Background: The overall age-adjusted seroprevalence of herpes simplex virus(HSV) type 1 is 62.6% and of HSV type 2 is 17%. If a test could diagnose more than HSV immunoglobin G-positive patients, at least these serologically positive patients will benefit from antiviral agents, as do patients with HSV-associated erythema multiforme. Although a high serum immunoglobin E level is an important diagnostic criterion for atopic dermatitis, about 15% of patients have normal serum IgE. Hence, this common and disabling skin disease remains pathophysiologically unclear.
Methods: A one-step, two-minute cytologic microscopic Quick Tzanck test (QTT) was used to determine and follow-up mucocutaneous HSV infections. Serum IgE and HSV IgG antibody levels were also evaluated to study the relationship between atopic dermatitis and HSV-associated dermatitis.
Results: The QTT showed 787 HSV-positive patients, of whom 578 (73%) were also HSV IgG-positive. HSV antibody levels and mean age were positively correlated. Serum IgE levels were normal in 495 (63%) patients and high in 292 (37%) patients.
Conclusions: Patients with normal and high IgE responded well to antiviral agents (valacyclovir and acyclovir) in addition to previous treatment for dermatitis, which suggests that HSV-associated dermatitis may include atopic dermatitis. Moreover, that the QTT diagnosed more than HSV-seropositive patients shows the possibility and importance of a systemic search for HSV-associated lesions in seropositive patients. Early diagnosis and treatment can shorten the clinical course and help attenuate the infection.
KEY WORDS: herpes simplex virus, quick Tzanck test, erythema multiforme, atopic dermatitis, intrinsic atopic dermatitis
1. herpes simplex virus: HSV
2. quick Tzanck test: QTT
3. antibody: Ab
4. herpes simplex virus immunoglobulin G: HSVIgG
5. immunoglobulin E: IgE
6. cell-mediated immunity: CMI
7. enzyme immunoassay: EIA
8.topical corticosteroids: TCS
The herpes simplex viruses 1 and 2 (HSV-1 and HSV-2) are among the most common agents that infect humans. People with HSV antibody (Ab) can regularly be shown to harbor a latent virus of either type in an appropriate ganglion, and that the virus may be activated by many dissimilar stimuli, both in vivo1 and in vitro.2 Erythema multiforme, which appears 1-10 days after recurrent herpes, is the result of cell-mediated immunity (CMI) against viral antigen-positive cells.3,4 One study5 reported that children with eczema herpeticum and atopic dermatitis with recurrent HSV infection at multiple skin sites all showed a positive stimulation index to HSV antigens and a high titer of HSV IgG antibody. This study suggests that the immune reaction to HSV may manifest as a type of dermatitis other than erythema multiforme.
A study6 of 779 women attending a sexually transmitted disease center reported that HSV-2 Ab was the most sensitive way to confirm symptomatic reactivation and to detect asymptomatic genital herpes. The overall age-adjusted seroprevalence of HSV-1 is 62.6%, and that of HSV-2 is 17%.7 If the serologic test is also useful for detecting HSV mucocutaneous infection in dermatology, many patients will also benefit from the antiviral therapy used for HSV-associated erythema multiforme.8,9 Atopic dermatitis is the most disabling condition among skin diseases, with a lifetime prevalence of 10-20% in children and 1-3% in adults.10 To study the relationship between atopic dermatitis and patients with cytologically proved HSV infection, the serum levels of IgE and HSVIgG Ab of 787 outpatients were also evaluated.
Materials and Methods
We retrospectively studied patients that visited our clinic for skin eruptions from 4 January through 28 December 2011. Patients with typical single HSV infections were not included. If the clinical symptoms were considered to be induced by HSV infection, a QTT was done. Patients with a positive QTT were included. The clinical manifestations of the 787 included patients were eczema, vesiculopapular plaque, erythema multiforme, folliculitis, and prurigo.
