Herpes Zoster Associated with Cutaneous Small-vessel Vasculitis: A Rare Case Report with Review of Literature

Sir,

Herpes zoster (HZ) is a common disease caused by reactivation of varicella-zoster virus (VZV).[1] Besides the classical vesicular rash on the skin, VZV is known to cause extra-cutaneous manifestations, including vasculopathy of different sized vessels.[2,3] VZV vasculopathy is a well-recognised entity in central nervous system (CNS); however, only few data have been published on cutaneous small-vessel vasculitis (CSVV) in HZ. Herein, we present a case of HZ with CSVV and a review of the literature.

A 53-year-old woman with a history of acute myeloid leukaemia and allogeneic stem cell transplantation was admitted to our department with complaints of painful lesions in left gluteal region and upper leg for 2 days. On examination, purpuric papules/plaques with central necrohaemorrhagic crusts were seen in dermatomal distribution [Figure 1]. Punch biopsy showed intraepidermal bulla with viral nuclear inclusions and giant cell formations, as well as perivascular mononuclear inflammation, leukocytoclasia and fibrinoid necrosis around superficial dermal capillaries [Figure 2]. To exclude the presence of herpes simplex virus (HSV), an immunohistochemical staining for HSV and plasma HSV-1/HSV-2 PCR were performed and resulted in negative. After routine laboratory screenings, systemic involvement of vasculitis was excluded. Based on these findings, the patient was diagnosed with HZ with CSVV. She was started on valacyclovir 3 × 1000 mg/day and analgesics. After 7 days, complete resolution of the cutaneous lesions was observed without sequelae and no additional systemic therapy was required for CSVV. She did not develop postherpetic neuralgia (PHN) or vasculopathy of CNS during 2 months of follow-up.

Figure 1.

Purpuric papules and plaques on an erythematous base with occasional central black haemorrhagic and necrotic crusts on (a) left gluteal region and (b) left upper leg

Figure 2.

Skin biopsy, haematoxylin-eosin stain, (a) intraepidermal bulla formation, erythrocyte extravasation and perivascular inflammation in the superficial dermis (×40 original magnification), (b) viral nuclear inclusions and giant cell formations in the cells within the bulla (arrows) (×400 original magnification) and (c) superficial dermal vessel with leukocytoclastic vasculitis (arrows) (×200 original magnification)

Vascular changes associated with VZV are vessel wall thickening, stenosis and inflammatory infiltrate with abundant neutrophils. VZV is suggested to spread transaxonally from neural ganglia to vessel walls.[4] It can infect endothelial cells directly from adjacent nerves and cause vascular damage including microthrombi formation and haemorrhage.[3,5] In 1984, Cohen and Trapuckd[6] described the first case of CSVV associated with HZ. After a detailed literature review, we found 10 published cases.[6,7,8,9,10,11,12,13,14,15] Clinicopathological features of present and reported cases are summarised in Table 1. The mean age was 57.18 ± 17.74 years, which can be explained by the fact that advanced age is a major risk factor for HZ.[1] Most cases, including ours, were immunocompromised individuals. Cutaneous findings were characterised by vesicles, palpable purpura and ulcerated nodules/plaques. The lesions were mostly on the lower extremities. Histopathological findings included intraepidermal blisters, multinucleated giant cells and leukocytoclastic vasculitis. In most cases, complete recovery was achieved with anti-viral agents and no patient required further systemic therapy for CSVV. It is estimated that PHN occurs in 5%–20% of patients with HZ; the absence of postherpetic neuralgia (PHN) in our patient can be explained by early treatment with valacyclovir.[16]

Table 1.

Clinical and histopathological features of the present and reported cases in the literature

