Herpes zoster is associated with herpes simplex and other infections in under 60 year-olds
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).
References (54)
- et al.
Contacts with varicella or with children and protection against herpes zoster in adults: a case-control study
Lancet
(2002 Aug 31) - et al.
Gender as an independent risk factor for herpes zoster: a population-based prospective study
Ann Epidemiol
(2006 Sep) - et al.
Herpes zoster: family history and psychological stress-case-control study
J Clin Virol
(2012 Oct) - et al.
Increased risk of herpes zoster in children with asthma: a population-based case-control study
J Pediatr
(2013 Sep) - et al.
Incidence and risk factors for herpes zoster among patients with inflammatory bowel disease
Clin Gastroenterol Hepatol
(2006 Dec) - et al.
What does epidemiology tell us about risk factors for herpes zoster?
Lancet Infect Dis
(2004 Jan) - et al.
Susceptibility to herpes labialis following multiple experimental exposures to ultraviolet radiation
Antiviral Res
(1995 Sep) - et al.
Family history and herpes zoster risk in the era of shingles vaccination
J Clin Virol
(2011 Dec) - et al.
Polymorphism of the IL-10 gene is associated with susceptibility to herpes zoster in Korea
J Dermatol Sci
(2007 Mar) - et al.
The participation of varicella zoster virus in relapses of multiple sclerosis
Clin Neurol Neurosurg
(2014 Apr)