Академический Документы
Профессиональный Документы
Культура Документы
MAJOR ARTICLE
Background. Herpes zoster is common and vaccine preventable. Stroke risk may be increased following zoster,
but evidence is sparse and could be explained by differences between people with and without zoster. Our objective
was to determine if stroke risk is increased following zoster.
Methods. Within-person comparisons were undertaken using the self-controlled case-series method and data
from the UK Clinical Practice Research Datalink (19872012). Participants had a rst-ever diagnosis of zoster and
stroke within the study period. Stroke incidence in periods following zoster was compared with incidence in other
time periods. Age-adjusted incidence ratios (IRs) and 95% condence intervals (CIs) were calculated.
There is mounting epidemiological evidence from dif- Herpes zoster is a signicant public health problem
ferent populations using different study designs of in aging populations, affecting 1 million Americans
strong associations between acute systemic infections per year and >88 650 immunocompetent people aged
and risk of acute vascular events [1, 2]. It is believed >60 years annually in the United Kingdom and result-
that the transient increase in risk relates to endothelial ing in signicant complications [46]. It occurs follow-
dysfunction on a background of arteriopathy with pla- ing reactivation of latent varicella zoster virus (VZV)
que rupture and hypercoagulability [3]. The effect of infection. The initial presentation consists of a painful
specic infections on acute vascular events including vesicular rash that can lead to prolonged pain and post-
stroke has been less explored. herpetic neuralgia (PHN), with a major impact on qual-
ity of life [5]. The importance of zoster and associated
complications are reected by the introduction of major
Received 30 September 2013; accepted 23 January 2014. adult vaccination programs in the United States, United
a
S. M. L. and C. M. contributed equally to this work. Kingdom, and elsewhere to prevent disease.
Correspondence: Sinad M. Langan, MB BCh BAO (Hons) MRCP MSc PhD, Fac-
ulty of Epidemiology & Population Health, London School of Hygiene & Tropical In addition to systemic inammation after the acute
Medicine, Keppel St, London WC1E 7HT, UK (sinead.langan@lshtm.ac.uk). reactivation of dormant VZV infection, zoster could in-
Clinical Infectious Diseases crease stroke risk by viral invasion of arterial walls and
The Author 2014. Published by Oxford University Press on behalf of the Infectious
Diseases Societyof America. This is an Open Access article distributed under the terms induction of vasculopathy [7]. Case reports have report-
of the Creative Commons Attribution License (http://creativecommons.org/licenses/ ed strokes following zoster [8, 9]. Two cohort studies of
by/3.0/), which permits unrestricted reuse, distribution, and reproduction in any
medium, provided the original work is properly cited.
adults from Taiwan showed a 1.3-fold (95% condence
DOI: 10.1093/cid/ciu098 interval [CI], 1.1- to 1.6-fold) and 4.5-fold (95% CI, 2.5-
2 CID Langan et al
or died, or the practice left the database. To ensure observation be retrospective diagnoses [21]) and the 4-week period prior to
of incident rather than prevalent or past zoster and stroke, the zoster (the chance of developing and presenting with zoster
study period (observation period for incident events) began 12 after an incident stroke may be different from other time peri-
months after the start of follow-up [19]. To restrict to rst-ever ods; hence, stroke incidence during this time may be lower or
episodes of incident zoster and stroke, we excluded individuals higher than during baseline). The primary analyses assessed
with evidence of zoster, PHN, or stroke before the study period. the effect of (1) zoster at any site and (2) zoster ophthalmicus
As our major interest was in incident arterial strokes, we addi- on stroke (all types). Additional analyses were undertaken for
tionally excluded individuals whose incident episode was a tran- each stroke type separately (cerebral infarctions, hemorrhagic,
sient ischemic attack (TIA) and those with subarachnoid and type-unspecied strokes). Conditional Poisson regression
hemorrhage or with specic established risk factors for subar- was used to calculate incidence ratios (IRs) and 95% condence
achnoid hemorrhage, such as cerebral aneurysms in the circle of intervals (CIs) for stroke within each stratum of the exposed pe-
Willis or arteriovenous malformations. Zoster can occasionally riod compared with baseline, adjusting for age in 5-year bands,
lead to cerebral aneurysms by damaging vessel walls; hence, in- with a sensitivity analysis adjusting for 2-year age bands. A fur-
dividuals with nonspecic cerebral aneurysms were not exclud- ther stratied analysis was undertaken to determine if stroke
ed from the study [7]. Individuals with a record of encephalitis risk following zoster was different between those who received
within 12 months after stroke were excluded, as these may rep- and those who did not receive antiviral treatment for zoster.
