Skin Original Research

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ORIGINAL RESEARCH

What is the True Etiology of “Recurrent Shingles”?

Ramya Vangipuram, MD1, Harrison P. Nguyen, MD, MBA, MPH, DTM2, Stephen K. Tyring, MD, PhD, MBA1,3

1Department of Dermatology, McGovern Medical School, Houston, Texas 2Department of Internal Medicine, Baylor College of Medicine, Houston, Texas 3Center for Clinical Studies, Houston, Texas

ABSTRACT

Purpose: To determine the true etiology of cases of putative recurrent shingles referred to a dermatology clinic.

Methods: A prospective cohort study of patients aged 15-87 years with reported recurrent herpes zoster was conducted. Vesicular fluid and serology for herpes simplex 1, 2, and varicella zoster virus immunoglobulins were obtained from patients presenting with vesicles. Biopsies were obtained from patients with ambiguous presentations.

Results: 44 patients (56%) had evidence of herpes simplex virus infection. 32% of patients had positive herpes simplex virus cultures or polymerase chain reaction sequencing, and 24% additional patients were diagnosed with presumptive simplex infection based on elevated antibody titers. 44% of patients had a diagnosis other than zoster or simplex. One individual had a positive viral culture for varicella zoster virus. 99% of patients who presented with suspected recurrent herpes zoster had no definitive evidence of varicella zoster virus reactivation.

Conclusions: The most common diagnosis was herpes simplex infection. Our results suggest that true recurrent shingles in immunocompetent patients is rare.

estimated incidence of 1-3%.1 However, INTRODUCTION many immunocompetent persons report being diagnosed with recurrent herpes Herpes zoster (shingles), caused by zoster, and recent studies have suggested reactivation of latent varicella–zoster virus, that the incidence of herpes zoster is characterized by a painful unilateral recurrences is more frequent than previously vesicular rash in a dermatomal distribution. reported, typically greater than 6%.2,3 The incidence and severity of herpes zoster Moreover, it is reported that increase with age, in association with a immunocompetent patients often experience decline in cell-mediated immunity.1 The more than two to three recurrent episodes, infection is usually limited to a single particularly in the same dermatome.2,3 occurrence; recurrence is typically However, the plausibility of recurrent herpes characteristic of immune compromise.1 In zoster has also been debated, with many immunocompetent persons, recurrent clinicians hypothesizing that recurrent zoster herpes zoster is thought to be rare, with an in immunocompetent patients is often a January 2021 Volume 5 Issue 1

Copyright 2021 The National Society for Cutaneous Medicine 7 SKIN misdiagnosis.4-8 The purpose of this study positive viral culture for varicella zoster. 99% was to determine the etiology of cutaneous of patients who presented with suspected eruptions that have been previously recurrent herpes zoster had no definitive diagnosed as “recurrent shingles”. evidence of varicella zoster virus reactivation. 43 patients (56%) had evidence of herpes simplex virus infection (Table 1). METHODS

DISCUSSION We performed a prospective cohort analysis of 78 patients who were referred to a community outpatient dermatology clinic Our results suggest that true recurrent with “recurrent shingles”. IRB approval was shingles in immunocompetent patients is not needed as all patients received the rare, as only 1 out of 78 patients had standard of care. Inclusion criteria consisted definitive evidence of latent varicella zoster of a unilateral zosteriform rash, reported virus reactivation. While population-based recurrence at same anatomical site, and/or studies suggesting that recurrences are recurring pain/discomfort at the same common utilize a larger sample size2,3, their anatomical site. Immunosuppression from results are confounded by the inclusion of illness and/or use of immunosuppressive immunocompromised patients and the lack agents were considered exclusionary. of sufficient laboratory or supporting data. Vesicular fluid was collected for varicella To date, there has only been one large zoster virus / herpes simplex virus 1 and 2 published report of laboratory-confirmed viral culture or polymerase chain reaction recurrences in immunocompetent patients (PCR) analysis. For lesions without vesicles over age 60: a herpes zoster vaccine study or in the absence of primary morphology, found that in a total of 1646 cases of herpes simplex-1 and -2 IgG specific established herpes zoster, only 5 were antibody assays were obtained. Results deemed recurrences.9 In immunocompetent were considered positive if IgG titers were patients, recurrent episodes occur in 1% to elevated. For clinically ambiguous 6% of cases.10-13 Our results emphasize the presentations, skin biopsies were importance of diagnostic validity in performed. classifying cases as true recurrent shingles.

