Dyshidrosis is a risk factor for herpes zoster
C.-Y. Hsu,1,2,3,4,5 Y.-C. Wang,6,7, C.-H. Kao8,9,*
Introduction
Dyshidrosis, a skin condition in which small, itchy, fluid-filled blisters appear on the hands or feet, can cause physical discomfort, psychological distress and occupational impairment.1
Although the global prevalence of dyshidrosis is unclear, the condition appears to be more common among Asians.2 Dyshidrosis
accounts for approximately 5% to 20% of all cases of hand dermatitis, and occurs most commonly in young adults,3 and
more frequently in hot seasons.4 Nickle contact might cause dyshidrosis, 5,6 endogenous factors such as stress-induced immune
system reactivity were also associated with dyshidrosis.7
Herpes zoster (HZ) is the reactivation of a latent varicella zoster virus (VZV) infection that has remained in a dorsal root ganglion after an initial exposure to varicella. The incidence of HZ
has been calculated to be 3–6 per 1000 person-years globally, and women have a higher incidence rate.8–14 HZ incidence has
been demonstrated to increase with age,12,13 and with immune
deficiencies, incidence in immuno-compromised patients was fourfold higher than that in the general population.9
Therefore, a relationship between dyshidrosis and HZ may
exist. The objective of this study was to investigate whether there is an association between dyshidrosis and HZ.
Methods and materials
Data source
This population-based cohort study was based on medical
records from 1996 to 2011 obtained through Taiwan’s the Longitudinal Health Insurance Database (LHID2000), a subset
of the National Health Insurance Research Database (NHIRD) that is administrated by the National Health research Institute. More than 99% of the country’s 23.72 million residents are enrolled in the National Health Insurance (NHI) program,
which requires low, uniform co-payments and offers full medical coverage.
by the NHI program and included in the LHID which
contains information, such as patients’ demographics and medical histories. To ensure personal privacy and data security, the identities of the insured population were encrypted. This study was approved from ethical review by China Medical University’s Institutional Review Board (CMU-REC-101-012). The International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) was used to identify dyshidrosis diagnoses.
Study participants
Dyshidrosis (ICD-9-CM: 705.81) case was defined as the patient having at least one hospital admission or at least three visits for outpatient medical services related to dyshidrosis in the
LHID2000. The group comprised of 8488 patients with newly identified dyshidrosis and with no history of HZ prior to diagnosis of dyshidrosis in 2001–2005. The date of initial dyshidrosis
diagnosis was set as the index date. To establish the non-dyshidrosis group, four controls per each dyshidrosis case were randomly selected from the LHID and were frequency-matched
according to age (5-years intervals), sex and index year. The dates of randomly selected outpatient or inpatients visits during the index years were selected as the index dates for the controls. Patients with missing demographic information or a diagnosis of HZ before the index date were excluded from our study. The follow-up period extended until HZ (ICD-9-CM 053) diagnosis, withdrawal from the insurance program, death, or the end of 2011 (Fig. 1).
Potential confounding risk factors were adjusted for included
demographic characteristics such as sex, age and history of comorbidities. The history of the following comorbidities was estimated
when occurring before the index date: hyperlipidaemia
(ICD-9-CM 272), hypertension (ICD-9-CM 401-405), viral hepatitis (ICD-9-CM 070), depression (ICD-9-CM 296.2–296.3,
300.4 and 311), anxiety (ICD-9-CM 300.0, 300.2, 300.3, 308.3 and 309.81), chronic kidney disease (CKD; ICD-9-CM 580-589), dermatitis 9-CM 690, 691 and 692), allergic rhinitis (ICD-9-CM 477), asthma (ICD-(ICD-9-CM 493), diabetes (ICD-(ICD-9-CM 250, A181), cancer (ICD-9-CM 140-208), rheumatoid arthritis (RA;
ICD-9-CM 714), HIV infection (ICD-9-CM 795.71, V08, 042 and 079.53). Antiviral treatment among our study subjects was noted, the patient had ever treated before the end of date were measured for adjustment.
