Article ID: WMC004846 ISSN 2046-1690

Herpes Simplex Virus-Associated Dermatitis with Either High or Normal IgE Responded Well to Antiviral Therapy: A Study of 787 Quick-Tzanck-Test-Positive Patients

Peer review status: No

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

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

Article ID: WMC004846 Article Type: Original Articles Submitted on:20-Mar-2015, 07:33:49 AM GMT Published on: 20-Mar-2015, 07:34:27 AM GMT Article URL: http://www.webmedcentral.com/article_view/4846 Subject Categories:DERMATOLOGY Keywords: virus, quick Tzanck test, erythema multiforme, atopic dermatitis, intrinsic atopic dermatitis How to cite the article:Hsiao L. Herpes Simplex Virus-Associated Dermatitis with Either High or Normal IgE Responded Well to Antiviral Therapy: A Study of 787 Quick-Tzanck-Test-Positive Patients. WebmedCentral DERMATOLOGY 2015;6(3):WMC004846 Copyright: 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. Source(s) of Funding: None

Competing Interests: None

Additional Files: HSVADWMC15

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Herpes Simplex Virus-Associated Dermatitis with Either High or Normal IgE Responded Well to Antiviral Therapy: A Study of 787 Quick-Tzanck-Test-Positive Patients

Author(s): Hsiao L

Abstract Abbreviations

Background: The overall age-adjusted 1. herpes simplex virus: HSV seroprevalence of herpes simplex virus(HSV) type 1 is 2. quick Tzanck test: QTT 62.6% and of HSV type 2 is 17%. If a test could 3. antibody: Ab diagnose more than HSV immunoglobin G-positive patients, at least these serologically positive patients 4. herpes simplex virus immunoglobulin G: HSVIgG will benefit from antiviral agents, as do patients with 5. immunoglobulin E: IgE HSV-associated erythema multiforme. Although a high 6. cell-mediated immunity: CMI serum immunoglobin E level is an important diagnostic criterion for atopic dermatitis, about 15% of patients 7. enzyme immunoassay: EIA have normal serum IgE. Hence, this common and 8.topical corticosteroids: TCS disabling skin disease remains pathophysiologically unclear. Introduction Methods: A one-step, two-minute cytologic microscopic Quick Tzanck test (QTT) was used to determine and follow-up mucocutaneous HSV The herpes simplex viruses 1 and 2 (HSV-1 and . Serum IgE and HSV IgG antibody levels HSV-2) are among the most common agents that were also evaluated to study the relationship between infect humans. People with HSV antibody (Ab) can atopic dermatitis and HSV-associated dermatitis. regularly be shown to harbor a latent virus of either type in an appropriate ganglion, and that the virus may Results: The QTT showed 787 HSV-positive patients, be activated by many dissimilar stimuli, both in vivo1 of whom 578 (73%) were also HSV IgG-positive. HSV and in vitro.2 Erythema multiforme, which appears antibody levels and mean age were positively 1-10 days after recurrent herpes, is the result of correlated. Serum IgE levels were normal in 495 (63%) cell-mediated immunity (CMI) against viral patients and high in 292 (37%) patients. antigen-positive cells.3,4 One study5 reported that Conclusions: Patients with normal and high IgE children with eczema herpeticum and atopic dermatitis responded well to antiviral agents (valacyclovir and with recurrent HSV at multiple skin sites all acyclovir) in addition to previous treatment for showed a positive stimulation index to HSV antigens dermatitis, which suggests that HSV-associated and a high titer of HSV IgG antibody. This study dermatitis may include atopic dermatitis. Moreover, suggests that the immune reaction to HSV may that the QTT diagnosed more than HSV-seropositive manifest as a type of dermatitis other than erythema patients shows the possibility and importance of a multiforme. systemic search for HSV-associated lesions in A study6 of 779 women attending a sexually seropositive patients. Early diagnosis and treatment transmitted disease center reported that HSV-2 Ab can shorten the clinical course and help attenuate the was the most sensitive way to confirm symptomatic infection. reactivation and to detect asymptomatic genital herpes. KEY WORDS: herpes simplex virus, quick Tzanck test, The overall age-adjusted seroprevalence of HSV-1 is erythema multiforme, atopic dermatitis, intrinsic atopic 62.6%, and that of HSV-2 is 17%.7 If the serologic test dermatitis is also useful for detecting HSV mucocutaneous infection in dermatology, many patients will also benefit from the antiviral therapy used for