In our study, the most common diagnosis RESULTS was herpes simplex infection (57%). Herpes simplex virus 2 was attributed to most cases Subjects were between 15 and 87 years of involving the buttocks while herpes simplex age; the average age was 54 years with a virus 1 was most frequently isolated on standard deviation of 19.4. 77% of patients lesions presenting on the face (Table 2). were female (n=60). 32% of patients These anatomical distributions correspond presenting with recurrent herpes zoster had to the sites of latency of herpes simplex positive herpes simplex virus cultures or virus 1 and herpes simplex virus 2 infection - PCR, and 24% additional patients were in the first and second divisions of the diagnosed with presumptive simplex trigeminal ganglion and in the sacral sensory infection based on elevated antibody titers. ganglia, respectively.14 Furthermore, the 44% of patients had a diagnosis other than average rate of recurrences reported by zoster or simplex. One individual had a patients (monthly for sacral/ herpes

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Table 1. Final diagnoses and characteristics of ages.15-19 In addition, well-characterized patients presenting with putative recurrent herpes manifestations of herpes simplex infections zoster. including herpes gladiatorum (n=2) and Number genital herpes (n=2) were also referred to Percentage (N = 78) our clinic as presumed recurrent shingles Final Diagnosis (Table 2). Herpes simplex 44 56% eruption Women have “recurrent shingles” due to Post-herpetic 14 19% herpes simplex virus far more frequently neuralgia (PHN) than do men; this is particularly true of PHN + Dermatitis 6 8% recurrent vesicles of the buttocks (Figures 1 Folliculitis 4 5% and 2), and for reasons unknown. Herpes Actinic keratosis 2 3% simplex virus reactivation is triggered by a Contact Dermatitis 2 3% variety of factors, including stress, UV- Herpes zoster 1 1% irradiation, or immunosuppression, along Excoriated ulcer 1 1% with menstruation and changes in female sex hormones. However, this does not Prurigo nodularis 1 1% appear to be sufficient to trigger varicella Fixed drug eruption 1 1% zoster virus reactivation.20 Arthropod assault 1 1% Anatomic Post-herpetic neuralgia was implicated in Distribution many cases of “recurrent shingles” and can Head/neck 19 26% be characterized further as post-herpetic Chest/Abdomen/Back 19 24% neuralgia with overlying unrelated skin Anogenital (including 30 38% conditions and post-herpetic neuralgia buttocks) without cutaneous manifestations (Table 1). Extremities (including 9 11% Post herpetic neuralgia was diagnosed in 14 posterior thigh) patients (19%) who presented with unilateral Multiple sites 1 1% recurrent intense pain or pruritus at a site of

Sex previous shingles and had no clear clinical Male 18 23% or diagnostic abnormalities. Post-herpetic Female 60 77% neuralgia is the most common complication of herpes zoster, and a significant cause of simplex virus 2 eruptions) and (every 3-4 morbidity.9-11 Recognition of post-herpetic months for trigeminal/ herpes simplex virus neuralgia allows for treatment to be tailored 1 eruptions) are consistent with rates of towards analgesic relief. recurrent simplex infection14, suggesting that more recurrences of vesicles suggest a Overlying skin conditions included folliculitis, much greater possibility of herpes simplex actinic keratosis, prurigo nodularis, contact virus. Zosteriform herpes simplex virus dermatitis, fixed drug eruption, and infections are encountered in up to 25% of arthropod assault. In addition, the cases initially diagnosed as herpes histopathology revealed a variety of zoster on a clinical base, particularly in the nonspecific inflammatory patterns facial dermatomes.15-19 These eruptions (spongiotic, interface, perifollicular, and occur in both primary and recurrent perivascular dermatitis). A variety of infections, and are observed in patients of all conditions are known to mimic the

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Table 2. Characteristics of Herpes Simplex Infection.