resent encephalitis initially misdiagnosed as stroke. When using the SCCS method, the occurrence of an event
must not alter the probability of subsequent exposure and
Exposure and Outcome must not censor the observation period. Risk of death is in-
Zoster Site
until weeks 512. Similar ndings were observed when combin- Ophthalmic 426
ing individuals with zoster in ophthalmic and other branches of Risk period post zoster
the trigeminal nerve (Table 3). 14 wk 6 1.82 (.814.10)
512 wk 22 3.38 (2.185.24)
Stratifying herpes zoster ophthalmicus analyses by receipt of
1326 wk 15 1.39 (.832.35)
oral antivirals also suggested a stronger effect among individuals
2752 wk 16 0.82 (.491.36)
Ophthalmic/other trigeminal 458
Risk period postzoster
Table 2. Age-Adjusted Incidence Ratios for Stroke in Risk 14 wk 6 1.74 (.773.91)
Periods Following Zoster 512 wk 22 3.23 (2.084.99)
1326 wk 16 1.41 (.852.33)
Outcome and Risk Period No. of Cases IRa (95% CI) 2752 wk 18 0.87 (.541.41)
Stroke (all types) 6584 Site unspecified 6126
Risk period after zoster Risk period postzoster
14 wk 90 1.63 (1.322.02) 14 wk 84 1.62 (1.302.02)
512 wk 149 1.42 (1.211.68) 512 wk 127 1.30 (1.091.55)
1326 wk 215 1.23 (1.071.42) 1326 wk 199 1.22 (1.061.41)
2752 wk 303 0.99 (.881.12) 2752 wk 285 1.00 (.891.13)
Abbreviations: CI, confidence interval; IR, incidence ratio. Abbreviations: CI, confidence interval; IR, incidence ratio.
a a
Incidence ratio, adjusting for age in 5-year bands. Incidence ratio adjusting for age in 5-year bands.
4 CID Langan et al
Table 4. Age-Adjusted Incidence Ratios for Stroke in Risk Periods Following Zoster, Stratied by Oral Antiviral Drug Prescriptions
Site of Zoster and Risk Period No. of Cases IRb (95% CI) No. of Cases IRb (95% CI)
Zoster (all) 3647 2937
Risk period post zoster
14 wk 38 1.23 (.891.71) 52 2.14 (1.622.84)
512 wk 75 1.28 (1.021.62) 74 1.61 (1.272.03)
1326 wk 117 1.19 (.991.44) 98 1.29 (1.051.58)
2752 wk 184 1.08 (.931.25) 119 0.89 (.741.07)
Ophthalmic 299 127
Risk period post zoster
14 wk 3 1.26 (.403.96) 3 3.27 (1.0210.44)
512 wk 12 2.57 (1.434.62) 10 5.47 (2.8010.71)
1326 wk 12 1.55 (.862.79) 3 1.00 (.313.18)
2752 wk 10 0.70 (.371.33) 6 1.12 (.482.59)
Site unspecified 3337 2789
Risk period post zoster
14 wk 35 1.23 (.881.73) 49 2.10 (1.582.81)
Similar increased rates of stroke following zoster were ob- Neither study adequately addressed key confounders, for exam-
served for arterial ischemic and hemorrhagic stroke (Supple- ple, BMI and atrial brillation. In addition, these studies did not
mentary Table 1). Sensitivity analyses including the day of assess the timing of increased risk following acute zoster. A re-
zoster in the exposed period, and including only individuals cent Danish registry cohort study identied increased stroke
aged 60 years, those whose follow-up ended within 90 days risks in the rst year following zoster, particularly within
following their stroke ( possibly indicating death due to stroke), 2 weeks of diagnosis. However, that study had important limi-
or those whose records were linked to HES did not modify study tations, including using antiviral treatment as a proxy for zoster
ndings (data not shown). Sensitivity analysis using 2-year age diagnoses and inadequate control for confounding. Hence, the
bands did not modify study ndings. study assessed the effect of treated zoster on stroke; also, the
exposed group would include off-label prescribing for herpes
DISCUSSION simplex virus whereas the unexposed group would include un-
treated individuals with zoster [22]. A UK cohort study reported
The key study nding was that acute zoster is associated with an increased risks of TIA and of stroke in adults of all ages and in
increased risk of stroke in the rst 6 months following zoster. those aged 1840 years, respectively, during up to 24 years of
Risk of incident stroke following zoster was higher for individ- follow-up following zoster [5]. This study used a cohort design,
uals with herpes zoster ophthalmicus or other zoster in the dis- and the results could be prone to residual confounding due to
tribution of the trigeminal nerve. Results also indicated that the between-person differences. Additionally, the research question
use of oral antiviral therapy to treat acute zoster was associated focused on long-term rather than acute effects of zoster on
with a less marked increase in incident strokes following zoster stroke.
