Urticaria or hives is characterised by short-lived dermal swelling (weals) anywhere on the body (Fig. 17.2). These usually itch and, except in some subtypes, resolve without bruising within 24 h (often within 10–20 min). They can form bizarre serpiginous or annular-shaped lesions. The latter show central clearing, not central necrosis as seen in erythema multiforme.

Figure 17.2 Urticaria.

Angio-oedema is a deeper form of swelling affecting the dermis and subcutis, usually affecting the mucous membranes, e.g. eyes, lips, tongue, genitals, and much less commonly the larynx and gastrointestinal tract. It is generally not itchy but can be painful and disappears within 72 h. It may occur in isolation or with urticaria (45% cases).

The incidence of urticaria/angio-oedema is about 15% in a person’s lifetime and both conditions are more common in atopics.

Case history

A 22-year-old woman presents in A&E with a 6-hour history of a florid raised red rash all over the body. It is very itchy and distressing and has caused swelling around her eyes and her right hand. Previous medical history was of atopic eczema as a child and mild hay fever.

On examination she had red, raised weals all over her body and periorbital swelling.

Diagnosis.

Urticaria with angio-oedema.

Classification of urticarias

Preferred regimes if no contraindications

• Loratidine 10–20 mg daily or cetirizine 10–20 mg daily or fexofenadine 180 mg daily (all non-sedating anti-histamines).

• Sedative anti-histamines, e.g. hydroxyzine 25–50 mg at night.

Refer: to dermatology department if no response to anti-histamines.

Refer: to type 1 allergy clinic (usually different to dermatology) only if allergic urticaria is suspected from history.

Management of severe angio-oedema

See p. 409.

• Adrenaline (epinephrine): 1 : 1000 (1 mg/mL) IM. Adult dose 0.5–1.0 mL.

• IV chlorphenamine: 10–20 mg (max. 40 mg/24 h).

• IV hydrocortisone succinate: 100–300 mg.

Home (injectable adrenaline) pens

These should never be prescribed lightly and only after full investigation in an allergy clinic when relevant allergens have been proven and where a genuine anaphylactic reaction has occurred. They are most commonly used in those severely allergic to nuts. Injectable adrenaline pens are not appropriate for isolated severe cutaneous urticaria or angio-oedema.

Patients/parents need to attend an allergy clinic to be instructed in both when and how to use the pens and, indeed, how frequently if the first injection only gives temporary relief (two pens should be prescribed).

Adrenaline (epinephrine) 1 : 1000 (1 mg/mL) is available in pre-loaded injections to deliver a dose of 0.3 or 0.5 mg (adult) or 0.15 mg (paediatric) and injections should be carried out by the patient.

Progress.

This patient was given prednisolone 30 mg daily for 7 days and started on loratidine 20 mg daily. The nature of the complaint was explained to her; no specific antigen was identified. She was seen by her doctor after 4 days and was completely free of symptoms. She continued with loratidine for 1 month.

Hereditary angio-oedema (HAE)

Skin lesions may develop and laryngeal obstruction can occur. Lesions appear as deep swellings with associated enlarging oedematous borders that last up to 2–4 days. Urticaria does not occur as part of HAE. Patients generally suffer from recurrent attacks of painful angio-oedema, which can be precipitated by minor trauma, emotional upset, infections and temperature change. Involvement of the gastrointestinal tract can cause severe acute pain and simulate a surgical emergency. Recurrent abdominal pain occurs often and starts in childhood. HAE is inherited in an autosomal dominant fashion with either a functional or absolute deficiency of C1 esterase inhibitor (C1-INH). 80% of cases give a positive family history (e.g. of sudden death). Acquired forms are seen in SLE or lymphoma.

Remember

Hereditary angio-oedema (HAE)

Patients can develop laryngeal obstruction requiring urgent treatment.

Investigations

Two blood samples need to be sent for both absolute levels and functional assay of C1-INH (discuss with laboratory first). Only do this test in patients with recurrent angio-oedema who do not have urticaria. Refer all such patients to local immunologist/dermatologist depending on local expertise.

