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Keywords:

  • erectile dysfunction;
  • herpes simplex virus;
  • national health insurance

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. Conflict of interest
  10. Authors' contribution
  11. References

Both erectile dysfunction (ED) and herpes simplex virus (HSV) infections are related to cardiovascular events. However, the relationship between ED and HSV infections remains undetermined. The aim of our study was to investigate the possible influence of HSV infections on the development of ED using the Taiwan National Health Insurance database. We identified patients with HSV type 1 or type 2 infections from the 1 000 000 sampling cohort data set. Male patients of age 18 years or older who had been diagnosed as cases of HSV infection since January 1, 2001 were enroled. Patients with previous history of stroke, spinal cord injury or malignancy were excluded. A control group was selected, comprising male patients without HSV infection, stroke, spinal cord injury or malignancy. The age, time of enrolment and comorbidities were matched in the two groups. A total of 1 717 HSV subjects (mean age 43.29 ± 15.97 years) and 6 864 control subjects were enroled. During an average of 3.91 ± 1.93 years' follow-up, HSV-infected subjects experienced a higher incidence of ED than control subjects (1.7% vs. 0.7%, respectively). The log-rank test showed that patients with HSV infections had a significantly higher incidence of ED than those without HSV infections (p < 0.001). After Cox proportional hazard regression model analysis, HSV infections were independently associated with the increased risk of ED (hazard ratio, 2.90; 95% CI, 1.82–4.63, p < 0.001). In conclusion, HSV infections were associated with risk of ED in this cohort.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. Conflict of interest
  10. Authors' contribution
  11. References

Sexual health is an important component of overall well-being, and erectile dysfunction (ED) has a significant negative impact on quality-of-life measures (Jønler et al., 1995). It has been reported that more than 150 million men suffer from ED worldwide, and the incidence continues to grow (Zusman et al., 1999). Although ED is defined as sexual disability, cardiovascular risk factors such as hypertension, diabetes and hyperlipidaemia are closely associated with the incidence of ED. Furthermore, subjects with ED have an increased risk of peripheral artery disease, coronary artery disease (CAD) and stroke (Montorsi et al., 2003a,b; Ponholzer et al., 2005; Thompson et al., 2005; Vlachopoulos et al., 2005; Montorsi et al., 2006; Chiurlia et al., 2005), indicating that ED at least shares some common pathogenesis with cardiovascular disease (CVD) and could be seen as the early manifestation of atherosclerosis (Montorsi et al., 2003a,b).

Herpes simplex virus (HSV) is one of the common viral infections in daily life (Belshe et al., 2012). It may cause watery blisters in the skin or mucous membranes of the mouth, lips or genitals. Sometimes, HSV causes very mild symptoms during outbreaks. However, it may persist in the body by becoming latent and hiding from the immune system in the cell bodies of nerves (Antinone & Smith, 2010). Increasingly, evidence has demonstrated that HSV infection not only causes mild skin or mucosa lesions but it is also associated with the occurrence of CVD (Fabricant et al., 1983; Yamashiroya et al., 1988; Roivainen et al., 2000; Siscovick et al., 2000; Zhu et al., 2001). As ED is now considered an early manifestation of CVD, the association between ED and HSV infection should be investigated as it still remains undetermined. Therefore, we conducted a nationwide population-based study using the Taiwan National Health Insurance database to investigate the impact of HSV infection on the development of ED.

Materials and methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. Conflict of interest
  10. Authors' contribution
  11. References

Database

The National Health Insurance programme in Taiwan has operated since 1995 and enrols nearly all the inhabitants of Taiwan (21 869 478 beneficiaries of 22 520 776 inhabitants at the end of 2002). Currently, the National Health Insurance Research Database at the National Health Research Institute in Miaoli (Taiwan) manages the complete National Health Insurance claims database and has published several dozen extracted data sets for researchers. The National Health Research Institute has released a cohort data set made of 1 000 000 randomly sampled people who were alive during 2000 and collected all records on these individuals from 1995 onwards. These random samples have been confirmed by the National Health Research Institute to be representative of the Taiwanese population. In this cohort data set, each patient's original identification number has been encrypted to protect privacy; however, the encrypting procedure is consistent, so that the linkage of claims belonging to the same patient is feasible within the National Health Insurance Research Database. This study was exempt from full review by the Institutional Review Board of Taipei Veterans General Hospital, as the data set used consisted of de-identified secondary data released to the public for research purposes.