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HSV-associated erythema multiforme.8,9 Atopic balloon cells, balloon cell nests, and giant cells in dermatitis is the most disabling condition among skin contrast to severe inflammatory infiltration. Rosette diseases, with a lifetime prevalence of 10-20% in formation. 10 children and 1-3% in adults. To study the relationship This 35-year-old patient had irregularly shaped red between atopic dermatitis and patients with plaques with erosions and crusts in their centers, and cytologically proved HSV infection, the serum levels of pustules on her back and shoulders for one month (Fig. IgE and HSVIgG Ab of 787 outpatients were also 1d). A QTT from a pustule surrounded by a rim of evaluated. erythema revealed that most of the epithelium had Materials and Methods 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 Participants surrounding the balloon cell to form the rosette was We retrospectively studied patients that visited our composed of many polymorphonuclear leukocytes and clinic for skin eruptions from 4 January through 28 some lymphocytes (Fig. 1g). December 2011. Patients with typical single HSV QTTs of the vesicles, vesicopapules, pustules, infections were not included. If the clinical symptoms erosions, and scales of the skin lesions were were considered to be induced by HSV infection, a evaluated by two dermatologists and diagnosed as QTT was done. Patients with a positive QTT were positive if the above cytologic findings were found.? included. The clinical manifestations of the 787 11 12 included patients were eczema, vesiculopapular Serum IgE (normal < 170 IU/ml) and HSVIgG plaque, erythema multiforme, folliculitis, and prurigo. (normal < 2.0) were measured using a fluorescence-enzyme immunoassay and an enzyme Quick Tzanck Test immunoassay (EIA), respectively, in the same Samples for the QTT were obtained from the vesicles, laboratory. vesicopapules, pustules, erosions, and scales of the Treatment of the patients skin lesions. The sample materials, including the epidermal sheet and vesicular content, were removed Anti-allergic agents and topical corticosteroids (TCS) using a fine tweezers. The sample, spread on a glass were prescribed to treat the dermatitis. Two antiviral slide, was covered with modified Giemsa stain solution agents, valacyclovir (500 mg) and acyclovir (200 mg), (Giemsa stain solution, isopropanol, and propylene were prescribed based on the result of the QTT. glycol in a ratio of 2:1:1) and covered with a cover Results glass. Excess stain solution was removed with a tissue, and then the sample was observed under a light microscope 2 minutes later. The QTTs of 787 patients were positive. The clinical Examples of positive cytologic findings in QTT manifestations of these cases of HSV-associated 1. Composed mainly of balloon cells, balloon cell nests, dermatitis included eczema, vesiculopapular plaque, and giant cells with scanty inflammatory infiltration. folliculitis, erythema multiforme, and prurigo. These This 33-year-old woman had many vesiculopapules patients all complained of itching, and some of itching over her face after one had appeared near her mouth combined with burning and tingling. Four hundred one week previously (Fig. 1a). She had a history of ninety-five (63%) of the 787 patients had normal levels three outbreaks of HSV combined with eczema over of serum IgE (< 170 IU/ml) and 292 patients (37%) her hands. Her HSV enzyme immunoassay (EIA) IgG had abnormal serum IgE (>170 IU/ml). titer was 65, and her IgE titer was 613 IU/ml. A QTT HSVAb-positive patients were defined as whose EIA from a vesicle revealed that cell groups were titer of the HSVIgG were over 2.0. Of the patients with distributed band-like and were covered by epithelium normal IgE, 381 (77%) were HSVAb-positive, as were (Fig. 1b). Under high magnification (X 400), the sizes 197 (67%) of those with abnormal IgE. The overall of the cells varied. All balloon cells had thick cell HSVAb-positive rate was 73% (Figure 2). membranes, swollen nuclei, and nuclear chromatin The mean age of the HSV Ab-positive patients was marginations. They gathered together to form balloon over 50, and that of the HSV Ab-negative patients was cell nests and giant cells (Fig. 1c). under 40 (Table 1a). The mean age of the patients 2. Loss of polarity of the spinous layer; cells with large with the same HSVIgG titer (>2.0, 32-64, 64-< 128, and irregular nuclei in the overlying epithelium. Scanty >128) (Table 1b) of the high IgE (> 170 IU/ml) group

