable.1
For instance, in prior studies, the presence of HZ was confirmed in >90% of physician-diagnosed cases based on expert review of clinical data,36
and 100% of clinically diagnosed cases based on polymerase chain reaction (PCR) testing.37
It is difficult to comprehensively assess the degree to which HZ may be categorically misdiagnosed as another condition; however, HZ was not found to be a common cause of unexplained unilateral pain,39
with evidence that a modest proportion of HZ cases may be misdiagnosed as herpes simplex.37
For the present study, it was not possible to compare diagnoses listed on healthcare claims with those found in the medical record. However, the overall incidence of HZ reported within the MarketScan population is quite similar to that reported in prior U.S. (following age and sex adjustment) and international studies utilizing electronic medical records.10,13,19
Finally, the identification of individuals with recent care for cancer, HIV infection or transplantation was based upon the observation of diagnosis, procedure, and drug codes related to these conditions/treatments on a health care claim. Thus, the caveats noted previously with respect to the accuracy of administrative coding apply. In addition, the potential exists for missed cases of cancer or HIV infection, particularly if HZ patients harbor occult disease that is not diagnosed until after the HZ diagnosis. However, several studies have established that HZ is not a marker for occult malignancy, with a risk of cancer following an HZ diagnosis similar to that observed within the general population.40–42
Similarly, prior U.S. analyses have not found HZ to be a harbinger of previously undiagnosed HIV infection.43,44
The accuracy of administrative coding for identifying individuals with the conditions/treatments examined in this analysis is expected to be adequate, given their relative severity, as evidenced by previous studies that have generally found claims data to be sufficiently reliable for identifying individuals with cancer.45,46
This paper has reported data from the largest and most geographically diverse U.S. study of HZ incidence to date. A higher incidence of HZ was observed among females than males and among individuals at older ages. Age- and sex-standardized results for overall HZ incidence from the present study were found to be comparable to rates from U.S. studies conducted 10 to 20 years earlier,10,22
and similar to those observed in Canada and Europe.11,13,19
Although the MarketScan population does not reflect a national random sample of the population, the majority of Americans (~70%) have private health insurance coverage similar to MarketScan enrollees.47
Extrapolated to the U.S. general population, results from this analysis would suggest that nearly 1 million new cases of HZ are diagnosed in the U.S. each year. It is hoped that emerging technologies will help to reduce this health burden.