Study patients

We identified patients with HSV type 1 and 2 infections from the 1,000,000 sampling cohort data set. The following patients were included: (i) male patients who were 18 years old or older; (ii) patients who were diagnosed as cases of HSV 1 and 2 infections [International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes 054.xx] since January 1, 2001. The diagnosis of HSV was based on the results of serum examinations including ELISA, antibody test or PCR in each individual case. The identification of HSV using insurance claim was valid and has been used in previous studies (Kang et al., 2009; Chiang et al., 2011).

The following patients were excluded: (i) patients diagnosed as cases of HSV 1 and 2 infections before January 1, 2001; (ii) patients diagnosed as cases of ED before enrolment; (iii) patients with previous ischaemic stroke, intracerebral haemorrhage, spinal cord injury or malignancy. A control group was selected from male patients without any HSV type 1 or 2 infections, ischaemic stroke, intracerebral haemorrhage, spinal cord injury or malignancy. The age and comorbidities were matched in the two groups. Comorbidities included pre-existing (in the year before enrolment) hypertension, diabetes mellitus, hyperlipidaemia, CAD, chronic lung disease and chronic renal disease. Concomitant medications (including antihypertensives and statins) were identified and classified by the National Drug Code and the Anatomic Therapeutic Chemical code, which is an internationally accepted classification system of drugs coordinated by the WHO Collaborating Center for Drug Statistics Methodology.

Erectile dysfunction measurement

All patients were followed up until December 31, 2007. In contrast to the diagnosis of ED using self-reporting questionnaires, the occurrence of ED was identified in hospital-based subjects who had visited hospital for evaluation and treatment. Our study endpoints included psychogenic ED (ICD-9-CM code 302.72) and organic ED (607.84). Similar identification for ED was considered valid and also used in other study (Chung et al., 2011; Huang et al., 2012; Keller & Lin, 2012; Keller et al., 2012).

Statistical analysis

Microsoft SQL Server 2005 was used for data management and computing. Statistical analysis was performed using SPSS software (Version 15.0; SPSS Inc., Chicago, IL, USA). All data were expressed as the frequency (percentage) or mean ± standard deviation. Parametric continuous data were compared between the case and control groups by unpaired Student's t-test. Categorical data were compared between the two groups with Chi-squared test and Yates' correction or Fisher's exact test as appropriate. Survival analysis was assessed using Kaplan–Meier analysis, with the significance based on the log-rank test. The survival time was calculated from the date of HSV infections diagnosed to the date of ED diagnosed. Multiple regression analysis was carried out using Cox proportional hazard regression analysis to evaluate the independent factor in determining the occurrence of ED. Statistical significance was inferred at a two-sided p-value of <0.05.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. Conflict of interest
  10. Authors' contribution
  11. References

A total of 1 717 male patients (mean age 43.29 ± 15.97 years) with newly diagnosed HSV type 1 or 2 infections were identified from the 1 000 000 sampling cohort data set between January 2001 and December 2007. Among the 1 717 patients, there were 1 478 patients with HSV-1 infection and 239 patients with HSV-2 infection. Another 6 864 male patients matched for age and comorbidities, not including for HSV infection, were enroled as the control group. The use of antihypertensives was similar in the two groups. Patients with HSV infection had more statin use than the control group (p = 0.021). The demographic parameters of the study subjects are shown in Table 1.

Table 1. Demographic data of the patients with and without herpes simplex virus (HSV) infections
VariablesHSV infectionsp-value
Yes (n = 1 717)No (n = 6 864)
  1. HSV: herpes simplex virus.

