E P I DE M I O L O G Y A N D HE A L T H S E R V IC E S RE SE AR CH
BJD
British Journal of Dermatology
Herpes zoster infection associated with acute coronary syndrome: a population-based retrospective cohort study C.-C. Wang,1,2 C.-L. Lin,3 Y.-J. Chang,3 G.-J. Wang,2 F.-C. Sung3,4 and C.-H. Kao2,5 1
Division of Cardiology, Department of Internal Medicine, Taichung Tzu-Chi Buddhist General Hospital, Taichung, Taiwan Graduate Institute of Clinical Medicine Science, College of Medicine, China Medical University, No. 2, Yuh-Der Road, Taichung 404, Taiwan 3 Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan 4 Department of Public Health, China Medical University, Taichung, Taiwan 5 Department of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan 2
Summary Correspondence Chia-Hung Kao. E-mail: [email protected]
Accepted for publication 1 December 2013
Funding sources This study was supported in part by the National Sciences Council, Executive Yuan grant number SC99-2621-M-039-001, China Medical University Hospital (grant number 1MS1), the Taiwan Ministry of Health and Welfare Clinical Trial and Research Center for Excellence (grant number DOH102-TD-B-111-004), Cancer Research Center of Excellence (MOHW103-TDB-111-03) and Taichung Tzu Chi General Hospital (TTCRD-101-22).
Conflicts of interest None declared. DOI 10.1111/bjd.12768
Background Vasculopathy in varicella zoster virus (VZV) infection and a proposed association between herpes virus infection and atherosclerosis suggest a possible link between VZV infection and vascular thrombosis. Objectives To determine the risk of acute coronary syndrome (ACS) associated with herpes zoster infection. Methods We used the Taiwan National Health Insurance Research Database to identify 57 958 patients newly diagnosed with herpes zoster between 1999 and 2010; 231 832 patients without herpes zoster were examined as the control group. Both cohorts were followed up until the end of 2010 to measure the incidence of ACS. Cox proportional-hazards regression and Kaplan–Meier analyses were used to measure the hazard ratios (HR) and the cumulative incidences of ACS, respectively. Results The incidence of ACS was 124-fold higher in the herpes zoster group than in the control group [368 vs. 296 per 10 000 person-years, 95% confidence interval (CI) 116–133]. After adjusting for age, sex and comorbidities, the HR of ACS for the herpes zoster group compared with the control group was 115 (95% CI 107–124). Analysis by the time lag (≤ 3 months, ≤ 1 year, > 1 year) showed that the incidence of ACS remained significantly higher in the herpes zoster group than in the control group, with an adjusted HR of 110 (95% CI 102–119) after the 1-year follow-up period. The Kaplan–Meier survival curve showed that the risk of ACS was significantly higher in the herpes zoster group than in the control group (P < 0001). Conclusion Herpes zoster infection is associated with an increased risk of ACS.
What’s already known about this topic?
• •
The relationships between coronary heart diseases and Chlamydia pneumonia, Helicobacter pylori, cytomegalovirus, herpes simplex virus, Mycobacterium tuberculosis, influenza and periodontal infections have been investigated. No population-based cohort study has investigated the association between herpes zoster infection and the development of acute coronary syndrome (ACS) in people.
What does this study add?
• •
1122
The incidence of ACS was 124-fold higher in the herpes zoster group than in the control group. The incidence of ACS remained significantly higher in the herpes zoster group than in the control group, with an adjusted hazard ratio of 114 after the 1-year followup period.
British Journal of Dermatology (2014) 170, pp1122–1129
© 2013 British Association of Dermatologists
Herpes zoster infection and ACS, C.-C. Wang et al. 1123
Varicella zoster virus (VZV) is a double-stranded DNA virus of the Herpesviridae family. VZV affects only humans, and the clinical manifestations of VZV infection are classified as varicella (chickenpox) or herpes zoster (shingles). The virus primarily infects children aged 5–9 years, manifesting as chickenpox, which is characterized by the cutaneous distribution of diffuse and scattered maculopapular vesicles. Subsequently, VZV infections become latent in cranial nerve and dorsal root ganglia and in autonomic ganglia. As cellular immunity to the VZV diminishes with age or in persons in an immunocompromised state, reactivation of the latent VZV may occur, resulting in shingles, which is characterized by unilateral vesicular eruptions within the affected dermatomes. Vasculopathy in VZV infection may result from the production of procoagulant antiphospholipid antibodies1 or immune complex mediated vasculitis; an association between herpes virus infection and atherosclerosis has also been proposed.2 These relationships suggest a possible link between VZV infection and vascular thrombosis. Previous studies of herpes zoster have focused primarily on its possible relationships with cerebrovascular stroke.3,4 Several cases of herpes zoster-induced vasculopathy and stroke have been reported, and it has been proposed that the herpes virus spreads transaxonally to the nascent blood vessels, where it induces inflammation and thrombotic responses. Recently, a large population-based cohort study has reported that the risk of stroke and herpes zoster ophthalmicus increased following a herpes zoster attack during the 1-year follow-up period.5 Several case reports have described peripheral arterial thrombosis in patients with concurrent herpes zoster infection.6,7 To our knowledge, no large population-based cohort study has investigated the association between herpes zoster infection and the development of acute coronary syndrome (ACS). We hypothesized that the risk of ACS increased following the reactivation of VZV infection in an Asian population-based cohort.
