Elsevier

Journal of Infection

Volume 70, Issue 2, February 2015, Pages 171-177
Journal of Infection

Herpes zoster is associated with herpes simplex and other infections in under 60 year-olds

https://doi.org/10.1016/j.jinf.2014.08.016Get rights and content

Highlights

  • Herpes zoster occurrence is associated with herpes simplex occurrence.

  • HZ-HS co-occurrence suggests a shared susceptibility for viral reactivation.

  • Herpes zoster occurrence is associated with the occurrence of common infections.

  • This co-occurrence suggests a broader susceptibility for infectious diseases.

Summary

Objectives

We assessed the association between herpes zoster (HZ) and herpes simplex (HS) occurrence whilst controlling for risk factors of HZ.

Methods

Using a Belgian general practitioner network, a retrospective cohort study with 3736 HZ patients and 14,076 age-gender-practice matched controls was performed, covering over 1.5 million patient-years. Multiple logistic regression was used with HZ as outcome and several diagnoses (malignancy, depression, diabetes mellitus, auto-immune diseases, asthma, multiple sclerosis, HIV, fractures), medications (systemic corticosteroids, biologicals, vaccination), HS and other infections as variables.

Results

HS was significantly associated with HZ for all analysed time intervals (up to five years) post HZ (OR of 3.51 [2.09 5.88] 95%CI one year post HZ) and to a lesser extent for time ranges pre HZ. Registration of other infections was significantly associated with HZ in all time intervals pre and post HZ (OR up to 1.37). Malignancy up to five years pre HZ, depression up to one year pre or post HZ, fractures up to two years pre HZ, asthma, auto-immune diseases, and immunosuppressive medication one year pre or post HZ were also associated with HZ.

Conclusions

HZ and HS occurrences are significantly associated and potentially share a common susceptibility beyond the known risk factors.

Introduction

Chickenpox is caused by primary infection with varicella-zoster virus (VZV), after which VZV remains latent in neural ganglia until reactivation. Symptomatic reactivation of VZV is known as herpes zoster (HZ) or shingles. Protection against HZ is assumed to be closely regulated by VZV-specific cellular immunity. Indeed, symptomatic VZV reactivation occurs frequently in known immunocompromised persons.1 Furthermore, some studies found HZ to be predictive of a later diagnosed malignancy.2 In addition, several studies have noted VZV-specific cellular immunity to decline with ageing3, 4 which is reflected by the steep increase in HZ incidence with age.5 Moreover, acquisition of chickenpox <1 year of age has been identified as a risk factor for HZ in childhood,6 likely due to the limited development of VZV-specific cellular immunity at that young age.7 VZV vaccine-induced boosting of primarily cellular immunity has been shown to be effective against the occurrence of HZ.8 Interestingly, re-exposure to chickenpox has been shown to cause a temporary rise in VZV-specific cellular immunity4, 9, 10, 11 and was hypothesized and shown to protect against HZ.12, 13, 14

Epidemiological studies have identified several risk factors associated with HZ such as being female15 or Caucasian,16 recent mechanical trauma,17 chemical exposure,18 negative life events19 and depression.20 Irwin et al. presented in several studies an association between depression and lower VZV-specific cellular immunity.21, 22 Various clinical co-morbidities, thought to have an effect on cellular immunity either directly or via immunosuppressive medication, were also shown to be associated with HZ: diabetes mellitus,23 systemic lupus erythematosus,24 asthma (in children),25 inflammatory bowel diseases26 and rheumatoid arthritis.27 Medications implicated in the occurrence of HZ are “disease modifying anti-rheumatic drugs”,27 oral corticosteroids,28 TNF-alpha inhibitors29 and recently statins.30 A reduced intake of fruit, vegetables and micronutrients was found in HZ31 and post-herpetic neuralgia32 patients, respectively.

Although some studies found a peak in HZ incidence during the late spring – early summer months, many other studies did not (see review by Thomas and Hall33). Interestingly, Zak-Prelich et al. found support for an association between UV radiation intensity and HZ on exposed body regions,34 a finding which is reminiscent of the inductive effect of UV radiation on cold sores caused by herpes simplex virus (HSV).35 A host genetic susceptibility for HZ has been established by both epidemiological36 and genetic association studies.37 The host defence against the related HSV type 1 and 2 was also associated with host genetic variants for genes responsible for Toll-like receptors38 and HLA molecules.39 Recently, CMV seropositivity was found to be associated with both HSV-140 and VZV reactivation.41

In view of the above, VZV and HSV reactivation possibly share common elements such as the sensitivity for UV radiation, host genetic susceptibility and susceptibility for the effects of CMV infection. The present case–control study set out to investigate whether HZ occurrence was associated with herpes simplex in patients younger than 60 years seen in general practice, whilst controlling for known risk factors. In addition, we hypothesized that herpes zoster patients could be more prone to infections.

Section snippets

Population

Data was obtained from a representative Flemish (Belgian region) general practitioner (GP) registration network (Intego) with more than 90 GPs and over 1.5 million patient-years (for more details see2). Diagnoses were classified according to ICPC-2 (International Classification of Primary Care)42 and medications were classified according to the WHO's Anatomical Therapeutic Chemical (ATC) classification system.43 For the present study, diagnoses and prescribed medications registered from

Herpes zoster association analysis

Figure 1, Figure 2 show the results of the univariate and multiple logistic regression analyses, respectively (See Supplementary Table S2 for more details). Malignancy 0–5 year pre HZ (P < 0.001), depression 0–1 year pre/post HZ (P = 0.0011), auto-immune diseases (P = 0.016), asthma (P = 0.034), fractures 0–2 year pre HZ (P = 0.026), herpes simplex 0–1 year post HZ (P < 0.001), other infections 0–1 year pre HZ (P < 0.001), other infections 0–1 year post HZ (P < 0.001) and systemic

Discussion

Our case–control study used diagnosis and medication data registered during a time period of 18 years from a network of general practitioners in Belgium. Through our analysis of 3736 HZ patients younger than 60 years and their controls we found a clear and convincing association between HZ and herpes simplex registration, even after controlling for known risk factors for HZ such as the use of corticosteroids. Although this association was the highest in the years following HZ occurrence (OR up

Funding

This work was supported by grants of the Research Foundation Flanders [project grant, predoctoral fellowship to B.O., postdoctoral fellowships to J.B.]; the University of Antwerp [Special Research Fund predoctoral fellowship to L.W.] and the Flemish Health Ministry. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests

P.V.D. acts as chief and principal investigator for vaccine trials conducted on behalf of the University of Antwerp, for which the University obtains research grants from vaccine companies. B.O., F.B., S.B., I.T., I.D., S.E., J.B., S.C. and P.B. report no conflicts of interest.

Acknowledgements

This work would not have been possible without the collaboration of all general practitioners of the Intego network. We are also grateful for the data sent by the Royal Meteorological Institute of Belgium (KMI).

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