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was younger than that of the normal IgE (< 170 IU/ml) there were no more large lichenified plaques. There group (Table 1c). were two pustules surrounded by erythema on the Clinical pictures, cytologic findings, and effect of posterior aspect of his left lower leg, and two healed the antiviral agent lesions on the right side (Fig.4c). The QTT taken from a pustule over his lower leg revealed balloon cells with HSV Ab-positive patients with normal serum IgE thick cell membranes, and a giant cell with This 77-year-old man had itchy erythema on his right degenerated nuclei (Fig. 4d). Intranuclear inclusion inguinal area and a stinging pain on his right scrotum bodies were clearly observed in the nuclei of the (Fig. 3a). He had been diagnosed with herpes labialis balloon cells in a balloon cell nest (Fig. 4e). 9 years previously. Because his QTT was positive (Fig. This 23-year-old man (IgE: 1272 IU/ml, HSVIgG > 128) 3b), he was treated with valacyclovir for 5 days, with presented with itchy verrucous plaques from his face anti-allergic agents for 8 days, and with low potency to lower extremity and with many small papules TCS. Six days later, there was no more erythema on disseminated between the plaques for 2 years. the inner side of his right inguinal area or right scrotum Despite his history of an annual recurrence of herpes (Fig. 3c). The patient's pain was also relieved. The EIA labialis for the previous 8 years, he had been treated titer of his HSIgG was 65, and serum IgE was 19.5 for atopic dermatitis with anti-allergic agents and TCS, IU/ml. but no antiviral agent. Because the QTT from the small This 24-year-old woman was pregnant for 5 months. papules over his left knee was positive on the first visit, She had itchy red plaques of various sizes over her he was treated with 2 tablets of valacyclovir per day trunk, mammary region, and lower abdomen (Fig. 3d). for 5 days combined with narrow band ultraviolet B She also had keratosis pilaris with punched-out phototherapy. The necessity of the additional erosions on her left shin (Fig. 3e). Because the EIA valacyclovir treatment (1 tablet a day after dinner) was titer of her HSVIgG was 123 and her QTT was positive determined by his once or twice monthly QTT results. (Fig. 3f), she was treated with valacyclovir and Many small papules disseminated between the antihistamine for 5 days and medium potency TCS. plaques were seen in the picture taken 6 weeks after This patient had been treated for atopic dermatitis for his first visit (Fig. 4f). Thirteen weeks after his first visit, 10 years until a QTT revealed balloon cells from her the plaques were flatter and not as red, and there palm 2 years ago. She has been treated with were similar eruptions on the dorsum of his hands (Fig. valacyclovir three times since. Her serum IgE was 4g). The size of a large plaque with verrucous nodules 39.4 IU/ml. above his right ankle (Fig. 4h) decreased as the HSV Ab-positive patients with abnormal IgE antiviral therapy continued, and it became flat eleven weeks later (Fig. 4i). This 27-year-old man presented with large itchy plaques together with lichenification 2 years ago. He There were no side effects or drug eruptions that led had been treated for atopic dermatitis for 10 years with to discontinuing antiviral therapy in any of the 787 anti-allergic agents and TCS. Because the QTT from patients. the pustules of a plaque was positive on his first visit, Discussion he was given additional medical therapy: 2 tablets of valacyclovir per day for 5 days. Narrow-band ultraviolet B phototherapy was also started. The The Tzanck test was introduced in 1947.13Compared necessity of the additional valacyclovir treatment (1 with a polymerase chain reaction (PCR), the Tzanck tablet a day after dinner) was determined by his once test was confirmed to have a sensitivity of 76.9% and or twice monthly QTT results. The EIA titer of his a specificity of 100% in a study of 98 patients ( 77 HSVIgG was 78.4, and his serum IgE level was 17220 patients with recurrent herpes simplex and 21 patients IU/ml at the beginning. The HSVIgG rose to 87.2 and with herpes zoster ).14 Its practical use and importance the IgE fell to 10660 IU/ml one year later. The latest in diagnosing HSV infection, bullous diseases, and (33 months after the antiviral therapy) HSVIgG was epidermal tumors have been recently reconfirmed.15, 16 greater than 128 and the IgE fell to 4485 IU/ml. The advantages of the QTT used in this study are that Clinical pictures taken 2 years after beginning antiviral it is a one-step test, takes only 2 minutes, and involves therapy showed recurrent HSV labialis (Fig.4a), which a microscopic cytological analysis that needs no was noticed for the first time in his life. There were lengthy procedures such as washing or dipping tissue several small red edematous nodules and plaques of samples into solutions; thus, nearly all the sample various sizes on his thigh compatible with cells, including the epidermis and vesicular cavity of HSV-associated erythema multiforme (Fig. 4b), but the lesion, are preserved. The ballooned keratinocytes