Age (years)43.29 ± 15.0743.33 ± 15.230.926
Hypertension 361(21%)1 444(21%)0.991
Diabetes mellitus206(12%)820(11.9%)0.953
Hyperlipidaemia327(19%)1 306(19%)0.986
Coronary artery disease219(12.8%)872(12.7%)0.955
Chronic lung disease425(24.8%)1 700(24.8%)0.990
Chronic renal disease123(7.2%)488(7.1%)0.938
Antihypertensives117(6.8%)438(6.4%)0.514
Statins69(4.0%)201(2.9%)0.021

During an average of 3.91 ± 1.93 years' follow-up period, 29 (1.7%) of the patients with HSV infections experienced the occurrence of ED, and 46 subjects (0.7%) from the comparison cohort experienced the occurrence of ED. The log-rank test showed that patients with HSV infections had a significantly higher incidence of ED than those without HSV infections (p < 0.001). Figure 1 shows the results of a Kaplan–Meier analysis. After Cox proportional hazard regression model analysis, HSV infection (hazard ratio [HR], 2.87; 95% confidence interval [CI], 1.80–4.58, < 0.001) was independently associated with the increased risk of ED. Both HSV-1 (HR, 2.29; 95% CI, 1.35–3.88, p = 0.002) and HSV-2 infections (HR, 6.27; 95% CI, 3.05–12.92, p < 0.001) increased the risk of ED (Table 2).

Table 2. Herpes simplex virus infection and erectile dysfunction
VariableCrude hazard ratio(95% CI)p-valueAdjusted hazard ratio(95% CI)p-value
  1. CI: confidence interval, ED: erectile dysfunction, HSV: herpes simplex virus.

All HSV (n = 1 717)
All ED2.87(1.80–4.57)<0.0012.87(1.80–4.58)<0.001
Psychogenic ED2.98(0.97–9.12)0.0563.00(0.98–9.20)0.055
Organic ED2.85(1.70–4.75)<0.0012.84(1.70–4.74)<0.001
HSV-1 (n = 1 478)
All ED2.30(1.36–3.90)0.0022.29(1.35–3.88)0.002
Psychogenic ED2.06(0.55–7.79)0.2862.09(0.55–7.88)0.279
Organic ED2.35(1.32–4.17)0.0042.33(1.31–4.14)0.004
HSV-2 (n = 239)
All ED6.01(2.94–12.29)<0.0016.27(3.05–12.92)<0.001
Psychogenic ED8.00(1.69–37.78)0.0099.34(1.94–44.94)0.005
Organic ED5.61(2.50–12.58)<0.0015.71(2.52–12.91)<0.001
image

Figure 1. Kaplan–Meier curves of the freedom from erectile dysfunction in the patients. Group 1 included patients with herpes simplex virus (HSV) infections, and group 2 included those patients without HSV infections. There was a statistically significantly difference between the two curves (log-rank test, < 0.001).

Download figure to PowerPoint

We further divided the endpoints into psychogenic ED and organic ED. Overall, HSV infections increased the risk of organic ED (HR, 2.84; 95% CI, 1.70–4.84, p < 0.001) but not psychogenic ED (HR, 3.00; 95% CI, 0.98–9.20, p = 0.055). Among them, HSV-1 infections increased the risk of organic ED (HR, 2.33; 95% CI, 1.31–4.14, p = 0.004) but not psychogenic ED (HR, 2.09; 95% CI, 0.55–7.88, p = 0.279). However, HSV-2 infections increased the risk of both psychogenic ED (HR, 9.34; 95% CI, 1.94–44.94, p = 0.005) and organic ED (HR, 5.71; 95% CI, 2.52–12.91, p < 0.001) (Table 2).

Regarding the treatment for HSV, we further divided the patients into two groups, including 278 patients who needed acyclovir and 1 439 patients not needing acyclovir. Both the patients needing acyclovir (HR, 4.46; 95% CI, 1.87–10.63, p = 0.001) and those not needing acyclovir (HR, 2.62; 95% CI, 1.58–4.33, p < 0.001) had increased risk of ED (Table 3).

Table 3. Herpes simplex virus infection and erectile dysfunction according to treatment
VariableCrude hazard ratio(95% CI)p-valueAdjusted hazard ratio(95% CI)p-value
  1. CI: confidence interval, ED: erectile dysfunction, HSV: herpes simplex virus.

