This study examined the association between herpes zoster infection and risk of peripheral arterial disease using a nationwide cohort in Taiwan. The study found that patients with herpes zoster had a 13% higher risk of developing peripheral arterial disease compared to those without herpes zoster, after adjusting for risk factors. Female sex and older age were also associated with small increases in risk. While antiviral treatment for herpes zoster did not affect risk of peripheral arterial disease, larger prospective studies are still needed to determine if treatment can reduce risk.

1. JOURNAL CLUB -
COHORT STUDY.
PRESENTED BY: GUIDED BY:
DR. SUBRAHAM PANY. DR. JYOTIRANJAN SAHOO.

2. Herpes Zoster infection increases the risk
of peripheral arterial disease
A nationwide cohort study

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6. HERPES ZOSTER INFECTION INCREASES THE RISK OF
PERIPHERAL ARTERIAL DISEASE
A NATIONWIDE COHORT STUDY
• AUTHORS: Te-Yu Lin, Fu-Chi Yang, Cheng-Li Lin, Chia-Hung Kao,
Hsin-Yi Lo & Tse-Yen Yang
• Received: 19 April 2016 / Received in final form: 15 June 2016
• Accepted: 11 July 2016
• http://dx.doi.org/10.1097/MD.0000000000004480

7. INTRODUCTION
• Varicella-zoster virus (VZV) causes 2 distinct clinical diseases: varicella and
herpes zoster (HZ).
• Varicella, more commonly called chickenpox, is a primary infection resulting
from exposure to the virus.
• The virus primarily infects children aged younger than 13 years, and the
infection is characterized by the cutaneous distribution of diffuse
maculopapules, vesicles, and scabs in various disease stages.
• VZV infections then become latent in the dorsal root & autonomic ganglia.

8. • Spontaneous reactivation or host cell-mediated immunity decrease, such
as in cases of cancer, transplant, and AIDS, may occur later in life.
• Peripheral arterial disease (PAD) is a circulatory disease that impairs
adequate blood flow to peripheral tissues and causes tissue damage.
• Atherosclerosis is the major pathophysiology of PAD.
• The traditional risk factors for PAD are older age, male sex, hypertension,
diabetes, hyperlipidaemia, obesity, smoking, and a family history of
vascular diseases.
INTRODUCTION (CONT.…)

9. • Varicella-zoster virus reactivation causes meningoencephalitis, myelitis,
ocular disorders, and vasculopathy.
• VZV-induced vasculopathy encompasses 2 major spectrums:
• Large-vessel vasculopathy and
• small-vessel vasculopathy.
INTRODUCTION (CONT.…)

10. WHAT IS ALREADY KNOWN ON THIS SUBJECT ?
• Chang et al. observed the prevalence of PAD in the general population is
12% to 14%.
• Recent epidemiological studies from Taiwan, Denmark, and the United
Kingdom have revealed an increased risk of stroke after VZV infection.
• In addition, Wang et al observed that HZ infection is associated with an
increased risk of acute coronary syndrome.

11. WHAT THIS PAPER ADDS ?
(OBJECTIVE OF THE STUDY)
• However, no epidemiological studies have determined the association
between HZ infection and PAD.
• Therefore, this population-based retrospective cohort study was conducted
to investigate whether HZ infection increases the risk of PAD.

12. METHODOLOGY:
DATA SOURCE:
The present study was conducted using data from the Longitudinal Health
Insurance Database 2000 (LHID2000) obtained from Taiwan's National Health
Insurance (NHI) program.
The representativeness of the LHID2000 to the entire Taiwan population has been
validated by previous studies, and all patient information in the database are
anonymized and deidentified.
The diseases were coded according to ICD-9-CM diagnosis codes, 2001 edition.

13. ETHICAL APPROVAL:
The Ethics Review Board of China Medical University and Hospital in Taiwan
approved this study (CMUH104-REC2–115).
STUDY PARTICIPANTS:
The HZ cohort comprised patients newly diagnosed with HZ between January 1,
2000 and December 31, 2010; the diagnosis date was set as the index date.
Patients with a history of PAD before the index date or incomplete age or sex
information were excluded.
The non-HZ cohort patients were randomly identified from the LHID2000 during
the same period, with exclusion criteria similar to that for the HZ cohort.
Four patients from the non-HZ cohort were frequency-matched with each
patient from the HZ cohort with respect to sex, age (at 5-year intervals), and
index year.

14. OUTCOME AND COMORBIDITIES:
The main outcome of this study was newly diagnosed PAD during follow-up.
The patients were followed from the index date until PAD diagnosis, withdrawal
from the insurance system, death, or December 31, 2011, whichever occurred
first.
Baseline comorbidities, namely obesity, tobacco dependency, hypertension,
hyperlipidaemia, heart failure, coronary artery disease, diabetes, stroke, chronic
obstructive pulmonary disease, and asthma.
Acyclovir and Valaciclovir were the antiviral treatment of HZ infection.

15. STATISTICAL ANALYSIS
• The distributions of demographic data and comorbidities were compared between
the HZ and non-HZ cohorts by using chi-square and t tests.
• Cumulative incidence curves of PAD for both cohorts by using the Kaplan–Meier
method and the curve difference of both cohorts by using the log-rank test was
determined.
• The incidence densities of PAD were estimated for each cohort and stratified by
sex, age, and comorbidities.
• Univariable and multivariable Cox proportional-hazards regression analyses were
performed to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs)
of PAD development for the HZ cohort compared with those for the non-HZ
cohort.