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with marginated nucleoplasm and multinucleated and indirectly spread via the hands and underwear.27 keratinocytes, which are diagnostic of the early Detecting HSV DNA within the epidermis using PCR in herpetic infection found in step sections of herpes vivo,28 in cultured keratinocytes,29 and in non-herpetic incognito,17 are also seen in a positive QTT and are areas of patients with eczema herpeticum27 supports one criterion for a positive QTT. the notion that subclinical HSV infection may spread Although the QTT does not preserve morphology as during every recurrence. A prospective analysis of 30 well as does a traditional Giemsa's stain, the QTT genital specimens by Cone et al, which used HSV makes it possible to observe nearly all the cells in the cultures and polymerase chain reactions in 100 specimen, and it has been used to diagnose typical asymptomatic pregnant women, found that the and atypical HSV infection in 27 cases18 and in frequency of infants exposed to HSV DNA-containing Darier's disease.19 Single, typical HSV infection was genital secretions from HSV-seropositive mothers is not included in this study. Positive findings from about eight times greater than previously reported. patients with multiple vesiculopapules reveal many Hence, if a QTT is not done, patients with a recurrent balloon cells, balloon cell nests, and giant cells. multiple plaque type of HSV infection may be Scanty inflammatory infiltration indicates active viral diagnosed with and treated for atopic dermatitis, as proliferation. On the other hand, the dense patient 2 was. Misdiagnosing HSV-infected pregnant inflammatory infiltration of polymorphonuclear women may be associated with an increased leukocytes, eosinophils, and lymphocytes accords with frequency of HSV transmission to their infants. the CMI that targets HSV-infected cells in animal The HSV IgG levels in 11 of 14 patients rose between models.20-22 The QTT enables observation of the in the 5th and the 20th days after the patients had been vivo histopathologic evidence that the immune system infected with HSV.31 Our study also showed that HSV is defending against and reducing the number of IgG levels were parallel to the mean age. HSV-infected cells through rosette formation-balloon Consequently, patients more than 50 years old require cells surrounded by inflammatory cells during each special attention for HSV-associated dermatitis. recurrence. The stronger the degree of the CMI in Atopy is a personal or familial tendency to produce IgE immunocompetent individuals, the greater the Ab in response to low doses of allergens, usually likelihood that HSV-infected cells will be overwhelmed proteins, and to develop typical symptoms such as by the dense inflammatory infiltration and hinder the asthma, rhinoconjunctivitis, or dermatitis. Because the proper diagnosis. Our study includes itchy eczemas, allergens are difficult-to-avoid airborne and food vesiculopapular plaques, erythema multiforme, allergens, the treatment for atopic dermatitis is still not folliculitis, and prurigo, which are the most common satisfactory.10,32 Patient 3 (Fig. 4a) was treated for types of dermatitis encountered in skin clinics. atopic dermatitis for 10 years with anti-allergic agents Consequently, these patients may have been treated and TCS. Antiviral therapy not only cured the itchy as having , drug eruption, or atopic large plaques and lichenification, but also significantly dermatitis. lowered the IgE level from 17220 IU/ml to 4485 IU/ml In the group with normal IgE, 381 (77%) patients with in 33 months. Patient 4 (Fig. 4f) was treated for atopic a positive QTT had a positive HSV serologic test; in dermatitis for 2 years, despite his history of annual the group with high IgE (Abnormal), 197 (67%) had a recurrences of herpes simplex labialis for 8 years. positive HSV serologic test. This result is consistent Small papules between the itching plaques over his with the concept that one cannot rule out the left knee provided the clue for the QTT-based possibility that a patient without HSV IgG Ab does not diagnosis of HSV infection. There are many reports have HSV-infected cells.23 The 10- to 15-year higher concerning the seroconversion of IgM, IgG, and IgA mean age of the patients with positive HSV IgG in both following a natural viral infection or immunization with groups may reflect a time delay and individual a virus,20-24,33 yet there is little information about differences for seroconversion.23,24 antivirus IgE Ab. Increased total serum IgE during 34 Patient 1 (Fig. 3a) had a history of HS labialis, and acute virus infection, during the acute phase of 35 patient 2 (fig. 3d) had HSV-associated dermatitis on infectious mononucleosis, and in the children of 36 37 her hands. Recurrences may be in different and atopic parents was reported around 1980. Ida et al. distant locations because asymptomatic reported a mouse model for the development of IgE occurs in primary23,25 and recurrent herpes infections26 anti-HSV Abs either after immunization with in immunocompetent hosts. Detecting HSV in ultralight-inactivated virus or after natural infection in non-herpetic areas of patients with eczema 1983. That patients with more than five recurrences herpeticum suggests that they may also be directly per year had IgE serum levels significantly higher than

