Keloids After Herpes Zoster: Report of Wolf’s Isotopic Phenomenon and Literature Review

Introduction

Herpes zoster is an infectious skin disease caused by the reactivation of varicella zoster virus (VZV), which spreads along sensory nerves to the dermatomes and manifests clinically as multiple blistering rashes with pain in a dermatomal pattern. Wolf’s post-herpetic isotopic response refers to the appearance of another disease, unrelated to herpes zoster, in the same area as herpes zoster, based on the healing of herpes zoster or subtle changes (scarring, pigmentation).

Common case reports of this phenomenon currently include granuloma, psoriasis, lichen planus, and skin tumors.¹ Keloids are the result of fibroblast proliferation and excessive collagen deposition, which usually occur at the site of trauma or surgical injury.² In addition, keloid after herpes zoster is a very rare condition. In the present study, we reported a case of keloids after herpes zoster with a lesion in the same location as the previous herpes zoster. We supposed this was a typical example of WIR.

Case Report

A 76-year-old man had a history of progressively expanding and pruritic keloids on the right trunk and arm for 3 years. He was diagnosed with “herpes zoster” 3 years ago at another hospital due to erythema and blisters with pain on the right side of his trunk and arm. Erythema was distributed on the right side of the chest and back, and arm, which is locally fused into bands with a cluster of blisters on it. Erythema unilaterally occurred, with local ulceration and conscious paroxysmal pain. He was treated with vaxilovir for 2 weeks. The patient refused to conduct the histopathological examination. One month later, keloid-like lesions appeared after the erythema and blisters regressed. In the follow-up, he noticed that his scar became prominent, expanded, and gradually began to show keloid features. The patient denied having any serious skin infection at that time, and tried topicalasiaticoside ointment. However, he did not experience disease relief, and the keloids progressively increased in size, even beyond the edges of the original lesion. He also had localized itching and pain around the keloids and the entire dermatome, and his breathing was affected, leading to poor sleep. For the last 3 months, the patient received topical injections of the compound betamethasone in the scar, once a month for 3 times. The effect of these injections was little and resulted in localized burst of the scar, crusting and hyperpigmentation. The patient had no previous history of keloids or family history and was HIV-negative. Physical examination: multiple plaques in the right trunk and arm, corresponding to dermatomes T2–T3 and T7, with the largest located in the right chest T2-T3 dermatome, measuring 19 cm (L) × 5 cm (W), with a firm texture and irregular boundaries, together with a small amount of hyperpigmentation, and painful to touch (Figure 1A and B). Further polarizing dermoscopy (PD) examination showed that this lesion had erythematous background with white streaks scattered across the blood vessels, indicating the features of fibrosis. Reflectance confocal microscopy (RCM) results revealed that dermal collagen fibers were arranged in dense bundles (Figure 2A and B). Given the large size of the lesion and the poor results of local steroid injections, local radiation therapy after surgical excision was recommended for this patient. However, he did not accept this treatment scheme.

Figure 1 Dermatomal distribution of keloids at the site of healed herpes zoster. (A) The patient had multiple plaques in the right trunk and arm, corresponding to dermatomes T2–T3 and T7, with the largest located in the right chest T2-T3 dermatome, measuring 19 cm (L) × 5 cm (W); (B) The patient had a right dorsal plaque, not beyond the midline.

Figure 2 Polarizing dermoscopy and reflectance confocal microscopy examination. (A) Polarizing dermoscopy (PD) examination showed that this lesion had erythematous background with white streaks scattered across the blood vessels, indicating the features of fibrosis; (B) reflectance confocal microscopy (RCM) results revealed that dermal collagen fibers were arranged in dense bundles.

Discussion

Wolf’s isotopic response (WIR), first described in 1955, refers to a new dermatosis occurring in the same location as another healed and unrelated dermatosis. In 1995, Wolf et al recognized this dermatologic phenomenon and provided a precise definition of WIR.³ In 2017, Wolf et al⁴ expanded this criterion of WIR, and argued that scars, pigment changes, and other subtle changes that occur in the secondary dermatosis due to the first should also be included. Keloids, an abnormal proliferation of scar tissue formed after a skin injury, are characterized by fibroblast proliferation and excessive collagen deposition. It is commonly seen on the sternum, shoulders, back of the neck, and earlobes. Many factors, such as trauma, infection, skin tension, darker skin ethnicity, and genetic predisposition, play a crucial role in the development of keloid scars. They are not only aesthetically unpleasant but also accompanied by symptoms of pain, itching, and functional impairments that can significantly affect the patient’s quality of life.⁵

