CED
Clinical dermatology • Concise report
Clinical and Experimental Dermatology
Persistent erythema multiforme associated with Epstein–Barr virus infection N. Turnbull,1 D. Hawkins,2 M. Atkins,3 N. Francis4 and N. Roberts1 Departments of 1Dermatology and 2Genitourinary Medicine, Chelsea and Westminster Hospital, London, UK; 3Department of Virology, Hammersmith Hospital, London, UK; and 4Department of Histopathology, Imperial College Healthcare NHS Trust UK doi:10.1111/ced.12243
Summary
Erythema multiforme (EM) is a common, self-limiting condition. Recurrent EM is a well-recognised variant, often associated with herpes simplex virus infection. It is frequently managed with prophylactic aciclovir. Anecdotal reports suggest that recurrent EM may be associated with the use of corticosteroids. Persistent EM, however, is a rare variant, with few cases reported in the literature. It has a protracted course often with atypical and inflammatory lesions. It has been associated with occult viral infections, particularly Epstein–Barr Virus (EBV), as well as inflammatory bowel disease and malignancy. We report a case of EM associated with EBV infection.
Persistent erythema multiforme (EM) is rare. It has been associated in case reports with malignancy, inflammatory bowel disease, and viral infections including cytomegalovirus, herpes simplex virus (HSV) and Epstein–Barr virus (EBV). The role of corticosteroids in the management of EM is unclear, and may be detrimental. An underlying driving factor should be considered and treated if found. Azathioprine may be a helpful therapeutic option in persistent EM. We report a case of persistent EM, a rare variant, which was related to EBV infection and responded to treatment with ganciclovir.
Report A 30-year-old woman presented in June 2011 with oral ulceration and a rash that had begun 2 days after she had been started on tramadol hydrochloride for back pain. She had no relevant medical history, and no history of cold sores or genital herpes. She had mouth ulceration and classic targetoid lesions on her limbs, consistent with EM. She was started on prednisolone 40 mg daily, and discharged on a tapering dose. Correspondence: Dr Nicholas Turnbull, Department of Pathology, Warwick Hospital, Lakin Road, Warwick, Warwickshire, CV34 5BW, UK E-mail: [email protected] Conflict of interest: none declared. Accepted for publication 3 July 2013
154
Clinical and Experimental Dermatology (2014) 39, pp154–157
In August 2011, the patient presented to our service because her oral lesions had worsened and her skin lesions had started to ulcerate. She reported lethargy, but had no other systemic symptoms. We treated her with intravenous (IV) aciclovir 5 mg/kg and 60 mg of prednisolone. Topical clobetasol 0.1% ointment was used on any new skin and lip lesions. After 7 days, the patient was discharged with a tapering prednisolone dose and oral aciclovir 400 mg twice daily. She was also started on bone-protection medication. Weaning the patient from our corticosteroid treatment seemed to correspond with the recurrence of her lesions. Her predominantly acral lesions were ulcerated and bullous. The following month, we started the patient on ciclosporin 2.5 mg/kg as a steroid-sparing agent. Multiple biopsies were taken, and there was no suggestion of a differential diagnosis such as pemphigus (Fig. 1). Results of direct and indirect immunofluorescence tests were negative. A malignancy screen including mammogram, cervical smear, blood film, and computed tomography of the chest, abdomen and pelvis were negative. Results for HSV serology tests and swabs for HSV DNA PCR were persistently negative. Over the next 3 months, the patient was maintained on ciclosporin 5 mg/kg. Prednisolone could not be reduced without flare. She responded to IV immunoglobulins on two occasions in October and January. In
ª 2013 British Association of Dermatologists
Persistent erythema multiforme & EBV N. Turnbull et al.
Figure 1 Lichenoid infiltrate of lymphocytes in the papillary
dermis, basal cell hydropic degeneration, cytoid bodies and dyskeratotic cells in the epidermis, features in keeping with erythema multiforme. (haematoxylin and eosin, original magnification 9 100).