Patients and methods We analysed a subset of data from the reimbursement claims provided by the National Health Research Institute in Taiwan. The claims database contains information from 13 insurance programmes. Taiwan implemented a universal insurance system in March 1995. The National Health Insurance (NHI) system provides health care for 99% of the 23 million citizens of Taiwan through contracts with 97% of the health-care facilities.8 We reviewed the reimbursement claims of the NHI that had been previously extracted and compiled in the NHI Research Database (NHIRD). The NHIRD claims records contained information on both ambulatory and inpatient medical services from 1996 to 2010, and diagnoses were coded based on the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). The patients’ personal information was encrypted to ensure privacy. To ensure the accuracy of the claims data, the Bureau of NHI (BNHI) invites experts to review claims by randomly sampling every 100 outpatient claims and every 15 inpatient © 2013 British Association of Dermatologists
claims. False claims and unnecessary treatment result in severe penalties from BNHI.9 Several studies have demonstrated the high accuracy and validity of ICD-9 diagnosis in NHIRD.8,10 Our study was approved by the ethics review board of the China Medical University (CMU-REC-101-012). Participants and outcome measures Patients newly diagnosed with herpes zoster (ICD-9-CM code 053) between 1999 and 2010 were included in our study cohort. The index date was defined as the date of the first clinical visit for herpes zoster. We excluded patients with a history of ACS (ICD-9-CM codes 410, 4111) or with missing age or sex information at the baseline. The herpes zoster cohort to nonherpes zoster cohort was selected at a 1:4 ratio in order to enhance the power of statistical tests and to prevent an insufficient number of ACS cases in the stratified analysis. The nonherpes zoster cohort was selected using a simple random sampling method to four randomly selected insured people from NHI beneficiaries without herpes zoster status for every person with herpes zoster in the same period, frequency matched by age, sex and index year of herpes zoster diagnosis. Subjects in both the herpes zoster and nonherpes zoster cohorts were followed up until they were diagnosed with ACS or censored because of loss of follow-up, withdrawal from insurance, death or until the end of 2010. Definition of exposure At least three previous claims for ambulatory or inpatient care for a single diagnosis before the index date represented a comorbidity at the baseline. The baseline comorbidities considered were hypertension (ICD-9-CM codes 401–405), diabetes mellitus (ICD-9-CM code 250), hyperlipidaemia (ICD9-CM code 272) and cerebral vascular disease (ICD-9-CM codes 430–438), chronic obstructive pulmonary disease (COPD; ICD-9-CM codes 491–493, 494, 496), renal dysfunction (ICD-9-CM codes 580–589) and cancer (ICD-9-CM codes 140–208). Acyclovir and valacyclovir were the antiviral treatments for herpes zoster infection. Famciclovir was not considered because it was not imported into Taiwan until 2011. Statistical analysis The distributions of categorical demographics and clinical characteristics among the herpes zoster and the control groups were compared using the v2 test. Patients were classified based on socioeconomic status; occupation [white-collar workers (professionals, managers and administrative workers), bluecollar workers (farmers, fishermen and industrial labourers) or ‘other’ (retired, unemployed and low-income patients)]; urbanization (urbanization level was categorized by the population density of the residential area into two groups, with urban as the most urbanized and rural as the least urbanized) and monthly income (new Taiwan dollars 15 000, 15 000– 22 799 and > 22 800). We used a Poisson regression model British Journal of Dermatology (2014) 170, pp1122–1129
1124 Herpes zoster infection and ACS, C.-C. Wang et al.
to estimate the ratios of the rates for the herpes zoster group and the rates of the control group. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using a multivariable Cox proportional-hazards regression model to examine associations between herpes zoster and the incidence of ACS. Variables considered in the multivariate analysis included sex, age, frequency of medical visits, urbanization, monthly income (in new Taiwan dollars), occupation, comorbidities and medication status. We have also addressed the attributable risk and 95% CI from herpes infection.11 All analyses were performed using SAS version 9.2 (SAS, Cary, NC, U.S.A.), and two-tailed P-values < 005 were considered statistically significant.
