In this study we have estimated the burden of acute herpes zoster by utilizing National Swedish Health Care Registers. The disease burden has been studied using three separate approaches: analyzing antiviral medication prescription data, demonstrating zoster-related hospitalizations, including complications, and herpes zoster-related mortality. However, the study lacks an estimation of the total burden of disease related to VZV reactivation since analyses of prescriptions, hospitalizations, and mortality related to PHN are not included in the analysis. A strength of this study is the solid national data from the Swedish National Patient Register with a very low number of dropouts or lack of principal diagnoses, which are estimated to occur in only one percent of cases, respectively . Primary care visits are not analyzed in this study because no national health care register has been established for such visits in Sweden.
The Swedish National Pharmacy Register provides an exclusive opportunity to analyze prescription patterns since each prescription is linked to the unique personal identity number of the patient. The prescription data may be regarded as an indirect measurement of the herpes zoster incidence and primary care visits in Sweden. This assumption is plausible since, in this study, most antiviral medication prescriptions for herpes zoster were found to be written by doctors in primary care (data not shown). Similar findings were reported in an Australian study . In Sweden, patients under 50 years of age are not recommended antiviral treatment  and it was found that approximately 70% of the prescriptions were distributed to patients over 50 years of age. Thus, a theoretical association of the antiviral prescription data with the incidence of herpes zoster is only feasible for the population over 50-year-old population, and older. This results in a national minimum incidence of herpes zoster in Sweden of 621/100,000 for females and 404/100,000 for males in the population age 50 and older, based on antiviral prescriptions. Recently, a review of European studies, focusing on total population incidence of herpes zoster, stated that in the 21 included studies the incidence in all ages was 2–4.6/1000 inhabitants/year which is in line with our results . In the review by Thomas et al., where studies from both Europe and USA were included, the incidence in all ages varied from 3.6 to 14.2/1000 inhabitants/year . However, methodological differences are frequent and direct comparisons of studies must address this circumstance.
The analysis of the prescription data has some inherent uncertainties. Even if precautions have been taken to exclude prescriptions not related to herpes zoster, the data may contain prescriptions for patients who received antiviral treatment in the dosage for herpes zoster for other indications than herpes zoster. However, the Swedish Medical Product Agency does not recommend treatment with dosages compatible with that used in herpes zoster disease except for herpes simplex meningitis , a relatively rare disease compared to herpes zoster disease. The possible inclusion of non-herpes-zoster-related patients is a limitation of the study and may result in an overestimation of the prescription rates. On the other hand, the number of patients with herpes zoster most likely exceeds the number of prescriptions, since immunocompetent patients under 50 years of age with uncomplicated herpes zoster are not recommended antiviral treatment in Sweden . In the review by Pinchinat et al. , prescription studies were not considered as reliable as prospective studies in health care facilities or retrospective studies of herpes zoster cases identified through the review of medical files when calculation the incidence of herpes zoster. However, an overestimation of cases in our study is less likely since only approximately 72% of the patients diagnosed (ICD -10) with herpes zoster in primary care receive a prescription of antivirals (Dr. Lars Rombo, personal communication).
In the present study, hospital cases with non-primary and primary diagnoses of herpes zoster disease were analyzed. Herpes zoster occurs more often in elderly people, but it is not unusual that hospitalization is the result of other diseases. Thus, herpes zoster may be recorded as a non-primary cause in these cases. At the same time, it cannot be ruled out that patients with PHN might be misdiagnosed as a herpes zoster case in the group of non-primary causes. On adding herpes zoster as a non-primary diagnosis to the analysis, it was estimated that the annual average number of hospitalized patients was 1,179, while the annual average number of patients with a primary diagnosis was 636. However, for the herpes zoster complications and age-stratified hospitalizations, only primary diagnoses were examined to ensure a causal link to herpes zoster.
The disease burden in hospitals is significant, expressed in the rates of hospitalization, and is similar to that in a recent report from France . In the present study, the majority of the hospitalizations occurred in patients over 50 years of age. The increase in hospitalization rates followed a particular pattern and there was a stepwise increase between the age groups (Figure 2). In the group 80 years or older there was nearly a three-fold increase in the hospitalization rates compared to the previous age-group, reaching about 61/100,000 and 53/100,000 in females and males, respectively.
In a recent study from South Korea, it was demonstrated that the hospitalization rates were increasing from 2003 to 2007 . It was speculated that this finding was related to a relative increase in the size of the elderly population along with an increasing number of patients with immune deficiencies. We did not note such an increase in hospitalization rates in our study. However, the annual number of antiviral prescriptions for herpes zoster increased by an average of 1,059 (p = 0.033) during the study period. It is likely that cases of herpes zoster will increase in the coming decades due to a growing elderly population. According to the National Population Statistics in Sweden, the life expectancy in this population is projected to increase from approximately 83.1 to 86.3 years in females and from 79.1 to 83.6 years in males between the years 2009 and 2050.
Herpes zoster complications were recorded in approximately a third of hospitalized female cases while about a fourth of male cases developed complications. Complications stemming from the peripheral and central nervous systems dominated, quite similar to the findings in the recent study in France . There are reports of increased numbers of cases detected after the introduction of VZV quantitative PCR on cerebrospinal fluid samples  and this method was implemented during the study period in Sweden. Thus, nervous system involvement may have been underestimated or underdiagnosed in the study. Zoster with other complications, disseminated herpes zoster, and zoster opthalmicus were also quite common, demonstrating the broad spectrum of complications during herpes zoster disease. Bacterial superinfections (which are included in zoster with other complications) with septicemia and phlegmone are serious complications, nearly as common as the nervous system complications.
The predominance of females was one of the major findings in this study and was demonstrated in all the analyses, i.e. the antiviral prescription, hospitalization and mortality rates. The pattern of female predominance was most pronounced for prescription rates where female patients had generally higher rates of prescription of antivirals than males (rate ratio 1.61; 95% CI, 1.57 to 1.65). The female predominance was particularly evident in the 50–59 age group where female patients had generally higher rates of prescription of antivirals compared to males (rate ratio 1.83, 95% CI, 1.68 to 1.99). The pattern of female predominance was also seen for hospitalization rates, where females in all age-groups were significantly more often hospitalized compared to males (rate ratio 1.40; 95% CI, 1.20 to 1.64). In the European review by Pinchinat et al., the incidence rates were systematically higher in females than in men in the included studies confirming the results of this study [22, 25–28]. Even though a predominance in females of antiviral prescriptions was demonstrated in several age groups in the present study, it cannot be excluded that this finding is related to a different health care seeking pattern for herpes zoster between the sexes in Sweden . In addition, gender difference in the incidence of herpes zoster might be due to immunological or hormonal differences between men and women. However, this issue is out of the scope of the present study and should be further explored.