February 2012, her ciclosporin was stopped, as it was ineffective and was causing hypertrichosis and hypertension. Aciclovir was changed to famciclovir 500 mg twice daily. The following month, she was started on azathioprine, which was increased to 2 mg/kg over 2 months. However, the disease continued to flare whenever prednisolone was reduced. Lesions continued to develop persistently and relentlessly, and these were ulcerated and bullous (Fig. 2). The disease process was not self-limiting. We felt the condition represented persistent EM. There were no symptoms of inflammatory bowel disease, and full blood count and haematinics were normal. HSV serology and swabs were repeatedly negative. EBV DNA, detected by quantitative PCR of EDTA-treated whole blood, gave a value of 4000 copies/mL. Results for EBV viral capsid antigen (VCA) IgG and anti-EBV nuclear antigen IgG were positive, and EBV VCA IgM was negative, which, taken together with the EBV
(a)
(b)
(c)
(d)
(e)
(f)
Figure 2 (a) Prominent oral mucosal
lesions; (b) buccal mucosal erosions; (c) crusted lesions on the dorsa of the hands; (d) acrally distributed inflammatory crusted and erosive lesions on the arms; (e) crusted and erosive lesions on the medial leg; and (f) acrally distributed inflammatory lesions.
ª 2013 British Association of Dermatologists
Clinical and Experimental Dermatology (2014) 39, pp154–157
155
Persistent erythema multiforme & EBV N. Turnbull et al.
PCR results, was consistent with a past EBV infection (> 8 weeks earlier) and probable reactivation.1 After discussion with virology and HIV/genital urinary medicine specialists and in the absence of other significant findings, the patient was started on IV ganciclovir. A 14-day IV induction dose schedule of 900 mg twice daily was followed by oral valganciclovir 450 mg daily. This reduced oral dose was chosen because valganciclovir and ganciclovir have been associated with bone-marrow suppression, and the patient was taking azathioprine concurrently (Fig. 3). After starting the treatment, the patient noticed an immediate improvement in her skin and oral lesions. This improvement continued while she remained on oral valganciclovir, and 6 weeks into the treatment she stopped developing any new lesions. We were then able to wean her off corticosteroids also. The EBV DNA PCR level in whole blood became undetectable, and remained so while the patient was on treatment. Unfortunately, after 3 months of remission, the patient developed a sudden drop in her haemoglobin, and was diagnosed with red cell aplasia, thus ganciclovir and azathioprine were stopped, after which the red cell aplasia resolved. The patient began to develop further skin lesions; however, these were much less frequent than previously, and they responded to topical therapy. Persistent EM is a rare variant of the classic selflimiting form of EM. It is part of a spectrum with another recognized variant, recurrent EM. There are only around 20 reported cases of persistent EM in the literature.2 EM is characterized by the appearance of typical and atypical cutaneous and mucosal lesions. It classically ceases within a month of onset. Recurrent EM is well described, and typically is preceded by clinical or subclinical HSV infection. Prophylactic aciclovir therapy can reduce or stop recurrences. Persistent EM typically has a protracted course lasting months to years, and may produce atypical lesions. These lesions are often more inflammatory, necrotic or bullous than in other forms of EM, as seen in this case. Persistent EM has been associated with malignancy,3 inflammatory bowel disease,4 and viral infections.5 It has been suggested in the literature that virally driven (and certainly HSV-driven) EM may have a protracted course in patients on corticosteroid therapy.6 Erythroderma was precipitated in a patient given corticosteroids for persistent EM caused by influenza virus infection.7 Our patient had active EBV replication. Persistent EM has been associated with EBV reactivation and infection,5 but this is the first such case, to our knowledge, in which EBV DNA has been quantified using real-time
156
Clinical and Experimental Dermatology (2014) 39, pp154–157
Figure 3 Treatment timeline.
PCR. Corticosteroids, antivirals and immunomodulatory agents including dapsone, mycophenolate mofetil and azathioprine8–10 have been reported to be successful treatments. Our patient flared when we reduced her corticosteroids, and was not helped by the addition of ciclosporin or azathioprine. Her improvement seemed to correlate with the addition of ganciclovir and inhibition
ª 2013 British Association of Dermatologists
Persistent erythema multiforme & EBV N. Turnbull et al.
of EBV replication. Unfortunately, she developed red cell aplasia. Both azathioprine and ganciclovir are associated with bone-marrow suppression and dyscrasias. Cessation of both drugs led to resolution of the red cell aplasia but also resulted in recurrence of the persistent EM. Although the patient continues to develop lesions, her condition is considerably more manageable and acceptable than before treatment with ganciclovir.