Quick Tzanck Test
Samples for the QTT were obtained from the vesicles, vesicopapules, pustules, erosions, and 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.
Examples of positive cytologic findings in QTT
1. Composed mainly of balloon cells, balloon cell nests, and giant cells with scanty inflammatory infiltration.
This 33-year-old woman had many vesiculopapules over her face after one had appeared near her mouth one week previously (Fig. 1a). She had a history of three outbreaks of HSV combined with eczema over her hands. Her HSV enzyme immunoassay (EIA) IgG titer was 65, and her IgE titer was 613 IU/ml. A QTT from a vesicle revealed that cell groups were distributed band-like and were covered by epithelium (Fig. 1b). Under high magnification (X 400), the sizes of the cells varied. All balloon cells had thick cell membranes, swollen nuclei, and nuclear chromatin marginations. They gathered together to form balloon cell nests and giant cells (Fig. 1c).
2. Loss of polarity of the spinous layer; cells with large and irregular nuclei in the overlying epithelium. Scanty balloon cells, balloon cell nests, and giant cells in contrast to severe inflammatory infiltration. Rosette formation.
This 35-year-old patient had irregularly shaped red plaques with erosions and crusts in their centers, and pustules on her back and shoulders for one month (Fig. 1d). A QTT from a pustule surrounded by a rim of erythema revealed that most of the epithelium had been replaced by sheets of cells with large nuclei (Fig. 1e). Balloon cell nests were surrounded by inflammatory infiltration to form rosettes (Fig. 1f). High magnification revealed that the inflammatory infiltration surrounding the balloon cell to form the rosette was composed of many polymorphonuclear leukocytes and some lymphocytes (Fig. 1g).
QTTs of the vesicles, vesicopapules, pustules, erosions, and scales of the skin lesions were evaluated by two dermatologists and diagnosed as positive if the above cytologic findings were found.?
Serum IgE11 (normal < 170 IU/ml) and HSVIgG12 (normal < 2.0) were measured using a fluorescence-enzyme immunoassay and an enzyme immunoassay (EIA), respectively, in the same laboratory.
Treatment of the patients
Anti-allergic agents and topical corticosteroids (TCS) were prescribed to treat the dermatitis. Two antiviral agents, valacyclovir (500 mg) and acyclovir (200 mg), were prescribed based on the result of the QTT.
The QTTs of 787 patients were positive. The clinical manifestations of these cases of HSV-associated dermatitis included eczema, vesiculopapular plaque, folliculitis, erythema multiforme, and prurigo. These patients all complained of itching, and some of itching combined with burning and tingling. Four hundred ninety-five (63%) of the 787 patients had normal levels of serum IgE (< 170 IU/ml) and 292 patients (37%) had abnormal serum IgE (>170 IU/ml). HSVAb-positive patients were defined as whose EIA titer of the HSVIgG were over 2.0. Of the patients with normal IgE, 381 (77%) were HSVAb-positive, as were 197 (67%) of those with abnormal IgE. The overall HSVAb-positive rate was 73% (Figure 2).
The mean age of the HSV Ab-positive patients was over 50, and that of the HSV Ab-negative patients was under 40 (Table 1a). The mean age of the patients with the same HSVIgG titer (>2.0, 32-64, 64-< 128, >128) (Table 1b) of the high IgE (> 170 IU/ml) group was younger than that of the normal IgE (< 170 IU/ml) group (Table 1c).
Clinical pictures, cytologic findings, and effect of the antiviral agent
HSV Ab-positive patients with normal serum IgE
This 77-year-old man had itchy erythema on his right inguinal area and a stinging pain on his right scrotum (Fig. 3a). He had been diagnosed with herpes labialis 9 years previously. Because his QTT was positive (Fig. 3b), he was treated with valacyclovir for 5 days, with anti-allergic agents for 8 days, and with low potency TCS. Six days later, there was no more erythema on the inner side of his right inguinal area or right scrotum (Fig. 3c). The patient's pain was also relieved. The EIA titer of his HSIgG was 65, and serum IgE was 19.5 IU/ml.
