Chapter 24 Skin disease
Skin diseases have a high prevalence throughout the world. In developing countries infectious diseases such as tuberculosis, leprosy and onchocerciasis are common, whereas in developed countries inflammatory disorders such as eczema and acne are common. Skin disorders can be inherited, e.g. Ehlers–Danlos syndrome, a part of normal development, e.g. acne vulgaris, or may present as part of a systemic disorder, e.g. systemic lupus erythematosus (SLE). Approximately 25% of the UK population will develop a skin problem and skin disease accounts for 10% of the workload of family doctors. The common reasons that people with a rash present, are itching or pain, disturbed sleep, anxiety, depression, lack of self-confidence (if rash is obviously visible); and interfering with work (such as allergic hand eczema in a chef, builder or hairdresser).
Functions of the skin
The epidermis is a stratified epithelium of ectodermal origin that arises from dividing basal keratinocytes. The downward projections of the epidermis into the dermis are called the ‘rete ridges’. The lower epidermal cells (basal layer) produce a variety of keratin filaments and desmosomal proteins (e.g. desmoglein and desmoplakin), which make up the ‘cytoskeleton’. This confers strength to the epidermis preventing it shedding. Higher up in the granular layer, complex lipids are secreted by the keratinocytes and these form into intercellular lipid bilayers, which act as a semipermeable skin barrier. The upper cells (stratum corneum) lose their nuclei and become surrounded by a tough impermeable ‘envelope’ of various proteins (loricrin, involucrin, filaggrin and keratin). Changes in lipid metabolism and protein expression in the outer layers allow normal shedding of keratinocytes.
Keratinocytes can secrete a variety of cytokines (e.g. interleukins, gamma-interferon, tumour necrosis factor alpha) in response to tissue injury or in certain skin diseases. These play a role in specific immune function, cutaneous inflammation and tissue repair. There is a further layer of protection against microbial invasion – the innate immune system of the skin. This comprises neutrophils and macrophages as well as keratinocyte-produced antimicrobial peptides (called β-defensins and cathelicidins). Expression of these peptides is both constitutive and induced by skin inflammation and they are active against infection and play a role in wound healing. A deficiency of these peptides may account for the susceptibility of people with atopic eczema to skin infection.
Langerhans’ cells are dendritic cells found in the supra-basal layer. They derive from the bone marrow and express the cytokine CCR6. They are guided to normal skin, which contains a CCR6 agonist called macrophage inflammatory protein 3α. Langerhans’ cells endocytose extracellular antigens in the skin and then migrate to local lymph nodes for T cell presentation and thus act as antigen-presenting cells.
The basement membrane zone (see Fig. 24.27) is a complex proteinaceous structure consisting of type IV, VII and XVII collagen, hemidesmosomal proteins, integrins and laminin. Collectively, they hold the skin together, keeping the epidermis firmly attached to the dermis. Inherited or autoimmune-induced deficiencies of these proteins can cause skin fragility and a variety of blistering diseases (see p. 1221).
The dermis is of mesodermal origin and contains blood and lymphatic vessels, nerves, muscle, appendages (e.g. sweat glands, sebaceous glands and hair follicles) and a variety of immune cells such as mast cells and lymphocytes. It is a matrix of collagen and elastin in a ground substance.
Hairs arise from a downgrowth of epidermal keratinocytes into the dermis. The hair shaft has an inner and outer root sheath, a cortex and sometimes a medulla. The lower portion of the hair follicle consists of an expanded bulb (which also contains melanocytes) surrounding a richly innervated and vascularized dermal papilla. The hair regrows from the bulb after shedding. There are three types of hair:
All hair follicles follow a growth cycle: anagen (growth phase), catagen (involution phase), telogen (shedding phase). At any one time, most hairs (>90%) will be in the anagen phase, which is typically 3–5 years for scalp hair.
Examination entails looking and feeling a rash (for terminology, see Table 24.1). It should include an assessment of nails, hair and mucosal surfaces even if these are recorded as unaffected. The following terms are used to describe distribution: flexural, extensor, acral (hands and feet), symmetrical, localized, widespread, facial, unilateral, linear, centripetal (trunk more than limbs), annular and reticulate (lacey network or mesh like).
Electron microscopy, viral culture and PCR
Systemic lupus erythematosus
Allergic contact eczema
Cytology (red cells)
Dermatoscopy (direct microscopy of skin)
Assessment of pigmented lesions
The skin’s normal bacterial flora prevents colonization by pathogenic organisms. A break in epidermal integrity by trauma, leg ulcers, fungal infections (e.g. athlete’s foot) or abnormal scaling of the skin (e.g. in eczema) can allow infection. Nasal carriage of bacteria can be a source of reinfection.