Results Baseline characteristics A total of 57 958 herpes zoster patients and 231 832 control patients were included in our study (Table 1). Among all patients, 601% were < 55 years old and 526% were women. Over half were white-collar workers. The herpes zoster group exhibited significantly higher rates of comorbidities at the baseline. Hypertension (285% vs. 251%), followed by hyperlipidaemia (186% vs. 155%), COPD (112% vs. 887%), renal dysfunction (705% vs. 523%), diabetes mellitus (109% vs. 93%), cancer (343% vs. 224%) and cerebral vascular disease (90% vs. 79%) showed discrepancies in prevalence. Attributable risks and 95% CIs Approximately 22% of the ACS incidence in the herpes cohort would be eliminated if the herpes exposure was eliminated (95% CI 11–32%). In other words, the excess ACS due to herpes zoster was 22%. Incidence rate ratios and hazard ratios of acute coronary syndrome Over the 12-year follow-up period, 1053 patients with herpes zoster and 3318 control patients were diagnosed with ACS (Table 2). The incidence rates for the herpes zoster and the control groups were 368 and 296 per 10 000 person-years, respectively. The overall adjusted HR (aHR) of ACS was 115 for patients with herpes zoster (95% CI 107–124). In both groups, ACS occurred more frequently in men than in women. Herpes zoster patients over the age of 65 years had a higher incidence of ACS (25%) than the age-matched controls, and the risk of ACS progressively increased with increasing age. The risk of ACS was higher among people living in urban areas than in rural areas (aHR 108, 95% CI 102–115). The risk of ACS was highest among the lowest income group (aHR 131, 95% CI 119–145). The presence of hypertension, hyperlipidemia, diabetes mellitus, cerebral vascular disease, COPD and renal dysfunction was also associated with a higher British Journal of Dermatology (2014) 170, pp1122–1129
incidence of ACS. We further divided the herpes zoster group into two subgroups according to treatment. Patients treated with antivirals exhibited a higher incidence rate of ACS than those who were not treated with antivirals, but this difference was not significant after adjusting for all potential variables (aHR 096, 95% CI 080–115) (Table 4). Acute coronary syndrome in relation to time since herpes zoster diagnosis Analysis divided by the length of follow-up periods showed that the risk of ACS among the two cohorts did not differ significantly within 1 year after herpes zoster was diagnosed. After the 1-year follow-up period, the herpes zoster group had a significantly higher risk of ACS than the nonherpes zoster group (aHR 110, 95% CI 102–119) (Table 5). Kaplan– Meier survival analysis showed that patients with herpes zoster infections had significantly higher ACS rates than the control patients (log-rank test, P < 0001; Fig. 1).
Discussion Our study demonstrated that herpes zoster infection is associated with an increased risk of ACS. After adjusting for all potential covariates, including baseline comorbidities, socioeconomic status and medication, the association between the infection and the development of ACS remained significant. Association between varicella zoster virus infection and ischaemic heart disease In the literature, the increased risk of cerebrovascular events and peripheral vascular thromboembolism following a herpes zoster attack has been established.12–15 Massano et al.14 described the development of acute occlusions in the left common iliac and right femoral arteries in a 39-year-old man 1 week after VZV infection. In addition, Peyton et al.15 reported two cases with varicella pneumonia and coexisting severe lower limb ischaemia caused by thrombosis of the profounda femoris and tibial arteries. However, the relationship between herpes zoster infection and ACS has been rarely discussed. A study of the association between herpes virus infection and the incidence of coronary heart disease (CHD) found no significant difference in the risk of CHD in patients with a baseline history of shingles compared with control patients.16 However, this lack of an association may have resulted from a smaller sample size and a shorter follow-up duration than in our study. A case–control study showed that a higher proportion of patients was seropositive to four or more herpes virus (high herpetic burden) in the ischaemic heart disease group than in the control group.17 Therefore, the relationship between VZV infection and CHD remains controversial. Compared with previous studies, our study considered a larger population and longer duration of follow-up. We proposed that following a herpes zoster attack the risk of ACS increased in the long-term follow-up period. © 2013 British Association of Dermatologists
Herpes zoster infection and ACS, C.-C. Wang et al. 1125 Table 1 Demographic characteristics and comorbidity in patients with and without herpes zoster
Herpes zoster
Variables
No (n = 231 832)
Yes (n = 57 958)
n
%
n
%
474 526
27 457 30 501
474 526
100
337 264 170 229
19 517 15 308 9872 13 261
337 264 170 229
100
415 585
23 972 33 986
414 586
064
364 425 211
19 358 24 967 13 633
334 431 235
< 0001
512 351 136 446
29 860 20 826 7272 254
515 359 126 247
< 0001
< 0001
251 93 155 79 887
16 491 6318 10 799 5209 6486
285 109 186 90 112
< < < <
1 year 2693
Herpes zoster cohort a
Person-years
Rate
Event
Person-years
Ratea
IRR (95% CI)
b
57 045 261 729 905 539
326 239 297
58 193 860
14 252 54 174 232 182
407 356 370
125 (121–129)** 124 (120–128)** 125 (121–128)**
120 (089–162) 114 (094–139) 110 (102–119)*
aHR (95% CI)
IRR, incidence rate ratio; CI, confidence interval; aHR, adjusted hazard ratio. aRate per 1000 person-years. baHR, adjusted for age, sex, urbanization, monthly income (new Taiwan dollars), occupation, frequency of medical visits, hypertension, diabetes mellitus, hyperlipidemia, cerebral vascular disease, chronic obstructive pulmonary disease, renal function, cancer and medication in Cox proportional-hazards regression model. *P < 005, **P < 0001.
