Vulvar herpes zoster infection: a rare and challenging diagnosis

Abstract

A 26-year-old woman under immunosuppression with infliximab due to Crohn’s disease was referred to the gynaecology emergency room with dispersed and coalescing vesicular lesions on the vulvar region extending to the right lower limb involving S2–S3 dermatome, associated with severe pain. Clinical history, physical examination and serological testing was consistent with herpes zoster infection. The patient was treated with valaciclovir for 14 days and cefradine for 7 days (due to the possibility of secondary bacterial infection). Significant symptomatic improvement was noted after 1 week. The 1-year follow-up was unremarkable. According to our knowledge and review of the literature, this is one of the few cases reported of vulvar herpes zoster, especially related to infliximab.

Background

Herpes zoster is an infection which occurs when varicella zoster virus (VZV) is reactivated from its latent state in a posterior dorsal root ganglion. VZV usually affects the thoracic and lumbar nerves and their dermatomes (T3–L3), whereas sacral plexus herpes is extremely rare (4%–8%).¹ The involvement of the vulvar area is even rarer in sacral herpes. In the literature, very few cases of genital zoster have been reported in women. The use of molecular technology has allowed a reliable and unexpected diagnosis of genital zoster infections in female patients who present genital lesions.²

Herpes zoster infection frequently occurs in older patients and those infected with HIV, however, it is more frequent and severe in immunocompromised patients because their cell-mediated immunity is decreased.

Symptoms usually begin with a painful and erythematous papules rash along the affected dermatome, followed by a vesicular eruption which is usually diagnostic within 2–3 days. Grouped vesicles or bullae are the predominant manifestation throughout several days, and finally the rash becomes pustular within 3–4 days.

Lesions are typically unilateral and do not cross the midline of the body. Furthermore, the site is usually hyperaesthetic, and pain may be severe.³

Case presentation

This case report refers to a 26-year-old woman with Crohn’s disease and previous ileocolic resection, and who has been under immunosuppression with infliximab for the last 4 years. She was referred to our gynaecology emergency room due to the onset of vesicular lesions of varying dimensions on the vulvar region extending to the right lower limb associated with severe pain. Pain and skin lesions had started 4 days before admission to hospital.

No sexual risk behaviour was reported.

On examination, dispersed and coalescing vesicular lesions on an erythematous base of variable dimensions (5–15 mm) were seen on the right labium majorus and pubic mound forming blisters/bullae which extended to the homolateral inguinal region, medial and posterior thigh surface, and popliteal and plantar region. An ulcerative lesion was also visible on the right labium majorus medial surface (figures 1–3). There was no associated lymphadenopathy.

Figure 1.

(A) Dispersed and coalescing vesicular lesions on an erythematous base of variable dimensions (5–15 mm) from the right labium majorus, pubic mound and inguinal region to the medial and posterior thigh region. (B) Female pelvic dermatomal territories: S2 dermatome from the buttocks to the posteromedial aspect of the thigh; S3 dermatome from perineal area to the medial aspect of the buttocks.

Figure 2.

An ulcerative lesion in the upper right labium majorus.

Figure 3.

(A) Small vesicular lesions on the popliteal region (arrow). (B) Leg dermatomal territories: S2 dermatome from posteromedial aspect of the thigh to popliteal region and calcaneous. (C) Coalescing lesions on the plantar region.

Investigations

Serological testing revealed:

1. VZV IgG positive, VZV IgM positive.

2. Herpes simplex virus type 1 (HSV-1) IgG negative, HSV-1 IgM negative.

3. Herpes simplex virus type 2 (HSV-2) IgG negative, HSV-2 IgM negative.

4. HIV-1/2 antibody negative.

5. Anti-treponema pallidum antibody: negative.

Lesion swab microbiologic examination: negative

Differential diagnosis

A healthcare professional might often be trained and/or conditioned to make clinical conclusions in which an ulcerative and/or vesicular lesion on the genital area is most likely caused by HSV. In most cases, it certainly may be true, but one must bear in mind other medical conditions.

Zoster and HSV infections are frequently diagnosed by the clinical appearance of a lesion and its anatomic location. Due to rarity of VZV in the genital area, one of the initial diagnostic hypothesis was HSV infection since it causes nearly similar lesions and, especially in immunosuppressed patients, the clinical presentation can be more severe and atypical thus mimic a dermatomal distribution. Bear in mind, VZV is detected in nearly 3% of genital lesion samples in adults which were initially presumed to be genital herpes infection.²

Seeing that the size (1–2 cm) and the appearance of fluid-filled blisters (bullae) could be signs of a common and highly contagious skin infection, namely bullous impetigo, lesion swabs were taken for diagnosis, which later excluded this medical condition.

Though initially syphilis is usually a single lesion, there may be multiple sores, especially in immunosuppressed patients. Therefore, laboratory tests were also performed to rule out syphilis, since the ulcerative lesion described in our patient could be a chancre (a firm, painless, non-itchy skin ulceration usually between 1 and 2 cm in diameter).

