Case Report

By Dr. Lily Hsiao
Corresponding Author Dr. Lily Hsiao
Moriya Eye and Skin Clinic, 5-7-1, Mizukino - Japan 302-0121
Submitting Author Dr. Lily Hsiao

Darier's disease, herpes simplex virus infection, quick Tzanck test, continuous oral antiviral therapy

Hsiao L. Considerable Remission after Continuous Oral Antiviral Therapy in Darier's Disease: Two Sisters. WebmedCentral VIROLOGY 2012;3(12):WMC003883
doi: 10.9754/journal.wmc.2012.003883

This is an open-access article distributed under the terms of the Creative Commons Attribution License(CC-BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Submitted on: 11 Dec 2012 12:16:16 PM GMT
Published on: 11 Dec 2012 01:42:20 PM GMT


Background: Darier’s disease is an autosomal dominant transmitted disease with variable penetrance. In addition to bacterial and fungal infection, Darier’s disease may be accompanied by recurrent localized or widespread herpes simplex virus (HSV) infection. However, early recognition may be hindered by its complex clinical picture. A delayed diagnosis may result in visceral dissemination and death. A readily available, quick, noninvasive, bedside cytologic diagnostic technique is required for early diagnosis.

Methods: A one-step, two-minute cytologic microscopic quick Tzanck test was used to find and follow the degree of the HSV infection in 2 sisters with Darier’s disease. Because it is quick and noninvasive, a bedside follow-up to determine the necessity of continuing antiviral therapy is possible.

Results: The cytopathic changes including balloon cells, giant cells, and inclusion bodies revealed a severe and persistent HSV infection in erosive plaques and keratotic papules. Continuous therapy with oral acyclovir (400 mg bid) was prescribed after a routine 5-day course of acyclovir or valacyclovir. Obvious mitigation of itching and pain occurred 3 months after this therapy. Normal skin appeared, and gradual but satisfactory clinical and cytologic improvement occurred. The antiviral therapy continued for more than 4 years without adverse effects.

Conclusions: The quick Tzanck test was helpful for detecting virus-infected cells and monitoring the treatment of Darier’s disease complicated by HSV infection. Although the quick Tzanck test cannot diagnose type-1 or -2 HSV antigens as specifically as can an immunohistochemical Tzanck test, it is a handy screening tool. Continuous oral antiviral therapy proved safe and effective.


Darier’s disease (DD), also known as Darier-White disease, is a dominantly inherited disease that was described separately by Darier and White in 1889 (1,2,3). From onset at around puberty, the disease continues to progress, fluctuating in severity and gradually becoming aggravated. It may be complicated by pyogenic, fungal, and herpes simplex virus (HSV) infections. Twenty patients with DD comorbid with a spreading type of HSV infection called Kaposi’s varicelliform eruption (KVE) were reported in Japan between 1982 and 2005. Antiviral treatment was not only effective, but the extent of the DD also decreased in eight patients (4). In one patient with DD, immunohistochemistry of a Tzanck smear revealed the presence of type-1 HSV specific antigens in the DD skin lesions; the patient died because of lung abscesses caused by severe HSV infection (5). This patient’s diagnosis was delayed because the HSV serologic test was negative. Polymerase chain reaction (PCR) analysis proved to be a specific and sensitive means of detecting viral genomes in patients with negative HSV serologic tests (6,7). However, after comparing the reliability and considering the expense and time needed, the oldest and simplest test, Tzanck’s test, was recommended as an easy, reproducible, and inexpensive diagnostic technique (8). A 1-step, 2-minute, non-invasive, bedside-available, quick Tzanck test (QTT) (9) was used to diagnose and follow the severity of HSV infections in two sisters in a family DD.


Darier’s disease (DD)
Herpes simplex virus (HSV)
Quick Tzanck test (QTT)
Kaposi’s varicelliform eruption (KVE)
Polymerase chain reaction (PCR)

Materials And Methods

Samples for the QTT were obtained from the vesicles, pustules, vesicopapules, erosions, or scales of the skin lesions. The sample materials, including the epidermal sheet and vesicular content, were removed using a fine tweezers. The sample, spread on a glass slide, was covered with modified Giemsa stain solution (Giemsa stain solution, isopropanol and propylene glycol in a ratio of 2:1:1) and covered with a cover glass. Excess stain solution was removed with a tissue, and then the sample was observed under a light microscope 2 minutes later.

Case Reports

Family history

These 2 patients were brought up in a family with 3 children. Their mother and one brother between them were also diagnosed with DD based on typical clinical features and histopathologic findings. Her mother also had scleroderma. The younger sister (the patient in Case 1) is single and has no sexual partner. The older sister (the patient in Case 2) was married at the age of 26. She had two sons and one daughter. The elder brother had a primary infection that manifested as KVE when he was one year old. He then had a recurrent HSV infection over the scalp. The other two children’s HSV infections were milder.

