ERYTHEMA MULTIFORME MAJOR IN HIV PATIENT

Nur Camelia1*, Syamsul Arifin2, Yosep Ferdinand Rahmat Sugianto3, Retno Indar Widayati4,
Diah Adriani Malik5.
1,2,3,4,5
Departement of Dermatovenereology, Faculty of Medicine, Diponegoro University/
Dr.Kariadi Hospital, Jl. Dr. Sutomo No. 16 Semarang-Indonesia.
*Telephone : 082137904965, email: amelkulkel@gmail.com

Abstract
Erythema multiforme major (EM major) is an acute self-limiting mucocutaneous reaction
characterized by a patognomonic target lesion or iris lesion with involvement with mucous
membranes. Erythema multiforme can affect all ages but is mostly found in the young adults
age group. Erythema multiforme predominantly affects men rather than women. The exact
etiology of this disorder is not yet known. The trigger factors of EM major are mainly infection,
drugs, physical factors, systemic disease, malignancy, and pregnancy. All antiretroviral drugs
(ARV) can potentially cause allergic reaction, and the most frequent is Nevirapine. Patients with
HIV/AIDS have high risk to suffer from drug eruption. A 45-years-old man with positive HIV
presented with an erythematous rash on his chest and arms, and bleeding on his lips’ mucosa.
The patient had been receiving ARV treatment consisted of Zidovudine, Lamivudine and
Nevirapine for two weeks. Clinical examination showed target lesions on chest and arms, and
erosion and hemorrhagic crust on his lips. CD4 count: 30 cells/mm3. Histopathological
examination was consistent with erythema multiforme findings. The initial therapy was the
cessation of the suspected causative agent (Nevirapine). This patient was given
methylprednisolone injection 125 mg daily, loratadine tablet 10 mg/day and topical
triamcinolone acetonide for his lips. Significant clinical improvement was found after 10 days
of treatment.
Keywords: erythema multiforme, HIV, ARV, Nevirapine

Introduction
Erythema multiforme (EM) is an acute, usually mild, and often relapsing mucocutaneous
syndrome. EM is defined only by its clinical characteristics, target-shaped plaques with or
without central blisters.1 The subtypes of EM are EM minor (skin lesions without involvement
of mucous membranes), EM major (skin lesions with involvement of mucous membranes),
Herpes-associated erythema multiforme, and mucosal erythema multiforme. Even though the
minor form of EM is more frequent than the major form. EM major is predominantly observed
in young adults and is very uncommon during childhood. There is a slight male preponderance,
but no racial bias. The exact incidence rate of EM major is not known.1,2 Many factors have
been implicated in the etiology of EM major, including numerous infectious agents, physical
agents, x-ray therapy, pregnancy, internal malignancies and drugs. In approximately 50% of
cases no cause can be found. EM major is frequently associated with viral infection, most often
herpes simplex, and Mycoplasma pneumoniae infection.3,4
All antiretroviral drugs (ARV) can potentially cause allergic reaction.5 Generally, the
occurence of EM major in patients with HIV has been reported in ARV treatment-treated
patients. Severe rash such as stevens-johnsons syndrome (SJS) or EM major would indicate
change in the ARV treatment regimen. A variety of factors have been implicated in the
pathogenesis of EM major. The underlying mechanisms have been extensively investigated for
herpes-associated EM. It is unknown whether similar mechanisms apply to EM major due to
other causes.1,2,4
No spesific objective markers or criteria are required for a diagnosis of EM major. The
important clues to diagnosis continue to be the clinical history and clinical findings.2 The
prodromal symptoms, morphologic configuration of the lesions, and intensity of systemic
symptoms vary. Milder forms of the disease may be preceded by malaise, fever, or itching and
burning at the site where the eruption will occur. The cutaneous eruptions are most distinctive,
and classification is based on their form.3 Skin lesions in EM are typical (regular round shape,
well-defined border with 3 different concentric zones) and/or atypical raised targets (poorly
defined border, 2 zones) appear mainly on the limbs, sometimes also on the face and trunk. 6,7
Mucosal lesions may occur in up to 70% of cases. The most common sites are the lips and
buccal mucosa.1,3,6
Biopsy from the lesion on histopathological examination demonstrate inflammation
characterized by perivascular mononuclear infiltrate, edema of the upper dermis, apoptosis of
keratinocytes with focal epidermal necrosis and subepidermal bulla formation.7,8
The best treatment for EM major is to identify and remove its cause. Oral mucosal
involvement may be treated with topical steroids, and anti-inflamatory or anaesthetic mouth
washes. Ocular involvement requires the early help of an opthalmologist.9,10 In extensive cases
of EM major, systemic corticosteroids have been used.11 Although EM is usually self-limiting, it
can lead to reccurent disease. However, EM major in HIV patient is rare and whether EM in
HIV patient clinically is different with the non-HIV patient. This case is reported to increase our
understanding about the clinical variation in presentation of EM major in HIV patients and
corresponding management.

