Dermatology
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A 25 year old man presents to the Emergency Department with a rash. He describes the rash starting on the backs of his hands and spreading up his arms. He is otherwise well and has no past medical history. On examination you note he has a healing cold sore, but there is otherwise no mucosal involvement. What is the diagnosis?
Answer:
Erythema multiforme (EM) is a mild, self-limiting, potentially recurring, mucocutaneous inflammatory condition. The disease is characterised clinically by target lesions, which can be described as annular erythematous rings with an outer erythematous zone and central blistering sandwiching a zone of normal skin tone. It typically presents in a symmetrical distribution of lesions over the dorsal surfaces of the extensor extremities with minimal mucous membrane involvement. The lesions usually erupt over 24 to 48 hours and last for 1 to 2 weeks. It is generally related to infectious diseases and not drug exposure. The most commonly associated infections are herpes simplex virus and Mycoplasma pneumoniae.Stevens Johnson Syndrome and Toxic Epidermal Necrolysis
Dermatology
Last Updated: 21st March 2023
Stevens-Johnson syndrome (SJS) is a severe skin detachment with mucocutaneous complications. It is an immune reaction to foreign antigens. SJS is a more severe form of erythema multiforme major and a less severe manifestation of toxic epidermal necrolysis (TEN). Both SJS and TEN are characterised by the detachment of epidermis from the papillary dermis at the epidermal-dermal junction, manifesting as a papulomacular rash and bullae.
Classification is dependent on the percentage of skin involvement:
- Erythema multiforme major has target lesions
- SJS has <10% total body surface area (TBSA) involvement
- SJS/TEN overlap has 10% to 30% TBSA involvement
- TEN has >30% TBSA involvement
Causes
SJS and TEN may be associated with a preceding history of medication use, most commonly anticonvulsants, antibiotics, and non-steroidal anti-inflammatory drugs, or of infection.
Implicated drugs:
- Anticonvulsants (e.g. carbamazepine, phenobarbital, phenytoin, valproic acid, lamotrigine)
- Antibiotics (e.g. sulfonamides, aminopenicillins, quinolones, cephalosporins)
- Non-steroidal anti-inflammatory drugs and selective COX-2 inhibitors
- Antifungals
- Antiretrovirals (e.g. nevirapine, abacavir) and antivirals (e.g. telaprevir, aciclovir)
- Anthelmintics
- Analgesics (e.g. paracetamol)
- Antimalarials
- Azathioprine
- Sulfasalazine
- Allopurinol
- Tranexamic acid
- Corticosteroids
- Psychotropic agents
- Chlormezanone
- Anticancer drugs (e.g. bendamustine, busulfan, chlorambucil)
- Retinoids
Implicated infections:
- Upper respiratory tract infections
- Pharyngitis
- Otitis media
- Mycoplasma pneumoniae
- Herpes
- Epstein-Barr virus
- Cytomegaloviruses
Clinical features
When seen very early in the course of the disease, signs and symptoms may appear relatively mild. However, the condition typically progresses over a number of days, so close monitoring and regular re-assessment is essential.
Symptoms include a sudden rash or a rash that develops after a new medicine is started. Blisters or macules and flat atypical target lesions, diffuse erythema, and Nikolsky's sign (epidermal layer easily sloughs off when pressure is applied to the affected area) may be noted. Mucosal involvement presents with erosions or ulceration of the eyes, lips, mouth, pharynx, oesophagus, gastrointestinal tract, kidneys, liver, anus, genital area, or urethra. Other potential presenting features include fever, swelling of the tongue, diarrhoea, vomiting, dysuria, enlarged lymph nodes, arthralgias, arthritis, bronchitis, shortness of breath, wheezing, hypotension, and dehydration.
Examine the patient as for a burn patient, primarily assessing the status of the airway, breathing, and circulation (ABCs). Assessment of the percentage of body surface area involved is important in classifying SJS or TEN using e.g. the rule of 9s or the Lund-Browder burn estimate chart.