Acyclovir
Yes (n = 278)3.94(1.68–9.23)0.0024.46(1.87–10.63)0.001
No (= 1 439)2.68(1.62–4.43)<0.0012.62(1.58–4.33)<0.001

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. Conflict of interest
  10. Authors' contribution
  11. References

The main finding of our study was that HSV infections were associated with risk of ED in this cohort. This suggests that HSV may play an important role in determining future risk of ED occurrence.

Accumulating evidence shows that ED may be the early clinical manifestation of systemic vascular diseases and carry an independent risk for CVD (Montorsi et al., 2003a,b, 2006; Chiurlia et al., 2005; Ponholzer et al., 2005; Thompson et al., 2005; Vlachopoulos et al., 2005). ED has been reported to be associated with elevated high-sensitivity C-reactive protein (CRP) values and correlated with magnitude of flow-mediated dilation impairment of the brachial artery (Chiurlia et al., 2005), the indicator of endothelial dysfunction. In addition, it has been reported that ED is correlated with coronary calcification and atherosclerotic plaque (Chiurlia et al., 2005; Vlachopoulos et al., 2005; Montorsi et al., 2006) and usually precedes the development of clinically evident CVD (Montorsi et al., 2003a,b, 2006; Chiurlia et al., 2005; Vlachopoulos et al., 2005). Altogether, these findings indicate that ED should be considered as a disease entity of early atherosclerosis and might share common pathophysiological mechanisms with CVD.

Inflammatory stimuli may impair arterial function both on an acute and chronic basis (Hingorani et al., 2000; Vita et al., 2004), and inflammation caused by viral or bacterial pathogens has been considered to play an important role in the process of atherosclerosis. As a common infection, more and more clinical observations have demonstrated that HSV not only relates to mild skin or mucosa lesions but it is also associated with the occurrence of CVD. Fabricant et al. (Fabricant et al., 1983) has reported that infection with Marek's disease herpesvirus may lead to atherosclerosis in specific pathogen-free normocholesterolemic chickens, possibly because of the alteration of smooth muscle cell lipid metabolism. Yamashiroya et al. identified HSV and cytomegalovirus in the plaque of coronary arteries and thoracic aortas of young trauma victims (Yamashiroya et al., 1988). The findings support the concept that herpesviruses may potentially play a direct or indirect role in the pathogenesis of human atherosclerosis. In the Helsinki Heart Study (Roivainen et al., 2000), HSV type 1 as well as Chlamydia pneumoniae was found to increase the risk of CAD. Zhu et al. has reported that HSV type 2 (hazard ratio, 1.5; 95% CI, 1.0–2.2), cytomegalovirus (hazard ratio, 2.0; 95% CI, 1.4–3.2) and hepatitis A viruses (hazard ratio, 1.6; 95% CI, 1.1–2.3) increase the risk of myocardial infarction and cardiovascular death (Zhu et al., 2001). Siscovick et al. have shown that the risk of myocardial infarction and CAD death correlates with the presence of IgG antibodies to HSV type 1 (odds ratio, 2.0; hazard ratio, 1.1–3.6) (Siscovick et al., 2000), further supporting that HSV infection may contribute to the formation of atherosclerosis and adverse outcome.

As inflammation may play an important role in the process of atherosclerosis and CVD, it may contribute to the development of ED, which might share common pathophysiological mechanisms with CVD. Elevated serum inflammatory markers such as CRP, IL-6, IL-1β, TNF-α, intercellular adhesion molecule and vascular cell adhesion molecule have been reported in patients with ED (Vlachopoulos et al., 2006; Eaton et al., 2007), which may reveal sustained low-grade inflammation in patients with ED. Our current study is the first study to demonstrate the significant association between HSV infections and future ED development. There are several possible mechanisms. First, HSV infections may impair endothelial-dependent or -independent smooth muscle relaxation, which is important in determining erectile function (Sullivan et al., 1999; Kirby et al., 2005). Recent studies have also demonstrated that cytokines associated with HSV infections, such as leukotrienes, bradykinin, reactive oxygen species and TNF-α, may affect vascular function and be involved in the formation of ED (Vlachopoulos et al., 2006; Eaton et al., 2007; Carneiro et al., 2010). Second, HSV infections may lead to lipid accumulation and result in occlusion of the cavernosal arteries by atherosclerotic plaques (Visser & Vercellotti, 1993). In addition, HSV infection of endothelial cells may attract leucocytes with subsequent inflammatory damage, activate procoagulant changes on endothelium with increased thrombin generation and platelet adhesion and change its interaction with extracellular matrix proteins (Visser & Vercellotti, 1993). As the diameters of the cavernosal arteries are smaller than large coronary arteries, they may be more sensitive to atherosclerosis (Billups et al., 2005). Therefore, ED has been considered as the early manifestation of CVD. With the progression of atherosclerosis, HSV infections may cause the obstruction of penile arteries and involve systemic vasculatures.

