A recent study conducted by Yi-Chen Chen and colleagues found a significant association between COVID-19 infection and an increased risk of developing herpes zoster (HZ), also known as shingles. In this article, we will discuss the findings of this retrospective cohort study and explore the potential implications of this association.
Herpes Zoster: An Overview
Herpes zoster (HZ), commonly known as shingles, is a viral infection caused by the reactivation of the varicella-zoster virus (VZV), which is responsible for chickenpox. After a person recovers from chickenpox, the virus remains inactive in the body, and it can reactivate years later as HZ. HZ is a painful condition characterized by a rash or blisters that usually appear on one side of the body.
The condition can lead to long-term complications, such as post-herpetic neuralgia (PHN), which is characterized by persistent pain that can last for months or even years after the rash has healed. HZ has also been associated with an increased risk of cardiovascular events, such as stroke and myocardial infarction (MI).
Association between COVID-19 and Herpes Zoster
Yi-Chen Chen and colleagues conducted a retrospective cohort study to investigate the association between COVID-19 infection and the risk of developing herpes zoster. The study included 2,442,686 patients who had been diagnosed with COVID-19 between January 2020 and March 2022. The researchers followed these patients for a median of 6 months after their COVID-19 diagnosis to determine whether they developed herpes zoster.
The results of the study showed that the incidence of herpes zoster was significantly higher among patients with COVID-19 compared to the general population. Specifically, the incidence of herpes zoster was 1.67 times higher in the COVID-19 cohort compared to a control group of individuals who did not have COVID-19. The increased risk of herpes zoster was observed across all age groups, but it was highest among patients aged 50 years and older.
Implications of the Association between COVID-19 and Herpes Zoster
The association between COVID-19 and herpes zoster has several potential implications. First, it suggests that COVID-19 may have long-term effects on the immune system, which could increase the risk of developing other viral infections. Second, it highlights the importance of monitoring patients with COVID-19 for the development of herpes zoster and providing appropriate treatment if necessary.
To reduce the risk of HZ and its associated health problems, several vaccines are available. The most commonly used vaccine is the zoster vaccine live, which is recommended for adults aged 50 years and older. This vaccine is highly effective in preventing HZ and can also reduce the severity of symptoms if HZ does occur. In addition, antiviral medications such as acyclovir, valacyclovir, and famciclovir can be used to treat HZ and reduce the risk of complications.
Herpes zoster and long-term vascular risk
A recent retrospective cohort study published in February 2023 in the journal Scientific Reports (s41598-023-29667-w) investigated the relationship between shingles and long-term vascular risk.
In the current analysis, we investigated whether suffering from an acute episode of HZ is associated with increased long-term vascular risk using an extensive HMO computerized database. Though they failed to reach significance after 5 years of follow up, our results nonetheless show that HZ infection trended towards a long-term increased risk of ischemic events in our cohort, including both cerebro vascular and coronary events. The risk of MACCE was 19% higher among HZ sufferers in the first year of follow up, and this risk was sustained for at least 4.4 years following the episode. It was not affected by the administration of antiviral agents during the HZ episode.
Previous studies have primarily reported increased short-term (weeks to months) stroke risk after an HZ episode. Schink et al.8 demonstrated that stroke risk increased in the first week following HZ infection and then fell over the subsequent 6–12-month follow-up period. Minassiant et al.9 observed an increase in stroke incidence a few weeks after HZ infection and a gradual decline in the risk of stroke in the following weeks.
Sreenivasan et al.10 reported a peak in stroke incidence 2 weeks following HZ infection when analyzing a vast database (4.6 million enrollees) in Denmark followed by the moderation of this risk over a 1-year period. A similar pattern of increased risk of stroke in the following weeks after HZ infection and then declining risk during the following months was also demonstrated by Langan et al.11. A meta-analysis conducted by Liu et al.12 summarizing data from eight studies likewise showed a short-term increase in stroke risk followed by a decline in such risk following HZ infection, with the highest level of risk during the first 2 weeks (risk ratio [RR]: 2.36), with the RR falling to 1.56, 1.17, and 1.03 at 1, 3, and 6 months, respectively.