Management

Patients are unresponsive to anti-histamines, which can exacerbate the condition, systemic steroids and adrenaline (epinephrine). Refer all patients for management: acute treatment of choice in A&E is intravenous (C1-INH) concentrates. If unavailable, fresh frozen plasma can be used. Most already diagnosed cases/families will know where local supplies of C1-INH are to be found. Icatibant (a bradykinin antagonist) and ecallantide (a kallikrein inhibitor) are also of benefit in acute attacks.

In adults, chronic treatment or ‘prophylaxis’ with attenuated androgens, e.g. stanozolol or danazol, is required if episodes are frequent.

Further reading

Morgan BP. Hereditary angioedema – therapies old and new. N Engl J Med. 2010;363:581–583. (and 513–22, 523–31, 532–41)

Sun-induced rash

Case history

A 24-year-old-arrived in A&E with blisters on her face and arms. She had fallen asleep on the beach in the sun. She had applied factor 4 sunscreen and was surprised that she had developed an itchy rash. On examination she had papules and a few vesicles over the exposed areas.

Remember

• Always take a drug history in somebody who is photosensitive (e.g. doxycycline, amiodarone)

• Always keep SLE and porphyrias in mind for any photosensitivity case where diagnosis is not obvious.

What is the diagnosis?

This is polymorphic light eruption, which occurs in 10–20% of the population. The rash appears some hours after the exposure and can last for several hours or a few days following exposure. The rash may be papular or papulovesicular. This patient also had evidence of sunburn – remember, factor 4 does not protect for very long.

Differential diagnosis

Common

• Polymorphic light eruption

• Sunburn

• Sunscreen allergy leading to photocontact dermatitis (presents as eczema rather than papules/vesicles)

• Drug-induced photosensitive rash (eg doxycycline, amiodarone).

Rare

• Photosensitive eczema

• Lupus erythematosus (all forms)

• Porphyrias

• Actinic prurigo

• Solar urticaria (very rare) gives rise to a rash immediately after sun exposure.

Note: ‘prickly heat’ or ‘heat rash’(miliaria) are incorrect labels often given to polymorphic light eruption. This is an intensely itchy papular eruption in the flexures in hot humid conditions. It is due to blockage of the sweat ducts and does not require sun exposure and is also not on sun-exposed skin.

Information

UVA and UVB

• Medium wavelengths 280–310 nm (UVB): cause sunburn and long-term skin changes, e.g. ageing/cancer

• Long wavelengths 310–400 nm (UVA): do not cause sunburn (unless high doses through glass) but do cause photodermatoses. Also contribute to long-term skin damage

• Sunscreen preparations protect against UVB: the sun protection factor (SPF) number gives an indication of the amount of time that a person is protected against burning compared to unprotected skin. Most sunscreens also protect against UVA by utilising reflectants or chemical absorbers

Most sunscreens are insufficiently applied (and not reapplied after bathing) and so do not give the protection suggested by the SPF factor.

How would you treat this patient?

No treatment was necessary for this young woman because she was virtually asymptomatic. She was given a leaflet on sun exposure and told that her type of rash usually tended to improve over the summer period.

Refer: to dermatology department if condition is not controlled by use of sun block and advise to slowly increase sun exposure in spring/early summer.

If the rash becomes worse each year, consider desensitising with low-dose PUVA each spring or short bursts of oral prednisolone 30 mg daily for 1 week for an attack.

Further reading

Lehmann P. Sun exposed skin disease. Clinics in Dermatol. 2011;29:180–188.

Generalised rash or eruption

Erythroderma means red skin. By definition, it is the term used when > 90% of the skin is involved. Erythroderma is not an extensive maculopapular rash.

Case history

A 63-year-old man presents in A&E unwell, shivering and red all over. He has suffered with chronic plaque psoriasis for 40 years and has been managed on topical therapy only. He smells of alcohol and admits to being a heavy drinker.

Examination reveals erythroderma and multiple tiny pustules over the trunk. He has a pyrexia of 39.5°C and is clinically dehydrated.

