Introduction

Herpes zoster (HZ), caused by reactivation of latent varicella-zoster virus (VZV) in ganglia, is an acute infectious dermatosis characterized by unilateral, dermatomal clusters of vesicles often accompanied by neuralgia. Wolf’s isotopic response (WIR) refers to developing a new, unrelated skin disorder at the site of a previously healed cutaneous condition. HZ is WIR’s most frequently reported antecedent disease, followed by herpes simplex, varicella, and thrombophlebitis. When occurring after HZ, this phenomenon is termed Wolf’s post-herpetic isotopic response (PHIR). Manifestations of PHIR include granulomatous reactions, primary/metastatic tumours, leukemic/lymphomatous infiltrates, dysimmune disorders, secondary infections, acne, and epidermal cysts. The interval between the two conditions varies widely (days to years), and the pathogenesis remains unclear, with viral, immune, neural, and vascular hypotheses proposed. Herpetiform pemphigus (HP) is a rare autoimmune bullous disorder characterized by clinical features mimicking dermatitis herpetiformis and histopathological changes typical of pemphigus. Its core mechanism involves abnormal immune attacks on intercellular junction structures in the skin, leading to intraepidermal blister formation—notably, no PHIR presenting as HP has been documented in the literature. Herein, we describe a case of PHIR manifesting as HP. Identifying this case may give clinicians a new perspective, emphasizing the need to consider immune-mediated bullous diseases in new skin lesions developing after herpes zoster resolution.

Case Presentation

The patient was a 76-year-old male who presented to our department on March 14, 2023, due to “scattered erythema, blisters, and itching all over the body for 15 days”. One month prior, the patient had consulted our department for “herpes zoster (HZ) on the right lateral waist, abdomen, and back” and received 14 days of treatment, including antiviral therapy, nerve nutrition, and pain relief, after which the rash healed and the patient was discharged on February 27, 2023. Post-discharge, the patient occasionally experienced distending pain in the herpes-affected skin area of the right lateral waist, abdomen, and back, where large pigmentation spots remained. Fifteen days before the current presentation, the patient noticed small blisters and papules scattered along the edges of the previously healed HZ lesion area on the right lateral waist, abdomen, and back. These blisters recurred repeatedly within the original HZ lesion area. They gradually involved the entire body after 7 days, predominantly affecting the right lateral waist, abdomen, back, and proximal regions of both lower limbs, accompanied by intense itching, frequent scratching, and no pain. Thus, the patient revisited our hospital and was admitted to the dermatology department with a tentative diagnosis of “bullous pemphigoid (BP)?”. The patient had a history of hypertension for over one year and was treated with oral Irbesartan 0.15g QD with well-controlled blood pressure. The patient also had a history of smoking and alcohol consumption for over 20 years. There was no history of drug allergies, family history of hereditary diseases, or similar skin diseases. On admission, the patient’s vital signs were stable Dermatological examination (Figures 1–3) revealed scattered annular erythemas varying across the entire body, most prominent on the right lateral waist, abdomen, back, and proximal lower limbs. Some erythemas coalesced into patchy formations with slightly elevated edges, where millet- to mung bean-sized blisters were observable. A few blisters were arranged in a circular or semi-circular configuration with clear blister fluid. The central part of the erythemas showed erosion, exudation, and crusting, and the Nikolsky sign was negative. The right lateral waist, abdomen, and back displayed extensive pigmented macules in a horizontal band-shaped distribution.

Figure 1 Right lumboabdominal skin lesions.

Figure 2 Right lower back skin lesions.

Figure 3 Lesions of proximal lower limbs.

Initially diagnosed with bullous pemphigoid, the patient was treated with oral minocycline, nicotinamide, and topical ointments after full communication with the patient and family and obtaining informed consent. After five days of treatment, existing skin lesions showed signs of regression, but new blisters continued to develop, predominantly on the right thoracoabdominal region and proximal thighs. Laboratory and auxiliary examinations showed: Blood cell analysis showed elevated eosinophil percentage (15.7%, normal range: 0.4–8%) and absolute eosinophil count (0.94×10⁹/L, normal range: 0.02–0.52×10⁹/L), with red and white blood cell counts and differential classifications within normal limits. Blood biochemistry showed low total protein levels (57.99g/L, normal range: 65–85g/L) and albumin 3 (4.10g/L, normal range: 40–55g/L). Blood glucose, electrolytes, liver and kidney function, C-reactive protein, routine stool and urine tests, hepatitis B surface antigen and antibody, and HIV antibody all showed normal results. Serum varicella-zoster virus (VZV) DNA polymerase chain reaction (PCR) testing revealed a negative result for VZV. Enzyme-linked immunosorbent assays (ELISA)for IgG and IgE autoantibodies against Desmoglein(Dsg)1, Dsg3 and BP antigen II (BP180), BP antigen I (BP230) were all negative. The histopathological findings of the skin lesion on the right thigh (Figure 4) revealed the formation of an intraepidermal blister. A large number of eosinophils and a small number of lymphocytes and neutrophils were observed within the blisters. In the superficial to deep layers of the dermis, perivascular infiltration of numerous eosinophils, scattered lymphocytes, and a few neutrophils was noted, with the infiltration predominantly in the superficial layer. Direct immunofluorescence(DIF) showed deposition of immunoglobulin G (IgG) and Complement component 3 (C3) at the intercellular portion of the epidermis (Figure 5), and immunoglobulin A (IgA), immunoglobulin M (IgM) and Fibrin (Fib) were negative.

