Perceived Psychological Stress and Risk of Herpes Zoster

A Nationwide Population-based Cohort Study

S.A.J. Schmidt; H.T. Sørensen; S.M. Langan; M. Vestergaard


The British Journal of Dermatology. 2021;185(1):130-138. 

In This Article

Abstract and Introduction


Background: Psychological stress may reduce cellular immunity, but its role in triggering latent infections, including herpes zoster (HZ), is controversial.

Objectives: To examine the association between perceived psychological stress and risk of HZ.

Methods: In a linked registry-based cohort study, we followed 77 310 persons aged 40 years or older who participated in the 2010 Danish National Health Survey from 1 May 2010 until HZ diagnosis, death, emigration or 1 July 2014, whichever occurred first. We computed hazard ratios (HRs) of HZ associated with Cohen's Perceived Stress Scale (PSS) score (range 0–40) using Cox regression with age as the timescale, adjusted for sex, immunosuppressive and selected chronic conditions, immunosuppressive drugs, and sociodemographic, lifestyle and anthropometric factors. The PSS measures chronic stress perceived by an individual in response to various demands of daily life. We modelled the PSS score using quintiles and a restricted cubic spline function.

Results: The unadjusted rate of HZ varied from 5·53 to 7·20 per 1000 person-years from the lowest to the highest PSS score quintile. Compared with the lowest PSS score quintile, the adjusted HR for HZ was 1·00 [95% confidence interval (CI) 0·86–1·16], 1·08 (95% CI 0·92–1·26), 1·05 (95% CI 0·90–1·23) and 1·14 (95% CI 0·97–1·34) for the second to the fifth quintile, respectively. In cubic spline analyses, PSS scores < 20 were not associated with increased HR of HZ, but thereafter the HR increased linearly from 1·10 (95% CI 0·85–1·41) to 2·22 (95% CI 1·32–3·75).

Conclusions: Our study indicated that high levels of psychological stress are associated with increased risk of HZ.


Acute and chronic psychological stress are associated with decreased counts and activity of cytotoxic lymphocytes, mediated mainly through hyperarousal of the sympathetic nervous system and the hypothalamic–pituitary–adrenal axis.[1,2] Depression of cellular immune function could possibly increase the risk of reactivation of latent infections,[1,2] such as the varicella zoster virus (VZV), which causes herpes zoster (HZ).[3]

Previous studies on stress and the risk of HZ have reported conflicting results. Two large registry-based studies (a case–control study and a self-controlled case series) found no increase in HZ risk following partner bereavement, which is a severe stressor.[4,5] In contrast, five small studies observed an increase in the relative risk of HZ of 40% or more among persons reporting a wide range of negative life events compared with those not reporting such events,[6–10] but possible selection and recall bias,[6–10] lack of interviewer blinding[7–10] and small sample sizes raise doubts regarding these findings.[6–10] Furthermore, the use of negative life events as objective indicators of stress may not provide a valid and complete picture of the association between stress and HZ, as psychological stress depends on the type and duration of the stressor and on personal coping mechanisms.[2] Only one small cohort study from Japan examined the risk of HZ associated with perceived stress in daily life. This study found that men with very high stress levels had an approximately twofold higher risk of HZ compared with those reporting low stress levels.[11] However, stress was crudely measured by asking participants to rate their overall level of daily stress, dose–response analyses were not provided and the sample size was limited (< 10 outcomes among men and women reporting a very high stress level).

We addressed the limitations of previous studies in a large population-based cohort study on the association between psychological stress and the risk of HZ in persons aged 40 years or older. We based the study on a large nationwide Danish survey, which included a validated instrument to measure perceived stress in various aspects of daily life and performed dose–response analyses to avoid disregarding any potential threshold effects.