Authors, year of publication	Age	Sex	Comorbidities	Clinical presentation	Localisation	Histopathology	Immunohistochemistry, PCR or viral culture for VZV	Therapy/Outcome
Cohen et al., 1984[6]	67	M	Valvular heart disease, abdominal aortic aneurysm, streptococcal endocarditis and petechial rash treated with prednisone	Haemorrhagic vesicles	Right hypothenar eminence, face, abdomen, right hip and buttock	Intraepidermal vesiculation with ballooning and reticular degeneration, multinucleated giant epithelial cells, eosinophilic intranuclear inclusions and leukocytoclastic vasculitis of dermal venules	Viral culture for VZV was positive	Spontaneous resolution
Erhard et al., 1995[7]	62	M	Mycosis fungoides under methotrexate 17.5 mg twice a week	Sharply demarcated, indurated erythematous nodules and confluent necrotic plaques with central, shallow ulcerations	Right cheek and medial chin	Dermal necrosis surrounded by a perivascular and periadnexal lymphohistiocytic infiltrate, severe obliterative vasculitis of the dermal vessels, nuclear inclusion bodies of Cowdry type A in endothelial cells without ballooning degeneration, giant cells, and vesicles in the epidermis.	Viral culture for VZV was positive and VZV-specific IgG was detected in low titre by indirect immunofluorescence	Systemic acyclovir/Healing with moderate scarring
Uhoda et al., 2000[8]	22	M	Primary mediastinal large B cell lymphoma under cyclophosphamide, vincristine, doxorubicin, prednisone, bleomycin and methotrexate	Reddish nodules	Right axilla and right hand	Superficial and deep perivascular lymphoid infiltrate, swollen endothelial cells and dense nuclear chromatin, red blood cell extravasation without epidermal alterations mediated by viruses	Immunochemical stains for VZV were positive.	Iv acyclovir/Complete resolution
Wollina and Schönlebe, 2012[9]	58	M	Pulmonary sarcoidosis under prednisolone 7.5 mg/day	Initially palpable purpura and later on typical grouped vesicles of herpes zoster	Right upper and lower leg	Intraepithelial vesiculation with acantholysis and formation of ghost cells, lympho- monocytic perivascular infiltrate with leukocytoclasia in dermis	VZV-specific IgG was detected in low titre by direct immunofluorescence	Oral brivudine/Complete resolution
Wong et al., 2013[10]	57	M	Ulcerative colitis under methylprednisolone 80 mg/day mesalamine 2400 mg/day	Purpuric rash	Left lower trunk and left lower extremity	Focal epidermal erosions with acantholytic squamous cells, multinucleation, nuclear molding and chromatin margination along with lymphocytic vasculitis with red blood cell extravasation, endothelial cell swelling and frequent nuclear dust in the dermal venules	NA	Iv acyclovir/gradual improvement over 2 weeks
Tanaka et al., 2014[11]	72	M	Rheumatoid arthritis under methotrexate 8 mg/week, prednisolone 5 mg/day and bucillamine 200 mg/day	Ulcer with surrounding small erythematous, bullous lesions and scattered necrosis	Left fifth toe and the dorsum of the left foot	Leukocytoclastic vasculitis with fibrinoid degeneration in the reticular dermis and subcutaneous tissue without the epidermal involvement typical of VZV	Immunochemical stains for VZV were positive.	Iv acyclovir/Significant improvement
Burgard et al., 2018[12]	72	M	Not mentioned/immunocompetent patient	Multiple patchy lesions, orange-red in colour with dusky foci and a peripheral rim of pallor	Left upper leg	Dense perivascular and patchy lichenoid infiltrate with extravasated erythrocytes, leukocytoclasia and papillary oedema without the epidermis changes, acantholysis or ghost cells	Swab VZV PCR and immunochemical stains for VZV were positive.	NA
Clark et al., 2018[13]	66	M	Hypertension, chronic kidney disease and multisystem sarcoidosis under methotrexate 15 mg/week and prednisolone 5–40 mg/day	Multiple well- demarcated 1–3 cm ulcers with multiple scattered violaceous papules	Left lower leg	Epidermal necrosis with sparse perivascular and interstitial inflammatory infiltrate, leukocytoclasis, sebaceous gland necrosis, fibrin exudation and thrombosis of small vessels in superficial dermis	Plasma VZV PCR and immunochemical stains for VZV were positive.	Iv acyclovir and oral valacyclovir/Significant improvement
Cury-Martins et al., 2019[14]	26	M	Acute lymphoid leukaemia under POMP regimen (prednisone, vincristine, methotrexate, mercaptopurine)	Deep infiltrated and ulcerated nodules with tense blisters	Bilateral upper and lower legs	Intraepidermal blister with ballooning, acantholytic keratinocytes, multinucleated cells and fibrinoid necrosis and thrombosis of vessels of the hypodermis	NA	Iv and oral acyclovir/Complete healing with residual atrophic scars
Alvarez- Salafranca et al.,2020[15]	74	M	Chronic kidney disease, type 2 diabetes mellitus, and chronic obstructive pulmonary disease	Purpuric non-confluent papules and vesicles	Bilateral lower legs and dorsum of the feet	Intraepidermal vesicle with acantholytic keratinocytes, multinucleation, intranuclear inclusion bodies and superficial dermis with perivascular inflammatory infiltrate with vasculitic changes	Swab VZV PCR was positive	Oral acyclovir/Complete resolution
Present report	53	F	Acute myeloid leukaemia under sorafenib 400 mg/day	Purpuric papules and plaques on an erythematous base with central haemorrhagic and necrotic crusts	Left gluteal area and upper leg	Intraepidermal bulla formation with nuclear inclusions, giant cell formations and superficial dermal vessels with leukocytoclastic vasculitis	NA	Oral valacyclovir/Complete resolution

F, female; M, male; NA, not available

In conclusion, all previously reported cases and our case had a clinically distinctive appearance that prompted dermatologists to obtain a biopsy. Nevertheless, given the well-known vasculopathic effects of VZV, it is possible that this phenomenon is more common than reported. Although the clinical picture is alarming, this association appears quite benign and has no further complications. However, future studies are needed to elucidate the clinical implications of HZ with CSSV.

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