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did patients with few recurrences during the active only to patients, but also for those of us committed to phase of a single HSV infection was reported in 1986.38 mitigating and controlling this common yet concealed Moreover, in 2011, patients with atopic dermatitis infectious disease. The possible morbidity of HSV complicated with eczema herpeticum were reported39 infection is greater than 62.6%. The QTT can not only to have higher IgE than did patients with atopic provide an early diagnosis, but it can also allow dermatitis not complicated with eczema herpeticum. physicians to follow and monitor the treatment of Antiviral and antisepsis therapy caused a more HSV-associated dermatitis. Consequently, it dramatic improvement than did anti-inflammatory eventually should be possible to change the prognosis compounds, which implied that spreading of the HSV of a large part of the etiologically unknown eczemas worsened atopic dermatitis.39 Kotani et al.40 reported in such as atopic dermatitis. 2012 that the plasma concentrations of LIGHT (homologous to lymphotoxins, exhibits inducible References expression, competes with herpes simplex virus glycoprotein D for herpes simplex virus entry mediator (HVEM), and expressed by T lymphocytes) in 29 1. Carton, C.A.& Kilbourne, E.D. Activation of latent patients with atopic dermatitis were significantly higher herpes by trigeminal sensory root section. New Engl J than those in healthy individuals. Its concentrations Med. 246, 172-176 (1952). correlated with IgE and decreased when symptoms 2. Baringer, J.R.& Swoveland, P. Recovery of improved because of treatment. Several studies have herpes-simplex virus from human trigeminal shown that LIGHT-HVEM interaction contribute to CMI ganglions. New Engl J Med. 288, 648-650 (1973) toward HSV. HVEM has been proved to be one of the 3. Nikkels, A.F.& Pierard, G.E. Treatment of three cell surface receptors responsible for the entry of muco-cutaneous presentation of herpes simplex virus HSV into cells.41 All these studies and our data support infections.Am J Clin Dermatol. 3, 475-487 (2002). the notion that patients diagnosed with atopic dermatitis, even those with extremely high serum IgE, 4. Sokumbi, O.& Wetter, D.A. Clinical features, such as patient 3, may actually be undergoing an HSV diagnosis, and treatment of erythema multiforme: a reactivation-induced CMI that manifests as chronic review for the practicing dermatologist. Inter J dermatitis. Derrmatol. 51, 889-902 (2012). Four hundred ninety-five (63%) of the 787 5. Goodyear, H.M. et al. Immunologic studies of QTT-positive patients whose serum IgE levels were herpes simplex virus infection in children with atopic normal may correspond to the 15% of patients with dermatitis. Br J Dermatol. 134, 85-93 (1996 ). atopic dermatitis classified as intrinsic atopic dermatitis 6. Koutsky, L..A. el al. Underdiagnosis of genital due to normal serum IgE.32,42,43 Our study provides a herpes by current clilnical and viral-isolation diagnostic method and proposes that the procedures. N Engl J Med. 326, 1533-1539 (1992). pathophysiology of the patients with normal and high 7. Xu, F. et al. Trends in herpes simplex virus type 1 IgE are the same. Treating these patients with antiviral and type 2 seroprevalence in the United States. JAMA. therapy and follow-up using the QTT may change their 296, No 8: 964-973 (2006). prognosis, as it has with most of our patients. Because the dermatitis we treated was caused by an immune 8. Lemak, M.A. Duvic, M. & Bean, S.F. Oral acyclovir reaction to HSV infection, early diagnosis and for the prevention of herpes-associated erythema treatment can shorten the clinical course and multiforme. J Am Acad Dermatol. 15, 50-54 (1986). contribute to decreasing the infection source. 9. Tatnall, F.M. Schofield, J.K. & Leigh, I.M. A Immunosuppressant agents are thus contraindicated, double-blind, placebo-controlled trial of continuous unless the HSV-infected cells is proved to be negative. acyclovir therapy in recurrent erythema multiforme. Br The number of patients with typical HSV J Dermatol. 132, 267-70 (1995). recrudescence is small compared with the overall 10. Leung, D.Y.& Bieber, T. Atopic dermatitis. Lancet age-adjusted seroprevalence of HSV type 1 (62.6%) 361,151-160 (2003). and HSV type 2 (17%)7 and has been considered due 11. Di Lorenzo, G. et al. A study of age-related IgE to asymptomatic recurrences.30 In the present study, pathophysiological changes. Mech Ageing Dev. 124 (4), the QTT helped to diagnose more than just 445-448 (2003). HSV-seropositive patients. This suggests that a thorough systemic search for atypical HSV-associated 12. Denoyel, G.A. Gaspar, A. & Nouyrigat, C. Enzyme lesions is possible and very important. It matters not immunoassay for measurement of antibodies to herpes simplex virus infection: comparison with