Case
A 45 year-old Indonesian man was treated in Dr.Kariadi Hospital Semarang. The patient
was a consult from internal medicine department with HIV (+) and 8 days fever observation.
The patient complained of erythematous rashes on his chest and arms since 4 days before
admitting to hospital. The patient also complained of bleeding on his lips’ mucosa since 3 days
before admitting to hospital. The patient had a history of HIV screening (+) 3 weeks ago at
Hospital in Salatiga. The patient had been receiving ARV treatment consisted of Zidovudine,
Lamivudine and Nevirapine for two weeks. After taking the drugs, initially the patient
complained of fever, odynophagia and mouth ulcers, then erythematous rashes on his chest and
arms. The rash was felt slightly itchy. Patients never had such a skin disease before. Any history
of drug allergy or food allergy was denied. History of malignant disease and radiation treatment
was denied. History of recurrent or relapsing vesicles on the body and around the mouth was
denied. History of changing partners and having sexual relation other than with his wife was
denied. History of any injury to the genital denied, the patient never got a blood transfusion and
illicit drug use was denied. No member of his family experienced the same complaints and
illness. The patient works as a Civil Servant. The patient used health insurance from the
goverment. Patient’s social economy appeared to be adequate.
On physical examination, the patient was composmentis. Height 168 cm, weight 75 kg,
blood pressure: 120/70 mmHg, heart rate: 84 beats / minute, respiratory rate: 22 breaths/minute,
and axillar temperature: 38oC. On clinical examination showed target lesion on chest and arms,
and erosion and hemorrhagic crust on his lips. (Fig.1 and Fig.2)

Figure 1. (A) Atypical target lesions on patient's chest, (B) Hemorrhagic crust on patient's lips
 Figure 2. Clinical improvement after 10 days (A) on the chest, (B) on the lips' mucosa.

The routine laboratorium examination result was normal. The Voluntary Counselling and
Testing (VCT) result was reactive with CD4 count 30 cells/ml. Histopathological examination
showed the lesion tissue covered by keratinized stratified squamous cell epithelium with
parakeratosis. The dermis appeared to be oedematous, hyperemic. Skin adnexa was surrounded
by dense lymphocytes, histiocytes, PMN leucocytes infiltrate, no extravasasion nor malignancy
sign found.
The initial therapy was the cessation of the suspected causative agent (Nevirapine) and
advise to the HIV specialist to change ARV treatment regimens. Treatment was given
methylprednisolone injection 125 mg/day for 3 days, followed by methylprednisolone injection
62,5 mg/day for 3 days, followed by methylprednisolon tablet 16 mg twice daily for 3 days,
followed by methylprednisolon tablet 16 mg/day for 3 days, ranitidine injection 50 mg twice
daily, loratadine tablet 10 mg/day and topical triamcinolone acetonide 0,1% in orabase for the
lips' mucosa and benzydamine Hcl gargle twice daily.

