Cutaneous drug reactions usually develop 1–2 weeks following initiation of a medication; however, some severe adverse reactions may present later (e.g. 4–6 weeks) after treatment initiation.
• Exanthematous/Morbilliform drug eruption: ~50% of cutaneous drug reactions. Generalized and symmetrical maculopapular erythema ± scaling and pruritus (see Fig. 12.1). Absence of systemic symptoms/signs. Resolves rapidly when drug is stopped. May require symptomatic treatment.
• Urticaria: ~25% of drug reactions. Sudden onset of intensely pruritic erythematous/oedematous skin lesions that resolve within 24h. May be associated with angio-oedema where there is deeper tissue oedema that can involve mucous membranes. May also be associated with life-threatening anaphylaxis in which oropharyngeal irritation, bronchospasm, hypotension, and tachycardia can be seen ( Anaphylaxis, p. [link]). Most cases due to an IgE-mediated allergic reaction; however, certain drugs (e.g. opiates and radiocontrast media) can act directly on mast cells to liberate histamine or lead to leukotrienes (e.g. NSAIDs). Urticarial eruptions due to serum sickness may persist and have associated systemic symptoms.
• Fixed drug eruption: isolated, well-demarcated erythematous lesions, often on the extremities, face, or genitalia that can be painful/blister. Rechallenge may cause recurrent lesions at the same site. Common drugs include sulfonamides, tetracyclines, barbiturates, and NSAIDs.
• Photosensitive drug eruptions: cutaneous reaction limited to sun-exposed sites. May be due to either a phototoxic reaction (non-immune, e.g. tetracyclines, NSAIDs, and fluoroquinolones) or a photoallergic reaction (immune-mediated, e.g. thiazide diuretics and sulfonamides). Some drugs cause photosensitive porphyria cutanea tarda or photo-onycholysis.
• Erythema multiforme (EM): rapid onset of erythematous lesions with a typical ‘target’ appearance (see Fig. 12.2), often affecting the extremities or the face. Severe ‘EM major’ variant involves mucous membranes. EM more commonly has an infectious aetiology but may be triggered by certain medications.
• Acute generalized exanthematous pustulosis (AGEP): rapid onset of widespread sterile pustules, often starting in skin creases. Associated with fever and leucocytosis. More rapid onset than generalized pustular psoriasis ( Generalized pustular psoriasis, pp. [link]–[link]).
• Drug reaction with eosinophilia and systemic symptoms (DRESS): presents as an exanthematous drug eruption, but associated with fever and systemic symptoms, which commonly include facial oedema, lymphadenopathy, and drug-induced hepatitis. Common drugs include anticonvulsants, sulfonamides, and allopurinol. Associated with ~10% mortality.
• Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN): life-threatening immune-mediated epidermal necrolysis, triggered by drug hypersensitivity ( Stevens–Johnson syndrome and toxic epidermal necrolysis, pp. [link]–[link]). Disease spectrum defined by the extent of body surface area involved (SJS <10%; SJS–TEN overlap 10–30%; TEN >30%). Mucosal involvement in both. Reported due to wide range of drugs, but mostly frequently sulfonamides, anticonvulsants, and antiretrovirals.
• The ‘severe cutaneous adverse reactions’ (SCAR) refer to AGEP, DRESS, SJS, and TEN. These are often grouped together, as they are associated with systemic involvement, hospitalization, and high morbidity/mortality.
• Peripheral drug eosinophilia is seen in certain drug reactions, such as DRESS, but is uncommon across all cutaneous drug reactions.
• Parenteral drug administration is more commonly associated with anaphylaxis.
• Cutaneous drug reactions are more common in patients with HIV.
(See Box 12.1.)
• Severe angio-oedema and anaphylaxis require immediate treatment ( Anaphylaxis, p. [link]).
• Stop any responsible drugs, and prescribe an alternative if necessary. Hospitalized patients receiving numerous drugs should be assessed carefully, and all non-essential therapy discontinued.
• Most cutaneous drug reactions rapidly resolve on discontinuing the causative medication. Symptoms can be alleviated and resolution expedited with sedating/non-sedating antihistamines, a medium-potency topical steroid, and frequent applications of emollients.