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complement fixation, immunofluorescent-antibody, and simplex virus in non-herpetic areas of patients with neutralization techniques. J Clin Microbiol. 11 (2) eczema herpeticum. Dermatology. 200, 104-107 ,114-119 (1980). (2000). 13. Tzanck, A. Le Cyto-diagnostic immédiate en 28. Miura, S. Smith, C.C. Burnett, J.W. & Aurelian, L. dermatologie. Ann Dermatol Venereol. 7, 68-70 Detection of viral DNA with in skin of healed recurrent (1947). herpes simplex infection and erythema multiforme 14. Ozcan, A. et al. Comparison of the Tzanck test lesions. J Invest Dermatol. 98, 68-72 (1992). and polymerase chain reaction in the diagnosis of 29. Syrjänen, S. Mikola, H. Nykänen, M.& Hukkanen, cutaneous herpes simplex and varicella zoster virus V. In vitro establishment of lytic and nonproductive infection. Int J Dermatol . 46, 1177-1179 (2007). infection by herpes simplex virus type 1 in 15. Ruocco, E. Brunetti, G. Vecchio, M. Del & Ruocco, three-dimensional keratinocytes culture. J virol. 70, V. The practical use of cytology for diagnosis in 6524-6528 (1996). dermatology. J Eur Acad Dermatol Venereol. 25(2), 30. Cone, R.W. et al. Frequent detection of genital 125-129 (2011). herpes simplex virus DNA by polymerase chain 16. Durdu, M. Seçkin, D.& Baba, M. The Tzanck reaction among pregnant women. JAMA. 272, smear test: rediscovery of a practical diagnostic tool. 792-796 (1994). SKINmed . 9, 23-32 (2011). 31. Yamabe, H. Haruo, T. Nakakawa, M. & Otani, H. 17. Resnik, K.S. & DiLeonard, M. Herpes incognito. Studies on serodiagnosis of herpes simplex virus Am J Dermatopath. 22 (2), 144-150 ( 2000). infection by EIA antiboby titer. J of Clinical Therapeutics & Medicines. 26 (5), 1097-1101 (1991). 18. Hsiao, L. & Chien, H.P. The 2-minute quick Tzanck test to diagnose herpes simplex viral infection: 32. Roguedas-Contios, A.M. & Misery, L. What is cytologic and clinical atlas of skin diseases including intrinsic atopic dermatitis? Clinic Rev Allerg Immunol. atopic dermatitis. HO-CHI publication, Taipei, Taiwan 41, 233-236 (2011). 2011. 33. Ogra, P.L. Morag, A. Tiku, M.L.& Notkins AL eds. 19. Hsiao, L. Considerable remission after continuous Humoral immune response to viral infections. Viral oral antiviral therapy in Darier's Disease: two sisters. Immunology and Immunopathology. Academic Press. WebmedCentral VIROLOGY . 3(12), WMC003883 New York, San Francisco, London, 57-77. 1975. (2012) 34. Perelmutter, L. Pontvin, L. & Phillip, P. 20. Wildy, P. & Gell, P.G.H. The host response to Immunoglobulin E response during viral infections. J herpes simplex virus. Br Med Bull. 41, 86-91 (1985). Allergy Clin Immunol. 64, 127-130 (1979). 21. Kent, J.R. & Fraser, N.W. The cellular response to 35. Bahna, S.L. Horwitz, C.A. Fiala, M.& Heiner, D.C. herpes simplex virus type-1 (HSV-1) during latency IgE response in heterophil-positive infectious and reactivation. J Neurovirol. 11, 376-383 (2005). mononucleosis. J Allergy Clin Immunol. 62, 167-173 (1978). 22. Bystrická, M. & Russ, G. Immunity in latent herpes simplex virus infection. Acta Virol. 49, 159-167 (2005). 36. Rick, O.L. German, D.L. & Mills J. Development of allergy in children. I. Association with virus infection.J 23. Burkhart, C.G. Focus on: herpes acquision and Allergy Clin Immunol. 63: 228-241 (1979). transmission. J Drug Dermatol. 4 (3), 378-383 (2005). 37. Ida, S. Siraganian, R.P.& Notkins, A.L. Cell-bound 24. Ashley-Morrow, R. Krantz, E. & Wald, A. Time and circulating IgE antibody to herpes simplex virus. J course of seroconversion by herpeselect ELISA after Gen Virol. 64, 533-537 (1983). acquisition of genital herpes simplex virus type 1 (HSV-1) or HSV-2. Sex Trans Dis. 30, 310-314 (2002). 38. Lagacé-Simard, J. Portnoy, J.D. & Wainberg, M.A. High levels of IgE in patients suffering from frequent 25. Harel, L. et al Presence of viremia in patients with recurrent herpes simplex lesions. J Allergy Clin primary herpetic gingivostomatitis. Clin Infect Dis.39, Immunol. 77(4), 582-585 (1986 Apr). 636-640 (2004). 39. Hinz, T. et al. Atopic derma-respiratory syndrome 26. Brice, SL. et al. Detection of herpes simplex virus is a correlate of eczema herpetium. Allergy. 66(7), DNA in the peripheral blood during acute recurrent 925-933 (2011). herpes labialis. J Am Acad Dermatol. 26, 594-598 (1992). 40. Kotani, H. et al. Increased plasma LIGHT levels in patients with atopic dermatitis. Clin Exp Immunol. 27. Amatsu, A& Yoshida, M. Detection of herpes 168(3), 318-324 (2012).

