Introduction

Facial herpes simplex (FHS), commonly referred to as cold sores, orofacial herpes, fever blisters, sun blisters, or herpes labialis, is a widespread condition. Clinically, it may present as herpes labialis (affecting the lips and surrounding areas), herpetic gingivostomatitis (involving the oral cavity), or herpetic keratitis (affecting the eyes). It is characterized by recurrent, self-limiting episodes of tender and painful clusters of blisters that appear on the mucous membranes or on erythematous, swollen areas of the skin. The eruptions heal without scaring. FHS is caused by both herpes simplex virus types 1 or 2 [1–3].

The recurrence of FHS is classically triggered and activated by multiple factors such psychosocial stress, surgical trauma, menstruation, hyperthermia, sunlight exposure, and some drugs, like corticosteroids [1]. Beyond recurrence, complications of facial herpes simplex (FHS) often include persistent pain, cosmetic concerns, and associated social limitations. In some individuals might leave sequelae like leukoderma of the lips after herpes labialis, moreover, a new depigmentation on and around the lips might appear after the recurrent attack of herpes labialis [4,5]. Another reported problem following FHS is an activation of most acute cases of erythema multiforme (EM) [2,6]. Recently, the novel coronavirus-19 has been described to be associated with EM [2,7,8].

EM is an immune-mediated cutaneous and mucosal condition. It is typically presented as a symmetric distribution of multiple targetoid red color lesions with circular rings in an acral distribution mainly involving the dorsal surfaces of hands and feet, and extensor parts of elbows and knees [9,10] Within 1-4 weeks of EM attack, a complete recovery typically occurs, without scars apart from transient hypopigmentation or hyperpigmentation [10].

Vitiligo is a common inflammatory autoimmune disease resulting from deficiency, absence or dysfunction of melanocytes, causing patchy loss of skin pigmentation [11]. The isomorphic or Koebner’s phenomenon is frequently detected in psoriasis, lichen planus and vitiligo that is triggered by several factors like trauma, sunburn, chemical matters, and (bacterial, fungal and viral) infections. The mechanism behind the isomorphic phenomenon remains vague, uncommonly, herpes simplex, chicken pox and measles viruses have been pronounced as activating factors [12].

Accordingly, the aim of the present study is to document all cases of vitiligo that developed following post-herpetic erythema multiforme or herpes simplex facialis, and to assess their various clinical presentations.

Materials and Methods

This a case series descriptive study that was carried out during the period that extended from 2019 to 2024 years, at the Department of Dermatology, Baghdad Teaching Hospital, Baghdad, Iraq. Where all patients had a history of recurrent herpes simplex infection of the face that was followed by erythema multiforme or by vitiligo. All participants had Fitzpatrick skin types III and IV. A full record of all patients was obtained, regarding demographic features, other suspected precipitating factors concerning the present problem, duration of vitiligo and sites of involvement, family history for close relatives, the coexistence of other autoimmune diseases, and previous treatments. The severity of the disease is calculated depending on the Vitiligo Area Severity Index (VASI), where one hand unit of vitiligo involvement is roughly equal to 1% of the whole surface area of the body (100%= complete depigmentation) [13].

Furthermore, a confirmatory test thorough Wood’s light examination was recorded. Blood sampling was sent for analysis by the enzyme-linked immunosorbent assay (ELISA) to detect IgG immunoglobulins against herpes simplex virus type 1 (anti-HSV-1 IgG). The announcement of Helsinki in 1964 as well as its modification in October 2024 was surveyed during the study. Variables were entered and analyzed using SPSS (Statistical Package for the Social Sciences), version 29 (IBM Corp., 2022, Armonk, NY, USA). Data were summarized using frequencies and percentages, as well as means and standard deviations where applicable.

Results

Over five years, a total of 30 patients were complaining of post-herpetic vitiligo characterized by white Ivory colored by Wood’s light examination, their ages ranged from 8 to 50 years with a mean of 18 years. The cohort included 27(90%) males and 3(10%) females, resulting in a ratio of 9:1. The average frequency of FHS recurrence was six episodes per year. A positive family history of vitiligo was reported in 7(33.33%) patients. The median duration of vitiligo was 11 months, ranging from 2 to 28 months. Based on the VASI, 1-10% body surface area involvement was observed in 27(90%) cases. Half of the participants denied experiencing any stressful events prior to the onset of herpes simplex or vitiligo. All serological results of anti-HSV-1 IgG were positive. However, depending on the appropriate clinical evaluation and diagnostic criteria, the study was divided into two parts (Table 1):

Table 1: Demographic features of post-herpetic vitiligo including post-EM vitiligo and post-herpetic vitiligo n=30.