References 1 Health Protection Agency. UK Standards for Microbiology Investigations. Epstein-Barr Virus Serology, 2012; 51: 1–11. Available at: http://www.hpa.org.uk/webc/ HPAwebFile/HPAweb_C/1317131313375. 2 Sokumbi O, Wetter DA. Clinical features, diagnosis, and treatment of erythema multiforme: a review for the practicing dermatologist. Int J Dermatol 2012; 51: 889–902. 3 Davidson DM, Jegasothy BV. Atypical erythema multiforme: a marker of malignancy? Cutis 1980; 105: 465–7.
ª 2013 British Association of Dermatologists
4 Chapman RS, Forsyth A, MacQueen A. Erythema multiforme in association with active ulcerative colitis and Crohn’s disease. Dermatologica 1977; 154: 32–8. 5 Drago F, Romagnoli M, Loj A et al. Epstein-Barr virus related persistent erythema multiforme in chronic fatigue syndrome. Arch Dermatol 1992; 128: 217–22. 6 Sen P, Chua SH. A case of recurrent erythema multiforme and its therapeutic complications. Ann Acad Med Singapore 2004; 33: 793–6. 7 Pavlovic MD, Karadaglic DM, Kandolf LO, Mijuskovic ZP. Persistent erythema multiforme: a report of three cases. J Eur Acad Dermatol Venereol 2001; 15: 54–8. 8 Hoffman LD, Hoffman MD. Dapsone in the treatment of persistent erythema multiforme. J Drugs Dermatol 2006; 5: 375–6. 9 Davis MD, Rogers RS 3rd, Pittelkow MR. Recurrent erythema multiforme/Stevens-Johnson syndrome: response to mycophenolate mofetil. Arch Dermatol 2002; 138: 1547–50. 10 Jones RR. Azathioprine therapy in the management of persistent erythema multiforme. Br J Dermatol 1981; 105: 465–8.
Clinical and Experimental Dermatology (2014) 39, pp154–157
157
Clinical dermatology • Concise report
Clinical and Experimental Dermatology
Persistent erythema multiforme associated with Epstein–Barr virus infection N. Turnbull,1 D. Hawkins,2 M. Atkins,3 N. Francis4 and N. Roberts1 Departments of 1Dermatology and 2Genitourinary Medicine, Chelsea and Westminster Hospital, London, UK; 3Department of Virology, Hammersmith Hospital, London, UK; and 4Department of Histopathology, Imperial College Healthcare NHS Trust UK doi:10.1111/ced.12243
Summary
Erythema multiforme (EM) is a common, self-limiting condition. Recurrent EM is a well-recognised variant, often associated with herpes simplex virus infection. It is frequently managed with prophylactic aciclovir. Anecdotal reports suggest that recurrent EM may be associated with the use of corticosteroids. Persistent EM, however, is a rare variant, with few cases reported in the literature. It has a protracted course often with atypical and inflammatory lesions. It has been associated with occult viral infections, particularly Epstein–Barr Virus (EBV), as well as inflammatory bowel disease and malignancy. We report a case of EM associated with EBV infection.
Persistent erythema multiforme (EM) is rare. It has been associated in case reports with malignancy, inflammatory bowel disease, and viral infections including cytomegalovirus, herpes simplex virus (HSV) and Epstein–Barr virus (EBV). The role of corticosteroids in the management of EM is unclear, and may be detrimental. An underlying driving factor should be considered and treated if found. Azathioprine may be a helpful therapeutic option in persistent EM. We report a case of persistent EM, a rare variant, which was related to EBV infection and responded to treatment with ganciclovir.