Statistical analysis
All statistical analyses were performed using SAS 9.3 statistical package (SAS Institute Inc., North Carolina, USA); a P-value <0.05 in two-tailed tests was considered to be significant. To evaluate the variance in potential risk factor distribution at baseline between the dyshidrosis and non-dyshidrosis groups, we
used the chi-square test to determine the difference in categorical variables and used the Student’s t-test to determine the difference in continuous variables. The incidence rate in the two
cohorts was estimated by stratifying each variable. The incidence rate ratios (IRRs) and 95% confidence intervals (95% CIs) of HZ were calculated using a Poisson regression model, and the non-dyshidrosis cohort was the reference group. The association between dyshidrosis and the risk of HZ after adjustment for age,
sex and comorbidities was assessed using a multivariate Cox proportional hazard model and presented through adjusted hazard ratios
(aHRs) and 95% CIs. We also measured the number of used hospital care service per year due to dyshidrosis during the study period and further analysed the association between the number of visits and HZ by Cox proportional hazard model too. We used R software (R Foundation for Statistical Computing, Vienna, Austria) to conduct a Kaplan–
Meier analysis and measure the cumulative incidence of HZ in
the two groups, and used the log-rank test to determine the differences between the two cumulative incidence curves.
Results
Among the 8488 patients with dyshidrosis and 33 952 controls without dyshidrosis who were analysed in this study, there was no significant difference in the distribution between age and sex. Both groups had a mean age of 32.7 years (Table 1). Several comorbidities such as hyperlipidaemia (9.50% vs. 7.21%), hypertension (10.4% vs. 9.32%), viral hepatitis (3.45% vs.
2.46%), anxiety (5.76% vs. 3.87%), CKD (4.30% vs. 3.78%), dermatitis (56.4% vs. 23.3%), allergic rhinitis (17.8% vs. 11.7%),
more prevalent in the dyshidrosis group than in the control group. The percentage of dyshidrosis patients with antiviral treatment was 2.60% (n = 221).
Figure 2 (log-rank test, P < 0.001) shows that the overall
cumulative incidence of HZ was significantly higher in the dyshidrosis group (dashed line) than in the non-dyshidrosis group
(solid line). Table 2 shows the incidence rate, IRR and aHR of HZ in the two groups. The overall IRR of HZ was 1.53-fold higher in the dyshidrosis group than in the non-dyshidrosis group (incidence rate: 4.65 vs. 3.04 per 1000 person-year). After we adjusted for the confounding risk factors, the overall aHR of HZ was 1.31 (95% CI: 1.14–1.50) in the dyshidrosis group compared with the non-dyshidrosis group. Among women, the aHR
of HZ was 1.25-fold higher (95% CI: 1.05–1.49) for the dyshidrosis group. Men with dyshidrosis had a higher risk of HZ
than did men without dyshidrosis (aHR: 1.44, 95% CI: 1.16– 1.80). Stratified by age, patients with dyshidrosis aged <65 years had a significantly higher risk of HZ than did non-dyshidrosis individuals in the same age group (aHR: 1.35, 95% CI: 1.06–1.71 for <35 years old; aHR: 1.33, 95% CI: 1.11–1.60 for 35–64 years old). Regardless of comorbidities, patients with dyshidrosis had a higher risk of HZ than did individuals without dyshidrosis. When patients without antiviral treatment, the risk of HZ was obvious in dyshidrosis group than non-dyshidrosis group (aHR: 1.36, 95% CI: 1.18–1.56).
Table 3 shows a comparison of the dyshidrosis and non-dyshidrosis groups stratified according to comorbidities, and presents
the risk of HZ in patients with dyshidrosis and without comorbidities, such as hyperlipidaemia (aHR: 1.34, 95% CI: 1.15–1.56), hypertension (aHR: 1.28, 95% CI: 1.09–1.50), viral hepatitis (aHR: 1.32, 95% CI: 1.14–1.52), depression (aHR: 1.31, 95% CI: 1.13–1.50), anxiety (aHR: 1.35, 95% CI: 1.17–1.55), CKD (aHR: 1.34, 95% CI: 1.17–1.55), dermatitis (aHR: 1.56, 95% CI: 1.28–1.90), allergic rhinitis (aHR: 1.33, 95% CI: 1.15– 1.55), asthma (aHR: 1.35, 95% CI: 1.17–1.56), diabetes
(aHR: 1.33, 95% CI: 1.15–1.54), cancer (aHR: 1.32, 95% CI: 1.15–1.51), RA (aHR: 1.31, 95% CI: 1.14–1.51) and HIV infection
specially comorbidity type, the significantly risk of HZ was presented in dyshidrosis group than non-dyshidrosis group.
Table 4 shows the association between the average number of
outpatient and inpatient visits attributable to dyshidrosis exacerbation and developing HZ. The risk of HZ increased with
increasing medical visits in the dyshidrosis group. The aHR of HZ increased from 1.95 (95%: 1.52–2.48) among those who made two visit to 4.54 (95%: 3.60–5.73) among those who made 3 or more visits (P for trend <0.0001).