• If SCAR is considered, specialist advice should be sought urgently. The patient will require assessment for systemic involvement, including general examination and blood tests (FBC, U&Es, and LFTs), and may require hospitalization. Oral steroids (prednisolone 0.5–1mg/kg/day) may be required for EM, AGEP, or DRESS but should be given only under specialist supervision. The management of SJS/TEN is considered separately ( Stevens–Johnson syndrome and toxic epidermal necrolysis, pp. [link]–[link]).
• Persistent reactions, despite withdrawal of medication(s), raise the possibility of other causes to rash or SCAR.
• Although a rechallenge (oral/topical) with a suspected drug may provide a definitive diagnosis, subsequent reactions may be more severe. If fixed drug eruption is considered, patch testing may aid the diagnosis. If IgE-mediated hypersensitivity is considered, the patient should be referred to an allergist for assessment.
• Skin biopsy may aid in the diagnosis of certain drug reactions such as fixed drug eruptions, EM, and AGEP; however, the diagnosis is often clinical.
• Urticaria presents with sudden-onset intensely pruritic, oedematous skin lesions (‘wheals’), with surrounding erythema (‘flare’), that may coalesce to form larger plaques. Usually resolves within 24h to leave normal skin. New lesions may develop repeatedly.
• Angio-oedema presents with sudden-onset tissue swelling (deep dermis/subcutis oedema) that may be itchy/painful. Can involve mucous membranes, leading to upper respiratory tract obstruction.
• In severe urticaria/angio-oedema, systemic symptoms may predominate, with the development of anaphylaxis characterized by shock and collapse ( Anaphylaxis, p. [link]). Features include bronchospasm, hypotension, and tachycardia.
• Urticaria/angio-oedema are divided between acute (<6wk history) and chronic (>6wk history) presentations.
• Environmental allergens, e.g. nuts, shellfish, pollens, dust mite.
• Drugs, e.g. antibiotics (e.g. penicillins), NSAIDs, opiates, contrast media.
• Bee/wasp stings.
• Physical causes, e.g. dermographism, cold/heat contact, delayed pressure, vibration, and sunlight exposure.
• Others, e.g. cholinergic (heat/exercise), contact, aquagenic.
• Conditions associated with urticaria, e.g. urticarial vasculitis, autoimmune disorders (e.g. SLE), and acquired/hereditary C1-esterase inhibitor deficiency (angio-oedema only).
• Acute urticaria/angio-oedema are most commonly triggered by environmental (either allergens or drugs) exposure, which should be elicited in the history, or can be idiopathic.
• Dermographism is the most common form of physical urticaria; briskly stroking the skin with a firm object induces linear wheals.
• Contact urticaria usually occurs within minutes after direct contact with various agents such as plants, aeroallergens, foods (such as cheese, eggs, fish), or latex. Contact sensitivity to latex products has a high incidence of anaphylaxis.
• Urticarial lesions that persist for >24h and leave darkened patches (bruise-like) may indicate urticarial vasculitis. Seek specialist advice, as should be confirmed with vasculitic screen and skin biopsy.
• Anaphylactic reactions require immediate treatment ( Anaphylaxis, p. [link]).
• Lay the patient flat.
• Secure the airway and give O2.
• Establish cardiac/pulse oximetry monitoring.
• Give IM adrenaline 0.5mg (0.5mL of 1:1000 adrenaline injection), and repeat every 5min according to BP, pulse, and respiratory function. IV adrenaline may be required if the patient is severely ill with poor circulation ( Anaphylaxis, p. [link]).
• Establish IV access (large-bore), and start IV fluids if hypotensive.
• Give IV hydrocortisone 100–300mg and IV chlorphenamine 10–20mg. Continue H1-antagonist (e.g. oral chlorphenamine 4mg every 4–6h) for at least 24–48h, and continue if urticaria and pruritus persist.
• If the patient deteriorates, start IV aminophylline infusion (see Box 2.6). Patients on β-blockers may not respond to adrenaline injection and may require IV salbutamol infusion.