Report A 30-year-old woman presented in June 2011 with oral ulceration and a rash that had begun 2 days after she had been started on tramadol hydrochloride for back pain. She had no relevant medical history, and no history of cold sores or genital herpes. She had mouth ulceration and classic targetoid lesions on her limbs, consistent with EM. She was started on prednisolone 40 mg daily, and discharged on a tapering dose. Correspondence: Dr Nicholas Turnbull, Department of Pathology, Warwick Hospital, Lakin Road, Warwick, Warwickshire, CV34 5BW, UK E-mail: [email protected] Conflict of interest: none declared. Accepted for publication 3 July 2013
154
Clinical and Experimental Dermatology (2014) 39, pp154–157
In August 2011, the patient presented to our service because her oral lesions had worsened and her skin lesions had started to ulcerate. She reported lethargy, but had no other systemic symptoms. We treated her with intravenous (IV) aciclovir 5 mg/kg and 60 mg of prednisolone. Topical clobetasol 0.1% ointment was used on any new skin and lip lesions. After 7 days, the patient was discharged with a tapering prednisolone dose and oral aciclovir 400 mg twice daily. She was also started on bone-protection medication. Weaning the patient from our corticosteroid treatment seemed to correspond with the recurrence of her lesions. Her predominantly acral lesions were ulcerated and bullous. The following month, we started the patient on ciclosporin 2.5 mg/kg as a steroid-sparing agent. Multiple biopsies were taken, and there was no suggestion of a differential diagnosis such as pemphigus (Fig. 1). Results of direct and indirect immunofluorescence tests were negative. A malignancy screen including mammogram, cervical smear, blood film, and computed tomography of the chest, abdomen and pelvis were negative. Results for HSV serology tests and swabs for HSV DNA PCR were persistently negative. Over the next 3 months, the patient was maintained on ciclosporin 5 mg/kg. Prednisolone could not be reduced without flare. She responded to IV immunoglobulins on two occasions in October and January. In
ª 2013 British Association of Dermatologists
Persistent erythema multiforme & EBV N. Turnbull et al.
Figure 1 Lichenoid infiltrate of lymphocytes in the papillary
dermis, basal cell hydropic degeneration, cytoid bodies and dyskeratotic cells in the epidermis, features in keeping with erythema multiforme. (haematoxylin and eosin, original magnification 9 100).
February 2012, her ciclosporin was stopped, as it was ineffective and was causing hypertrichosis and hypertension. Aciclovir was changed to famciclovir 500 mg twice daily. The following month, she was started on azathioprine, which was increased to 2 mg/kg over 2 months. However, the disease continued to flare whenever prednisolone was reduced. Lesions continued to develop persistently and relentlessly, and these were ulcerated and bullous (Fig. 2). The disease process was not self-limiting. We felt the condition represented persistent EM. There were no symptoms of inflammatory bowel disease, and full blood count and haematinics were normal. HSV serology and swabs were repeatedly negative. EBV DNA, detected by quantitative PCR of EDTA-treated whole blood, gave a value of 4000 copies/mL. Results for EBV viral capsid antigen (VCA) IgG and anti-EBV nuclear antigen IgG were positive, and EBV VCA IgM was negative, which, taken together with the EBV
(a)
(b)
(c)
(d)
(e)
(f)
Figure 2 (a) Prominent oral mucosal
lesions; (b) buccal mucosal erosions; (c) crusted lesions on the dorsa of the hands; (d) acrally distributed inflammatory crusted and erosive lesions on the arms; (e) crusted and erosive lesions on the medial leg; and (f) acrally distributed inflammatory lesions.
ª 2013 British Association of Dermatologists
Clinical and Experimental Dermatology (2014) 39, pp154–157
155
Persistent erythema multiforme & EBV N. Turnbull et al.