Clinical

Take a comprehensive history of onset, past history, previous skin disease, family history, medication, occupation and other systemic symptoms. These include chills, flu-like symptoms and itching and burning of the skin. A full skin examination, including nails, mouth, genitals, scalp and hair, should be performed, as well as a general examination of lymph nodes and organomegaly.

Differential diagnosis

• Cutaneous T-cell lymphoma (mycosis fungoides, Sézary syndrome)

• Pemphigus foliaceus.

Are there any complications you should look out for?

Check for:

• High-output cardiac failure from increased blood flow

• Hypothermia from heat loss

• Fluid loss

• Hypoalbuminaemia

• Increased BMR, i.e. catabolic

• Capillary leak syndrome in very severe cases of psoriasis can give rise to ARDS (Note: this can be seen in severe drug rash).

Pruritus

Differentiate whether there is a visible rash that is itchy or if there is ‘normal looking’ skin (with no rash other than scratch marks) that is itchy.

Case history

A 19-year-old white man presents with a 6-week history of an itchy skin which has been ‘driving him mad’ especially at night-time and he can’t sleep. He is fed up with his doctor, who said he had scabies and has treated him four times with malathion without benefit. PMH/SH nil relevant. He had bad asthma as a child.

On examination he had multiple small red papules on trunk, around nipples, wrists, axillae and on the penis. These were accompanied by marked excoriations. No burrows were seen. A few lesions were seen on the soles of the feet.

Diagnosis.

Scabies. The diagnosis of scabies was made on clinical grounds. Burrows are not always present but the distribution of non-specific papules (occasionally vesicles) is highly suggestive. Sites commonly involved are axillae, nipples, penis, wrists, palms, soles and web spaces. The face/head is spared in adults. Scabies can be confirmed by skin scraping and microscopy. He lived with his girlfriend (who was unaffected) and had recently visited a prostitute, who may have been the source of infection.

General management of urticaria

Treat primary skin disease. Refer to dermatology.

• Eczema: moisturisers and topical corticosteroids

• Psoriasis: tar, vitamin D₃ ointments, mild to moderate topical steroids, dithranol (causes staining)

• Urticaria: non-sedating anti-histamines (see p. 553)

• Lichen planus: superpotent topical steroids/oral steroids

• Systemic diseases: see individual disease for treatment.

Investigations

• Primary skin diseases: most cases can be diagnosed on clinical grounds but scrapings for direct microscopy (scabies), punch biopsy (+ immunofluorescence), serum IgE for atopic disease are helpful

• Systemic diseases: FBC, U&Es, LFTs, iron, folate, vitamin B₁₂, TFTs, autoimmune hepatitis screen, including mitochondrial antibodies, endomysial/gliadin antibodies. Consider serum Igs/protein electrophoresis/CXR in selected cases

Progress

• Scabies: malathion was given to him and his girlfriend. He was told to be careful in applying malathion all over his body, including crevices of his body and webs of his fingers. This should be washed off after 24 hours. Sexual contacts (if known), even if asymptomatic and no rash, should be given two treatments 7 days apart.

• Repeated scabies prescription leads to irritant dermatitis. Patients should be warned that the itching can go on for 1 month after successful treatment of scabies. Therefore give some crotamiton or topical steroid rather than further scabies prescription.

This patient’s scabies, on this occasion, was treated successfully because he was meticulous in the application of malathion.

Further reading

Batchelor JM, Grindlay DJC, Williams HC. What’s new in atopic eczema? An analysis of systematic reviews published in 2008 and 2009. Clinical and Experimental Dermatology. 2010;35:823–828.

Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis. Section 6, J Am Acad Dermatol. 2011. Feb 7 Epub

Cutaneous adverse drug reactions (ADR)

The true incidence is unknown as many go unreported but the skin is the most commonly affected organ, involved in 30% of reported ADRs.

Pre-existing disease (SLE, CLL, HIV), advancing age (poly-pharmacy, reduced renal and hepatic clearance), sensitivity to other drugs (e.g. penicillins: 10% cross-reactivity with cephalosporins) can all increase susceptibility to the development of ADRs.