Figure 4 Histopathology of right thigh skin lesions (HE × 40).

Figure 5 (a and b) DIF showed reticular lattice deposition of C3 and IgG between Interspinous epidermal cells.

Five days after admission, the final diagnosis was confirmed as the post-herpetic isotopic response (PHIR) in herpetiform pemphigus based on clinical manifestations, laboratory results, and histopathological findings. Consequently, with the patient’s informed consent, the treatment regimen was adjusted: minocycline and nicotinamide were discontinued, and an intravenous drip of methylprednisolone sodium succinate (40mg/day) was initiated for immunosuppression, along with cefuroxime sodium (1.5 g every 8 hours) for infection prevention, supplemented by symptomatic and supportive measures. After one week of treatment, the patient’s original vesicles were absorbed, dried, and crusted, with no new vesicles. The patient reported no significant generalized itching, and the methylprednisolone dosage was reduced to 32 mg/day. After five days of clinical observation, the patient was discharged with no new cutaneous lesions (including erythema and vesicles) and no itching or pain. At discharge, the patient had numerous scattered dark brown scabs and pigmented macules on the trunk and limbs, with large pigmented macules and scars on the right lateral waist and back. The patient was instructed to return for regular follow-ups and gradually taper off corticosteroids. During the 18-month follow-up, the corticosteroid dosage was gradually tapered and eventually discontinued, with the patient achieving complete remission and remaining relapse-free.

Discussion

Wolf’s isotopic response(WIR) refers to the occurrence of another unrelated or differently-natured skin disease at the site of a previously healed skin condition. First reported by neurologist Wyburn-Mason in 1955,¹ this concept was first summarized and defined as “isotopic response” by Wolf et al in 1995.² In 2017, the definition was expanded to include new skin diseases arising at sites of pigmentation changes or scars from prior dermatoses.³ HZ is WIR’s most common antecedent disease, followed by herpes simplex, varicella, and thrombophlebitis.⁴ Clinical manifestations are diverse and categorized into granulomatous reactions, primary/metastatic tumours, leukemic/lymphomatous infiltrations, immune disorders, infections, acne, skin cysts, etc.^5,6 In this case, the patient had no previous history of HP. Notably, the initial lesions of HP were strictly distributed along the pigmented area left by HZ, a feature highly consistent with the core definition of WIR that “primarily involves the original lesion area”, providing a fundamental basis for the diagnosis. Although the lesions generalized to the whole body 7 days after onset, the clinical manifestation broke through the typical “localized to the original site” pattern, which may represent a special case of post-herpetic isotopic response and belongs to the extended variant of WIR. The unique evolution of this case provides a new observational dimension for the clinical spectrum of isotopic response, making it academically valuable for reporting.

HP, a rare autoimmune bullous disorder first described by Jablonska et al in 1975,⁶ is a pemphigus subtype characterized by clinical features mimicking dermatitis herpetiformis and immunopathological characteristics of pemphigus, comprising approximately 7% of all pemphigus cases. Its etiology remains incompletely understood, with proposed associations with infections, trauma, diet, and medications.^7,8 HP typically presents as annular erythema with or without blisters, urticarial lesions, or edematous erythema with crusting, featuring negative Nikolsky’s sign and predilection for the trunk and extremities, often sparing oral mucosa. Histopathology shows intraepidermal blisters with eosinophilic/neutrophilic infiltration and intraepidermal clefts (with or without acantholysis). Direct immunofluorescence (DIF) reveals IgG ± C3 deposition between keratinocytes. Specific autoantibody testing detects anti-Dsg1/3 and anti-desmocollin (Dsc) 1–3 antibodies by ELISA.^9,10 Recently, cases of HP with isolated anti-Dsc antibodies (negative for anti-Dsg) have been reported.¹¹ In this case, HP diagnosis was supported by clinical, histological, and immunofluorescence findings despite negative anti-Dsg1/3 antibodies. Reports indicate anti-Dsc antibodies may have pathogenic potential in atypical pemphigus, interfering with desmosomal assembly in vivo,¹² though their precise role remains unclear. The patient’s pemphigus likely resulted from anti-Dsc autoantibodies. Dscs, belonging to the cadherin superfamily, provide structural support to desmosomes and are crucial for intercellular adhesion. Approximately 60% of HP patients have Dsc rather than Dsg antibodies; thus, Dsc-related studies are warranted when HP is suspected, but Dsg antibodies are negative.¹³ Further research on Dsc is needed in this case.