Part I: Post-Herpetic Erythema Multiforme

A total of 37 patients with post-herpetic EM were included, comprising 29 cases were males and eight females, with ages ranging from 8 to 60 years (median age: 18 years). In all cases, facial herpes simplex preceded the onset of EM by 3-4 days (Fig. 1).

Figure 1: Two patients presenting with erythema multiforme triggered by herpes simplex-l.

Vitiligo following post-herpetic EM was identified in 9 male patients (24.3%), all aged between 8 and 15 years. In these cases, vitiligo was consistently located around the mouth, specifically the lips (100%). Additional sites of involvement included arms (5 cases, 55.5%), legs (5 cases, 55.5%), hands (2 cases, 22.2%), and eyes (1 case, 11.1%) (Fig. 2). According to VASI scoring, all patients in this group showed 1-10% surface area involvement.

Figure 2: Three different patients presented with post-herpetic vitiligo of lips that disseminated as postherpetic erythema multiforme-vitiligo.

Part II: Post-Herpetic Vitiligo

This group included 21 patients with post-herpetic vitiligo, comprising 18 (85.71%) males and 3 (14.29%) females, aged between 10 and 45 years, with a mean age of 14 years. All patients reported a history of recurrent herpes simplex facialis, with leukoderma developing after each episode. Multiple vitiligo patches were typically observed around the upper and lower lips (Fig. 3). Based on VASI scoring, 1 to 10% body surface area involvement was observed in 18 (85.71%) patients. Progression to generalized (ordinary) vitiligo occurred in only 3 (14.28%) cases.

Figure 3: Three different men, presenting with post-herpetic vitiligo of lips and around the mouth, each patient has multiple extended patches of vitiligo according to frequency of herpes attacks.

Discussion

The face, particularly the lips, is often considered an important indicator of various systemic and dermatological conditions, including pallor, hypopigmentation, hyperpigmentation, and cyanosis. In 1984, Sharquie et al. were the first to report that recurrent herpes simplex (HS) infection of the lips was frequently followed by episodes of acute erythema multiforme (EM) and the development of skin leukoderma [4,5]. Recently, there has been growing concern regarding the differentiation between leukoderma, vitiligo, and other forms of post-inflammatory hypopigmentation. Therefore, this study suggests a potential causal link between the onset of vitiligo and facial herpes simplex infection, in addition to its development as a sequela of post-herpetic erythema multiforme.

Surprisingly, vitiligo was found to be more common among males than females, with a male-to-female ratio of 9:1. This contrasts with previous reports, which showed an equal distribution between the sexes, although women are more likely to seek medical consultation, particularly when facial involvement is present [14,15]. The predominance of male participants can be attributed to several factors. First, the small sample size of the subgroup; biological differences may play a role, as androgens can influence skin immune responses and melanocyte behavior differently from estrogens; additionally, males are known to exhibit distinct immune response profiles compared to females. Environmental and behavioral factors may also contribute, including greater exposure to sunlight, trauma, or stressors; moreover, men tend to use sun protection, lip balms, and skincare products less frequently, which may increase their susceptibility to skin damage and subsequent pigmentary disorders.

It has also been reported that approximately one-third of individuals with vitiligo exhibit a positive Koebner phenomenon [5,16]. In the current study, all cases of vitiligo could be considered as Koebner reactions following herpes simplex infection, with each episode of herpes triggering the development of new vitiligo patches. While the association between herpes infection and vitiligo is not yet fully understood, we speculate that recurrent herpetic infections may alter the function of related genes through a mechanism known as epigenetic modification [17,18].

A family history of vitiligo was observed in approximately one-third of patients, a figure slightly higher than that reported in previous epidemiological research. This finding underscores the role of genetic factors and the familial tendency of vitiligo [15,19]. In the current study, all patients exhibited a median vitiligo duration of 11 months, with involvement of 1-10% of the body surface area and a tendency for localized spread. Progression to generalized (ordinary) vitiligo was observed in 14.28% of cases. Additionally, half of the participants reported a history of stressful events. These findings suggest an elevated risk of vitiligo development among patients with facial herpes simplex (FHS).