Case history (1)

A 24-year-old man developed a severe sore throat and a fever. He was seen by his doctor, who diagnosed a streptococcal sore throat and prescribed amoxicillin. Two days later he presented with a macropapular rash (Fig. 17.4).

Figure 17.4 Maculopapular rash following amoxicillin therapy in infectious mononucleosis.

On examination he was noted to have cervical lymphadenopathy and a small palpable spleen. Infectious mononucleosis was diagnosed with a monospot test and the amoxicillin was stopped.

Remember

Never use amoxicillin in a patient unless glandular fever has been excluded.

Case history (2)

A 54-year-old doctor presented with a 1-year history of early morning stiffness of her hands and Raynaud’s. She had self-medicated with a number of NSAIDs which had helped to ease the pain and stiffness. She was seen by a rheumatologist who found a slight deformity of her fingers but no other signs of rheumatoid arthritis. In view of the long history, she was prescribed sulphasalazine as a disease-modifying drug. A month later she developed a severe, itchy, morbilliform rash all over her body. This settled on stopping the sulphasalazine, which contains a sulphonamide and 5-ASA.

Progress.

Both cases resolved on stopping the drugs.

Remember

Always discuss the harm/benefit ratio of drugs with your patient. Also review their current drug therapy and check for interactions.

Skin reactions specific to drugs

Fixed drug eruptions are very rare. They develop within 24 h of drug ingestion and are usually localised areas showing sharply demarcated, round, red, oedematous (and sometimes bullous) plaques that become violaceous or hyperpigmented with time. Lesions recur at the same site on re-exposure to the drug.

Pigmentation caused by drugs

• Long-term amiodarone or chlorpromazine: purple/slate-grey pigmentation on sun-exposed sites

• Long-term minocycline: blue/black pigmentation of skin, nails, buccal mucosa, scars (may be irrreversible)

• Mepacrine: reversible yellow skin pigmentation

• Bleomycin: flagellate erythema then hyperpigmentation of trunk.

Rashes potentially caused by drugs

There are many different reaction patterns and only a few common ones will be considered here:

Maculopapular/exanthematic eruptions

This is the most common type of cutaneous ADR. It is thought to be a cell-mediated reaction (may also be immune complex) involving CD8 T cells (Table 17.1). There are widespread, symmetrical, itchy eruptions. Macules and papules may become confluent and develop into a sheet-like erythema, sometimes with fever and eosinophilia. When due to a drug, it usually begins on the trunk. Suspect a viral aetiology if it starts on the face and moves down and if there is associated lymphadenopathy and conjunctivitis. After withdrawal of the drug, it usually settles over 2 weeks.

Table 17.1 Pathogenesis of some cutaneous ADRs (hypersensitivity reactions)

Note: if this eruption has progressed rapidly over 24 h it may herald the onset of the following:

Erythroderma..

In which > 90% of the skin surface is erythematous and inflamed. 10% of cases are drug induced (e.g. sulphonamides, sulphonylureas, penicillins, barbiturates, allopurinol, gold, mercury, arsenicals).

Toxic epidermal necrolysis (TEN)..

The development of vesicles and/or bullae and skin tenderness raises this possibility (this might then be followed by ‘sheeting off’ of the epidermis, see below). Mucosal involvement also suggests TEN.

Anti-convulsant hypersensitivity syndrome..

This is not just a severe ADR from an anti-convulsant but a distinct syndrome that, if undiagnosed, can lead to the death of patients if they are changed over to a different anti-convulsant that cross-reacts. The rash normally starts 2–4 weeks after starting any of the aromatic anti-convulsants (carbamazepine, phenytoin, phenobarbital, primidone). The rash is a non-specific maculopapular eruption that may involve mucosal surfaces and occasionally pustulates. The distinguishing clinical features from a ‘normal’ ADR are any of the following features:

• Fever

• Hepatosplenomegaly/lymphadenopathy

• Conjunctivitis/peri-orbital oedema

• Arthralgia

• Pharyngitis

• Severe malaise.

Blood tests may show:

• Eosinophilia

• Lymphocytosis with atypical lymphocytes

• Raised hepatic transferases.