In this case, HP developed 15 days after the HZ resolution, with a very short interval between the two episodes, necessitating differentiation from Disseminated herpes zoster (DHZ). HZ is characterized by clustered vesicles distributed along sensory nerve branches, with histopathology showing intraepidermal vesicles accompanied by ballooning degeneration of keratinocytes and eosinophilic intranuclear inclusions (Cowdry type A). DHZ is a systemic hematogenous virus that spreads, manifesting as more than 20 varicella-like lesions throughout the body or visceral involvement.¹⁴ The patient did not receive antiviral therapy yet demonstrated a favourable response to glucocorticoid treatment, suggesting an immune-mediated disease rather than a viral infection from a therapeutic perspective. Additionally, histopathological and immunofluorescence findings clearly distinguished it from viral infection. Furthermore, HP is often misdiagnosed as bullous pemphigoid (BP) due to clinical similarities, but pathological differentiation is key: BP features subepidermal blisters, whereas this case showed intraepidermal blisters. Therefore, based on this observation, the diagnosis of bullous pemphigoid can be excluded. HP typically follows a chronic course, and currently, there is no standardized treatment protocol. Dapsone and/or glucocorticoids remain the preferred treatments.⁸ Mild cases can be managed with low-dose glucocorticoids or dapsone alone; for cases with disease progression or ineffective glucocorticoid treatment, combination therapy with medications such as cyclophosphamide, Sulfapyridine, azathioprine, methotrexate, and minocycline can be considered. Plasma exchange and intravenous immunoglobulin administration also effectively control the disease.^9,10 In the realm of biologics, there exists a documented case report wherein a severe case of HP was successfully managed with rituximab.¹⁵ Compared with other types of pemphigus, HP has a favourable prognosis, with a few cases progressing to pemphigus vulgaris, pemphigus foliaceous, or pemphigus erythematosus. In this case, minocycline and nicotinamide showed some limited therapeutic effect. However, the administration of glucocorticoids resulted in satisfactory clinical outcomes.

The etiopathogenesis of PHIR has not been comprehensively clarified. It is likely associated with the pathophysiological reactions induced by VZV infection, encompassing viral, immunological, vascular, and neurological elements. Mahajan et al postulated that the Wolf’s isotopic response stems from neuropeptides and neural signals from damaged nerve terminals.¹⁶ Some scholars have defined skin areas that are more vulnerable either genetically or through acquired means as “immunocompromised (or immunologically unstable) districts(ICDs)”. This concept elucidates why previously injured skin sites are susceptible to opportunistic infections, tumours, and heightened immune responses. Potentially, this is due to local lymphatic drainage obstruction, which impedes the regular migration of immunocompetent cells and/or causes damage to the sensory nerve fibres that secrete immune-related peptides. This situation, in turn, leads to local immune dysregulation and the localized onset of immune-related rashes or skin diseases.^17,18 HZ typically affects the elderly, immunosuppressed individuals, or those with immune deficiencies, and its occurrence is closely linked to the body’s immune state. HZ is caused by VZV reactivation, a contagious neurotropic double-stranded DNA virus that damages peripheral sensory nerve fibres and skin nerve terminals, disrupts neuromodulator release, induces neuroimmune instability, and alters local immune mechanisms. Local skin lesions in herpes-infected areas often exhibit severe neuroimmune dysfunction, making them preferential sites for subsequent immune-related skin diseases.¹⁹ Tabosa et al suggested that post-HZ Wolf’s isotopic responses predominantly occur in immunocompromised skin regions.²⁰ Goon et al reported the first instance of pemphigus vulgaris developing 17 days after the resolution of varicella lesions. They hypothesized an etiopathogenesis in which varicella infection exposes intraepidermal epitopes to the immune system, resulting in the production of anti-intercellular antibodies or cross-reactivity between the initial immune response triggered by varicella infection and intraepidermal autoantigens, thus triggering autoimmune diseases.²¹ Additionally, literature reports indicate that VZV infection can initiate or exacerbate pemphigus progression, possibly through non-specific immune activation by viral infections.^22–24 Increased humoral and cellular factors activate immune responses, leading to autoimmune diseases in genetically predisposed individuals.^25–27 As a subtype of pemphigus, the development of HP isotopic response after HZ in this patient is hypothesized to be related to VZV infection and subsequent local and systemic skin immune impairment. However, due to the lack of relevant case reports for reference, the data analysis of this case has certain limitations.

Conclusion

This case provides new case evidence for the clinical diversity of WIR. It highlights the need for clinicians to consider immune-related bullous diseases in new skin lesions following HZ healing. It suggests a potential association between viral infection and local immune imbalance. Due to the limited research, the specific relationship between viral infection and local/systemic immune dysregulation in pathogenesis requires further validation through more cases and in-depth molecular and immunological studies.