In our current study, we found that patients both with and without acyclovir treatment had increased risk of ED. Patients who needed acyclovir treatment had higher risk of ED than those not needing acyclovir treatment. However, patients needing acyclovir treatment may be those with more disease severity. Further study is needed to clarify whether the treatment of HSV can ameliorate ED.

The strength of our study is the use of a population-based data set, enroling a large sample size, and enabling us to trace prospectively the differences between the two groups. However, there are some limitations in our study. First, the diagnosis of HSV infection is identified using the ICD-9 code from database. This study was conducted with the National Health Insurance Database, in which the diagnosis was supposed to be confirmed clinically by the individual physicians in charge. However, it is not known whether the diagnosis of HSV was made based on the results of serum examinations including ELISA, antibody test or PCR in each individual case. This was also not checked externally in our study. Similar analyses to identify virus infection have been used and proven valid in previous studies (Kang et al., 2009; Chiang et al., 2011). Second, personal information such as body weight, smoking habit, biochemistry profiles and hormonal status were not available. Third, psychogenic problems may also have an impact on ED. However, such information was not available in our study. Finally, the diagnosis of ED is made in a similar way, which has been used and proven valid in previous studies (Chung et al., 2011; Huang et al., 2012; Keller & Lin, 2012; Keller et al., 2012). However, discussing sexuality is still relatively taboo in Asian countries. The status of ED in our study was recognized from hospital visit records, not through questionnaires. This may have generated bias towards subjects who may have more significant symptoms and disease severity. These factors contribute to the seemingly low frequency of ED as compared with studies from Western countries. Therefore, the association of ED with HSV infection may apply to those subjects with more significant disease but not those with only positive serologic HSV antigen titres (Roivainen et al., 2000; Siscovick et al., 2000; Zhu et al., 2001) or being subjectively evaluated. Thus, it has higher clinical implication in our daily practice.

Conclusions

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. Conflict of interest
  10. Authors' contribution
  11. References

This study demonstrates the association of HSV infection and future development of ED, suggesting HSV may play an important role in determining future risk of ED occurrence. The current findings may call for potential therapeutic strategies such as avoiding HSV infections or improving HSV treatment for ED prevention.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. Conflict of interest
  10. Authors' contribution
  11. References

This study was partly supported by research grants V99B1-011, V99C1-125, V100B-004 and V100B-013 from Taipei Veterans General Hospital, Taipei, Taiwan; CI-97-13 and CI-98-16 from the Yen Tjing Ling Medical Foundation, Taipei, Taiwan; NSC 100-2314-B-075-055 and UST-UCSD International Center of Excellence in Advanced Bio-engineering NSC-99-2911-I-009-101-A2 from the National Science Council.

Authors' contribution

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. Conflict of interest
  10. Authors' contribution
  11. References

C.-C. Huang was the principal investigator in this study and contributed to the study conception and design, implementation, statistical analysis, interpretation and the preparation of the manuscript. W.-L. Chan contributed to the study conception and design, implementation and the preparation of the manuscript. Y.-C. Chen and T.-J. Chen contributed to statistical analysis, interpretation and the preparation of the manuscript. C.-M. Chung and P.-H. Huang contributed to the study conception and design and statistical interpretation. S.-J. Lin contributed to the study conception and design. J.-W. Chen and H.-B. Leu supervised the study execution and contributed to the study conception and design, implementation, statistical interpretation, the preparation and finalization of the manuscript. All authors approved the final manuscript for publication.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. Conflict of interest
  10. Authors' contribution
  11. References