• Acute urticaria ± angio-oedema is usually not life-threatening, unless associated with anaphylaxis or upper airway obstruction. If airway obstruction, treat as anaphylaxis and get urgent specialist advice for airway management. Otherwise:
• Give oral antihistamines such as hydroxyzine 25mg or chlorphenamine 4mg.
• A single dose of oral prednisolone (0.5–1mg/kg) may be given but should not be continued without specialist advice.
• When the patient’s condition has stabilized, discharge on regular maintenance treatment with oral non-sedating antihistamine (nsAH) (e.g. cetirizine 10mg/24h, levocetirizine 5mg/24h, desloratadine 5mg/24h, or fexofenadine 180mg/24h).
• Consider referral to a specialist for assessment (prick test) of IgE-mediated hypersensitivity or if no clear trigger for acute urticaria/angio-oedema established. Patch tests are not usually indicated in urticaria/angio-oedema.
• Patients with contact sensitivity to latex should use alternatives such as vinyl gloves. Such individuals should be warned to use only non-latex polyurethane condoms.
• Chronic idiopathic urticaria/angio-oedema can often be managed with long-term maintenance nsAH therapy. Treatment-resistant chronic urticaria should be referred for specialist advice, to evaluate for other causes and to guide management. Future treatment may include high-dose/combination nsAH, leukotriene antagonists, or systemic immunosuppressants, e.g. omalizumab (anti-IgE monoclonal antibody).
Acute onset of widespread epidermal blistering (necrolysis) with mucosal involvement, often preceded a few days by prodromal fever, malaise, and upper respiratory tract discomfort. Rash may initially mimic an exanthematous drug reaction but then rapidly progresses to purpuric macules, atypical target lesions, and confluent necrolysis.
• SJS and TEN represent the same condition within a severity spectrum, defined by the extent of body surface area involved (SJS <10%; SJS–TEN overlap 10–30%; TEN >30%).
• Necrolysis describes epidermal separation that results in loss of irregular epidermal sheets, rather like a large burn. It should be distinguished from discrete intact blisters characteristic of autoimmune bullous diseases.
• Epidermal detachment can be provoked with gentle lateral pressure (Nikolsky sign)—a useful test, although not specific, of SJS/TEN.
• Involves mucous membranes (i.e. oral, ocular, GI, and urogenital)—the extent of which must be assessed. Can also involve the respiratory tract.
• Differential diagnosis of SJS/TEN includes EM major, autoimmune blistering diseases, bullous lupus erythematosus, AGEP, and staphylococcal scalded skin syndrome (SSSS). In SSSS, there is loss of just the superficial epidermis in response to staphylococcal toxins, which is more common in children.
• Skin biopsy for histological assessment, with negative direct immunofluorescence, can support the diagnosis of SJS/TEN and aid the exclusion of other blistering skin conditions.
• Drug-induced—antibiotics (commonly sulfonamides), anticonvulsants, antiretroviral therapy (commonly nevirapine), certain NSAIDs, allopurinol, and sulfasalazine.
• SJS can be secondary to certain infections (e.g. Mycoplasma), although rare.
Adverse prognostic factors
• Age >40 years.
• Tachycardia >120bpm.
• Epidermal detachment >10% of body surface area.
• Blood urea >10mmol/L.
• Serum glucose >14mmol/L.
• Serum bicarbonate <20mmol/L.
Using these clinical parameters, mortality can be predicted using the SCORTEN prognostic index,1 ranging from 0 (1% mortality) to 7 points (99% mortality).
(See Box 12.2.)
The priorities are:
1 To identify and discontinue the causative drug.
2 To get specialist advice and multidisciplinary assessment/care.
3 Supportive care.
4 Screening for, and treatment of, sepsis.
5 To limit future complications.
Identify the cause
• Document a thorough drug history from the patient (and/or relatives), including over-the-counter and traditional/herbal medicines and previous adverse reactions to medications. Document the chronological association with the onset of symptoms (prodrome/rash).
• SJS/TEN usually develops 7–21 days after first administration of the culprit drug, or within 48h if previously sensitized to the drug.
• Identify the causative agent and discontinue. If the patient is receiving multiple drugs, stop all non-essential therapy.