Impetigo is a highly infectious skin disease most common in children (Fig. 24.2). It presents as weeping, exudative areas with a typical honey-coloured crust on the surface. It is spread by direct contact. The term ‘scrum pox’ refers to impetigo spread between rugby players. Staphylococci or group A β-haemolytic streptococci are the causative agents: skin swabs should be taken.
Impetigo is usually treated with oral antibiotics for 7–10 days (flucloxacillin 500 mg four times daily for Staphylococcus; phenoxymethylpenicillin 500 mg four times daily for Streptococcus). Other close contacts should be examined and children should avoid school for 1 week after starting therapy. If impetigo appears resistant to treatment or recurrent, take nasal swabs and check other family members. Nasal mupirocin (three times daily for 1 week) is useful to eradicate nasal carriage, especially in hospital staff. Community-acquired MRSA (in chapter 4) is increasingly recognized as a cause of superficial skin infections and treatment should be governed by bacterial sensitivities.
Rarely Staphylococcus releases an exfoliating toxin which acts high up in the epidermis: toxin A causes blistering at the site of infection (bullous impetigo), toxin B spreads through the body causing more widespread blistering (staphylococcal scalded skin syndrome, SSSS). The latter is more common in childhood with very low mortality rates. In adults it is often associated with renal disease or immunosuppression, and mortality rates increase to 50%. Both these toxins cleave desmoglein 1 (a desmosomal protein) so mucosal involvement does not occur (this is analogous to pemphigus foliaceous which has the same target antigen, p. 1222).
SSSS can mimic toxic epidermal necrolysis (TEN, see p. 1231). It can be differentiated in two ways: mucosal involvement only occurs in TEN, and skin biopsy shows a more superficial split in SSSS (intraepidermal) than in TEN (subepidermal). Both bullous impetigo and SSSS are treated with anti-staphylococcal antibiotics (e.g. flucloxacillin) and supportive care.
Cellulitis presents as a hot, sometimes tender area of confluent erythema of the skin due to infection of the deep subcutaneous layer. It often affects the lower leg, causing an upward-spreading, hot erythema, and occasionally will blister, especially if oedema is prominent. It may also be seen affecting one side of the face. Patients are often unwell with a high temperature. It is usually caused by a β-haemolytic streptococcus, rarely a staphylococcus, and sometimes community-acquired MRSA (in chapter 4). In the immunosuppressed or diabetic patient Gram-negative organisms or anaerobes should be suspected.
There may be an obvious portal of entry for infection such as a recent abrasion or a venous leg ulcer. The web spaces of the toes should be examined for fungal infection. Skin swabs are usually unhelpful. Confirmation of infection is best done serologically: antistreptolysin O titre (ASOT) and antiDNAse B titre (ADB).
Erysipelas is the term used for a more superficial infection (often on the face) of the dermis and upper subcutaneous layer that clinically presents with a well-defined edge. However, erysipelas and cellulitis overlap so it is often impossible to make a meaningful distinction.
Treatment is with phenoxymethylpenicillin (or erythromycin) and flucloxacillin (all 500 mg four times daily). If disease is widespread, treatment with antibiotics should be given intravenously for 3–5 days followed by at least 2 weeks of oral therapy. It is also necessary to treat any identifiable underlying cause. If cellulitis is recurrent, low-dose antibiotic prophylaxis (e.g. phenoxymethylpenicillin 500 mg twice daily) is used as each episode will cause further lymphatic damage. Post-cellulitic oedema is common and predisposes to further episodes of cellulitis.
Ecthyma is also an infection due to Streptococcus or Staphylococcus aureus or occasionally both. It presents as chronic well-demarcated, deeply ulcerative lesions sometimes with an exudative crust. It is commoner in developing countries, being associated with poor nutrition and hygiene. It is rare in the UK but is seen more commonly in intravenous drug users and people with HIV infection.
Erythrasma is caused by Corynebacterium minutissimum. It usually presents as an orange-brown flexural rash, and is often seen in the axillae or toe web spaces (Fig. 24.3). It is frequently misdiagnosed as a fungal infection. The rash shows a dramatic coral pink fluorescence under Wood’s (ultraviolet) light.