Differential diagnosis
- Drug rash with eosinophilia and systemic symptoms (DRESS)
- Staphylococcal scalded skin syndrome
- Toxic shock syndrome
- Graft-versus-host disease
- Vesicant/blister agent poisoning
- Erythema multiforme
- Burns
- Paraneoplastic pemphigus
- Generalised bullous fixed drug eruption
- Acute generalised exanthematous pustulosis
Investigations
Tests include:
- Glucose, phosphate, magnesium, bicarbonate: to determine and correct abnormalities that may be present
- FBC: for baseline
- Blood culture: should be sent to rule out infection with Staphylococcus or Streptococcus species causing toxic shock syndrome or scalded skin syndrome
- LFTs: indicated to rule out hepatic damage
- Arterial blood gases and saturation of oxygen: to assess for respiratory compromise
- Serum electrolytes and urea: to assess any hypovolaemia
- Creatinine level: to exclude renal failure
The definitive test for SJS, SJS/TEN overlap, and TEN is a skin biopsy (assessed in conjunction with clinical presentation). A dermatologist should take a biopsy at the transition point of blistering, to assess the level of skin desquamation. The separation will occur at the epidermal-papillary dermal junction, with the presence of necrotic cells and lymphocytes. Direct immunofluorescence may be performed on the perilesional biopsy to exclude autoimmune blistering disease.
Management
SJS and TEN are similar to second-degree burns in terms of physiological effects. Optimal daily wound care, nutrition, critical care, pain management, and supportive care are provided in a burn centre or a specialised wound care or dermatology intensive care unit. Exact treatment will depend on the extent of skin involvement, but the same general principles are applicable to both SJS and TEN.
- Upon diagnosis, withdraw the causative agent immediately.
- Airway management
- Those that present late and those with more severe disease may be in a more critical condition. One of the potential complications of SJS/TEN is mucosal involvement of the upper and lower respiratory tract, with vesicle formation, ulceration, and actual mucosal sloughing that may lead to laryngeal stridor, along with possible retractions and oedema of the nasopharynx. If there is respiratory distress or oedema of the oropharyngeal tissues, intubation may be necessary to maintain the airway.
- Anticoagulation
- Provided the patient does not require therapeutic anticoagulation on admission, start the patient on prophylactic anticoagulation with a low molecular weight heparin such as enoxaparin.
- Dressings
- Use dressings and topical antibacterial agents to cover cleansed wounds to prevent infection. Choice of dressing is usually determined by physician preference and availability. Depending on the dressing and condition of the wound, change dressings 1 to 2 times a day up to every 2 to 3 days.
- Fluid management
- If a patient is vomiting frequently, dehydration may occur. In addition, depending on the extent of the skin sloughing, the patient may be losing significant amounts of fluids through the denuded skin surface. If the patient can take fluids orally, encourage them to do so. Otherwise, start intravenous fluids such as lactated Ringer's solution or 0.9% sodium chloride to hydrate the patient. Regardless of the calculated quantity of fluid required, the clinical evaluation of patient response is extremely important. Fluid resuscitation is monitored by urine output. It is important that an adult has a urine output of 0.5 mL/kg/hour and children weighing <30 kg have an output of 1 mL/kg/hour.
- Pain management
- Give analgesics according to the severity of symptoms. Do not use non-steroidal anti-inflammatory drugs unless other medicines, such as opioids or paracetamol, do not work. Patients will require more pain medicine during dressing changes.
- Nutritional support
- Administer nutritional support in patients with stomatitis who are unable to tolerate eating orally, feeding the patient either orally or via enteral feeding tube. Do not use hyperalimentation unless absolutely necessary. Administer a soothing mouthwash for oral hygiene in people with oral mucous membrane involvement.
- Ocular involvement
- All patients manifesting signs and symptoms of SJS/TEN should have an ophthalmological consultation and a full examination upon admission, in a bid to preserve vision and reduce complications. Coverage of the entire ocular surface with amniotic membrane, together with intensive short-term topical corticosteroids, during the acute phase of SJS and TEN has been shown to be associated with preservation of good visual acuity and an intact ocular surface.
- Intravenous immunoglobulin
- There are no clear indications regarding administration of intravenous immunoglobulin (IVIG). Some clinicians give IVIG to patients with a rapidly progressing rash involving at least 6% TBSA. Others only give IVIG when 20% TBSA is affected. There are no definitive randomised controlled trials to guide treatment.