Patients with SJS/TEN should be cared for by a multidisciplinary and multi-professional team led by clinicians with experience in cutaneous medicine and skin failure.
• Patients with significant epidermal loss (>10%) should be admitted to an intensive care setting (ICU or burns unit) where they should be barrier-nursed on a pressure-relieving mattress in a warm side room, with regular monitoring of core temperature.
• Skin care:
• Patients should be handled carefully, and unnecessary adhesive monitoring devices avoided.
• Greasy emollients should be applied every 4–6h to the skin, such as 50% white soft paraffin/50% liquid paraffin (‘50/50’) or aerosolized emollients, followed by a non-adherent absorbent dressing.
• Detached epidermis should not be debrided/removed. Where the dermis is exposed, non-adhesive silicone dressings should be applied.
• The skin can be cleaned daily with antiseptic products (e.g. chlorhexidine).
• Pain control:
• Pain control should be frequently assessed and managed with regular paracetamol and opiate analgesics, as required.
• Additional pain relief (e.g. short-acting opiate or Entonox®) may be required before dressing changes.
• Eye care:
• GI care:
• Oral mucosal surfaces should be cleaned every 4–6h with an antiseptic (e.g. chlorhexidine) and an anti-inflammatory (e.g. benzydamine).
• If there is extensive oral mucositis that limits food intake, nutritional intake should be supported via NG feeding.
• Nasopharyngeal involvement may result in airway obstruction and necessitate ventilation.
• Prophylactic H2-antagonist or PPI should be given to limit the risk of gastritis/ulceration.
• Urogenital care:
• Catheterization should be considered if there is dysuria or obstruction, to aid fluid management and limit stricture formation.
• Urogenital skin and mucosa should be regularly assessed.
• Fluid balance should be monitored closely, as there will be high insensible losses. If possible, fluids should be administered PO or via an NG tube. Avoid IV lines to reduce the risk of sepsis.
• Daily blood tests, including FBC, U&Es, LFTs, and glucose (hyperglycaemia can cause an osmotic diuresis, increasing fluid loss).
• Prophylactic anticoagulation with LMWH, if not contraindicated.
• SJS/TEN patients should be barrier-nursed in a side room.
• IV lines should be removed as soon as possible to reduce infection risk.
• Multiple skin sites, mucosal sites, sputum, and urine should be cultured at least every 48h.
• Prophylactic antibiotics are only indicated if the risk of sepsis is extremely high such as severe neutropenia or a heavy single-strain bacterial colonization of the skin. Prophylactic topical antibiotics (e.g. skin/eyes) are generally not recommended.
• If febrile, blood cultures should be taken daily; however, fever is a common feature of TEN and does not always indicate an infection.
• Antibiotics should be started if there is positive blood, urine, or sputum culture or indirect evidence of sepsis such as hypothermia, hypotension, fever, decreasing level of consciousness, or reduced urinary output.
Specific systemic therapy
• Systemic treatments that have been used in SJS/TEN include corticosteroids, ciclosporin, and IVIG; however, there is no clear consensus from published studies that any of these improve outcome. Further controlled trials are required to establish the role of these treatments in SJS/TEN. Therefore, these treatments should only be started following specialist advice, as local guidelines may vary.
The British Association of Dermatologists have published guidelines on the management of SJS/TEN.2
1. Bastuji-Garin S, Fouchard N, Bertocchi M, Roujeau JC, Revuz J, Wolkenstein P. SCORTEN: a severity-of-illness score for toxic epidermal necrolysis. J Invest Dermatol 2000;115:149–53.Find this resource:
2. Creamer D, Walsh SA, Dziewulski P, et al. U.K. guidelines for the management of Stevens–Johnson syndrome/toxic epidermal necrolysis in adults 2016. Br J Dermatol 2016;174:1194–227.Find this resource:
• Exfoliative dermatitis affecting >90% of the body surface area. Can be acute or chronic in presentation, with acute erythroderma more likely to present as an emergency.
• Associated scale can be fine (pityriasiform) or coarse (psoriasiform).
• Itch is common.