PCR results, was consistent with a past EBV infection (> 8 weeks earlier) and probable reactivation.1 After discussion with virology and HIV/genital urinary medicine specialists and in the absence of other significant findings, the patient was started on IV ganciclovir. A 14-day IV induction dose schedule of 900 mg twice daily was followed by oral valganciclovir 450 mg daily. This reduced oral dose was chosen because valganciclovir and ganciclovir have been associated with bone-marrow suppression, and the patient was taking azathioprine concurrently (Fig. 3). After starting the treatment, the patient noticed an immediate improvement in her skin and oral lesions. This improvement continued while she remained on oral valganciclovir, and 6 weeks into the treatment she stopped developing any new lesions. We were then able to wean her off corticosteroids also. The EBV DNA PCR level in whole blood became undetectable, and remained so while the patient was on treatment. Unfortunately, after 3 months of remission, the patient developed a sudden drop in her haemoglobin, and was diagnosed with red cell aplasia, thus ganciclovir and azathioprine were stopped, after which the red cell aplasia resolved. The patient began to develop further skin lesions; however, these were much less frequent than previously, and they responded to topical therapy. Persistent EM is a rare variant of the classic selflimiting form of EM. It is part of a spectrum with another recognized variant, recurrent EM. There are only around 20 reported cases of persistent EM in the literature.2 EM is characterized by the appearance of typical and atypical cutaneous and mucosal lesions. It classically ceases within a month of onset. Recurrent EM is well described, and typically is preceded by clinical or subclinical HSV infection. Prophylactic aciclovir therapy can reduce or stop recurrences. Persistent EM typically has a protracted course lasting months to years, and may produce atypical lesions. These lesions are often more inflammatory, necrotic or bullous than in other forms of EM, as seen in this case. Persistent EM has been associated with malignancy,3 inflammatory bowel disease,4 and viral infections.5 It has been suggested in the literature that virally driven (and certainly HSV-driven) EM may have a protracted course in patients on corticosteroid therapy.6 Erythroderma was precipitated in a patient given corticosteroids for persistent EM caused by influenza virus infection.7 Our patient had active EBV replication. Persistent EM has been associated with EBV reactivation and infection,5 but this is the first such case, to our knowledge, in which EBV DNA has been quantified using real-time
156
Clinical and Experimental Dermatology (2014) 39, pp154–157
Figure 3 Treatment timeline.
PCR. Corticosteroids, antivirals and immunomodulatory agents including dapsone, mycophenolate mofetil and azathioprine8–10 have been reported to be successful treatments. Our patient flared when we reduced her corticosteroids, and was not helped by the addition of ciclosporin or azathioprine. Her improvement seemed to correlate with the addition of ganciclovir and inhibition
ª 2013 British Association of Dermatologists
Persistent erythema multiforme & EBV N. Turnbull et al.
of EBV replication. Unfortunately, she developed red cell aplasia. Both azathioprine and ganciclovir are associated with bone-marrow suppression and dyscrasias. Cessation of both drugs led to resolution of the red cell aplasia but also resulted in recurrence of the persistent EM. Although the patient continues to develop lesions, her condition is considerably more manageable and acceptable than before treatment with ganciclovir.
References 1 Health Protection Agency. UK Standards for Microbiology Investigations. Epstein-Barr Virus Serology, 2012; 51: 1–11. Available at: http://www.hpa.org.uk/webc/ HPAwebFile/HPAweb_C/1317131313375. 2 Sokumbi O, Wetter DA. Clinical features, diagnosis, and treatment of erythema multiforme: a review for the practicing dermatologist. Int J Dermatol 2012; 51: 889–902. 3 Davidson DM, Jegasothy BV. Atypical erythema multiforme: a marker of malignancy? Cutis 1980; 105: 465–7.
ª 2013 British Association of Dermatologists
4 Chapman RS, Forsyth A, MacQueen A. Erythema multiforme in association with active ulcerative colitis and Crohn’s disease. Dermatologica 1977; 154: 32–8. 5 Drago F, Romagnoli M, Loj A et al. Epstein-Barr virus related persistent erythema multiforme in chronic fatigue syndrome. Arch Dermatol 1992; 128: 217–22. 6 Sen P, Chua SH. A case of recurrent erythema multiforme and its therapeutic complications. Ann Acad Med Singapore 2004; 33: 793–6. 7 Pavlovic MD, Karadaglic DM, Kandolf LO, Mijuskovic ZP. Persistent erythema multiforme: a report of three cases. J Eur Acad Dermatol Venereol 2001; 15: 54–8. 8 Hoffman LD, Hoffman MD. Dapsone in the treatment of persistent erythema multiforme. J Drugs Dermatol 2006; 5: 375–6. 9 Davis MD, Rogers RS 3rd, Pittelkow MR. Recurrent erythema multiforme/Stevens-Johnson syndrome: response to mycophenolate mofetil. Arch Dermatol 2002; 138: 1547–50. 10 Jones RR. Azathioprine therapy in the management of persistent erythema multiforme. Br J Dermatol 1981; 105: 465–8.
Clinical and Experimental Dermatology (2014) 39, pp154–157
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