Therefore, criteria that may help distinguish early vitiligo from leukoderma include well-defined margins, a positive Wood’s lamp test, a family history of vitiligo, localized extension of lesions, and the presence of a typical Koebner phenomenon.

Erythema multiforme (EM) is a mucocutaneous, immune-mediated condition frequently triggered by herpes simplex virus (HSV), and is sometimes followed by transient pigmentary changes after recovery [2,10]. It has been proposed that viral antigens initiate an autoreactive T-cell response, leading to inflammation and the production of interferon-gamma, which subsequently upregulates various cytokines and chemokines. Additionally, there is increased sequestration of circulating monocytes, leukocytes, and natural killer cells within the epidermis [20]. These findings align with observations in the current study, where cases of post-herpetic EM were reported. Notably, post-herpetic erythema multiforme-associated vitiligo was identified in 24.3% of patients, primarily affecting the lips, arms, and legs, and less frequently the hands and eyes. The association between vitiligo and EM supports the hypothesis of an underlying autoimmune process, involving immune cytotoxic reactions directed against viral infections. A possible epigenetic mechanism may also be involved, wherein viral agents alter the function of genes related to melanocyte activity, leading to depigmentation [18].

Previous research has demonstrated that viral antigens can contribute to the reactivation of psoriatic lesions [21]. This finding closely parallels the current study, in which all patients had a history of recurrent herpes simplex facialis (FHS), followed by hypopigmentation around the upper and lower lips. Sharquie strongly suggested that FHS infection may play a triggering role in the pathogenesis of vitiligo [18].

A similar mechanism may underline the isomorphic phenomenon observed in lip vitiligo following recurrent herpes simplex infections. It is proposed that repetitive HSV attacks may trigger vitiligo through the release of substance P, a neuropeptide involved in inflammatory responses, thereby supporting this hypothesis. Recent studies have reported significantly higher rates of anti-HSV-1/2 IgG positivity in patients with vitiligo compared to healthy controls. Furthermore, there is compelling evidence that HSV-1 can directly target melanocytes, inducing apoptosis. These findings support the hypothesis that HSV-1 infection may act as a triggering factor in the development of vitiligo [22,23]. Additionally, a previous study suggested that vitiligo may be triggered by viral infections, including cytomegalovirus, which was detected in the depigmented skin of some patients with vitiligo but was absent in the skin of control participants [24]. Additional research has reported that hepatitis C virus (HCV) infection may act as a triggering factor for adult-onset vitiligo [25]. Furthermore, an experimental study involving herpesvirus vaccination in turkeys and chickens strongly supports a link between viral exposure and a higher incidence of vitiligo [26].

Although this observational study highlights a potentially curable triggering factor of vitiligo, it has no molecular or histopathological analyses that were performed, which could have provided stronger evidence to support the proposed role of HSV in vitiligo pathogenesis. Besides, the study lacked a matched control group of patients with herpes simplex infection who did not develop vitiligo, making it difficult to establish a strong causal relationship.

Conclusion

The present study establishes a potential causal link between facial herpes simplex and the onset of vitiligo, which may appear either directly after the infection, primarily around the lips, or potentially occurring as a sequela of post-herpetic erythema multiforme, affecting both the lips and limbs. Several mechanisms may explain this association; however, the epigenetic pathway remains the most compelling hypothesis to account for the observed connection. Nevertheless, further research is urgently needed to provide a definitive, objective explanation. Finally, this raises an important question: could herpes simplex genitalis also act as a triggering factor for vitiligo?

REFERENCES

1.  Gopinath D, Koe KH, Maharajan MK, Panda S. A comprehensive overview of epidemiology, pathogenesis and the management of herpes labialis. Viruses. 2023;15:225.

2.  Sharquie KE, Al-Kafaji KA. Incedence of Skin Disorders in Iraqi Infants and Children. J University of Babylon for Pure and Applied Sciences. 1997;2:511-23.

3.  Harmenberg J, Öberg B, Spruance S. Prevention of ulcerative lesions by episodic treatment of recurrent herpes labialis:a literature review. Acta Derm Venereol. 2010;90:122-30.

4.  Bose S. Herpes labialis-induced isomorphic phenomenon in lip leucoderma. J Eur Acad Dermatol Venereol. 2008;22:500-1.

5.  Sharquie KE. Common hypopigmented skin disorders in Baghdad teaching hospital. Iraqi J Community Medicine. 2011;24:258-60.