Discussion
The diagnosis erythema multiforme mayor in HIV patient was made based on anamnesis,
clinical examination, and histopathological examination. EM major is a sudden eruption that
can occur at any age, affecting men more often than women, with prodromal symptoms before
eruption such as fever, malaise.1,2 The cause can be infection (HSV, fungi, bacteria, virus), and
drugs.1,2,3,4,12
HIV patients are susceptible to drug allergies due to the chronic viral provocation that
made memory T cells to react promptly with immunogens from the drugs. The drugs that most
frequently found to cause allergy in HIV patients are sulfonamides (sulfa) and antiretroviral
groups non-nucleotid reverse transcriptase inhibitors (NNRTIs): Delavirdine, Efavirenz and
especially Nevirapine.5, Our case indicates that Nevirapine may provoke EM major.
On clinical examination showed target lesion on chest and arms, and erosion and
hemorrhagic crust on his lips. EM major is a self-limiting inflammatory disease, characterized
clinically by "target" or "iris" skin lesions with mucous involvement.1,2,10,12,13 EM major in HIV
patient clinically is different with the non-HIV patient, that clinically EM major in HIV patient
is milder than EM major in non-HIV patient, because in HIV patient there is immunodeficiency.
Most allergic syndromes associated with antiviral medications consist of mild to moderate
delayed rash without other serious manifestations.14
In EM major, necrotic keratinocytes, sometimes spongiosis, edema of the papillary dermis,
perivaskular or interface lymphocytes, and sometimes extravasated erythrocytes were found.8,15
Laboratory studies and skin biopsies are not required in all case of EM major. However,
laboratory evaluation and histopathology may assist in confirming the diagnosis, determining
the inciting factor and ruling out other diseases in the differential diagnosis.12
 The differential diagnosis with SJS can be excluded because lesions in SJS are widespread,
often confluent purpuric macules or atypical, flat targets (without palpable edema or infiltration)
on which blisters develop. In SJS, there are epidermal detachment related to the body surface
area (BSA) <10% and at least 2 involvement of mucous membranes. In contrast, in EM major,
typical and/or atypical raised targets appear mainly on the limbs, sometimes also on the face and
trunk.6,7 EM minor also can be excluded because in EM minor presents target lesions without
involvement of mucous membranes.1,2,12,13
The initial treatment for EM major is to identify and remove its cause. The therapeutic
options include topical and systemic treatment of the acute eruption as well as prophylactic
treatment of recurrent disease. Topical therapy includes topical antiseptics for eroded skin
lesions and oral anaesthetic and antiseptic solutions with topical corticosteroids for mucosal
involvement. Oral antihistamines for 3 or 4 days may reduce the stinging and burning of the
skin. In severe forms of EM with functional impairment, early therapy with systemic
corticosteroids (e.g. prednisone [0.5–1 mg/kg/day] or pulse methylprednisolone [20 mg/kg/day
for 3 days]) should be considered.2,12,13
The prognosis of this case is quo ad vitam ad bonam, quo ad sanam dubia ad bonam, and
quo ad cosmetikam dubia ad bonam. Erythema multiforme major has a mortality rate less than
5% and is directly proportional to the total BSA of sloughed epithelium. Skin lesions usually
heal with hyperpigmentation and/or hypopigmentation. Scarring is usually absent, except after
secondary infection. Surprisingly, although the incidence of EM is increased among individuals
with HIV infection (approaching 1 case per 1000 individuals per year), they do not appear to
have a higher mortality rate.4

Conclusion
We have reported a case of erythema multiforme major in a 45-years old male patient with
HIV positive. The diagnosis was made on the basis of anamnesis, clinical examination, and
histopathological examination. On the anamnesis, the patient complained of erythematous
rashes on his chest and arms and bleeding on his lips’ mucosa after he had been receiving ARV
treatment consisted of Zidovudine, Lamivudine and Nevirapine for two weeks. On clinical
examination, we found target lesions on his chest and arms, and hemorrhagic crust on his lips’
mucosa. Histopathological examination was consistent with erythema multiforme findings. The
initial therapy was the cessation of Nevirapine. This patient was given methylprednisolone
injection 125 mg daily, loratadine tablet 10 mg/day and topical triamcinolone acetonide for his
lips. The prognosis of this case is quo ad vitam ad bonam, quo ad sanam dubia ad bonam, and
quo ad cosmetikam dubia ad bonam.

