Don’t live in a town where there are no doctors: toxic epidermal necrolysis initially misdiagnosed as oral thrush

Abstract

Toxic epidermal necrolysis (TEN) is a rare but life threatening skin disease that is most commonly drug induced. The exact pathogenesis of TEN is still unknown and many drugs, including prednisolone, cyclosporin and intravenous immunoglobulin (IVIG), have been used in an attempt to halt the disease process. The use of IVIG in particular is controversial. Recently, the US Food and Drug Administration (FDA) has made a labelling change to the drug information for carbamazepine. Owing to recent data implicating the HLA allele B*1502 as a marker for carbamazepine induced Stevens–Johnson syndrome and TEN in Han Chinese, the FDA recommends genotyping all Asians for the allele. We present an interesting case of carbamazepine induced TEN which was confused with oral thrush, had no skin lesions on presentation, and had an excellent response to a 5 day course of methylprednisolone and high dose IVIG in combination.

Background

Toxic epidermal necrolysis (TEN) is a severe drug reaction with high mortality. Treatment is supportive and use of corticosteroids and immunoglobulins, singly or in combination, is controversial.^16,17 Our case highlights the usefulness of history, examination and combined use of high dose intravenous immunoglobulins (IVIG) and methylprednisolone in the management of TEN. Also mucosal involvement may precede the skin lesions and assessment of individual cases for endoscopy is important to avoid dangerous sequelae.

Case presentation

A 46-year-old woman with diabetes mellitus, who was being treated with oral hypoglycaemic agents, presented with dysphagia and odynophagia of 2 days duration. The doctor in the emergency room consulted the ear, nose and throat (ENT) specialist, who examined the patient, diagnosed oral thrush (fig 1), and discharged her on nystatin suspension. Since the patient could not swallow, a medical specialist was consulted who held the same opinion and discharged the patient. When the patient refused to go home, the medical director on call consulted the medical team again, and following reassessment the patient was sent to the endoscopy department because of the dysphagia. After an initial assessment the endoscopist admitted the patient for parenteral fluids and, in view of the facial erythema and ulcerated lips, consulted a dermatologist. The dermatologist discharged the patient on chlorpheniramine maleate orally. It took 11 h for the patient to reach the inpatient ward from the emergency department.

Figure 1.

Slough on the patient’s tongue (mistaken as oral thrush) and facial erythema.

The patient was then seen by an internist who, on questioning her further, found that she had been recently started on carbamazepine 200 mg daily and citalopram 10 mg daily by a psychiatrist for abnormal behaviour, following a family dispute 2 weeks before the most recent complaint. Examination revealed a conscious, oriented patient with stable vital signs but who was febrile (temperature 39.0°C). Local examination revealed a sloughed oral mucosa (fig 1) with diffuse oral and pharyngeal ulceration. Her face was puffy with erythema, and her lips were swollen and ulcerated. The palms of her hands and soles of her feet were also erythematous. Complete blood counts were: haemoglobin of 12.2 g/dl (normal range (NR) 13–15 g/dl for females), platelet count 228000/mm³ (NR 150–450), total leucocyte count 6.1/mm³ (NR 4.0–11.0); erythrocyte sedimentation rate was 124 mm/h, and serum chemistry was normal except blood glucose was 21 mmol/l (normal 7.0 mmol/l).

An initial diagnosis of TEN caused by an adverse drug reaction to carbamazepine was made. All outside medications were stopped, and the patient was started on parenteral fluids, methylprednisolone 125 mg every 6 h and IVIG 3 g/kg body weight. During the next 8 h the patient exhibited generalised blistering and an erythematous macular skin rash on her face, neck, upper chest and back (figs 2 and 3). Intravenous hydration was increased and the patient was isolated. Repeat cell counts revealed leucopenia of 2.1/mm³, haemoglobin of 12.4 g/dl, and normal platelet count. Insulin was used to control the sugar values. On day 3, the skin on her face, trunk, back, hands and feet started to peel off, leaving red-raw areas. Antibiotics were given to cover against Pseudomonas and Staphylococcus species mainly, and fluconazole was added as an antifungal. On day 5 there were no new lesions and the skin started to heal; by then the patient was tolerating an oral liquid diet, and the methylprednisolone and IVIG were stopped after the 5 day course was complete. The patient was under close observation, and gradually improved with total leucocyte counts of 4.23, 5.12, and 6.8/mm³. HIV serology was negative, and C reactive protein was 12. mg/dl (normal <0.8). On day 14 the patient was stable, the lesions were healing (fig 4), and she was discharged with a follow-up after 2 weeks. At this stage, the patient’s old nails were separating and being replaced by new nails (fig 5). The patient was advised to avoid carbamazepine and related drugs in the future.