This 24-year-old woman was pregnant for 5 months. She had itchy red plaques of various sizes over her trunk, mammary region, and lower abdomen (Fig. 3d). She also had keratosis pilaris with punched-out erosions on her left shin (Fig. 3e). Because the EIA titer of her HSVIgG was 123 and her QTT was positive (Fig. 3f), she was treated with valacyclovir and antihistamine for 5 days and medium potency TCS. This patient had been treated for atopic dermatitis for 10 years until a QTT revealed balloon cells from her palm 2 years ago. She has been treated with valacyclovir three times since. Her serum IgE was 39.4 IU/ml.
HSV Ab-positive patients with abnormal IgE
This 27-year-old man presented with large itchy plaques together with lichenification 2 years ago. He had been treated for atopic dermatitis for 10 years with anti-allergic agents and TCS. Because the QTT from the pustules of a plaque was positive on his first visit, he was given additional medical therapy: 2 tablets of valacyclovir per day for 5 days. Narrow-band ultraviolet B phototherapy was also started. The necessity of the additional valacyclovir treatment (1 tablet a day after dinner) was determined by his once or twice monthly QTT results. The EIA titer of his HSVIgG was 78.4, and his serum IgE level was 17220 IU/ml at the beginning. The HSVIgG rose to 87.2 and the IgE fell to 10660 IU/ml one year later. The latest (33 months after the antiviral therapy) HSVIgG was greater than 128 and the IgE fell to 4485 IU/ml. Clinical pictures taken 2 years after beginning antiviral therapy showed recurrent HSV labialis (Fig.4a), which was noticed for the first time in his life. There were several small red edematous nodules and plaques of various sizes on his thigh compatible with HSV-associated erythema multiforme (Fig. 4b), but there were no more large lichenified plaques. There were two pustules surrounded by erythema on the posterior aspect of his left lower leg, and two healed lesions on the right side (Fig.4c). The QTT taken from a pustule over his lower leg revealed balloon cells with thick cell membranes, and a giant cell with degenerated nuclei (Fig. 4d). Intranuclear inclusion bodies were clearly observed in the nuclei of the balloon cells in a balloon cell nest (Fig. 4e).
This 23-year-old man (IgE: 1272 IU/ml, HSVIgG > 128) presented with itchy verrucous plaques from his face to lower extremity and with many small papules disseminated between the plaques for 2 years. Despite his history of an annual recurrence of herpes labialis for the previous 8 years, he had been treated for atopic dermatitis with anti-allergic agents and TCS, but no antiviral agent. Because the QTT from the small papules over his left knee was positive on the first visit, he was treated with 2 tablets of valacyclovir per day for 5 days combined with narrow band ultraviolet B phototherapy. The necessity of the additional valacyclovir treatment (1 tablet a day after dinner) was determined by his once or twice monthly QTT results. Many small papules disseminated between the plaques were seen in the picture taken 6 weeks after his first visit (Fig. 4f). Thirteen weeks after his first visit, the plaques were flatter and not as red, and there were similar eruptions on the dorsum of his hands (Fig. 4g). The size of a large plaque with verrucous nodules above his right ankle (Fig. 4h) decreased as the antiviral therapy continued, and it became flat eleven weeks later (Fig. 4i).
There were no side effects or drug eruptions that led to discontinuing antiviral therapy in any of the 787 patients.