Interestingly, Marra et al.13 found no association between HZ and stroke over a long 3-year follow-up interval. Early post-HZ stroke and AMI risk has been attributed to a hypercoagulable state caused by prothrombotic autoimmune antibodies such as anticardiolipin forming during the HZ infection14, circulating immune complexes, and systemic inflammation15.
In their retrospective study, Breuer et al. showed that the HR for TIA and MI but not stroke were increased in all patients with HZ16. However, HZ patients included in this study had significantly more cardiovascular risk factors (diabetes, hypercholesterolemia, hypertension, smoking) than matched control subjects, which accounted for a major bias in the long term follow-up of vascular events in HZ subjects.
This can also be said of the Danish study aforementioned though both studies identified the risk of stroke and TIA to be highest in those whose HZ occurred under the age of 40 years10,16. While our study did not segregate age groups, our robust adjustment method mitigated this bias and gave us a more neutral analysis of the long term effects of HZ on all major adverse cardiac and cardiovascular events, including stroke, TIA, MI.
In their propspective study, Curhan et al. demonstrated similar results to our observations and showed a long term implication of HZ in stroke and coronary heart disease 17. Though they based their analysis off of self reported information on HZ without considering treatment, our findings expand on their results, and together imply that the increased risk is not limited to the cerebrovascular system but instead represents an elevated level of systemic cerebrovascular and coronary risk 16.
It is difficult to determine from our results whether this increased risk is caused by the HZ event, potentially resulting from inflammatory and prothrombotic changes that may persist for years, or whether the HZ episode is instead a marker for increased vascular risk, with patients exhibiting greater vascular risk when being exposed to HZ.
Though former studies on the short-term7,11,18,19 and long-term10 cardiovascular outcomes after antiviral use in HZ patients exhibited significant positive effects, our results tend to show the opposite effect, even suggesting a negative outcome of antiviral treatments on long-term survival. This should be put in perspective as our study design did not allow us to review detailed information regarding treatment options, treatment plans, or patients’ therapeutic compliance over a 15-year follow-up period. However, we should also consider that in clinical practice, antiviral agents are more frequently given to HZ patients with underlying comorbid conditions. Though they received treatment in the acute phase of the infection, the long-term residual effects of HZ may have negatively impacted already fragile vascular homeostasis in these individuals, further decreasing long-term survival. Therefore, we believe that it is more reasonable to interpret HZ as a marker of high vascular risk rather than a causative factor.
The current study has some limitations. First, the case definition was based on administratively collected data, leaving cases of undiagnosed HZ patients unrecorded in the database. Such misclassification can potentially decrease the effect size toward the null hypothesis. Second, our data did not include HZ vaccination status, which could be a limitation given that recent literature has shown a decreased risk of neurologic post-infection sequelae in vaccinated patients 20.
Third, because our study focused mainly on the impact of HZ on vascular effects and did not comprise detailed information on vaccinations and treatments, only limited data regarding the long-term influence of HZ therapeutics on cardiovascular pathologies could be collected. Lastly, missing clinical details, such as HZ dermatome location, precluded any in-depth analysis of the exposure type or its implications. However, our study has some noteworthy strengths.
This is the first study to explore the risk of cardiovascular events in HZ patients compared with non-HZ patients over a 15-year period. In addition, the unique setup of a centralized healthcare system with a single tertiary hospital treating all the acute patients in the region allows for the reliable evaluation of vascular risk in a very large cohort of patients.
The findings of our study suggest that HZ is a long-term vascular risk marker. Based on our observation, clinicians should consider reevaluating the vascular risk profile of patients recovering from HZ. Further studies are warranted to determine how a history of HZ should be incorporated into cardiovascular risk calculators and to evaluate the long-term impact of vaccines and mitigation strategies on such risk.
Conclusion
The study conducted by Yi-Chen Chen and colleagues provides evidence of an association between COVID-19 infection and an increased risk of developing herpes zoster. This association has several potential implications for the long-term health of patients with COVID-19, as well as for vaccine development. Further research is needed to explore the mechanisms underlying this association and to determine the most effective strategies for preventing and treating herpes zoster in patients with COVID-19.
reference link :https://onlinelibrary.wiley.com/doi/full/10.1002/jmv.28745