Keloids after herpes zoster were rarely reported. According to the current report, we evaluated a total of 8 cases diagnosed with it; the specific clinical features, the time interval after herpes zoster infection, and the immunity are shown in Table 1. It is exhibited that four of these cases were patients combined with HIV. Patients with secondary disease of keloids were more inclined to have underlying diseases that lead to immune deficiency. Five cases occurred in the trunk area, commonly in dark skin and Asian skin, but dark skin has a predisposition to congenital keloid formation. This finding is similar with the previous studies demonstrating that keloid scar formation is more commonly seen in individuals of African, Asian, and, to a lesser extent, Latin American or Mediterranean descent, which associates with the darker pigmentation factor.^6,7 Currently, some case reports about keloids after herpes zoster in patients with immune deficiency, mainly HIV patients. Koley et al⁸ described a rare case of recurrent herpes zoster in an HIV-positive male where the lesions healed with the formation of keloids in both episodes. Another case series reported on herpes zoster infections triggered by HIV infection in four seropositive HIV patients and one patient with recurrent carcinoma after radiotherapy.⁹ However, few case reports have demonstrated keloids after herpes zoster in Chinese patients without immune deficiency. Here, the isotopic response of herpes zoster was manifested by typical keloid manifestation in this patient.

Table 1 Characteristics of Reported Cases with Keloids at the Site of the Original Herpes Zoster

Although case reports of WIR have increased in recent years, due to the lack of large population-based studies of post herpes zoster isotopic response, there is little known about the exact incidence and specific mechanism of it in the literature. Considering that herpes zoster is the most common initial disease, it is suspected that there is a viral association.¹⁶ Herpes zoster is caused by the reactivation of VZV, which is more commonly seen in individuals older than 50 years and immunocompromised patients due to T-cell-mediated immune decline. It usually begins as an erythematous papule in a single or successive dermatomal pattern, spanning multiple areas, usually not exceeding the midline. VZV infection can cause local anatomic changes such as scar formation, microcirculation change, collagen rearrangement, and impaired local immune defense. During the course of herpes zoster, VZV is activated in the dorsal root ganglion, travels through the intraepidermal nerve endings to the basal keratinocytes, and makes massive VZV replication, breaking through the basement membrane to infect dermal dendritic cells, which play an important role in skin healing. VZV can affect the normal function of dendritic cells, leading to the tendency of scarring. In addition, darker skin has more dermal dendritic cells, which possibly explains their greater tendency to scarring.¹⁷ In the present case, the patient with typical clinical manifestations including painful erythema and blisters was first manifested as “herpes zoster” 3 years ago, only after 1 month, keloid-like lesions appeared after the erythema and blisters regressed, indicating the potential relationship between herpes zoster lesions and keloids due to close time course. Of note, this patient exhibited breathing difficulty due to progressively increased keloids. It is important to elucidate that the size of the keloid alone is not the only factor that determines whether it will cause breathing difficulty, the location of the keloid and the extent of skin involvement are also important factors to consider.^18,19 For instance, severe keloids on the face and neck may cause difficulties in swallowing and breathing.

Multiple theories and evidence also suggest that not only viral factors but also more complex host factors (eg, vascular, immune, or neurological factors) are involved in the development of WIR. Possible mechanisms include the hypothesis of immunocompromised skin,²⁰ in which locoregional skin immune dysregulation occurs after a prior injury event, thereby increasing the risk of subsequent skin lesions, and different pathways can lead to impaired local skin function, such as trauma, infection, or vascular dysfunction. Regardless of the cause, over time the immunocompromised skin area may become a vulnerable site for opportunistic infection, inflammation, tumor, and abnormal immune response, usually confined to the area itself. Ruocco et al²⁰ explained the neural hypothesis, and it is so far the most favored one, that herpes zoster virus can cause Aδ and C nerve destruction in the middle and lower dermis, leading to the release of neuropeptides that regulate local immune and angiogenic responses. Multiple interactions between cutaneous nerves, the neuroendocrine axis and immune system influence the mechanism of new diseases. Mahajan et al²¹ studied these theories in detail and proposed a complex theory of isotopic response occurrence. However, none of the above hypotheses can singularly explain the pathogenesis of isotopic response. One or more, or all the factors, play a role in the causation of a new disease along the “locus minoris resistentiae”.

Conclusion

Herpes zoster is a common infectious disease, and the risk of isotopic reactions may be underestimated. Further studies are needed to understand the exact pathogenesis and epidemiology of this response. We speculated that immunological changes, namely increased sensitivity to the tissue antigens of primary varicella-zoster virus infection, and superficial trauma to the lesion area in the early stage due to herpes zoster, might play an important role in the development of keloids in our patient.