e-ISSN:2320-7949

p-ISSN:2322-0090

Research and Reviews: Journal of Dental Sciences

Management of Erythema Multiforme Secondary to Herpes simplex by Systemic
Acyclovir and Topical Corticosteroid: A Case Report.
Aadya Sharma1, Harkanwal Preet Singh2*, Prabhleen Kaur3, and Ishita Gupta4
1Department

of Oral and Maxillofacial Surgery, SGT Dental College, Hospital and Research Centre, Gurgaon,
Haryana, India.
2Department of Oral Pathology and Microbiology, Dasmesh Institute of Research and Dental Sciences, Faridkot,
Punjab, India.
3Medical Officer, PHC Gopalpur, Block Kalo Majra, Patiala, Punjab, India.
4Department of Oral Medicine and Radiology, SGT Dental College, Hospital and Research Centre, Gurgaon,
Haryana, India.

Research Article
Received: 03/07/2013
Revised: 29/07/2013
Accepted: 04/08/2013
*For Correspondence
Department of Oral Pathology
and Microbiology, Dasmesh
Institute of Research and Dental
Sciences, Faridkot, Punjab,
India.
Mobile: +91 9501544877.

ABSTRACT
Erythema multiforme (EM) is mucocutaneous disease which has
oral manifestations. It is clinically characterized by a minor form and a
major form. It presents a diagnostic dilemma because the oral cavity
has the ability to produce varied manifestations. Primary attacks of oral
EM are confined to the oral mucosa but the subsequent attacks can
produce more severe forms of EM involving the skin. Hence, it is
important to identify and distinguish them from other ulcerative disorders
involving oral cavity for early management. This article reports an unusual
case of Erythema multiforme with oral and lip lesions along with typical
target eye lesion at extremities. We emphasize on its early diagnosis and
timely management.

Keywords: Erythema multiforme,

Ulcers, Mucocutaneous
diseases, Herpes simplex virus.
INTRODUCTION
Erythema multiforme (EM) is a rare acute mucocutaneous condition caused by a hypersensitivity reaction
with the appearance of cytotoxic T lymphocytes in the epithelium that induce apoptosis in keratinocytes, which
leads to satellite cell necrosis [1]. It consists of a polymorphous eruption of macules, papules, and characteristics
target lesions (central bullae or vesicle with surrounding concentric rash) distributed with a propensity for the distal
extremities [2].
It is classified into minor and major type. EM minor shows ulcerations involving a single mucosal site with
typical skin target lesions. EM major shows ulcerations involving more than one mucous membrane with skin target
lesions. These lesions can be triggered by HSV infections or adverse drug reactions. Steven Johnson syndrome is a
more severe condition characterized by wide spread small blisters on torso and mucosal ulcerations with atypical
skin target lesions triggered by drug intake. Typical target skin lesions are necessary along with mucosal ulcerations
to consider diagnosing them as EM minor and major [3]. We, hereby report a case of Erythema multiforme with oral
and skin lesions in 15 year old boy of Asian ethnic.
MATERIALS AND METHODS
Case Report
A 15 year-old boy presented with history of swelling, pain and ulceration on upper and lower lip since 2
week. (Figure 1)

RRJDS | Volume 1 | Issue 3 | October-December, 2013

45

e-ISSN:2320-7949
p-ISSN:2322-0090

Figure 1: Extra-oral photograph showing ulcers and crustation on lower and upper lip.
Initially there were small ulcers which latter transformed into large extensive ulcerated areas Patient gave
history of fever and sore throat 1 week back, followed by vesicle formation and ulcerations on lips. Oral lesions
appeared first followed by skin lesions. Oral lesions were associated with severe intermittent pain which was
aggravated on mastication. No any relevant medical history was observed. The patient reported no prolonged drug
intake and hospitalization. Family and drug history were non-significant. All the vital signs were within normal
range. Extra-oral examination showed ulcerations and crustation on lower and upper lip (Figure 1) and multiple
fluid-filled round vesicles with central necrotic areas (target lesions) with erythematous halo present on hands
(Figure 2) and arms. (Figure 3)

Figure 2: Photograph of hand showing central black necrotic area surrounded by erythematous halo.

Figure 3: Photograph of arms showing concentric necrotic area surrounded by erythematous halo. (Target-eye
lesion)
Bilateral submandibular lymph nodes were enlarged and tender. On intraoral examination, multiple diffuse
irregular ulcerations of upper and lower labial mucosa and also on palate and ventral surface of tongue.(Figure 4)

RRJDS | Volume 1 | Issue 3 | October-December, 2013

46

e-ISSN:2320-7949
p-ISSN:2322-0090

Figure 4: Intra-oral photograph showing diffuse ulceration on palate and tongue.