16. • The multivariable Cox models were adjusted for age, sex, and comorbidities of
obesity, tobacco dependency, hypertension, hyperlipidaemia, heart failure, CAD,
diabetes, stroke, COPD, and asthma.
• To investigate whether antiviral treatment for HZ affects the risk of PAD, the HZ
cohort were divided into 2 subgroups according to the administered antiviral
treatment and compared the differences in the risk of PAD.
• All statistical analyses were performed using SAS 9.4 software and the incidence
curve was calculated using R software.
• A 2-sided P value of <0.05 was considered significant.
STATISTICAL ANALYSIS (CONT.)

17. RESULTS
• 35,391 patients
were enrolled in
the HZ cohort
and 141,556
patients in the
non-HZ cohort,
with similar sex &
age distributions.

18. • The cumulative incidence of
PAD estimated using
Kaplan–Meier analysis was
significantly different
among the 2 cohorts over
the follow-up period
(P < 0.001).

19. After adjustment for age, sex, and comorbidities, the incidence density rates of
PAD were higher in the HZ cohort than in the non-HZ cohort (4.64 vs 3.81 per
1000 person-years), with an adjusted HR (aHR) of 1.13 (95% CI 1.09–1.16)

20. • Compared with the male patients,
the female patients had a 3%
increased aHR of PAD (aHR 1.03, 95%
CI 1.00–1.06); this aHR increased 4%
risk (aHR 1.04, 95% CI 1.03–1.04)
with age (in 1-year intervals).
• The risk of PAD was higher in patients
with diabetes, hypertension, tobacco
dependency, hyperlipidaemia, CAD,
heart failure, and stroke.

21. The risk of PAD was not significantly higher in the patients with HZ who received the
antiviral treatment than in those who did not receive the treatment (aHR 1.00, 95%
CI 0.92–1.08)

22. DISCUSSION
• This study is the first to elucidate the risk of PAD in patients with HZ by using a
nationwide database.
• In this population-based cohort study, we adjusted several traditional risk factors
for PAD and reported that HZ is an independent risk factor for PAD.
• The risk of PAD was 13% increased in the HZ cohort than in the non-HZ cohort.
• Most patients with HZ in this study were women, and PAD risks increased in both
men and women with HZ.
• The study revealed that in addition to well-known risk factors such as
hypertension, diabetes, and hyperlipidaemia, HZ is also a risk factor for PAD.

23. CONFOUNDERS:
First, the NHI reimburses the cost of antiviral therapy only for immunocompromised
patients and those with complications. The patients who received the antiviral
treatment may have had more comorbidities and traditional risk factors for PAD
than did the patients who did not receive the treatment.
Second, the NHI reimburses expenses for only 5 to 10 days of antiviral treatment.
Third, the treatment initiation time and patient compliance were unavailable in the
National Health Insurance Research Database.

24. RECOMMENDATIONS & CONCLUSION:
• Additional prospective randomized controlled studies are necessary to
determine whether antiviral treatment effectively reduces the risk of PAD
after HZ infection.
• In conclusion, this study examined a nationwide population-based database
containing a relatively high number of HZ cases and revealed that patients
with HZ infection have a higher risk of PAD than do those without HZ.
Physicians should carefully monitor vascular complications when treating
patients with HZ.

25. STROBE STATEMENT
Item No
Recommendation
checklist
Title and abstract
1
(a) Indicate the study’s design with a commonly
used term in the title or the abstract

(b) Provide in the abstract an informative and
balanced summary of what was done and what was
found

Introduction
Background/rationale 2 Explain the scientific background and rationale for
the investigation being reported

Objectives 3 State specific objectives, including any prespecified
hypotheses


26. Methods
Study design 4 Present key elements of study design early in the paper

Setting 5 Describe the setting, locations, and relevant dates, including periods of
recruitment, exposure, follow-up, and data collection 
Participants 6 Give the eligibility criteria, and the sources and methods of selection of
participants

Variables 7 Clearly define all outcomes, exposures, predictors, potential
confounders, and effect modifiers. Give diagnostic criteria, if applicable

Data sources/
measurement
8 For each variable of interest, give sources of data and details of methods
of assessment (measurement). Describe comparability of assessment
methods if there is more than one group 

27. Bias 9 Describe any efforts to address potential sources of bias Mentioned
in conclusion
Study size 10 Explain how the study size was arrived at Not
mentioned
Quantitative
variables
11 Explain how quantitative variables were handled in the analyses.
If applicable, describe which groupings were chosen and why 
Statistical
methods
12 (a) Describe all statistical methods, including those used to
control for confounding 
(b) Describe any methods used to examine subgroups and
interactions 
(c) Explain how missing data were addressed Not
mentioned
(d) Cross-sectional study—If applicable, describe analytical
methods taking account of sampling strategy
NA
(e) Describe any sensitivity analyses NONE

28. Results
Participant
s
13
(a) Report numbers of individuals at each stage of study Not
mentioned
(b) Give reasons for non-participation at each stage Not
mentioned
(c) Consider use of a flow diagram Not
mentioned
Descriptiv
e data
14 (a) Give characteristics of study participants (eg demographic, clinical, social)
and information on exposures and potential confounders 
(b) Indicate number of participants with missing data for each variable of
interest
Not
mentioned
Outcome
data
15 Report numbers of outcome events or summary measures

Main
results
16 (a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates
and their precision.
Not
mentioned
(b) Report category boundaries when continuous variables were categorized Not
mentioned
(c) If relevant, consider translating estimates of relative risk into absolute risk for
a meaningful time period
Not
mentioned
Other
analyses
17 Report other analyses done—eg analyses of subgroups and interactions, and
sensitivity analyses