Case 1

A 38-year-old woman had itchy follicular keratotic papules over her scalp, along her nasolabial folds, on the nape of her neck, and on her axillae since she was a teenager. During 8 years of follow-up in our clinic, oral anti-allergic agents and topical corticosteroid ointments were prescribed to relieve her severe itching. Valacyclovir was effective for episodic painful vesiculopapules over the plaques after exposure to the sun. In November 2007, QTTs of the yellowish greasy papules over the nasolabial fold revealed numerous balloon cells and giant cells. The neutralizing antibody titer to HSV type 1 was 64 and that to HSV type 2 was 32. The patient had previously been diagnosed with DD based on histopathology using hematoxylin and eosin staining. A biopsy taken from papules on the left upper chest (Fig. 1) revealed acantholytic cells, suprabasal clefts, corps ronds, and grains in the parakeratotic stratum corneum, which confirmed DD (Fig. 2). QTTs of material from the vesicles in the same plaques showed that, in addition to the inflammatory cells that had infiltrated the follicular epithelium, two groups of abnormal cells were present. There were many balloon cells with large, pale nuclei, scant cytoplasm, and thick cell membranes. Some balloon cells had fused to form giant cells. The other type consisted of cells with plump eosinophilic cytoplasm and pyknotic nuclei (Fig. 3). Findings from the QTTs, together with serological tests, indicated DD complicated with HSV infection. Continuous therapy with oral Acyclovir (400 mg, bid) was started in March 2008 because of the persistent presence of the balloon and giant cells. The most evident improvement was a decrease in the itching and pain over several erosive scalp plaques that had annoyed the patient for a long time. Greasy and keratotic papules over the face, ears, and axillae (Fig. 4) became smaller after expelling pus and greasy plugs through the central pores. Four months later, normal skin appeared and increased (Fig. 5). The antiviral therapy was continued with either Acyclovir (400 mg, bid) or Valacyclovir (500 mg, once daily) monitored using the QTT. An anti-allergic agent was prescribed for relief of itching together with antiviral agent.

Narrow band ultraviolet B phototherapy for the anterior trunk was added two and a half years ago. Compared with the beginning of the continuous antiviral therapy (Fig. 6), the number of yellowish greasy papules along her nose substantially decreased. The erythema and small reddish keratotic papules over her forehead also greatly improved 4 years later(Fig. 7). There were nearly no red keratotic papules or plaques over the left upper chest, and only a few yellowish pustules (Fig.8). The patient has not exhibited any renal or hepatic dysfunction. Her immunoglobulin G level against HSV (enzyme immunoassay), which was checked several times, was always > 128.

Case 2

A 43-year-old woman (the older sister of the patient in Case 1) began experiencing enlarged red plaques beginning with itchy and burning papules in the scalp, nasolabial folds, subclavicular areas, axillae, and inframammary regions at the age of 10. After a biopsy had confirmed DD, a long-term regimen of local and oral retinoids failed to attenuate her symptoms. The patient visited our clinic in 1997. Despite supportive treatments, she had 3 episodes of painful vesicles over some parts of the diseased skin. The episodes were controlled using a routine 5-day course of either Acyclovir or Valacyclovir. A biopsy from the papillomatous lesion in the left axilla revealed hyperkeratosis with corps ronds and suprabasal clefts with acantholytic cells compatible with DD. No other abnormalities were apparent except a neutralizing antibody titer of 32 against type 1 HSV (November 2007) and an immunoglobulin G level > 128 against HSV (enzyme immunoassay) (April 2008). After one 5-day routine course of Valacyclovir, a QTT of material from the vesicles among crusted papules on the inframammary regions revealed numerous balloon cells, together with giant cells. The cytoplasm of these abnormal cells was scant. Some cells displayed eosinophilic inclusion bodies in their pale, large nuclei (Fig. 9). Both histopathological findings (hematoxylin-eosin staining and a QTT) and serological studies indicated DD complicated with a persistent HSV infection. Continuous therapy with Acyclovir (400 mg bid) was started in January 2008 and monitored using a weekly QTT. The intolerable itching was relieved within 8 weeks. The vesicles and pustules dried and desquamated, and the papules became smaller. Compared with 3 months earlier (Fig. 10), normal skin appeared in the inframammary area and the periphery of the diseased areas in the axillae (Fig. 11). The antiviral therapy was further continued with either Acyclovir (400 mg bid) or Valacyclovir (500 mg daily). An anti-allergic agent was also prescribed to relieve the itching. Narrow band UVB phototherapy for the anterior trunk was added two and half a years ago. The diseased areas gradually shrank in the inframammary area and periphery of the axillae after 4 years of this antiviral therapy (Fig. 12). A vesiculopapule was taken from her forehead with mild erythema and accentuated follicles (Fig. 13) for a QTT. The balloon cells with a high nuclear/cytoplasmic ratio gathered together to form balloon cell nests (Fig. 14). There were also giant cells and a large-sized aggregation of fungal spores (Fig. 15). Compatible with clinical improvement, there were substantially fewer HSV-infected cells than there had been 4 years before. The patient has not had any renal nor hepatic dysfunction. Her immunoglobulin G level against HSV (enzyme immunoassay) has been checked several times, and it has always been > 128.