In conclusion, patients with a history of herpes zoster infection are more likely to develop ACS than patients without such a history. Whether early aggressive antiviral treatment may prevent subsequent VZV-associated vasculopathy requires further investigation.
References
Fig 1. Acute coronary syndrome-free survival time for patients with herpes zoster and the control cohort in Taiwan.
study design and control measures for confounding factors, bias resulting from unknown confounding factors may have affected our results. Thirdly, all data in the NHIRD are anonymous. Thus, relevant clinical variables, such as blood pressure, imaging results, pathology findings and serum laboratory data were unavailable for our study patient cases. However, the data regarding herpes zoster and ACS diagnoses were nonetheless reliable. Fourthly, our study focused on the association between reactivation of VZV infection and the risk of ACS because we hypothesized that reactivation of VZV infection increased inflammation, the production of procoagulants and the induction of vasculitis. Because of the limited follow-up period, our results cannot be extrapolated to determine further whether patients with active shingles or during the incubation period have an increased risk of ACS. However, based on our literature review, we believe that reactivation of VZV infection could result in vasculopathy and is associated with an increased risk of ACS. Finally, we could only identify patients with VZV infection based on the ICD-9 codes and had no access to serology data for clinical validation. Therefore, this study was unable to clearly differentiate the suspected cases from the verified cases. British Journal of Dermatology (2014) 170, pp1122–1129
1 Uthman IW, Gharavi AE. Viral infections and antiphospholipid antibodies. Semin Arthritis Rheum 2002; 31:256–63. 2 Jacob HS, Visser M, Key NS et al. Herpes virus infection of the endothelium: new insights into atherosclerosis. Trans Am Clin Climatol Assoc 1992; 103:95–104. 3 Gilbert GJ. Herpes ophthalmicus and delayed contralateral hemiparesis. Relationship of the syndrome to central nervous system granulomatous angiitis. JAMA 1974; 229:302–4. 4 Rosenblum WI, Hadfield MG. Granulomatous angiitis of the nervous system in cases of herpes zoster and lymphosarcoma. Neurology 1972; 22:348–54. 5 Kang JH, Ho JD, Chen YH et al. Increased risk of stroke after a herpes zoster attack. A population-based follow-up study. Stroke 2009; 40:3443–8. € nal AB et al. Reactivated varicella zoster 6 Tezcan ME, Teksut TK, O virus may cause peripheral arterial thrombosis. J Rheumatol 2010; 37:1785–6. 7 Limb J, Binning A. Thrombosis associated with varicella zoster in an adult. Int J Infect Dis 2009; 13:e498–500. 8 Cheng CL, Kao YH, Lin SJ et al. Validation of the National Health Insurance Research Database with ischemic stroke cases in Taiwan. Pharmacoepidemiol Drug Saf 2011; 20:236–42. 9 Lin LY, Lee CH, Yu CC et al. Risk factors and incidence of ischemic stroke in Taiwanese with nonvalvular atrial fibrillation – A nation wide database analysis. Atherosclerosis 2011; 217:292–5. 10 Yu YB, Gau JP, Liu CY et al. A nation-wide analysis of venous thromboembolism in 497,180 cancer patients with the development and validation of a risk-stratification scoring system. Thromb Haemost 2012; 108:225–35. 11 Spiegelman D, Hertzmark E, Wand HC. Point and interval estimates of partial population attributable risk in cohort studies: examples and software. Cancer Causes Control 2007; 18:571–9. 12 Gilden DH, Randall JC, Mahalingam R. VZV vasculopathy and postherpetic neuralgia. Progress and perspective on antiviral therapy. Neurology 2005; 64:21–5. 13 Gilden D, Cohrs RJ, Mahalingam R et al. Varicella zoster virus vasculopathies: diverse clinical manifestations, laboratory features, pathogenesis, and treatment. Lancet Neurol 2009; 8:731–40.
