Acute and Emergency Dermatology

Question 1

Examples of acute and emergency dermatology

Answer 1

-Acute (and chronic) urticaria (including papular urticaria / insect bites / stings)
-Drug reactions including Stevens-Johnson syndrome / toxic epidermal necrolysis spectrum and the differential
diagnosis of viral exanthem
-Extensive blistering eruptions involving the skin +/- mucous membranes
-Erythroderma
-Eczema with secondary infection (including eczema herpeticum)
-Generalised pustular psoriasis
-Necrotising fasciitis
-Staphylococcal scalded skin syndrome

Question 2

What are blisters?

Answer 2

-Reflect the accumulation of extracellular fluid either within the epidermis; between the epidermis and the basement membrane; or between the dermis and the basement membrane.(Extracellular fluid deeper within the dermis is a weal, as you see in urticaria)

Question 3

What causes the fluid accumulation in blisters?

Answer 3

-Loss of adhesion between keratinocytes, or between the keratinocytes and the basement membrane, or the attachments of the dermis to the basement membrane.
-The defect in adherence may be due to defects in adhesion molecules on the cell membrane, or because the cell itself has lost it structural integrity and cannot metabolically support the molecules at the cell membrane

Question 4

Describe epidermolysis bullosa

Answer 4

-These disorders often present at birth or soon after birth, and are mostly due to inherited defects in molecules that are involved in adhesion between different components of skin (keratins and desmosomes)
-Can produce severe scarring

Question 5

Mechanism for inactivating adhesion molecules

Answer 5

1. Mutation
2. Autoantibodies (pemphigus)
3. Bacterial toxins

Question 6

What are the two types of pemphigus?

Answer 6

-Pemphigus vulgaris and pemphigus foliaceous
=Pempphigussss= superficial

=In pemphigus foliaceous, IgG antibodies act against desmoglein 1 (Dsg1)
=In pemphigus vulgaris the attack is on desmoglein 3 (Dsg3) +/- desmoglein 1 (Dsg1)

Question 7

Features of desmoglein proteins

Answer 7

1. Different desmogleins co-expressed in the same cells can compensate for the loss of the other.
2. The pattern of expression of Dsg1 and Dsg3 is different within skin.
3. The pattern of expression of Dsg1 and Dsg3 differs between skin and mucosae.

Question 8

Describe compensation between Dsg1 and Dsg3

Answer 8

-Dsg1 is present throughout skin, but is expressed most highly in the superficial layers.
-Dsg3 is expressed in skin in the basal and immediate suprabasal layers, but not in the superficial layers.

-If there are antibodies to Dsg1, as you see in pemphigus foliaceous, inactivation of Dsg1 leads to superficial blisters. This is because Dsg1 is the only one of the two desmogleins expressed in the superficial layers of skin, and so Dsg3 cannot compensate.
-If you have antibodies to Dsg3 only, then Dsg1 in skin can compensate for the lack of Dsg3: there is little or no blistering of skin.
-If however you have antibodies to Dsg1 and Dsg3 then blisters of skin result, and the result is pemphigus vulgaris: there is nothing left to do the ‘compensating’

Question 9

Dsg1 and Dsg3 compensation in the mucosae

Answer 9

-In the mucosae, there is very little Dsg1 expression and Dsg3 is expressed in all layers.
-Antibodies or inactivation of Dsg1 therefore produces no mucosal phenotype (pemphigus foliaceous).
-However, antibodies to Dsg3 will cause mucosal blisters and few or no skin blisters (mucosal dominant pemphigus vulgaris).
-However, if you have antibodies to both Dsg1 andDsg3 then you will have mucosal and extensive skin disease (mucocutaneous pemphigus vulgaris)

Question 10

Epidemiology of pemphigus

Answer 10

-Can occur at any age but it is most common in middle age.
-It is more common in some genetic ancestral groups such as certain Jewish populations

Question 11

What is Fogo selvagem?

Answer 11

-Rare variant of pemphigus foliaceous
-Arthropods may be important as a vector for an infective agent that precipitates the disease.
-‘Flaming fire’= burning pain.

Question 12

Clinical features of pemphigus

Answer 12

-Superficial blisters that break easily
-Patients may just present with erosions and crusts and be misdiagnosed as having eczema
(foliaceous more superficial than in vulgaris)
-Mucosal involvement in pemphigus vulgaris may involve the eyes, mouth, pharynx, larynx, oesophagus as well as the genitalia.
-Virtually all patient with pemphigus vulgaris develop painful erosions of the mouth.