exposure. These ndings from a large population-based data [11]. Our study has shown a signicantly increased risk of
source provide important insights into the temporality and stroke following zoster, in particular for zoster in the trigeminal
magnitude of stroke risk increase following zoster. nerve distribution. Use of the SCCS method is a unique ap-
Two previous cohort studies from Taiwan reported a 30% in- proach; its major advantage for this study question is that
creased risk of stroke in the year following zoster with a >4-fold xed confounders are implicitly controlled for, as analyses are
increased risk following herpes zoster ophthalmicus [10, 11]. within-person. Our ndings have demonstrated that the rst
6 CID Langan et al
the ndings, contributed to critical revision of the manuscript for important 13. General Practice Research Database. Available at: http://www.gprd.com/
intellectual content, and approved the nal version. C. M. and S. L. T. had products/database.asp. Accessed 14 July 2011.
full access to all the data in the study and take responsibility for the integrity 14. Herrett E, Thomas S, Schoonen W, Smeeth L, Hall A. Validation and
of the data and the accuracy of the data analysis. validity of diagnoses in the General Practice Research Database: a sys-
Disclaimer. The ndings and conclusions in this report are those of the tematic review. Br J Clin Pharmacol 2010; 69:414.
authors and do not necessarily represent the views of the UK Department of 15. Smeeth L, Cook C, Fombonne E, et al. MMR vaccination and pervasive
Health, the Stroke Association, or the Wellcome Trust. This article presents developmental disorders: a case-control study. Lancet 2004; 364:9639.
independent research funded in part by the National Institute for Health 16. Smeeth L, Thomas S, Hall A, Hubbard R, Farrington P, Vallance P. Risk
Research (NIHR). The funders had no role in study design, data collection of myocardial infarction and stroke after acute infection or vaccination.
and analysis, decision to publish, or preparation of the manuscript. N Engl J Med 2004; 351:26118.
Financial support. This work was supported by the Stroke Association 17. Smeeth L, Cook C, Thomas S, Hall AJ, Hubbard R, Vallance P. Risk of
(grant number TSA 2011/05); the NIHR (Clinician Scientist Fellowship to deep vein thrombosis and pulmonary embolism after acute infection in
S. M. L., grant number NIHR/CS/010/014, and Career Development Fellow- a community setting. Lancet 2006; 367:10759.
ship to S. L. T., grant number CDF 2010-03-032); and the Wellcome Trust 18. Farrington CP. Relative incidence estimation from case series for vac-
(Senior Fellowship in Clinical Science to L. S., grant number 098504/Z/12/Z). cine safety evaluation. Biometrics 1995; 51:22835.
Potential conicts of interest. All authors: No reported conicts. 19. Lewis J, Bilker W, Weinstein R, Strom B. The relationship between time
All authors have submitted the ICMJE Form for Disclosure of Potential since registration and measured incidence rates in the General Practice
Conicts of Interest. Conicts that the editors consider relevant to the con- Research Database. Pharmacoepidemiol Drug Saf 2005; 14:44351.
tent of the manuscript have been disclosed. 20. Minassian C, DAiuto F, Hingorani AD, Smeeth L. Invasive dental treat-
ment and risk for vascular events: a self-controlled case series. Ann In-
tern Med 2010; 153:499506.
References 21. Tata L, West J, Harrison T, Farrington P, Smith C, Hubbard R. Does
inuenza vaccination increase consultations, corticosteroid prescrip-
1. Ridker PM, Silvertown JD. Inammation, C-reactive protein, and athe- tions, or exacerbations in subjects with asthma or chronic obstructive