© 2013 British Association of Dermatologists
Herpes zoster infection and ACS, C.-C. Wang et al. 1129 14 Massano J, Ferreira D, Toledo T et al. Stroke and multiple peripheral thrombotic events in an adult with varicella. Eur J Neurol 2008; 15:e90–1. 15 Peyton BD, Cutler BS, Stewart FM et al. Spontaneous tibial artery thrombosis associated with varicella pneumonia and free protein S deficiency. J Vasc Surg 1998; 27:563–7. 16 Havlik RJ, Blackwelder WC, Kaslow R et al. Unlikely association between apparent herpes virus infection and coronary incidence at older ages. The Framingham Heart Study. Arterioscler Thromb Vasc Biol 1989; 9:877–80. 17 Esteban-Hernandez J, San RMJ, Gil R et al. Association between herpes burden and chronic ischemic heart disease: matched case– control study. Med Clin (Barc) 2011; 137:157–60. 18 Uthman I, Taher A, Khalil I. Hughes syndrome associated with varicella infection. Rheumatol Int 2001; 20:167–8.
© 2013 British Association of Dermatologists
19 Bodensteiner JB, Hille MR, Riggs JE. Clinical features of vascular thrombosis following varicella. Am J Dis Child 1992; 146:100–2. 20 Nagel MA, Traktinskiy I, Azarkh Y et al. Varicella zoster virus vasculopathy. Analysis of virus-infected arteries. Neurology 2011; 77:364–70. 21 Brisson M, Edmunds WJ, Law B et al. Epidemiology of varicella zoster infection in Canada and the United Kingdom. Epidemiol Infect 2011; 127:305–14. 22 Okamoto S, Hata A, Sadaoka K et al. Comparison of varicella zoster virus specific immunity to patients with diabetes mellitus and healthy individuals. J Infect Dis 2009; 200:1606–10. 23 Guilford T, Morris D, Gray D et al. Atherosclerosis: pathogenesis and increased occurrence in individuals with HIV and Mycobacterium tuberculosis infection. HIV AIDS (Aukl) 2010; 2:211–18.
British Journal of Dermatology (2014) 170, pp1122–1129
BJD
British Journal of Dermatology
Herpes zoster infection associated with acute coronary syndrome: a population-based retrospective cohort study C.-C. Wang,1,2 C.-L. Lin,3 Y.-J. Chang,3 G.-J. Wang,2 F.-C. Sung3,4 and C.-H. Kao2,5 1
Division of Cardiology, Department of Internal Medicine, Taichung Tzu-Chi Buddhist General Hospital, Taichung, Taiwan Graduate Institute of Clinical Medicine Science, College of Medicine, China Medical University, No. 2, Yuh-Der Road, Taichung 404, Taiwan 3 Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan 4 Department of Public Health, China Medical University, Taichung, Taiwan 5 Department of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan 2
Summary Correspondence Chia-Hung Kao. E-mail: [email protected]
Accepted for publication 1 December 2013
Funding sources This study was supported in part by the National Sciences Council, Executive Yuan grant number SC99-2621-M-039-001, China Medical University Hospital (grant number 1MS1), the Taiwan Ministry of Health and Welfare Clinical Trial and Research Center for Excellence (grant number DOH102-TD-B-111-004), Cancer Research Center of Excellence (MOHW103-TDB-111-03) and Taichung Tzu Chi General Hospital (TTCRD-101-22).
Conflicts of interest None declared. DOI 10.1111/bjd.12768
Background Vasculopathy in varicella zoster virus (VZV) infection and a proposed association between herpes virus infection and atherosclerosis suggest a possible link between VZV infection and vascular thrombosis. Objectives To determine the risk of acute coronary syndrome (ACS) associated with herpes zoster infection. Methods We used the Taiwan National Health Insurance Research Database to identify 57 958 patients newly diagnosed with herpes zoster between 1999 and 2010; 231 832 patients without herpes zoster were examined as the control group. Both cohorts were followed up until the end of 2010 to measure the incidence of ACS. Cox proportional-hazards regression and Kaplan–Meier analyses were used to measure the hazard ratios (HR) and the cumulative incidences of ACS, respectively. Results The incidence of ACS was 124-fold higher in the herpes zoster group than in the control group [368 vs. 296 per 10 000 person-years, 95% confidence interval (CI) 116–133]. After adjusting for age, sex and comorbidities, the HR of ACS for the herpes zoster group compared with the control group was 115 (95% CI 107–124). Analysis by the time lag (≤ 3 months, ≤ 1 year, > 1 year) showed that the incidence of ACS remained significantly higher in the herpes zoster group than in the control group, with an adjusted HR of 110 (95% CI 102–119) after the 1-year follow-up period. The Kaplan–Meier survival curve showed that the risk of ACS was significantly higher in the herpes zoster group than in the control group (P < 0001). Conclusion Herpes zoster infection is associated with an increased risk of ACS.