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Illustrations Illustration 1

Tables

Table 1a. Correlation between mean age and serum HSVIgG levels.

HSVAb-positive patients were more than 10 years older than HSVAb-negative patients in

both the normal (n = 495) and high (n = 292) IgE level groups.

Normal IgE: < 170 IU/ml (n = 495) Abnormal IgE:>170 IU/ml (n = 292) HSVIgG Men Women Men Women EIA titer (n) Mean Age (years) (n) Mean Age (years) (n) Mean Age (years) (n) Mean Age (years) < 2 38 39.1 76 39.6 49 39.3 46 37.7 > 2 97 57.5 284 55.2 88 51.8 109 51.1 Total 135 360 137 155

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Table 1b. Correlation between mean age and titer of HSVIgG in 197 patients with high IgE WMC004846 Downloaded from http://www.webmedcentral.com on 20-Mar-2015, 07:38:29 AM

(>170 IU/ml).

HSVIgG Men Women EIA titer (n) Mean Age (years) (n) Mean Age (years) 2-32 22 44.9 26 43.7 32-64 25 55.5 34 48.9 >64 29 55.9 35 56.9 >128 12 47.0 14 54.9

Total 88 109

Table 1c. Correlation between mean age and titer of HSVIgG in 381 patients with normal IgE

(< 170 IU/ml).

HSVIgG Men Women EIA titer (n) Mean Age (years) (n) Mean Age (years) 2-32 21 46.7 72 46.3 32-64 30 64.2 98 56.7 >64 29 57.9 93 59.6 >128 17 58.2 21 59.9

Total 97 284

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Illustration 2

Figure 1: Clinical presentation and positive QTT cytologic findings

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Illustration 3

Figure 2:Distribution regarding to the serum level of IgE and HSVIgG of the 787 QTT positive patients.

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Illustration 4

Fig. 3. Clinical presentations and QTT findings of HSV Ab-positive patients with normal serum IgE

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Illustration 5

Fig. 4.Clinical presentations and QTT findings of HSV Ab-positive patients with abnormal serum IgE

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