Hemorrhagic crusts were also noticed on lower lip which was tender on palpation. Haematologic
investigations revealed normal complete blood count. Serology tests showed positivity for Herpes simplex virus and
there was fourfold rise in antibody titer. In the light of available evidences, final confirmatory diagnosis recurrent
herpes associated erythema multiforme (HAEM) was given. The patent was treated with a 10-day course of
acyclovir (1000 mg/day), a topical dexamethasone elixir and acetaminophen. Oral and skin lesions healed
completely within 2 weeks. (Figure 5)

Figure 5: Intra-oral photograph showing complete resolution of lesion.

Patient was followed for 6 months without any evidence of recurrence.
DISCUSSION
EM is an acute, sometimes recurrent, mucocutaneous condition of uncertain etiopathogenesis. It usually
follows the administration of drugs or infections. Infection with HSV is the most common predisposing feature in the
development of EM minor. Both HSV types 1 and 2 have been shown to precipitate EM [4]. HSV DNA has been
detected in 60% of patients clinically diagnosed with recurrent HAM and in 50% of patients with recurrent idiopathic
erythema multiforme using polymerase chain reaction (PCR) of skin biopsy specimens [5]. Major differences
between drug induced and viral induced erythema multiforme is discussed in table 1 [6].
Several studies have demonstrated that the pathogenesis of HAEM is consistent with a delayed
hypersensitivity reaction. The disease begins with the transport of HSV DNA fragments by circulating peripheral
blood mononuclear CD34+ cells (Langerhans cell precursors) to keratinocytes, which leads to the recruitment of
HSV-specific CD4+ TH1 cells. The inflammatory cascade is initiated by interferon- (IFN-), which is released from
the CD4+ cells in response to viral antigens, and immunomediated epidermal damage subsequently begins. PCR
has been employed to detect the presence of HSV DNA in HAEM lesions and tissues, and HSV genes can also be
identified with reverse transcriptase. Serology to identify HSV-1 and HSV-2 and to detect specific IgM and IgG
antibodies may confirm a suspected history of HSV infection, although it is not necessary for diagnosis [7, 8]. In
present case serologic test showed positivity for HSV.
An intriguing question is why most HSV patients do not develop HAEM Some studies have implicated HLA
alleles B15(B62), B35, A33, DR53, DQB1*0301 and DQw3 in HAEM development; other HLA alleles (viz. A1) were
associated with the propensity to develop recurrent HSV lesions. Moreover, the incidence of DQB1*0302 was
increased in HAEM patients with mild mucous membranes involvement; whereas, an association with DQB1*0402
was seen in the disease form showing severe mucous membrane involvement. However, longitudinal studies
indicate that HAEM does not follow all the recurrent HSV episodes experienced by a given patient, and the factors
RRJDS | Volume 1 | Issue 3 | October-December, 2013

47

e-ISSN:2320-7949
p-ISSN:2322-0090
that determine which HSV episode will result in HAEM causation are still unknown. Most likely, HAEM development
is determined by the efficacy of HSV DNA dissemination to distant skin sites and its fragmentation during transport
[6].
Table 1: Differences between drug induced and viral induced erythema multiforme
Features
Causative Agent
Disease course
Prodrome
Predilection sites
Skin lesion
Mucosal
involvement
Constitutional
symptoms
Complications

HEAM (Herpes simplex virus associated

erythema multiforme)
HSV
Acute, Self-limited, recurrent (7-21 days after
HSV lesion)
Absent/moderate
Acral extremities, Target lesions, common

[6]

Absent/minimal

DIEM (Drug induced erythema

multiforme)
Drugs
Acute, self-limited not recurrent,
does not follow HSV lesion
Present
Acral extremities, Face, Target
lesions rare, Blisters
Prominent

Absent/moderate

Present/severe

None

Infrequent (pneumonia,
hemorrhage, GI, renal failure)
5-15%
Exocytic KC necrosis; acrosyringeal
concentration of necrotic KC; less
pronounced edema; mononuclear
infiltrate and CD8+ T cells
Lesional skin negative for HSV
DNA (PCR); positive for TNF-
(immunohistochemistry)

Mortality
Histopathology

None
Focal necrotic KC; moderate/pronounced
edema; mononuclear infiltrate with
predominant CD4+ T cells