What’s already known about this topic?
• •
The relationships between coronary heart diseases and Chlamydia pneumonia, Helicobacter pylori, cytomegalovirus, herpes simplex virus, Mycobacterium tuberculosis, influenza and periodontal infections have been investigated. No population-based cohort study has investigated the association between herpes zoster infection and the development of acute coronary syndrome (ACS) in people.
What does this study add?
• •
1122
The incidence of ACS was 124-fold higher in the herpes zoster group than in the control group. The incidence of ACS remained significantly higher in the herpes zoster group than in the control group, with an adjusted hazard ratio of 114 after the 1-year followup period.
British Journal of Dermatology (2014) 170, pp1122–1129
© 2013 British Association of Dermatologists
Herpes zoster infection and ACS, C.-C. Wang et al. 1123
Varicella zoster virus (VZV) is a double-stranded DNA virus of the Herpesviridae family. VZV affects only humans, and the clinical manifestations of VZV infection are classified as varicella (chickenpox) or herpes zoster (shingles). The virus primarily infects children aged 5–9 years, manifesting as chickenpox, which is characterized by the cutaneous distribution of diffuse and scattered maculopapular vesicles. Subsequently, VZV infections become latent in cranial nerve and dorsal root ganglia and in autonomic ganglia. As cellular immunity to the VZV diminishes with age or in persons in an immunocompromised state, reactivation of the latent VZV may occur, resulting in shingles, which is characterized by unilateral vesicular eruptions within the affected dermatomes. Vasculopathy in VZV infection may result from the production of procoagulant antiphospholipid antibodies1 or immune complex mediated vasculitis; an association between herpes virus infection and atherosclerosis has also been proposed.2 These relationships suggest a possible link between VZV infection and vascular thrombosis. Previous studies of herpes zoster have focused primarily on its possible relationships with cerebrovascular stroke.3,4 Several cases of herpes zoster-induced vasculopathy and stroke have been reported, and it has been proposed that the herpes virus spreads transaxonally to the nascent blood vessels, where it induces inflammation and thrombotic responses. Recently, a large population-based cohort study has reported that the risk of stroke and herpes zoster ophthalmicus increased following a herpes zoster attack during the 1-year follow-up period.5 Several case reports have described peripheral arterial thrombosis in patients with concurrent herpes zoster infection.6,7 To our knowledge, no large population-based cohort study has investigated the association between herpes zoster infection and the development of acute coronary syndrome (ACS). We hypothesized that the risk of ACS increased following the reactivation of VZV infection in an Asian population-based cohort.
Patients and methods We analysed a subset of data from the reimbursement claims provided by the National Health Research Institute in Taiwan. The claims database contains information from 13 insurance programmes. Taiwan implemented a universal insurance system in March 1995. The National Health Insurance (NHI) system provides health care for 99% of the 23 million citizens of Taiwan through contracts with 97% of the health-care facilities.8 We reviewed the reimbursement claims of the NHI that had been previously extracted and compiled in the NHI Research Database (NHIRD). The NHIRD claims records contained information on both ambulatory and inpatient medical services from 1996 to 2010, and diagnoses were coded based on the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). The patients’ personal information was encrypted to ensure privacy. To ensure the accuracy of the claims data, the Bureau of NHI (BNHI) invites experts to review claims by randomly sampling every 100 outpatient claims and every 15 inpatient © 2013 British Association of Dermatologists
claims. False claims and unnecessary treatment result in severe penalties from BNHI.9 Several studies have demonstrated the high accuracy and validity of ICD-9 diagnosis in NHIRD.8,10 Our study was approved by the ethics review board of the China Medical University (CMU-REC-101-012). Participants and outcome measures Patients newly diagnosed with herpes zoster (ICD-9-CM code 053) between 1999 and 2010 were included in our study cohort. The index date was defined as the date of the first clinical visit for herpes zoster. We excluded patients with a history of ACS (ICD-9-CM codes 410, 4111) or with missing age or sex information at the baseline. The herpes zoster cohort to nonherpes zoster cohort was selected at a 1:4 ratio in order to enhance the power of statistical tests and to prevent an insufficient number of ACS cases in the stratified analysis. The nonherpes zoster cohort was selected using a simple random sampling method to four randomly selected insured people from NHI beneficiaries without herpes zoster status for every person with herpes zoster in the same period, frequency matched by age, sex and index year of herpes zoster diagnosis. Subjects in both the herpes zoster and nonherpes zoster cohorts were