If the drug is not stopped immediately the patient may progress to multi-organ failure and need ITU care. All aromatic anti-convulsant drugs must be avoided in the future because further exposure is likely to lead to an even more severe reaction. Sodium valproate is a reasonable alternative.

Photosensitivity.

(see Table 17.2). Reactions range from erythema to blistering and characteristically spare the submental area, finger webs, under-eyebrow area and triangle of skin behind the ear lobe.

Lichenoid eruption.

(see Table 17.2). Similar to idiopathic lichen planus but often more widespread and rarely involves mucous membranes.

The spectrum of erythema mutiforme (EM), Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)

The classification of these diseases is confusing in the literature.

Erythema multiforme (EM)

10% of cases are drug related (the majority are post-infectious, e.g. HSV, mycoplasma). They are mild and self-limiting, and usually resolve within 2–4 weeks. They are characterised by target lesions of a central dusky erythema (sometimes with blistering), a pale oedematous ring and a peripheral erythematous ring. These usually occur acrally (extremities) and symmetrically on extensor surfaces. They involve palms and soles. Mucosal involvement may be present but is mild and limited to one mucosal surface, e.g. the oral cavity.

Stevens–Johnson syndrome (SJS) (also called erythema multiforme major)

This is a more severe and extensive eruption. Widespread atypical target lesions appear on the trunk, in which epidermal necrosis results in the formation of blisters and epidermal detachment involving < 10% of body surface area. At least two mucosal surfaces are involved (oral, ocular, genital). Mucosal lesions are often more prominent than skin lesions. Systemic toxicity may occur. Usually resolves within 6 weeks.

Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) overlap

When the extent of epidermal detachment is between 10% and 30% of the body surface area, in the presence of other features of SJS, this is considered an SJS/TEN overlap. The skin lesions are often necrotic blisters rather than target lesions and mucosal lesions are prominent and severe.

Established skin disease exacerbated by drugs (Table 17.2)

• Psoriasis: can be destabilised by lithium and possibly beta blockers and anti-malarials.

• Acne: can be aggravated by progesterone-containing contraceptives, lithium and corticosteroids.

• Rosacea: worse with topical steroids.

• Peri-oral dermatitis (POD): caused and exacerbated by topical steroids.

Table 17.2 Common drug associations

Maculopapular eruption	Photosensitivity	Lichenoid eruption
Antibiotics	Thiazides	Gold
(Penicillins, sulphonamides)	Sulphonamides	Beta blockers
Anticonvulsants	Amiodarone	Quinine/anti-malarials
(Carbamazepine, phenytoin)	Tetracycline	Thiazides
NSAIDs	Nalidixic acid	Allopurinol

Diagnosis of adverse drug reactions

The key elements to a diagnosis are a meticulous drug history and a high index of suspicion.

• Exclude other causes by history and examination.

• Take a careful drug history: remember to ask about over-the-counter preparations, e.g. laxatives, tonics and cough medicines, vitamins and complementary treatments.

• Start and stop dates of medication and relationship to onset of the rash.

• When the eruption begins from 7 to 21 days after the first administration of a drug or within 48 h if the drug has caused a similar reaction in the past, this is highly suggestive of an ADR.

• The timing is incompatible with an ADR if the drug was started after the onset of cutaneous or mucous membrane signs. If the onset is within 24 h of the first dose, or more than 21 days after stopping the drug, a drug aetiology is doubtful. If there are several drugs, each should be considered as a potential cause.

• Consult drug information for previous reports.

Further reading

Eshki M, Allanore L, Musette P, et al. Twelve-year analysis of severe cases of drug reaction with eosinophilia and systemic symptoms. Arch Dermatol. 2009;145:67–72.

HIV and the skin

• Up to 90% of HIV-positive patients will develop a mucocutaneous disease, sometimes related to drug therapy.

• 30–40% of people with AIDS will suffer from three different dermatoses.

• A rash may be the presenting sign of HIV infection or AIDS (remember that up to 30% receive their diagnosis of AIDS and HIV at the same time, suggesting a large pool of undiagnosed patients).