Figure 2.

Lesions on face, neck and chest.

Figure 3.

Lesions on upper back.

Figure 4.

Lesions on face, neck and chest during the healing phase.

Figure 5.

Old nails being replaced by new nails.

Differential diagnosis

• Erythema multiforme

• Erythroderma and other erythematous drug eruptions

• Acute generalised exanthematous pustulosis (AGEP) and other pustular drug eruptions

• Phototoxic eruptions

• Toxic shock syndrome (TSS)

• Staphylococcal scalded skin syndrome (SSSS) (in children)

• Paraneoplastic pemphigus

Discussion

TEN is a serious, devastating skin disease with a high mortality and multiple aetiologic factors. TEN, or Lyell syndrome, involves sloughing of >30% of the body surface area.¹ Mucous membranes are involved in nearly all cases.² Almost all the cases result from idiosyncratic drug reactions—that is, medications are the leading cause of Stevens–Johnson syndrome (SJS ) and TEN in both children and adults. However, infections, particularly Mycoplasma pneumonia and herpes viruses, are associated with a greater proportion of paediatric cases of SJS.^3,4 Although the pathophysiology of this disease is not well known, immune mechanisms and altered metabolism of drugs have been postulated.^5,6 Several death receptors and legends—Fas and Fas ligand being the most important to date—are expressed in the skin and have proven to be essential in contributing to its functional integrity. Recent data suggest that the activation of Fas through FasL is an initial important step leading to diffuse apoptotic cell death of epidermal cells in TEN. FasL mediates apoptotic cell death by binding to Fas, inducing the activation of caspases. Significant amounts of sFasL are secreted by peripheral blood mononuclear cells (PBMCs) in TEN and SJS, and plays a pivotal role in the pathomechanism of TEN.⁷

SJS and TEN typically have a prodrome of fever and influenza-like symptoms 1–3 days before the development of mucocutaneous lesions. Fever is usually higher with TEN, and often exceeds 39°C.⁸ Skin tenderness, photophobia, and conjunctival itching or burning may be early symptoms in both conditions. Certain clinical symptoms and signs, when present early in a drug reaction, are highly predictive of TEN or SJS⁹. These include:

• Confluent erythema (erythroderma)

• Facial oedema or central facial involvement +

• • skin pain

  • palpable purpura

  • skin necrosis

  • blisters and/or epidermal detachment

  • mucous membrane erosions and crusting

  • tongue swelling.

Our case had facial oedema and central facial involvement in addition to involvement of the tongue (fig 1).

Some risk factors have been identified that predispose individuals to TEN. These include genetic factors, like those with HLA-B* 1502 who are at sufficiently increased risk for SJS/TEN due to carbamazepine slow acetylators, and IL4 polymorphism. Other risk factors include HIV infection, neoplasia, radiation exposure, physical trauma, rapid and large drug dose administration, coingestants and viral infections, and systemic lupus erythematosus.^10–14 It is unknown whether diabetes mellitus is a risk factor in some patients.

Treatment mainly includes the immediate suspension of the offending drug and admission of the patient to a hospital with the capacity to provide intensive care support and to minimise the risk of infection; such a hospital should also have a facility, such as a burns unit, that is able to execute surgical debridement and cover the affected areas.^1,15 TEN is equivalent to a thermal burn. Some therapeutic interventions such as immunoglobulins and corticosteroids, either singly or in combination, have been used with variable results.^16,17 High dose γ-globulins and methylprednisolone in combination produced excellent results in our patient, decreasing morbidity, shortening the hospital stay, and resulting in an earlier recovery of the skin lesions which involved more than 70% of her body surface area. Thus, we recommend the combination of high dose IVIG and corticosteroids in cases of TEN with early presentation.

Learning points

• Drug reactions may have unusual presentations and awareness of their early warning signs are important to avoid missing a fatal condition such as toxic epidermal necrolysis (TEN).

• Proper drug history and careful examination are essential for diagnosing of drug reaction.

• Endoscopists need to assess the patient before undertaking a procedure, in order to avoid catastrophic complications in conditions like TEN which present with dysphagia due to mucosal involvement.

• Early treatment with a combination of high dose intravenous γ-globulins and methylprednisolone, in addition to hydration and supportive care, can decrease morbidity and mortality associated with TEN.