followed up until they were diagnosed with ACS or censored because of loss of follow-up, withdrawal from insurance, death or until the end of 2010. Definition of exposure At least three previous claims for ambulatory or inpatient care for a single diagnosis before the index date represented a comorbidity at the baseline. The baseline comorbidities considered were hypertension (ICD-9-CM codes 401–405), diabetes mellitus (ICD-9-CM code 250), hyperlipidaemia (ICD9-CM code 272) and cerebral vascular disease (ICD-9-CM codes 430–438), chronic obstructive pulmonary disease (COPD; ICD-9-CM codes 491–493, 494, 496), renal dysfunction (ICD-9-CM codes 580–589) and cancer (ICD-9-CM codes 140–208). Acyclovir and valacyclovir were the antiviral treatments for herpes zoster infection. Famciclovir was not considered because it was not imported into Taiwan until 2011. Statistical analysis The distributions of categorical demographics and clinical characteristics among the herpes zoster and the control groups were compared using the v2 test. Patients were classified based on socioeconomic status; occupation [white-collar workers (professionals, managers and administrative workers), bluecollar workers (farmers, fishermen and industrial labourers) or ‘other’ (retired, unemployed and low-income patients)]; urbanization (urbanization level was categorized by the population density of the residential area into two groups, with urban as the most urbanized and rural as the least urbanized) and monthly income (new Taiwan dollars 15 000, 15 000– 22 799 and > 22 800). We used a Poisson regression model British Journal of Dermatology (2014) 170, pp1122–1129
1124 Herpes zoster infection and ACS, C.-C. Wang et al.
to estimate the ratios of the rates for the herpes zoster group and the rates of the control group. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using a multivariable Cox proportional-hazards regression model to examine associations between herpes zoster and the incidence of ACS. Variables considered in the multivariate analysis included sex, age, frequency of medical visits, urbanization, monthly income (in new Taiwan dollars), occupation, comorbidities and medication status. We have also addressed the attributable risk and 95% CI from herpes infection.11 All analyses were performed using SAS version 9.2 (SAS, Cary, NC, U.S.A.), and two-tailed P-values < 005 were considered statistically significant.
Results Baseline characteristics A total of 57 958 herpes zoster patients and 231 832 control patients were included in our study (Table 1). Among all patients, 601% were < 55 years old and 526% were women. Over half were white-collar workers. The herpes zoster group exhibited significantly higher rates of comorbidities at the baseline. Hypertension (285% vs. 251%), followed by hyperlipidaemia (186% vs. 155%), COPD (112% vs. 887%), renal dysfunction (705% vs. 523%), diabetes mellitus (109% vs. 93%), cancer (343% vs. 224%) and cerebral vascular disease (90% vs. 79%) showed discrepancies in prevalence. Attributable risks and 95% CIs Approximately 22% of the ACS incidence in the herpes cohort would be eliminated if the herpes exposure was eliminated (95% CI 11–32%). In other words, the excess ACS due to herpes zoster was 22%. Incidence rate ratios and hazard ratios of acute coronary syndrome Over the 12-year follow-up period, 1053 patients with herpes zoster and 3318 control patients were diagnosed with ACS (Table 2). The incidence rates for the herpes zoster and the control groups were 368 and 296 per 10 000 person-years, respectively. The overall adjusted HR (aHR) of ACS was 115 for patients with herpes zoster (95% CI 107–124). In both groups, ACS occurred more frequently in men than in women. Herpes zoster patients over the age of 65 years had a higher incidence of ACS (25%) than the age-matched controls, and the risk of ACS progressively increased with increasing age. The risk of ACS was higher among people living in urban areas than in rural areas (aHR 108, 95% CI 102–115). The risk of ACS was highest among the lowest income group (aHR 131, 95% CI 119–145). The presence of hypertension, hyperlipidemia, diabetes mellitus, cerebral vascular disease, COPD and renal dysfunction was also associated with a higher British Journal of Dermatology (2014) 170, pp1122–1129
incidence of ACS. We further divided the herpes zoster group into two subgroups according to treatment. Patients treated with antivirals exhibited a higher incidence rate of ACS than those who were not treated with antivirals, but this difference was not significant after adjusting for all potential variables (aHR 096, 95% CI 080–115) (Table 4). Acute coronary syndrome in relation to time since herpes zoster diagnosis Analysis divided by the length of follow-up periods showed that the risk of ACS among the two cohorts did not differ significantly within 1 year after herpes zoster was diagnosed. After the 1-year follow-up period, the herpes zoster group had a significantly higher risk of ACS than the nonherpes zoster group (aHR 110, 95% CI 102–119) (Table 5). Kaplan– Meier survival analysis showed that patients with herpes zoster infections had significantly higher ACS rates than the control patients (log-rank test, P < 0001; Fig. 1).