Folliculitis is an inflammation of the hair follicle. It presents as itchy or tender papules and pustules. Staphylococcus aureus is frequently implicated. It is commoner in humid climates and when occlusive clothes are worn. A variant occurs in the beard area (called ‘sycosis barbae’), which is commoner in black Africans. This is probably caused by the ability of shaved hair to grow back into the skin, especially if the hair is naturally curly. Extensive, itchy folliculitis of the upper trunk and limbs should alert one to the possibility of underlying HIV infection. Folliculitis following use of hot tubs is due to Pseudomonas ovale.
Boils are a rather more deep-seated infection of the skin, often caused by Staphylococcus. These can cause painful red swellings. They are commoner in teenagers and often recurrent. Recurrent boils may rarely occur in diabetes mellitus or in immunosuppression. Large boils are sometimes called ‘carbuncles’. Swabs should be taken to check antibiotic sensitivity as community-acquired MRSA is an increasingly common cause.
This condition is characterized by a painful, discharging, chronic inflammation of the skin at sites rich in apocrine glands (axillae, groins, natal cleft). The cause is unknown but it is commoner in females and within some families it appears to be inherited in an autosomal dominant fashion. The initial lesion is occlusion of the hair follicle producing an inflammatory reaction that spreads to the apocrine glands. Clinically it presents after puberty with papules, nodules and abscesses which often progress to cysts and sinus formation. With time, scarring arises. The condition follows a chronic relapsing/remitting course and is worse in obese individuals.
Treatment is difficult but weight loss, ‘prophylactic’ antibiotics, oral retinoids, zinc and co-cyprindiol (2 mg cyproterone acetate + 35 µg ethinylestradiol in females only) have been tried. They should be used as for acne vulgaris (p. 1212). Severe recalcitrant cases have been treated with intravenous infliximab, a monoclonal antibody (p. 72). Surgery and skin grafting is sometimes required.
This is a superficial infection of the horny layer of the skin caused by a corynebacterium. It frequently involves the soles of the forefoot and appears as numerous small punched-out circular lesions of a rather macerated skin (e.g. as seen after prolonged immersion). There may be an associated hyperhidrosis of the feet and a prominent odour.
Indeterminate leprosy is the commonest clinical type, especially in children. This presents as small, hypopigmented or erythematous circular macules with occasional mild anaesthesia and scaling. This may resolve spontaneously or progress to one of the other types. Biopsy reveals a perineural granulomatous infiltrate and scant acid-fast bacilli.
Tuberculoid leprosy presents with a few larger, hypopigmented (see Fig. 4.28) or erythematous plaques with an active erythematous, often raised, rim. Lesions are usually markedly anaesthetic, dry and hairless, reflecting the nerve damage. Nerves may be enlarged and palpable. Biopsy shows a granulomatous infiltrate centred on nerves but no organisms.
Lepromatous leprosy presents with multiple inflammatory papules, plaques and nodules. Loss of the eyebrows (‘madarosis’) and nasal stuffiness are common. Skin thickening and severe disfigurement may follow. Anaesthesia is much less prominent. Biopsy shows numerous acid-fast bacilli.
Lupus vulgaris usually arises as a post-primary infection. It usually presents on the head or neck with red-brown nodules that look like apple jelly when pressed with a glass slide (‘diascopy’). They heal with scarring and new lesions slowly spread out to form a chronic solitary erythematous plaque. Chronic lesions are at high risk of developing squamous cell carcinoma.
Tuberculosis verrucosa cutis arises in people who are partially immune to tuberculosis but who suffer a further direct inoculation in the skin. It presents as warty lesions on a ‘cold’ erythematous base.
The tuberculides are a group of rashes caused by an immune manifestation of tuberculosis rather than direct infection. Erythema nodosum is the commonest and is discussed on page 1216. Erythema induratum (‘Bazin’s disease’) produces similar deep red nodules but these are usually found on the calves rather than the shins and they often ulcerate.
This is the commonest type of virus-induced rash and presents clinically as a widespread nonspecific erythematous maculopapular rash. It probably arises due to circulating immune complexes of antibody and viral antigen localizing to dermal blood vessels. The rash can be caused by many different viruses (e.g. echovirus, erythrovirus, human herpes virus-6, Epstein–Barr virus; see chapter 4) and so is rarely diagnostic. The rash will resolve spontaneously in 7–10 days.
Herpes simplex virus (HSV) occurs as two genomic subtypes. Most people are affected in early childhood with HSV type 1 but the infection is usually subclinical. Occasionally it can present with either clusters of painful blisters on the face or a painful gingivostomatitis. In some individuals cell-mediated immunity is poor and they get recurrent attacks of HSV, often manifest as cold sores. Immunosuppression can also cause a recrudescence of HSV. HSV can also autoinoculate into sites of trauma and present as painful blisters/pustules which may be seen for example on the fingers of healthcare workers (‘herpetic whitlow’).