Furthermore, a patient with genital ulcers is at risk of acquiring HIV, hence HIV serologic testing was also carried out.

Treatment

As our primary diagnostic hypothesis was herpes zoster infection, the patient was treated with oral valaciclovir 1 g every 8 hours (14 days) along with cefradine 500 mg every 12 hours (7 days) due to the hypothesis of secondary bacterial infection.

Outcome and follow-up

The follow-up assessment showed a favourable and significant symptomatic improvement after 1 week. On examination, the described lesions were in different healing stages, with itchy lesions on the right inguinal region. No new ulcerative or vesicular lesions were identified.

There were no short-term or long-term (1 year follow-up) complications reported.

Discussion

Herpes zoster infection is caused by a reactivation of VZV, which is characterised by localised, painful and vesicular lesions with a dermatomal and unilateral distribution. Genital dermatomes are involved in only up to 2% of cases, but this percentage is probably higher because herpes zoster infection is under-recognised.⁴ Very few cases of genital VZV have been reported (12 cases, 7 of whom are female children and 2 women, 1 of whom was pregnant and the other HIV positive).^4–9

The incidence of herpes zoster increases in patients with autoimmune diseases (such as Crohn’s disease as in our case report), primarily related to the use of immunosuppressive therapies such as tumour necrosis factor (TNF)-alpha inhibitors. The incidence of herpes zoster in the general population has been reported to range from 3.2 to 4.2 cases per 1000 patients/year,¹⁰ while the incidence increases to 10.6 per 1000 patients/year in patients receiving anti-TNF therapy.¹¹ Additionally, the incidence of herpes zoster is 2.7 per 1000 patients/year in the infliximab-treated Crohn’s disease group.¹² A significant positive association was found between herpes zoster and the treatment with monoclonal anti-TNF antibodies, especially infliximab.¹³

Herpes zoster in patients receiving TNF inhibitor therapy may result in a more severe and extensive disease involving multiple dermatomes: 45% bidermatomal (as in this case, namely S2 and S3 dermatomes), and 32% multidermatomal; potentially requiring hospitalisation.¹⁴

The majority of herpes zoster cases (79%) occurred between 6 and 36 months after the start of TNF inhibitor therapy; however, the timing of the onset of herpes zoster is not certain.¹⁵ In this case report, the herpes zoster infection occurred after 48 months of infliximab therapy.

When diagnosis is uncertain, laboratory confirmation is indicated and includes the PCR assay (which is the most sensitive test), direct fluorescent antibody (DFA) testing and viral culture. PCR, now widely available, can be used to detect VZV DNA rapidly and with a higher sensitivity. The ideal samples are swabs of unroofed vesicular lesions and scabs from crusted lesions. DFA testing is substantially less sensitive than PCR. Although VZV can be cultured, its growth rate is usually too slow for culturing to make a timely contribution to diagnosis.¹⁶ The utility of serological testing is moderate, but it can be useful when PCR testing is not available,⁵ as in this case report. Patients with herpes zoster may mount a transient IgM response and would be expected to mount a memory IgG response.¹⁶

Antiviral therapy is recommended for all immunocompromised patients. Oral therapy with either valacyclovir (1 g three times per day) or famcyclovir (500 mg three times per day) from 7 to 14 days is preferred to oral acyclovir due to its increased bioavailability and more simplified dosing schedule.¹³

Treatment of herpes zoster should start as soon as possible, ideally during the prodrome, since it is less likely to be effective if given >72 hours after skin lesions appear. Antiviral treatment decreases the severity and duration of the acute eruption and the rate of serious complications in immunocompromised patients.

Limited information has been published to date, regarding infections with VZV specifically during treatment with TNF inhibitors or other biological therapies, though it may not differ from that of immunocompetent patients, even in severe cases.¹³

The most frequent complication of herpes zoster is post-herpetic neuralgia (20%), which may last for several months or even years after the initial episode. Immunocompromised hosts are at risk of having more frequent episodes of herpes zoster and/or severe VZV-related complications which include cutaneous dissemination and visceral involvement.¹⁷

The detection of VZV has the likelihood of recurrence (fewer than 4%) and chickenpox risk transmission, since reactivation zoster lesions contain viable virus which can be sexually transmitted to a non-immune individual.

Vaccination remains a potential strategy for reducing the incidence of herpes zoster in the immunocompromised population, but there is insufficient evidence available to determine the safety of the live vaccine, especially in patients receiving TNF inhibitors.¹³

Learning points.

• Although an ulcerative/vesicular lesion in the genital area is most likely caused by HSV, one might bear in mind other less frequent medical conditions, such as varicella zoster virus infection.

• Sacral herpes zoster infection is extremely rare, and vulvar involvement is even rarer.

• The diagnosis of herpes zoster is generally based solely on the clinical presentation: unilateral, usually painful vesicular eruption with a well-defined dermatomal distribution.

• The person’s immune status is a key factor in determining the risk of developing herpes zoster, its management and prognosis.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).