Genetic studies of DD (10,11) have localized the autosomal dominant inherited gene to chromosome 12q23-24.1.. The causative gene in DD has been identified as ATP2A2, which is responsible for transporting calcium from the cytosol into the lumen of the endoplasmic reticulum (12). Furthermore, a molecular study provides evidence that desmosomes are not formed when intracellular Ca2+ concentrations are low, which causes defective cell adhesion (13). These latest findings coincide with ultrastructural observations in 1970 (14) and 1977 (15) which revealed that acantholysis in DD might be induced by a primary fault in the formation or maintenance of the intercellular contact layer. It is therefore possible that the persistent infection revealed by the QTT was caused by defective cell adhesion that increased viral access to keratinocytes.

Recurrent itchy, painful hyperkeratotic papules initially appeared at primary sites when the two sisters reached puberty, gradually spread (peripheral extension), and then formed plaques. The complex clinical features of greasy papules and hypertrophic, fissured, and malodorous plaques typical of DD make it clinically difficult to notice the exacerbation by secondary infection (5,16). Moreover, disseminated HSV infection is much more difficult to diagnose than bacterial and fungal infection (17-19). Type-I HSV infection in one patient with DD was diagnosed after histologic and immunohistochemical examinations, but the patient died of HSV-induced acute respiratory distress syndrome, according to the autopsy (5). In contrast to this first report of a lethal outcome of DD, after reviewing 163 patients, Burge and Wilkinson concluded that although DD is a chronic and unremitting burden, most patients manage to lead a relatively normal life because they have no comorbid illnesses (16). Sunlight, stress, heat, sweating, hospital admission, and surgery aggravate DD (4, 16, 20). These factors are also known to reactivate HSV infection (19). It seems that the prognosis of DD may depend on the severity of the HSV infection (4,5).

The advantage of QTT is that it is a one-step cytological microscopic analysis that needs no lengthy procedures such as washing or dipping tissue samples into solutions; thus, nearly all the sample tissue cells of the epidermis and vesicular cavity of the lesion are preserved. Although preserving the morphology is not as good as traditional Giemsa’s stain, the QTT makes it possible to observe nearly all the cells in the specimen. It proved to be useful in diagnosing 27 patients with typical and atypical cutaneous HSV infection. An atlas including the various clinical presentations, before and after antiviral treatment, and the cytologic findings respectively was published by Hsiao and Chien in 2011 (9). After a regular 5-day course of valacyclovir treatment for HSV infection, the QTT revealed remnant numbers of infected cells. Because maintenance doses of acyclovir are reported to prevent the recurrence of herpes-associated erythema multiform for periods of 10-26 months without significant adverse effects (21-23), the oral antiviral treatment for these two sisters was extended. Together with the clinical improvement, balloon cells and giant cells decreased gradually through 4 years of continuous oral antiviral therapy. There are still many balloon cells and some giant cells found in the latest QTT. Compared with the gradual aggravation during previous treatment for about 20 years, further antiviral therapy should be worthwhile.

Despite much progress in understanding the genetic abnormality in DD, disappointingly little improvement has been made in treatment strategies. Repairing the diseased gene in DD is a distant hope (24). Oral and topical retinoids and corticosteroids are recommended, yet they are accompanied by side effects and the risk of secondary infection (5,24). The two cases reported here show that DD may be complicated by persistent HSV infection rather than only by episodic infection, as previously claimed (4, 16, 20, 25). Immunohistochemistry specifically targeted HSV-1 and HSV-2 together with PCR and conventional histology used to study occult HSV colonization of bullous dermatitides (26) is the best diagnostic tool for determining whether acantholytic and dyskeratotic cells in DD are HSV-infected cells. Similarly, are corps ronds and grains consequences of HSV infection? Antiviral therapy then could be started at the onset of DD. The QTT may be a handy cytologic bedside follow-up to determine the necessity of the treatment as described in this case reports. There is hope for changing the prognosis of DD.

Continuous antiviral therapy leads to decreased asymptomatic viral shedding (19, 27, 28). Because the involved areas are much more extensive in DD than other typical HSV infection, efficacious treatment of patients with DD is important not only for patients with DD, but also for public health (28, 29). QTT is a simple and effective cytologic examination for determining the extent, severity, and potentiality of HSV infection in DD.


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1 review posted so far

Dear Professor Nikkels: Thank you very much for reviewing my article about Darier’s Disease. I have also learned a great deal from your papers on HSV infection. Because the HSV is DNA virus and is ... View more
Responded by Dr. Lily Hsiao on 03 Feb 2013 12:30:08 AM GMT

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