The Tzanck test was introduced in 1947.13Compared with a polymerase chain reaction (PCR), the Tzanck test was confirmed to have a sensitivity of 76.9% and a specificity of 100% in a study of 98 patients ( 77 patients with recurrent herpes simplex and 21 patients with herpes zoster ).14 Its practical use and importance in diagnosing HSV infection, bullous diseases, and epidermal tumors have been recently reconfirmed.15, 16 The advantages of the QTT used in this study are that it is a one-step test, takes only 2 minutes, and involves a microscopic cytological analysis that needs no lengthy procedures such as washing or dipping tissue samples into solutions; thus, nearly all the sample cells, including the epidermis and vesicular cavity of the lesion, are preserved. The ballooned keratinocytes with marginated nucleoplasm and multinucleated keratinocytes, which are diagnostic of the early herpetic infection found in step sections of herpes incognito,17 are also seen in a positive QTT and are one criterion for a positive QTT.
Although the QTT does not preserve morphology as well as does a traditional Giemsa's stain, the QTT makes it possible to observe nearly all the cells in the specimen, and it has been used to diagnose typical and atypical HSV infection in 27 cases18 and in Darier's disease.19 Single, typical HSV infection was not included in this study. Positive findings from patients with multiple vesiculopapules reveal many balloon cells, balloon cell nests, and giant cells. Scanty inflammatory infiltration indicates active viral proliferation. On the other hand, the dense inflammatory infiltration of polymorphonuclear leukocytes, eosinophils, and lymphocytes accords with the CMI that targets HSV-infected cells in animal models.20-22 The QTT enables observation of the in vivo histopathologic evidence that the immune system is defending against and reducing the number of HSV-infected cells through rosette formation-balloon cells surrounded by inflammatory cells during each recurrence. The stronger the degree of the CMI in immunocompetent individuals, the greater the likelihood that HSV-infected cells will be overwhelmed by the dense inflammatory infiltration and hinder the proper diagnosis. Our study includes itchy eczemas, vesiculopapular plaques, erythema multiforme, folliculitis, and prurigo, which are the most common types of dermatitis encountered in skin clinics. Consequently, these patients may have been treated as having contact dermatitis, drug eruption, or atopic dermatitis.
In the group with normal IgE, 381 (77%) patients with a positive QTT had a positive HSV serologic test; in the group with high IgE (Abnormal), 197 (67%) had a positive HSV serologic test. This result is consistent with the concept that one cannot rule out the possibility that a patient without HSV IgG Ab does not have HSV-infected cells.23 The 10- to 15-year higher mean age of the patients with positive HSV IgG in both groups may reflect a time delay and individual differences for seroconversion.23,24
Patient 1 (Fig. 3a) had a history of HS labialis, and patient 2 (fig. 3d) had HSV-associated dermatitis on her hands. Recurrences may be in different and distant locations because asymptomatic viremia occurs in primary23,25 and recurrent herpes infections26 in immunocompetent hosts. Detecting HSV in non-herpetic areas of patients with eczema herpeticum suggests that they may also be directly and indirectly spread via the hands and underwear.27 Detecting HSV DNA within the epidermis using PCR in vivo,28 in cultured keratinocytes,29 and in non-herpetic areas of patients with eczema herpeticum27 supports the notion that subclinical HSV infection may spread during every recurrence. A prospective analysis of genital specimens by Cone et al,30 which used HSV cultures and polymerase chain reactions in 100 asymptomatic pregnant women, found that the frequency of infants exposed to HSV DNA-containing genital secretions from HSV-seropositive mothers is about eight times greater than previously reported. Hence, if a QTT is not done, patients with a recurrent multiple plaque type of HSV infection may be diagnosed with and treated for atopic dermatitis, as patient 2 was. Misdiagnosing HSV-infected pregnant women may be associated with an increased frequency of HSV transmission to their infants.
The HSV IgG levels in 11 of 14 patients rose between the 5th and the 20th days after the patients had been infected with HSV.31 Our study also showed that HSV IgG levels were parallel to the mean age. Consequently, patients more than 50 years old require special attention for HSV-associated dermatitis.