Complications
- Dehydration
- Hypothermia
- Infection
- Acute compartment syndrome
- Acute respiratory distress syndrome
- Acute liver failure
- Acute renal failure
- Venous thromboembolism
- Ocular complications
- Pulmonary complications#
Erythema multiforme
- Erythema multiforme (EM) is a mild, self-limiting, potentially recurring, mucocutaneous inflammatory condition. The disease is characterised clinically by target lesions, which can be described as annular erythematous rings with an outer erythematous zone and central blistering sandwiching a zone of normal skin tone. It typically presents in a symmetrical distribution of lesions over the dorsal surfaces of the extensor extremities with minimal mucous membrane involvement. The lesions usually erupt over 24 to 48 hours and last for 1 to 2 weeks.
- It can be classified as EM minor or EM major. Erythema multiforme minor refers to EM without (or with only mild) mucosal disease (and without associated systemic symptoms). Erythema multiforme major is the term used to describe EM with severe mucosal involvement (and may have associated systemic symptoms, such as fever and arthralgias).
- It is generally related to infectious diseases and not drug exposure. The most commonly associated infections are herpes simplex virus and Mycoplasma pneumoniae. Other associated infections include hepatitis B, Epstein-Barr virus, cytomegalovirus, histoplasmosis (with concomitant erythema nodosum), orf (parapox virus that can be transmitted from sheep or goats to humans), coccidioidomycosis, Kawasaki disease, herpes zoster, and gardnerella.
- Associated drugs include aminopenicillins, docetaxel, tumour necrosis factor (TNF)-alpha inhibitors, antimalarials, anticonvulsants, and lidocaine injections. Statin medications have been associated with photo-induced lesions. Vaccines such as hepatitis B, smallpox, varicella, meningococcal, human papillomavirus, and hantavirus, and allergic response to contact allergens have also been known to elicit the disorder.
- EM is self-limiting, with management based on the following strategies:
- Supportive care to maintain hydration and prevent erosions from developing secondary bacterial infection
- Treatment of suspected precipitating infections
- Suppression therapy with antivirals if recurrent disease is caused by herpes simplex virus (HSV)
- Topical or systemic corticosteroids to reduce inflammation.
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- Biochemistry
- Blood Gases
- Haematology
| Biochemistry | Normal Value |
|---|---|
| Sodium | 135 – 145 mmol/l |
| Potassium | 3.0 – 4.5 mmol/l |
| Urea | 2.5 – 7.5 mmol/l |
| Glucose | 3.5 – 5.0 mmol/l |
| Creatinine | 35 – 135 μmol/l |
| Alanine Aminotransferase (ALT) | 5 – 35 U/l |
| Gamma-glutamyl Transferase (GGT) | < 65 U/l |
| Alkaline Phosphatase (ALP) | 30 – 135 U/l |
| Aspartate Aminotransferase (AST) | < 40 U/l |
| Total Protein | 60 – 80 g/l |
| Albumin | 35 – 50 g/l |
| Globulin | 2.4 – 3.5 g/dl |
| Amylase | < 70 U/l |
| Total Bilirubin | 3 – 17 μmol/l |
| Calcium | 2.1 – 2.5 mmol/l |
| Chloride | 95 – 105 mmol/l |
| Phosphate | 0.8 – 1.4 mmol/l |
| Haematology | Normal Value |
|---|---|
| Haemoglobin | 11.5 – 16.6 g/dl |
| White Blood Cells | 4.0 – 11.0 x 109/l |
| Platelets | 150 – 450 x 109/l |
| MCV | 80 – 96 fl |
| MCHC | 32 – 36 g/dl |
| Neutrophils | 2.0 – 7.5 x 109/l |
| Lymphocytes | 1.5 – 4.0 x 109/l |
| Monocytes | 0.3 – 1.0 x 109/l |
| Eosinophils | 0.1 – 0.5 x 109/l |
| Basophils | < 0.2 x 109/l |
| Reticulocytes | < 2% |
| Haematocrit | 0.35 – 0.49 |
| Red Cell Distribution Width | 11 – 15% |
| Blood Gases | Normal Value |
|---|---|
| pH | 7.35 – 7.45 |
| pO2 | 11 – 14 kPa |
| pCO2 | 4.5 – 6.0 kPa |
| Base Excess | -2 – +2 mmol/l |
| Bicarbonate | 24 – 30 mmol/l |
| Lactate | < 2 mmol/l |
