Is COVID-19 associated with increased risk of herpes zoster?

Article by Debra Kiss, PhD; Senior Medical Writer at EPG Health

Since the COVID-19 pandemic began, case reports have described herpes zoster (HZ) in patients soon after COVID-19 diagnosis^1,2, and more recently, reports have suggested an association between COVID-19 vaccination and HZ^3-6.

Although HZ (shingles) may be seen as a transient and inconvenient rash by some, it is a painful condition that can have significant patient burden, and may lead to more serious and chronic complications such as post-herpetic neuralgia and herpes zoster ophthalmicus, particularly for those aged 50 years and over^7-9.

So, is there a link between COVID-19, COVID-19 vaccines and HZ? And what does this mean for healthcare professionals and patients in the real-world? Let’s explore in more detail.

Incidence of HZ significantly increased after COVID-19 infection

In a recent large US retrospective cohort study of over 1.9 million individuals aged ≥50 years, a 15% higher incidence of HZ was reported for those diagnosed with COVID-19 compared to those never diagnosed with COVID-19 (adjusted incidence rate ratio [aIRR], 1.15; 95% CI, 1.07–1.24; P<0.001)¹. The increased risk of HZ was reported for up to 6 months following COVID-19 diagnosis, and was more pronounced after hospitalisation with COVID-19 (21%; aIRR, 1.21; 95% CI, 1.03–1.41; P=0.02)¹.

These findings, published by Bhavsar and colleagues (2022), were based on administrative health claims between March 2020 to February 2021 across two large US databases¹. Data from individuals with COVID-19 were exact-matched to data from those without COVID-19 by age, sex, presence of HZ risk factors, and healthcare cost levels¹.

While this study does support an increased risk of HZ for patients after COVID-19 diagnosis, the individuals included in this study were required to have no history of HZ and no history of vaccination against either COVID-19 or HZ¹, and most of the data was derived prior to COVID-19 mass vaccination¹. It is therefore unclear how the magnitude of increased risk of HZ after COVID-19 may translate to the current population in the US, now that 78.7% of the US population have received at least one dose of the COVID-19 vaccine, and 67.2% are fully vaccinated against COVID-19 (as of July 2022)¹⁰.

How might COVID-19 infection be associated with HZ?

After the initial infection with varicella zoster virus (VZV), sufficient VZV-specific T-cell immunity maintains viral latency². Declines in cell-mediated immunity, such as through aging or immunosuppression, may then trigger VZV reactivation and lead to HZ^1,2.

Studies suggest SARS-CoV-2 may impair or alter T-cell immune function^1,2, and a wide range of T-cell immune dysfunctions have been reported in patients with COVID-19, including lymphopenia and lymphocyte exhaustion².

Based on evidence to date, it is thought that infection with SARS-CoV-2 can result in T-cell immune dysfunction, which may then trigger VZV reactivation, leading to HZ^1,2

Is there an association between COVID vaccination and incidence of HZ?

Reactivation of VZV can be a rare adverse reaction to vaccines⁵. While some studies indicate an association between COVID-19 vaccination and HZ, overall HZ incidence in these studies was considered rare or negligible, and no causal relationship has been established¹¹.

Two large, real-world studies indicate a slightly increased risk of HZ after COVID-19 vaccination, compared with individuals who remained unvaccinated^5,6. This included a large, real-world international study of over 2 million patient records by Hertel and colleagues (2022), which reported an increased risk of HZ within 60 days of COVID-19 vaccination compared to unvaccinated patients (risk of developing HZ was 0.20% versus 0.11%, respectively; absolute risk difference of 0.09%, P<0.0001; 95% CI =0.079–0.100%)⁵. The relative risk was 1.802 (95% CI, 1.680–1.932) and odds ratio was 1.804 (95% CI = 1.682; 1.934)⁵. The second large study was a nested case control analysis using the US Vaccine Adverse Event Reporting System database (VAERS) by Gringeri and colleagues (2022), which indicated a slightly higher risk of VZV reactivation reporting after the Pfizer-BioNTech vaccine (reporting odds ratio or ROR=1.49; 95% CI = 1.42–1.57), while an ROR of <1 was found for the Moderna (ROR = 0.75; 95% CI = 0.71–0.79) and Janssen vaccines (ROR = 0.64; 95% CI, 0.57–0.71)⁶. However, the overall incidence of VZV reactivation across COVID-19 vaccinated individuals was 0.7 per 100,000 doses, which was considered clinically negligible by the authors, noting most cases were non-serious and considering the prevalence of HZ in the general population⁶.

Mixed findings have been reported across smaller studies^3,4. A systematic review and meta-analysis of 4 cohort studies reported no evidence for an association between COVID-19 vaccination and increased incidence of HZ compared to placebo (risk ratio [RR]: 1.06; 95% CI, 0.91–1.24)³; while a systematic review of 14 studies indicated a possible association, but no definite link could be established⁴.