• Patients may be febrile or hypothermic because of loss of temperature control mechanisms.
• Chronic erythroderma may be associated with nail dystrophy, diffuse hair loss, and ectropion. Palmo-plantar hyperkeratosis and peripheral lymphadenopathy may be prominent.
Erythroderma can be the clinical presentation of a wide range of different conditions:
• Common: dermatitis (atopic, contact, or seborrhoeic), psoriasis, drug reaction, or idiopathic.
• Rare: cutaneous T-cell lymphoma, pityriasis rubra pilaris, autoimmune bullous diseases, toxic shock syndrome, or paraneoplastic rash.
• Monitor FBC, U&Es, albumin, Ca2+, and LFTs regularly.
• Blood cultures and skin swabs. Sustained pyrexia, hypotension, or clinical deterioration should prompt a search for underlying sepsis.
• Skin biopsy should be performed, as histological features of the underlying causative condition are often present.
• Indirect immunofluorescence of blood serum and/or direct immunofluorescence of the skin biopsy should be performed in case of autoimmune bullous disease.
(See Box 12.3.)
• Discontinue all unnecessary medications.
• Nurse in a warm room, with regular monitoring of the core temperature and fluid balance. Patients should be nursed on a pressure-relieving mattress.
• Encourage oral fluids, a high-calorie diet, and protein supplements. NG feeding may be required. Avoid IV cannulae, as they can be a source of infection.
• Monitor fluid balance closely: daily weights and clinical examination (as allowed by the exfoliation). Catheterize, if necessary, for fluid management.
Liaise with a specialist early, as establishing a diagnosis will guide subsequent management.
• Skin should be treated every 4–6h with greasy emollients such as 50% white soft paraffin/50% liquid paraffin (‘50/50’).
• Wash with water and emollient soap substitutes.
• Oral sedating antihistamines such as hydroxyzine (25–100mg/24h in divided doses) may be beneficial, with the dose adjusted according to severity and weight.
• Application of topical steroids may be beneficial but should be initiated only under specialist supervision.
• Depending on the underlying cause, early systemic treatment may be required. For example, in erythrodermic atopic dermatitis, oral corticosteroids may be indicated, whereas in erythrodermic psoriasis, ciclosporin or a biologic medication may be indicated. Therefore, specialist advice must be sought prior to initiating systemic treatment.
• Rapid onset of widespread erythema and superficial pustules, usually in a patient with a history of plaque psoriasis. Pustules are often at the periphery of annular patches of erythema and may become confluent.
• Can be a rebound phenomenon triggered by rapid tapering/withdrawal of systemic corticosteroids in patients with plaque psoriasis. Localized pustular psoriasis can also be triggered by topical irritants (e.g. vitamin D analogues).
• Can present rarely in people with no prior history of plaque psoriasis, and a similar presentation can occur in pregnancy.
• Widespread disease (von Zumbusch-type), associated with pyrexia and systemic symptoms such as malaise, anorexia, and arthralgia.
• Differential diagnosis includes subcorneal pustular dermatosis, AGEP, and generalized HSV infection.
• There are repeated acute episodes of generalized pustulation, associated with pyrexia and systemic symptoms. Pustules resolve in 5–7 days and produce extensive superficial crusting but then rapidly recur.
• Patients with widespread disease can develop secondary septicaemia or ARDS.
• Elderly patients have a worse prognosis.
• Monitor FBC, U&Es, and LFTs regularly. A neutrophil leucocytosis is common. Can be associated with hypocalcaemia.
• Bacterial or viral infection should be excluded by appropriate swabs and culture/PCR. Pustules should be sterile. If febrile, take blood cultures.
• Perform ABGs if the patient is hypoxic or an abnormal CXR.
(See Box 12.4.)
Liaise with specialists at an early opportunity.
• Enforce bed rest; monitor the temperature and fluid balance closely.
• Oral fluids, with a high-calorie diet and protein supplements.
• Treat the skin every 4–6h with a greasy emollient, e.g. 50% white soft paraffin/50% liquid paraffin (‘50/50’).
• Bathe daily with emollients and antiseptic washes.