Gender Method of Detection Location Average

Recurrence Rate HSV-1 Male: 3 PCR/Viral Culture: 4 Trigeminal: 4 Every 3-4 months Female: 8 Serology: 7 Abdomen: 1 Buttocks: 2 Thoracic: 1 Suprapubic: 1 Herpes gladiatorum: 2 HSV-2 Male: 5 PCR/Viral Culture: 17 Buttocks: 22 Every 30 days Female: 28 Serology: 16 Posterior Thigh: 5 Thoracic: 3 Trigeminal: 1 Genital herpes: 2

Figure 1. Recurrent vesicular eruption on the buttock infections21, impetigo22, 23 bullous lesions24, of a female patient 25 and lichen planus . Such entities may be attributed to Wolf’s isotopic response, which describes the phenomenon of a cutaneous eruption that develops at the site of a healed, unrelated skin disease - most commonly herpes zoster. Recognition of this phenomenon allows the clinician to treat the primary illness.

Determining the etiology of the “recurrent

shingles” has public health implications Figure 2. Recurrent vesicular eruption on the buttock given the transmissibility of herpes simplex of a female patient virus in comparison to varicella zoster virus. Approximately 12% of patients aged 14-49 are herpes simplex virus 2 seropositive and 48% are herpes simplex virus 1 seropositive.26 In comparison, 99% of adults are varicella zoster virus seropositive due to natural infection with wildtype chickenpox or vaccination. Therefore, a person with “recurrent shingles” due to herpes simplex virus may unknowingly transmit the infection.

A limitation of this study is that it cannot establish with certainty a causal relationship between the patient presentation and HSV titers with IgG alone; only a presumptive

diagnosis of HSV infection can be made appearance and distribution of herpes based on serology, which indicates past zoster, including Staphylococcal skin exposure or recent shedding. Many patients January 2021 Volume 5 Issue 1