Atopy is a personal or familial tendency to produce IgE Ab in response to low doses of allergens, usually proteins, and to develop typical symptoms such as asthma, rhinoconjunctivitis, or dermatitis. Because the allergens are difficult-to-avoid airborne and food allergens, the treatment for atopic dermatitis is still not satisfactory.10,32 Patient 3 (Fig. 4a) was treated for atopic dermatitis for 10 years with anti-allergic agents and TCS. Antiviral therapy not only cured the itchy large plaques and lichenification, but also significantly lowered the IgE level from 17220 IU/ml to 4485 IU/ml in 33 months. Patient 4 (Fig. 4f) was treated for atopic dermatitis for 2 years, despite his history of annual recurrences of herpes simplex labialis for 8 years. Small papules between the itching plaques over his left knee provided the clue for the QTT-based diagnosis of HSV infection. There are many reports concerning the seroconversion of IgM, IgG, and IgA following a natural viral infection or immunization with a virus,20-24,33 yet there is little information about antivirus IgE Ab. Increased total serum IgE during acute virus infection,34 during the acute phase of infectious mononucleosis,35 and in the children of atopic parents36 was reported around 1980. Ida et al.37 reported a mouse model for the development of IgE anti-HSV Abs either after immunization with ultralight-inactivated virus or after natural infection in 1983. That patients with more than five recurrences per year had IgE serum levels significantly higher than did patients with few recurrences during the active phase of a single HSV infection was reported in 1986.38 Moreover, in 2011, patients with atopic dermatitis complicated with eczema herpeticum were reported39 to have higher IgE than did patients with atopic dermatitis not complicated with eczema herpeticum. Antiviral and antisepsis therapy caused a more dramatic improvement than did anti-inflammatory compounds, which implied that spreading of the HSV worsened atopic dermatitis.39 Kotani et al.40 reported in 2012 that the plasma concentrations of LIGHT (homologous to lymphotoxins, exhibits inducible expression, competes with herpes simplex virus glycoprotein D for herpes simplex virus entry mediator (HVEM), and expressed by T lymphocytes) in 29 patients with atopic dermatitis were significantly higher than those in healthy individuals. Its concentrations correlated with IgE and decreased when symptoms improved because of treatment. Several studies have shown that LIGHT-HVEM interaction contribute to CMI toward HSV. HVEM has been proved to be one of the three cell surface receptors responsible for the entry of HSV into cells.41 All these studies and our data support the notion that patients diagnosed with atopic dermatitis, even those with extremely high serum IgE, such as patient 3, may actually be undergoing an HSV reactivation-induced CMI that manifests as chronic dermatitis.
Four hundred ninety-five (63%) of the 787 QTT-positive patients whose serum IgE levels were normal may correspond to the 15% of patients with atopic dermatitis classified as intrinsic atopic dermatitis due to normal serum IgE.32,42,43 Our study provides a diagnostic method and proposes that the pathophysiology of the patients with normal and high IgE are the same. Treating these patients with antiviral therapy and follow-up using the QTT may change their prognosis, as it has with most of our patients. Because the dermatitis we treated was caused by an immune reaction to HSV infection, early diagnosis and treatment can shorten the clinical course and contribute to decreasing the infection source. Immunosuppressant agents are thus contraindicated, unless the HSV-infected cells is proved to be negative.
The number of patients with typical HSV recrudescence is small compared with the overall age-adjusted seroprevalence of HSV type 1 (62.6%) and HSV type 2 (17%)7 and has been considered due to asymptomatic recurrences.30 In the present study, the QTT helped to diagnose more than just HSV-seropositive patients. This suggests that a thorough systemic search for atypical HSV-associated lesions is possible and very important. It matters not only to patients, but also for those of us committed to mitigating and controlling this common yet concealed infectious disease. The possible morbidity of HSV infection is greater than 62.6%. The QTT can not only provide an early diagnosis, but it can also allow physicians to follow and monitor the treatment of HSV-associated dermatitis. Consequently, it eventually should be possible to change the prognosis of a large part of the etiologically unknown eczemas such as atopic dermatitis.
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