HSV type 2 infections are discussed on page 97. Other rare complications of HSV infection include corneal ulceration, eczema herpeticum, chronic perianal ulceration in AIDS patients and erythema multiforme.
Oral valaciclovir (500 mg twice daily for 5 days) is used for primary HSV and painful genital HSV. Cold sores are treated with aciclovir cream but this must be used early to be effective in shortening an attack; recurrent sores are treated with oral therapy. Attacks of herpes become less frequent with time. Intravenous aciclovir must be used in immunosuppressed patients.
‘Shingles’ results from a reactivation of VZV. It may be preceded by a prodromal phase of tingling or pain, which is then followed by a painful and tender blistering eruption in a dermatomal distribution (Fig. 24.4 and Fig. 4.15, p. 98). The blisters occur in crops, may become pustular and then crust over. The rash lasts 2–4 weeks and is usually more severe in the elderly. Occasionally more than one dermatome is involved.
Herpes zoster requires adequate analgesia and antibiotics (if secondary bacterial infection is present). Valaciclovir 1 g or famciclovir 250 mg three times daily for 7 days is used, or oral aciclovir 800 mg, five times daily for 7 days helps shorten the attack if given early in the illness. Brivudine 125 mg is also available. High-dose intravenous aciclovir is used in immunosuppressed patients. It remains unclear how useful aciclovir therapy is in preventing prolonged post-herpetic neuralgia.
Common warts are papular lesions with a coarse roughened surface, often seen on the hands and feet, but also on other sites. Small black dots (bleeding points) are often seen within the lesion (Fig. 24.5). If they occur on the face they are often elongated (‘filiform’) Children and adolescents are usually affected. Spread is by direct contact and is also associated with trauma.
Plantar warts (verrucae) is the term used for lesions on the soles of the feet. They often appear flat (‘inward growing’) although they have the same papillomatous surface change and black dots are often revealed if the skin is pared down (unlike callosities). Warts may be painful or tender if they are over pressure points or around nail folds.
Plane warts are much less common and are caused by certain HPV subtypes. They are clinically different and appear as very small, flesh-coloured or pigmented, flat-topped lesions (best seen with side-on lighting) with little in the way of surface change and no black dots within them. They are usually multiple and are frequently found on the face or the backs of the hands.
Anogenital warts are usually seen in adults and are normally transmitted by sexual contact. They are rare in childhood and, whilst child sex abuse should always be considered, it should be remembered they may well have been transmitted through non-sexual contact. HPV subtypes 16 and 18 are potentially oncogenic and are associated with cervical and anal carcinomas.
Common warts on the skin are surprisingly difficult to treat effectively but they almost always resolve spontaneously after months to years (with no scarring), presumably due to cell-mediated immune recognition. When they do resolve, they tend to do so rapidly within a few days.
Regular use of a topical keratolytic agent (e.g. 2–10% salicylic acid) over many months with weekly paring of the lesion helps speed up resolution in some patients and remains the mainstay of treatment. A course of cryotherapy (freezing) can also help. Cautery, surgery, carbon dioxide laser, alpha-interferon injection and bleomycin injection have all been used with variable success but are not recommended, as treatments may be very painful and can cause permanent scarring.
Genital warts are usually treated with cryotherapy, trichloroacetic acid, 5% imiquimod cream or topical podophyllin. People with genital warts (and their sexual partners) must be screened for other sexually transmitted diseases.
Molluscum contagiosum is a common cutaneous infection of childhood caused by the pox virus. Clinically, lesions are multiple small (1–3 mm) translucent papules which often look like fluid-filled vesicles but are in fact solid. Individual lesions may have a central depression called a punctum. They exhibit the Köbner phenomenon (p. 1208). They can occur at any body site including the genitalia. Transmission is by direct contact. Occasionally lesions may be up to 1 cm in diameter (‘giant molluscum’).
They usually continue to occur in crops over 6–12 months and rarely require treatment as they spontaneously resolve. Any form of localized trauma, including scratching, helps speed up resolution, and cryotherapy is used in older children. One per cent stabilized hydrogen peroxide cream or 5% imiquimod cream is used in younger children. Molluscum in an adult, especially if giant, should raise the underlying possibility of immunosuppression, especially HIV infection.