References
1. Roujeau JC. Erythema Multiforme. In: Goldsmith LA, Katz SI, Gilchrest BA, Paller AS,
Leffell DJ, Wolff K, editors. Fitzpatrick’s Dermatology in General Medicine, Eight
Edition. New York: Mc Graw-Hill Companies; 2012. p. 431-439.
2. French LE, Prins C. Erythema Multiforme, Stevens-Johnson Syndrome and Toxic
Epidermal Necrolysis. In: Bolognia JL, Jorizzo JL, Schaffer JV, editors. Dermatology,
Third Edition. China: Elsevier Saunders; 2012. p. 319-323.
3. Habif, TP. Hypersensitivity Syndromes and Vasculitis. In: Clinical Dermatology: A Color
Guide to Diagnosis and Therapy, Sixth Edition. China: Elsevier, Inc; 2016. p. 713-717.
4. Plaza JA, James WD. Erythema Multiforme. Last Update: Oct 20, 2017, cited 9 Jan 2017.
Available from URL: https://emedicine.medscape.com/article/1122915-overview.
5. Pudjiati SA. HIV-Related Drug Allergy. In: Adverse Cutaneus Drug Reactions: Caveats &
Essential Practices. Malang Dermatology and Venereology Update (MDVU) 2018.
Malang: January 2018. p.107-119.
6. Paulmann M, Mockenhaupt M. Fever in Stevens–Johnson Syndrome and Toxic Epidermal
Necrolysis in Pediatric Cases: Laboratory Work-up and Antibiotic Therapy. The Pediatric
Infectious Disease Journal. 36(5); May 2017. p.513-515.
7. Wolff K, Johnson RA, Saavedra AP, Roh EK. Erythema Multiforme (EM) Syndrome. In:
Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology, Eight Edition. New York:
Mc Graw-Hill Companies; 2017. p. 306-310.
8. Elder DE, Elenitsas R, Rubin AI, Loffereda M, Miller J, III OFM. Atlas and Synopsis of
Lever's Histopathology of The Skin, Third Edition. Philadelphia: Lippincott Williams and
Wilkins; 2013. p. 147-149.
9. Weller RB, Hunter HJA, Mann MW. Clinical Dermatology, Fifth Edition. Oxford: Wiley
Blackwell; 2015. p. 105-107.
10. Breathnach SM. Erythema Multiforme, Stevens-Johnson Syndrome and Toxic Epidermal
Necrolysis. In: Burns T, Breathnach S, Cox N, Griffiths C. Rook’s Textbook of
Dermatology Eight Edition. Singapore: Wiley Blackwell; 2010. p. 76.1-76.7.
11. James WD, Elston DM Berger TG. Erythema and Urticaria. In: Andrew’s Disease of the
Skin: Clinical Dermatology, Twelfth Edition. China: Elsevier, Inc; 2016. p. 137-139.
12. Simbli MA. Erythema Multiforme: Challenging Diagnosis for Internist. J Clin Case Rep
3:7; 2013. p.1-3.
13. David L, Swanson MD. Erythema Multiforme: Medline Plus Medical Encyclopedia.
ADAM Inc. Last Review Date: Oct 24, 2016, cited 9 Jan 2017. Available from URL:
https://medlineplus.gov/ency/article/000851.htm
14. Milpied-Homsi B, Moran EM, Phillips EJ. Antiviral Drug Allergy. Immunology and
allergy clinics of North America. 34(3); 2014.p.645-662.
15. Rapini RP. Reactive Erythemas. In: Practical Dermatopathology, Second Edition. New
York: Elsevier Saunder; 2012. h.64-65.