No causal relationship has been established between COVID-19 vaccines and HZ^4,6, and HZ is not listed as an expected or potential AE in the US product information for COVID-19 vaccines^11-13. The blinded portion of the Moderna Phase 3 clinical study did show a higher incidence of HZ in the COVID-19-vaccinated cohort compared to placebo (50 versus 23 reports, respectively), however this was among 30,346 study participants in total across the trial¹¹.

What does this mean in practice?

Overall, healthcare professionals should be aware of the possible increased risk of HZ during the COVID-19 pandemic, and consider timely therapeutic and preventive measures against HZ²

COVID-19 infection may be considered a risk factor for HZ in adults aged ≥50 years, and encouraging patients in this age group to receive HZ vaccination may help to reduce the burden of HZ during the COVID-19 pandemic¹.

Evidence suggests the risk of VZV reactivation may be increased with COVID-19 vaccination, but the overall incidence of HZ in these patients is considered low or rare/negligible^5,6. VZV reactivation is a well-established phenomenon with various infections and vaccines, and is not specific to COVID-19 vaccines^5,6.

The overall benefits of COVID-19 vaccination still far outweigh the risks, and COVID-19 vaccination remains strongly recommended, with a well-established safety profile supported by clinical evidence^5,6.

Want to learn more about herpes zoster?

Explore more about the impact of HZ on patients, and options for prevention and treatment in the herpes zoster section of Medthority.com.

References

1. Bhavsar A, Lonnet G, Wang C, Chatzikonstantinidou K, Parikh R, Brabant Y, et al. Increased Risk of Herpes Zoster in Adults ≥50 Years Old Diagnosed With COVID-19 in the United States. Open Forum Infectious Diseases. 2022;9(5).
2. Diez-Domingo J, Parikh R, Bhavsar AB, Cisneros E, McCormick N, Lecrenier N. Can COVID-19 Increase the Risk of Herpes Zoster? A Narrative Review. Dermatol Ther (Heidelb). 2021;11(4):1119-1126.
3. Chu CW, Jiesisibieke ZL, Yang YP, Wu PC, Lin HL, Tung TH. Association of COVID-19 vaccination with herpes zoster: a systematic review and meta-analysis. Expert Rev Vaccines. 2022;21(5):601-608.
4. Desai HD, Sharma K, Shah A, Patoliya J, Patil A, Hooshanginezhad Z, et al. Can SARS-CoV-2 vaccine increase the risk of reactivation of Varicella zoster? A systematic review. J Cosmet Dermatol. 2021;20(11):3350-3361.
5. Hertel M, Heiland M, Nahles S, von Laffert M, Mura C, Bourne PE, et al. Real-world evidence from over one million COVID-19 vaccinations is consistent with reactivation of the varicella-zoster virus. J Eur Acad Dermatol Venereol. 2022;36(8):1342-1348.
6. Gringeri M, Battini V, Cammarata G, Mosini G, Guarnieri G, Leoni C, et al. Herpes zoster and simplex reactivation following COVID-19 vaccination: new insights from a vaccine adverse event reporting system (VAERS) database analysis. Expert Rev Vaccines. 2022;21(5):675-684.
7. Curran D, Oostvogels L, Heineman T, Matthews S, McElhaney J, McNeil S, et al. Quality of Life Impact of an Adjuvanted Recombinant Zoster Vaccine in Adults Aged 50 Years and Older. J Gerontol A Biol Sci Med Sci. 2019;74(8):1231-1238.
8. Johnson RW, Bouhassira D, Kassianos G, Leplège A, Schmader KE, Weinke T. The impact of herpes zoster and post-herpetic neuralgia on quality-of-life. BMC Med. 2010;8:37.
9. Le P, Rothberg M. Herpes zoster infection. BMJ. 2019;364:k5095.
10. Centers for Disease Control and Prevention. CDC. COVID Data Tracker: COVID-19 Vaccinations in the United States. https://covid.cdc.gov/covid-data-tracker/#vaccinations_vacc-total-admin-rate-total. Accessed 22 July 2022.
11. Spikevax (COVID-19 vaccine, mRNA) Full Prescribing Information. January 2022. Available at: https://www.fda.gov/media/155675/download.
12. Comirnity (COVID-19 vaccine, mRNA) Full Prescribing Information. July 2022. Available at: https://www.fda.gov/media/154834/download. Accessed 22 July 2022.
13. Janssen COVID-19 Vaccine: Full Emergency Use Authorization (EUA) Prescribing Information. May 2022. Available at: https://www.janssenlabels.com/emergency-use-authorization/Janssen+COVID-19+Vaccine-HCP-fact-sheet.pdf. Accessed 22 July 2022.