Discussion Our study demonstrated that herpes zoster infection is associated with an increased risk of ACS. After adjusting for all potential covariates, including baseline comorbidities, socioeconomic status and medication, the association between the infection and the development of ACS remained significant. Association between varicella zoster virus infection and ischaemic heart disease In the literature, the increased risk of cerebrovascular events and peripheral vascular thromboembolism following a herpes zoster attack has been established.12–15 Massano et al.14 described the development of acute occlusions in the left common iliac and right femoral arteries in a 39-year-old man 1 week after VZV infection. In addition, Peyton et al.15 reported two cases with varicella pneumonia and coexisting severe lower limb ischaemia caused by thrombosis of the profounda femoris and tibial arteries. However, the relationship between herpes zoster infection and ACS has been rarely discussed. A study of the association between herpes virus infection and the incidence of coronary heart disease (CHD) found no significant difference in the risk of CHD in patients with a baseline history of shingles compared with control patients.16 However, this lack of an association may have resulted from a smaller sample size and a shorter follow-up duration than in our study. A case–control study showed that a higher proportion of patients was seropositive to four or more herpes virus (high herpetic burden) in the ischaemic heart disease group than in the control group.17 Therefore, the relationship between VZV infection and CHD remains controversial. Compared with previous studies, our study considered a larger population and longer duration of follow-up. We proposed that following a herpes zoster attack the risk of ACS increased in the long-term follow-up period. © 2013 British Association of Dermatologists
Herpes zoster infection and ACS, C.-C. Wang et al. 1125 Table 1 Demographic characteristics and comorbidity in patients with and without herpes zoster
Herpes zoster
Variables
No (n = 231 832)
Yes (n = 57 958)
n
%
n
%
474 526
27 457 30 501
474 526
100
337 264 170 229
19 517 15 308 9872 13 261
337 264 170 229
100
415 585
23 972 33 986
414 586
064
364 425 211
19 358 24 967 13 633
334 431 235
< 0001
512 351 136 446
29 860 20 826 7272 254
515 359 126 247
< 0001
< 0001
251 93 155 79 887
16 491 6318 10 799 5209 6486
285 109 186 90 112
< < < <
1 year 2693
Herpes zoster cohort a
Person-years
Rate
Event
Person-years
Ratea
IRR (95% CI)
b
57 045 261 729 905 539
326 239 297
58 193 860
14 252 54 174 232 182
407 356 370
125 (121–129)** 124 (120–128)** 125 (121–128)**
120 (089–162) 114 (094–139) 110 (102–119)*
aHR (95% CI)
IRR, incidence rate ratio; CI, confidence interval; aHR, adjusted hazard ratio. aRate per 1000 person-years. baHR, adjusted for age, sex, urbanization, monthly income (new Taiwan dollars), occupation, frequency of medical visits, hypertension, diabetes mellitus, hyperlipidemia, cerebral vascular disease, chronic obstructive pulmonary disease, renal function, cancer and medication in Cox proportional-hazards regression model. *P < 005, **P < 0001.
In conclusion, patients with a history of herpes zoster infection are more likely to develop ACS than patients without such a history. Whether early aggressive antiviral treatment may prevent subsequent VZV-associated vasculopathy requires further investigation.
References
Fig 1. Acute coronary syndrome-free survival time for patients with herpes zoster and the control cohort in Taiwan.
study design and control measures for confounding factors, bias resulting from unknown confounding factors may have affected our results. Thirdly, all data in the NHIRD are anonymous. Thus, relevant clinical variables, such as blood pressure, imaging results, pathology findings and serum laboratory data were unavailable for our study patient cases. However, the data regarding herpes zoster and ACS diagnoses were nonetheless reliable. Fourthly, our study focused on the association between reactivation of VZV infection and the risk of ACS because we hypothesized that reactivation of VZV infection increased inflammation, the production of procoagulants and the induction of vasculitis. Because of the limited follow-up period, our results cannot be extrapolated to determine further whether patients with active shingles or during the incubation period have an increased risk of ACS. However, based on our literature review, we believe that reactivation of VZV infection could result in vasculopathy and is associated with an increased risk of ACS. Finally, we could only identify patients with VZV infection based on the ICD-9 codes and had no access to serology data for clinical validation. Therefore, this study was unable to clearly differentiate the suspected cases from the verified cases. British Journal of Dermatology (2014) 170, pp1122–1129
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