Discussion
This is the first population-based study to identify dyshidrosis as a risk factor for HZ. We determined that patients with dyshidrosis were more likely to have HZ than were the controls without
dyshidrosis. After adjustment for age, index date and comorbidities, patients with dyshidrosis, particularly young adults, were
1.31 times more likely to develop HZ.
Dyshidrosis has been associated with allergic reactions to exogenous irritants such as nickel,5,6 and was demonstrated to
occur more frequently in hot weather.4 Photoinduced dyshidrosis
was also reported.15 Several authors have proposed that
endogenous factors such as stress are factors that aggravate dyshidrosis development.7,16 Stress is thought to exert effects on
immuno-modulation and oxidative stress pathways,17 causing
the release of noradrenalin and promoting skin dendritic cells migration to lymph nodes that results in increased T-cell responses.18 Niinai et al.19 reported two rare cases in which
patients experienced severe pompholyx following endoscopic thoracic sympathectomy. Thus, even the stress of minimally
invasive surgery could lead to dyshidrosis.
The incidence of HZ was shown to increase with age because age-dependent cellular immunity against VZV decreases.13 A
population-based study showed that the incidence of HZ
increased with age; the incidence was 5.18, 8.36, 11.09 and 11.77 per 1000 persons aged of 40–50, 50–60, 60–70 and older than
70 years respectively.12 A recent systemic review by Pinchinat et al.20 confirmed that the
incidence of HZ increased with age in
Europe, incidence was 1–4, 7–8 and 10 per 1000 adults among
Our results showed that patients younger than 65 years with dyshidrosis were more likely to develop HZ, the aHR was 1.35 and 1.33 in the <35 and 35–65 years age groups, respectively. There was no significant difference between patients aged
>65, probably because the influence of ageing or other factors was stronger than dyshidrosis.
The association between stress and HZ has been identified by several authors. Schmader et al.21 found that negative life events
increased the risk of HZ, albeit non-significantly. However, in a case–control study, Lasserre et al.22 found that recent negative
life events were significantly associated with HZ, patients with recent negative life events were 3.4 times more likely to develop HZ. Mehta et al. confirmed HZ can be reactivated in healthy people after stress. They examined VZV DNA from the saliva samples of eight astronauts taken before, during and after space flight. Only 1 of 112 saliva samples taken before space flight was positive for VZV DNA; however, 61 of 200 (30%) samples taken from all astronauts during and after space flight were positive for VZV DNA.23 Similarly, dyshidrosis is a stressor for infected
individuals that causes HZ development. Several studies have reported that women had a higher incidence of HZ than did men,9,11–13 however, we determined that men with dyshidrosis
had a slightly higher risk of HZ than did women (aHR 1.61 vs. 1.40). This difference may be due to relatively high levels of stress among men in Taiwan’s Confucianism-oriented society. We found that patients with no comorbidities had a significant high risk of HZ if they suffered from dyshidrosis. The association between dyshidrosis and HZ was existed. Furthermore,
patients with a high number of hospital visits attributable to dyshidrosis had a high risk of HZ, aHR were 1.95 and 4.54 for
patients who made 2 and >3 hospital visits per year respectively. The strong association between dyshidrosis and HZ was proved. The strengths of our study are: a population-based design with a large sample size, generalizability of findings and only few patients lost follow-up including study and control cohorts. In addition, NHIRD covers a highly representative sample of Taiwan’s general population because the reimbursement policy is
Taiwan. All insurance claims should be scrutinized by medical reimbursement specialists and peer review. However, this study has several limitations. First, dyshidrosis and HZ were diagnosed by individual physicians through subjective physical examinations. Diagnosis bias may exist between dermatologists and general practitioners. However, the patients with at least 3 times
diagnosis of dyshidrosis were coded in dyshidrosis group. Second, patient’ characteristics such as nutritional habits and lifestyle were not provided by the NHIRD; such characteristics are crucial factors because they might involve immunology. Third, “severity of disease” was not included in the NHIRD data; therefore, dyshidrosis and HZ severity could not be measured. The
location of lesions was also unavailable through the NHIRD.
However, severity of the disease seems associated with more hospital visits. The increasing risk of HZ with increasing medical
visits was found in our study, whether more immunosuppressive medications using in this population needs further study.
Finally, the NHI program covered payments for antiviral drugs used to treat HZ only when the lesions were near the eyes or genital. Self-payment for HZ treatment was not recorded in the NHIRD. Despite these limitations, our nationwide populationbased data avoided selection bias and provided sufficient statistical power for analysis.
Conclusion
Dyshidrosis is strongly associated with HZ. Patients treated for dyshidrosis should be warned of HZ risk.