6.  Alamon-Reig F, Castrejón N, Bosch-Amate X. Erythema Multiforme:When targets lead to diagnosis. Sultan Qaboos Univ Med J. 2021;21:666-7.

7.  Gargiulo L, Pavia G, Facheris P, Valenti M, Sacrini F, Narcisi A, et al. A fatal case of COVID-19 infection presenting with an erythema multiforme-like eruption and fever. Dermatol Ther. 2020;33:e13779.

8.  Soares A, Sokumbi O. Recent updates in the treatment of erythema multiforme. Medicina. 2021;57:921.

9.  Trayes KP, Love G, Studdiford JS. Erythema multiforme:recognition and management. Am Fam Physician. 2019;100:82-8.

10.  Wetter DA, Davis MD. Recurrent erythema multiforme:clinical characteristics, etiologic associations, and treatment in a series of 48 patients at Mayo Clinic, 2000 to 2007. J Am Acad Dermatol. 2010;62:45-53.

11.  Sharquie KE, Mehenna SH, Naji AA, Al-Azzawi H. Inflammatory changes in vitiligo:stage I and II depigmentation. Am J Dermatopathol. 2004;26:108-12.

12.  Sharquie KE, Sharquie IK, Al Hamza AN. Psoriasis, pityriasis alba, and vitiligo (PPV) are a triad of one disease:New observation. Our Dermatol Online. 2021;12:314-23.

13.  Bhor U, Pande S. Scoring systems in dermatology. Indian J Dermatol Venereol Leprol. 2006;72:315-21.

14.  Alikhan A, Felsten LM, Daly M, Petronic-Rosic V. Vitiligo:a comprehensive overview:part I. Introduction, epidemiology, quality of life, diagnosis, differential diagnosis, associations, histopathology, etiology, and work-up. J Am Acad Dermatol. 2011;65:473-91.

15.  Bergqvist C, Ezzedine K. Vitiligo:a review. Dermatology. 2020;236:571-92.

16.  Papadavid E, Yu R, Munn S, Chu A. Strict anatomical coexistence of vitiligo and psoriasis vulgaris–a Koebner phenomenon?Clin Exp Dermatol. 1996;21:138-40.

17.  Wagner RY, Luciani F, Cario-AndréM, Rubod A, Petit V, Benzekri L, et al. Altered E-cadherin levels and distribution in melanocytes precede clinical manifestations of vitiligo. J Invest Dermatol. 2015;135:1810-19.

18.  Sharquie IK, Sharquie KE. The role of epigenetics in immunosuppression in patients with infectious diseases as a fascinating applied observation. J Pak Assoc Dermatol. 2023;33:275-82.

19.  Henning SW, Jaishankar D, Barse LW, Dellacecca ER, Lancki N, Webb K, et al. The relationship between stress and vitiligo:Evaluating perceived stress and electronic medical record data. PLoS One. 2020;15:e0227909.

20.  Aurelian L, Ono F, Burnett J. Herpes simplex virus (HSV)-associated erythema multiforme (HAEM):a viral disease with an autoimmune component. Dermatol Online J. 2003;9:1.

21.  Bose S. Probable mechanism of varicella-induced koebnerization in psoriasis. Indian J Dermatol Venereol Leprol. 1995;61:70-1.

22.  Lan J, Hong Y, Qi R, Zheng S, Gao X. HSV-1 enters melanocytes and induces their apoptosis. J Pigmentary Disord. 2016;3:2376-0427.1000246.

23.  de Paula Ribeiro R, Lacerda KA, Guillo LA. Analysis of Serum Immunoglobulin G (IgG) Levels against Toxoplasma Gondii, Herpes Simplex Virus Types 1 and 2, Cytomegalovirus and Hepatitis C Virus in Vitiligo. Indian J Dermatol. 2023;68:588.

24.  Grimes PE, Sevall JS, Vojdani A. Cytomegalovirus DNA identified in skin biopsy specimens of patients with vitiligo. J Am Acad Dermatol. 1996;35:21-6.

25.  Fawzy MM, Hammad NM, Sharaf AL, Khattab F. Hepatitis C virus infection could be a risk factor for adult-onset vitiligo in Egyptian patients:A cross-sectional study. J Cosmet Dermatol. 2022;21:4983-9.

26.  Falcon DM, Byrne KA, Sales MA, Erf GF. Spontaneous immunological activities in the target tissue of vitiligo-prone Smyth and vitiligo-susceptible Brown lines of chicken. Front Immunol. 2024;24;15:1386727.