• Extensive crusting and exudation can be treated with topical potassium permanganate soaks.
• Avoid topical treatments (e.g. corticosteroids, vitamin D analogues, coal tar, and dithranol), unless under specialist supervision, as may cause severe irritation and exacerbation of the rash.
Poor prognostic features
• Pemphigus (higher mortality than other bullous diseases).
• Older age.
• Extensive involvement.
• Skin biopsy at the edge of a fresh blister for histology and direct immunofluorescence studies.
• Blood serum for indirect immunofluorescence studies.
Liaise with a specialist at an early opportunity. Management differs for each autoimmune bullous disease; therefore, it is important to rapidly establish a diagnosis.
• Intact blisters should be aspirated, where possible, and not de-roofed (i.e. the epidermis should be left in place). Examine for new blisters daily.
• If there is extensive blistering, greasy emollients should be applied frequently and a chlorhexidine bath additive used for washing. Diluted potassium permanganate soaks can be applied to weeping areas.
• Avoid adhesive dressings.
• Give oral nsAH (e.g. hydroxyzine) for pruritus.
• Monitor fluid balance carefully and FBC, U&Es, and LFTs.
Specific systemic therapy
Liaise with a specialist:
• Bullous pemphigoid: localized/mild disease may respond to super-potent topical steroids alone (e.g. clobetasol) and/or oral tetracyclines (e.g. doxycycline 200mg/day). Extensive disease will require systemic immunosuppression (e.g. prednisolone 0.5–1mg/kg/day), with the dose gradually reduced according to clinical response. Caution in patients with coexisting psoriasis vulgaris, as psoriasis may flare/pustulate with subsequent corticosteroid withdrawal.
• Pemphigus vulgaris: requires systemic immunosuppression (e.g. prednisolone 1mg/kg/day).
• Steroid-sparing agents, such as azathioprine or mycophenolate mofetil, are often used for the long-term management of bullous pemphigoid or pemphigus vulgaris once initial disease control has been achieved. Refractory disease may need to be treated with second-line agents, such as cyclophosphamide or rituximab (anti-CD20 mAb).
• Oral mucosal lesions may require additional regular antiseptic and anti-inflammatory mouthwashes, with good analgesia.
• If evidence of conjunctival disease, liaise with the ophthalmologist early.
• If the condition deteriorates, consider secondary bacterial or viral infection.
• Sudden onset of widespread umbilicated vesiculo-pustular lesions, which are painful. Lesions progress to haemorrhagic crusts and leave monomorphic punched-out erosions.
• Most common in patients with pre-existing atopic eczema but can occur in other pre-existing skin conditions, e.g. ichthyosis vulgaris and mycosis fungoides.
• Due to cutaneous HSV infection and may occur following a primary episode of herpes labialis or after contact with an infected individual.
• Patients usually pyrexial and tachycardic; however, cardiorespiratory collapse unusual.
• Lesions may also have a golden crust, as secondary staphylococcal infection (‘impetiginization’) is common.
• Early specialist advice is required, as patients may require hospitalization. Can progress rapidly, so localized disease should be treated aggressively.
• Assess carefully for involvement of the ocular branch of the trigeminal nerve if facial rash (i.e. associated involvement of the nose). If concern of ocular involvement, liaise with the ophthalmologist urgently.
• Start high-dose IV aciclovir at the earliest opportunity (up to 10mg/kg 8-hourly in the immunocompromised). If IV therapy not possible, give valaciclovir 500mg PO 12-hourly for 5–7 days.
• Use simple emollients. Aerosolized preparations are less painful to apply and limit topical spread of infection.
• Chlorhexidine and potassium permanganate soaks once or twice daily reduce excessive exudation.
• Secondary bacterial infection is common, so perform bacterial swabs daily to guide treatment. If clinical concern, have a low threshold to starting systemic antibiotic therapy.
• If concern of ocular involvement, liaise with the ophthalmologist early.
• Give oral nsAH for pruritus.
• If oral involvement, regular antiseptic and anti-inflammatory mouthwashes, with good analgesia.
• Avoid topical steroids for active dermatitis for at least 3–5 days until the infection is clinically resolving.