Laboratory
diagnosis

Lesional skin positive for HSV DNA (PCR) and

IFN- (immunohistochemistry)

The diagnosis of HAEM is clinical and is easier when the patient develops target lesions with a preceding or
coexisting HSV infection. The finding of typical skin or oral lesions (or both) in a patient with suspected HAEM
supports the clinical diagnosis. In our present case, diffuse ulcerations in the oral mucosa involving the buccal
mucosa, palate, labial mucosa and hemorrhagic crusts on the lips as well as the classic skin lesions were seen.
Treatment of EM depends on the severity of the lesions. Mild forms usually heal in 2-6 weeks; local wound care,
topical analgesics or anesthetics for pain control and a liquid diet are often indicated in these situations. For more
severe cases, intensive management with intravenous fluid therapy may be necessary. Oral antihistamines and
topical steroids may also be necessary to provide symptom relief. Systemic corticosteroids have been used
successfully in some patients, but evidence to support their use for EM is limited [4, 8, 9]. Recurrences are seen in
approximately 20%-25% of erythema multiforme cases. Although the disease resolves spontaneously in 10-20
days, patients may experience 2-24 episodes a year [10].
HAEM is often effectively managed with acyclovir (200 mg, 5 times a day for 5 days), but only if the
therapeutic scheme is started in the first few days. If erythema multiforme keeps recurring, a continuous low dose
of oral acyclovir is necessary. If acyclovir treatment fails, valacyclovir can also be prescribed (500 mg twice a day).
The latter has greater oral bioavailability and is more effective at suppressing recurrent HAEM [11].
CONCLUSION
Albeit, etiology of EM is not well defined, it seems to be having definite relationship between erythema
multiforme and herpetic infections. We emphasize that for its effective management causative agent should be first
recognized and then should be immediately removed. In the case reported here, erythema multiforme triggered by
HSV infection was diagnosed, and the disease was managed with continuous oral acyclovir therapy to prevent
recurrences.
REFERENCES
1.
2.
3.

Siegel MA, Balciunas BA. Oral presentation and management of vesiculobullous disorders. Semin
Dermatol. 1994; 13: 78-86.
Lamoreux MR, Sternbach MR, Hsu WT. Erythema multiforme. Am Fam Physician. 2006 Dec; 74 (11): 18838.
Joseph TI, Vargheese G, George D, Sathyan P. Drug induced oral erythema multiforme: A rare and less
recognized variant of erythema multiforme. J Oral Maxillofac Pathol. 2012; 16: 145-8.

RRJDS | Volume 1 | Issue 3 | October-December, 2013

48

4.
5.
6.
7.

8.
9.
10.
11.

e-ISSN:2320-7949
p-ISSN:2322-0090
Farthing P, Bagan JV, Scully C. Mucosal diseases series: Number IV: Erythema multiforme. Oral Dis. 2005;
11: 261-7.
Ng PP, Sun YJ, Tan HH, Tan SH. Detection of Herpes simplex virus genomic DNA in various subsets of
Erythema multiforme by polymerase chain reaction. Dermatology. 2003; 207(4): 349-53.
Aurelian L, Ono F, Burnett J. Herpes simplex virus (HSV)-associated erythema multiforme (HAEM): a viral
disease with an autoimmune component. Dermatol Online J. 2003; 9(1): 1.
Kokuba H, Aurelian L, Burnett JW. Herpes simplex virus associated erythema multiforme (HAEM) is
mechanistically distinct from drug-induced erythema multiforme: interferon- is expressed in HAEM lesions
and tumor necrosis factor- in drug-induced erythema multiforme lesions. J Invest Dermatol. 1999; 113(5):
808-15.
Osterne RL, de Matos Brito RG, Pacheco IA, Alves AP, Sousa FB. Management of erythema multiforme
associated with recurrent herpes infection: A case report. J Can Dent Assoc. 2009; 75: 597-601.
Weston WL. Herpes associated erythema multiforme. J Invest Dermatol. 2005; 124: 15-6.
Al-Johani KA, Fedele S, Porter SR. Erythema multiforme and related disorders. Oral Surg Oral Med Oral
Pathol Oral Radiol Endod. 2007; 103: 642-54.
Woo SB, Challacombe SJ. Management of recurrent oral Herpes simplex infections. Oral Surg Oral Med
Oral Pathol Oral Radiol Endod. 2007; 103(Suppl): S12.e1-18.

RRJDS | Volume 1 | Issue 3 | October-December, 2013

49