Our initial dermatologic examination revealed generalized scaly erythroderma on the neck, trunk, and extremities, sparing the face, palms, and soles (Figure 1). Multiple crusted and intact vesicles also were present overlying the erythematous plaques on the chest, back, and proximal extremities, most grouped in clusters. The patient endorsed new symptoms of pain and burning. Tzanck smear from the abdomen along with shave biopsies from the left flank and right abdomen were performed, and intravenous acyclovir was initiated immediately after these procedures.
Figure 1. A and B, Grouped crusted vesicles on a background of erythroderma on the trunk.
Viral cultures were taken but were incorrectly processed by the laboratory. Tzanck smear showed severe acute inflammation with numerous neutrophils, multinucleated giant cells with viral nuclear changes, and positive immunostaining for HSV and negative immunostaining for herpes zoster. Both pathology specimens revealed an intense acute mixed, mainly neutrophilic, inflammatory infiltrate extending into the deeper dermis as well as distorted and necrotic hair follicles, some of which displayed multinucleated epithelial cells with margination of chromatin that were positive for both HSV-1 and HSV-2 and negative for herpes zoster (Figure 2). The positivity of both HSV strains might represent co-infection or could be a cross-reaction of antibodies used in immunohistochemistry to the HSV antigens. There was acantholysis surrounding the ulceration and extending through the full thickness of the epidermis with a dilapidated brick wall pattern (Figure 3) as well as negative immunohistochemical staining for HSV-1 and HSV-2 antigens. The clinical and histological picture together, along with prior clinical and pathological reports, confirmed the diagnoses of acute erythrodermic HHD with HSV superinfection.
Figure 2. A, Positive immunostain for herpes simplex virus type 1 (original magnification ×40). B, Positive immunostain for herpes simplex virus type 2 (original magnification ×40).
Figure 3. A, Multinucleated giant cells in herpes simplex virus infection (H&E, original magnification ×400). B, Acantholysis extending through the full thickness of the epidermis with a dilapidated brick wall pattern (H&E, original magnification ×40).
The patient’s condition and pain improved within 24 hours on intravenous acyclovir. On the third day, his lesions were resolving and symptoms improved, so he was transitioned to oral acyclovir and discharged from the hospital. Follow-up in the dermatology outpatient clinic 1 week later revealed that all vesicles and papules had cleared, but the patient was still erythrodermic. Because HHD cannot always be distinguished histologically from other forms of pemphigus but yields a negative immunofluorescence, direct immunofluorescence and indirect immunofluorescence were obtained upon patient follow-up in the clinic and were both negative. Hepatitis C viral loads were undetectable. Consultations to gastroenterology and oncology teams were placed for consideration of systemic agents, and the patient was initiated on oral acitretin 25 mg daily, along with clobetasol as adjuvant therapy for any residual skin plaques. The laboratory results were closely monitored. Within 4 weeks after starting acitretin, the patient’s erythroderma had completely resolved. The patient has remained stable since then, except for one episode of secondary Staphylococcus infection that cleared on oral antibiotics. The patient remains stable and clear on oral acitretin 25 mg daily, with concomitant desonide cream and fluocinonide ointment as needed.
Hailey-Hailey disease is characterized by recurrent episodes of erythema, blisters, and plaques localized to intertriginous and perianal areas.1,2 Patients display a spectrum of lesions that vary in severity.8 Typical histologic examination reveals a dilapidated brick wall appearance. Pathology of well-developed lesions will show suprabasal acantholysis with minimal dyskeratosis.2
The generalized form of HHD is an extremely rare variant of the disease.10 Generalized HHD may resemble acute hypersensitivity reaction, erythema multiforme, and toxic epidermal necrolysis.1 Chronic diseases, such as psoriasis (as in this patient), also may contribute to a clinically confusing picture.8 Hailey-Hailey disease and psoriasis are thought to occasionally koebnerize (isomorphic response) to areas of trauma.16 Our patient experienced widespread erythematous papules and plaques not restricted to skin folds. His skin lesions continued to worsen over several months progressing to erythroderma. The presence of suprabasal acantholysis in a dilapidated brick wall pattern, along with the patient’s history, prior pathology reports, clinical picture, and negative direct immunofluorescence and indirect immunofluorescence studies helped to confirm the diagnosis of erythrodermic HHD.
Hailey-Hailey disease is caused by heterozygous mutations in the ATP2C1 gene on chromosome 3q21-24 coding for a Golgi ATPase called SPCA1 (secretory pathway calcium/manganese-ATPase).9 Subsequent disturbances in cytosolic-Golgi calcium concentrations interfere with epidermal keratinocyte adherence resulting in acantholytic disease. Studies of interfamilial and intrafamilial mutations fail to pinpoint a common mutation pattern among patients with generalized phenotypes,9 which further supports theories that intrinsic or extrinsic factors such as friction, heat, radiation, contact allergens, and infection affect the severity of HHD disease and not the type of mutation.3,9
Generalization of HHD is likely caused by nonspecific triggers in an already genetically disturbed epidermis.10 Interrupted epithelial function exposes skin to infections that exacerbate the underlying disease. Superimposing bacterial infections are commonly reported in HHD. Staphylococcus, Streptococcus, and Candida species colonize the skin and aggravate the disease.11 Much less commonly, HSV superinfection can complicate HHD.3-7 No data are currently available about the frequency or incidence of Herpesviridae in HHD.7 Some studies suggest that UVB light therapy can be an exacerbating factor in DAR and some but not all HHD patients,12,13 while other case reports14,15 document clinically improved responses using phototherapy for patients with HHD. Clinicians should remain suspicious and evaluate for HSV infection in refractory or sudden exacerbation of HHD.7 Furthermore, coexistent psoriasis and HHD also is a rare entity but has been described,8 which illustrates the importance of not attributing all skin manifestations to a previously diagnosed disorder but instead keeping an open mind in case new dermatologic conditions present themselves at a later time.
We present a rare case of erythrodermic HHD and coexistent psoriasis with HSV superinfection. We hope to draw awareness to this association of generalized HHD with both HSV and psoriasis to help clinicians make the correct diagnosis promptly in similar cases in the future.