Cases:

Two patients with HIV presented to the clinic with different rashes, both of which are commoner in HIV patients. One presented with an eosinophilic folliculitis and the other with Stevens-Johnson/toxic epidermal necrolysis (see Fig. 17.6a and b).

Figure 17.6 Rashes associated with HIV. a) Eosinophilic folliculitis – a classical HIV dermatosis (courtesy of Dr Michael Ardern Jones). b) Stevens-Johnson/toxic epidermal necrolysis is more common in HIV

(courtesy of Dr David Paige).

Progress:

Both patients were referred to the HIV specialist for HAART.

What dermatoses have commonly been the presenting illness of HIV (or indeed other causes of immunosuppression)?

• Extensive molluscum contagiosum in an adult

• Kaposi’s sarcoma

• Extensive seborrhoeic dermatitis or eosinophilic folliculitis

• Pruritic papular eruption (PPE; also called itchy folliculitis) of HIV

• Extensive oro-pharyngeal candida

• Hairy leucoplakia.

Why is the skin so frequently affected?

The exact mechanisms are not known but include:

• Immune deficiency: increased infection

• Poor immune surveillance: increased skin tumours

• Post infective: reactive arthritis

• Autoantibodies: Sjögren’s syndrome, polymyositis, ITP, pemphigoid, vitiligo, alopecia areata

• Aberrant immune function TH1 to TH2 switch: eczema, pruritus, PPE

• Graft-versus-host disease (GVHD): lichen planus, erythroderma.

What type of rashes are seen?

Many different rashes are seen, which can be arbitrarily divided:

• Cutaneous infection

• Opportunistic infection

• Malignancy (BCC, SCC, KS, malignant melanoma)

• Papulo-squamous/inflammatory

• Oral lesions.

HAART has reduced the incidence of all skin lesions.

How would you diagnose the rashes?

The diagnosis can be difficult as frequently the rash is very extensive or there is an atypical clinical presentation. One should always have a low index for doing:

• Skin biopsies: both for all the routine stains and for culture of bacteria, fungi, viruses and AFBs.

• Skin swabs.

• Serology screens.

• Investigation of other ‘organs’ such as blood, stools, sputum, bone marrow: furthermore, treatment is often problematic as HIV rashes (even those that are common in immunocompetent people) tend to be resistant to standard therapies and the use of immunosuppressive drugs is usually contraindicated.

Information

Cutaneous infections in HIV

• Bacterial: impetigo (Staphylococcus aureus), cellulitis/erysipelas (streptococci). Clinically, these infections tend to look much the same as in immunocompetent individuals. Deep-seated ecthyma may be seen.

• Viral:

– Herpes: may present with blisters, often extensive and ulcerative, especially perianally and orally

– Shingles/VZV: often painful, verrucous and extending over more than one dermatome and may be bilateral

• Fungal: dermatophyte and candidal infections are common in the skin and present typically. They often require systemic anti-fungal therapy for eradication (e.g. itraconazole 100 mg × 2 daily for 2–4 weeks)

What opportunistic infections occur in the immunocompromised and how would you distinguish between them?

Information

Failure to diagnose scabies (especially crusted scabies) can lead to a high proportion of medical staff becoming infected.

A variety of normally non-pathogenic organisms have been described in AIDS and other immunosuppressed patients. Clinically they are difficult to distinguish:

• Cutaneous CMV may present with blisters, ulcers or necrotic lesion.

• Fungi are common culprits and may present with nodules (often deep subcutaneous) or scaly papules (Cryptococcus is seen in the UK whereas Histoplasma is more common in the US).

• Scabies presents typically with itchy papules and burrows in the web spaces, the wrists, genitalia, palms/soles. Crusted scabies (‘Norwegian scabies’) presents atypically with a rather crusted eczematous-looking rash often centred around the web spaces and it may not be itchy.

• Non-tuberculous or ‘atypical’ mycobacteria are a particular problem in advanced AIDS and present with papules, nodules, ulcers or sporotrichosis-like lesions.

These infections can be localised to the skin but also present as a systemic infection. Malaise, fever, abdominal pain, headache or diarrhoea may be non-specifically suggestive of systemic infection. Biopsy and culture is the best way to diagnose these rashes.