Copyright 2021 The National Society for Cutaneous Medicine 10 SKIN who are seropositive for herpes simplex 4. Chien AJ. Why do so many clinicians believe that virus, especially type 2, were unaware of recurrent zoster is common? Derm Online J. 2007; 13 (2):2. their symptoms or had subclinical infection 5. Volpo A, Gatti A, Pica F. Frequency of Herpes and were unlikely to present for culture or Zoster Recurrence. Mayo Clin Proc. PCR analysis. 2011;86(2):584-587. 6. Pierson JC. Reluctance regarding recurrent herpes zoster J Am Acad Derm. 2017 CONCLUSION Apr;76(4):e143. 7. Sax P. Common Curbsides: The Patient with “Recurrent Zoster”. December 30, 2014. N Engl J In this study, laboratory evidence Med Journal Watch. Accessed 12 January 2019. substantiated the clinical observation that https://blogs.jwatch.org/hiv-id- the most common sites of suspected observations/index.php/common-curbsides-the- recurrent herpes zoster correlate with sites patient-with-recurrent-zoster/2014/12/30/ 8. Heskel NS, Hanifin JM. "Recurrent herpes where herpes simplex virus 1 and 2 zoster": an unproved entity? J Am Acad infections typically present, on orolabial and Dermatol. 1984 Mar;10(3):486-90. anogenital skin, respectively. Differentiating 9. Oxman MN, Levin MJ, Johnson GR, et al. A between zoster and simplex is critical in vaccine to prevent herpes zoster and reducing transmission of infection. Post- postherpetic neuralgia in older adults. N Engl J Med, 352 (2005), pp. 2271-2284 herpetic neuralgia, including cases with 10. Hope-Simpson R. The nature of herpes zoster: a superimposed unrelated cutaneous long-term study and a new hypothesis. Proc R manifestations, was also commonly Soc Med. 1965;58:9-20. misdiagnosed as recurrent shingles. Our 11. Ragozzino MW, Melton LJ III, Kurland LT, Chu results support that herpes simplex virus CP, Perry HO. Population-based study of herpes zoster and its sequelae. Medicine (Baltimore, commonly recurs but recurrence of zoster in Md). 1982;61:310-316. immunocompetent individuals is rare. 12. Hernandez, P.O., S. Javed, N. Mendoza, W. LaPolla, L.D. Hicks and S.K. Tyring. Family Conflict of Interest Disclosures: None history and herpes zoster risk in the era of shingles vaccination. J Clin Virol. 52:344-348; Funding: None 2011. 13. Hicks, L.D., R.H. Cook-Norris, N. Mendoza, V. Corresponding Author: Madkan, A. Arora, S.K. Tyring. Family history as Stephen K. Tyring, MD, PhD, MBA a risk factor for herpes zoster: a case-control 1401 Binz, Suite 200 study. Arch Dermatol. 144: 603-608; 2008. Houston, TX 77004 14. Lafferty WE, Coombs RW, Benedetti J, et al. Phone: 713-528-8818 Recurrences after Oral and Genital Herpes Email: [email protected] Simplex Virus Infection. N Engl J Med 1987; 316:1444–9. 15. Forrest WM, Kaufman HE (1976) Zosteriform References: herpes simplex. Am J Ophthalmol 81: 86-88. 1. Gnann JW Jr, Whitley RJ. Herpes zoster. N Engl 16. Kalman CM, Laskin OL (1986) Herpes zoster and J Med 2002;347:340-346 zosteriform herpes simplex virus infections in 2. Yawn BP, Wollan PC, Kurland MG et al. Herpes immunocompetent adults. Am J Med 81: 775- Zoster Recurrences more frequent than 778. [Crossref] previously reported. Mayo Clin Proc. 17. Rübben A, Baron JM, Grussendorf-Conen EI 2011;86(2):88-93. (1997) Routine detection of herpes simplex virus 3. Nakamura Y, Miyagawa F, Okazaki A, et al. and varicella zoster virus by polymerase chain Clinical and immunologic features of recurrent reaction reveals that initial herpes zoster is herpes zoster (HZ). J Am Acad Dermatol. 2016 frequently misdiagnosed as herpes simplex. Br J Nov;75(5):950-956.e1 Dermatol 137: 259-261. 18. Koh MJ, Seah PP, Teo RY (2008) Zosteriform herpes simplex. Singapore Med J 49: e59-60. January 2021 Volume 5 Issue 1

19. Aithal S, Kuruvila S, Ganguly S (2013) Zosteriform herpes simplex and herpes zoster: A clinical clue. Indian Dermatol Online J 4: 369. 20. Freeman ML, Sheridan BS, Bonneau RH, Hendricks RL: Psychological Stress Compromises CD8+ T Cell Control of Latent Herpes Simplex Virus Type 1 Infections. J Immunol. 2007, 179: 322-32 21. Schepp ED, Cohen PR. Zosteriform Staphylococcus aureus cutaneous infection: report of two patients with dermatomal bacterial infection. Skinmed. 2015;13:275–281. 22. Cohen PR. Zosteriform impetigo: Wolf's isotopic response in a cutaneous immunocompromised district. Dermatol Pract Concept. 2015 Jul 31;5(3):35-9. 23. Shetty S, Rao R, Pai S. Impetigo contagiosa in a zosteriform pattern. J Paediatr Child Health. 2016 Jun;52(6):684-5. 24. Chen SX, Cohen PR. Edema Bullae Mimicking Disseminated Herpes Zoster. Cureus. 2017 Oct; 9(10): e1780 25. Braun RP, Barua D, Masouyé I (1998) Zosteriform lichen planus after herpes zoster. Dermatology 197: 87-88. 26. McQuillan G, Kruszon-Moran D, Flagg EW, and Paulose-Ram R. Prevalence of Herpes Simplex Virus Type 1 and Type 2 in Persons Aged 14–49: United States, 2015–2016. NCHS Data Brief. 2018 Feb. No. 304.

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