-The Nikolsky sign is usually positive: if you rub apparently normal skin, a blister develops; or if you press on a blister, it spreads outwards.
-In pemphigus foliaceous the rash is common on the scalp, the face, chest and upper back. It is easily misdiagnosed as seborrhoeic dermatitis (because there is scaling, crusting, and erythema but no obvious blisters)

Question 13

Diagnosis of pemphigus

Answer 13

-Biopsy of the blister will show acantholysis (separation of keratinocytes from each other)
-A peri-lesional biopsy for direct immunofluorescence (IF) will confirm IgG intercellular staining within the epidermis (the exact location depends on whether it is pemphigus foliaceous or vulgaris).
-Indirect immunofluorescence against circulating antibodies are usually present and correlate to some extent with disease activity

Question 14

Management of pemphigus

Answer 14

-Large doses of systemic corticosteroids are required and immunosuppressive sparing agents such as azathioprine or mycophenolate are frequently used
-Drug treatment may be tapered off as circulating antibodies decline
-Patients who do not respond to the above may be treated with intravenous immunoglobulin, anti CD-20 antibodies (anti B cells) or cyclophosphamide
-Can be paraneoplastic syndrome

Question 15

What is pemphigoid?

Answer 15

-Antibody-mediated disease, only in this case the target antigen (or antigens) are against molecules involved in the anchoring of keratinocytes to the basement membrane (hemidesmosomes).
-As with pemphigus, the antibodies are not an epiphenomenon — they cause the disease. Pemphigoid is much more common than pemphigus

Question 16

Clinical features of pemphigoid

Answer 16

-Can occur at any age but is usually seen in those over 60.
-Its incidence may be increasing for reasons that are not understood.
-It is the most common immunobullous disorder.
-A typical clinical scenario, would be the development of itchy urticated lesions, which may precede the onset of blisters by several months.
=The early rash may be diagnosed as eczema and on occasions patients present with itch for several years before the development of any cutaneous signs.
-The blisters are larger, and more tense and robust than those found in pemphigus.
-Involvement of the mucosa is only found in ~20% patients (contrast with pemphigus vulgaris (~100%); and pemphigus foliaceous ~(0%)).

Question 17

What is pemphigoid gestationis?

Answer 17

-Type of pemphigoid seen during pregnancy (it was previously called Herpes Gestationis, but has nothing to do with the herpes virus).
-It is best viewed as the result of aberrant expression of paternal MHC on the placenta, and a maternal antibody response to placenta basement proteins, that cross react with the target hemidesmosomal proteins in skin

Question 18

Diagnosis of pemphigoid

Answer 18

Biopsies show an eosinophil rich inflammatory infiltrate and sub epidermal blisters with IgG immunofluorescence staining along the basement membrane visible on peri-lesional skin

Question 19

Treatment of pemphigoid

Answer 19

-Systemic corticosteroids/ localised pemphigoid, or even people with more diffuse pemphigoid, have been treated with very potent topical corticosteroids.
=If the rash is more widespread, then the topical corticosteroids have to be applied to all of the skin’s surface (ie all the non-blistered areas, too) — this is often impractical.
-Treatment is still usually with systemic prednisolone, with or without azathioprine, as a steroid sparing agent.
-Occasionally other immunosuppressives will need to be used.
-The course of the disease is chronic and the aim is to use the smallest dose of systemic immunosuppression compatible with clinical resolution.
=Remission will eventually occur in most patients.
-Mortality of patients with pemphigoid still remains significantly above that of matched controls (~ 20-40% at one year in some series), some of which likely reflects infections secondary to the immunosuppression.
-Other treatments for those that do not respond to standard management include intravenous immunoglobulins (IVIG), anti CD20 antibodies or cyclophosphamide

Question 20

What is dermatitis herpetiformis?

Answer 20

-Skin immunobullous disorder that is associated with GI gluten sensitivity.
-Most patients have evidence of this associated gluten sensitive enteropathy, but only a minority have clinical GI symptoms.

Question 21

Pathophysiology of DH

Answer 21

-Gliaden is a component of gluten.
=Once gliaden is absorbed, it is a substrate for a transglutaminase enzyme in the GI tract.
=Some people with particular HLA groups see this complex as foreign, and helper T cells lead to the production of IgA antibodies that interact with this gliaden/transglutaminase complex.
=A cross reaction with another type of transglutaminase that is found in skin then occurs.
=Epidermal transglutaminase, which plays a key role in the production of the cornified envelope, diffuses into the dermis, and circulating IgA antibodies bind to the transglutaminase there, resulting in immune complex deposition.
=This leads to the recruitment of neutrophils and the release of proteases.
=The result is a neutrophil abscess, with positive immunofluorescence staining for IgA within the dermal papillae.

Question 22

Clinical features of DH

Answer 22

-Patients with dermatitis herpetiformis have very intense itch, an itch that is often described as burning
-Small clusters of vesicles are present, most commonly on the wrists, extensor aspects of the elbow and knees, and the sacrum and buttocks.
-The rash may be much more extensive
-There is no mucosal involvement
-The intense itch (and hence scratch) mean that intact vesicles may not be easily found.
-term herpetiformis comes from the fact that there are often clusters of small blisters resembling the blisters seen in herpes simplex infection, but infection does not play a role

Question 23

Diagnosis of DH

Answer 23

-DH is a lifelong disease and immunopathologic confirmation of the diagnosis is essential (biopsy with immunofluorescence).
=Small polymorph abscesses in the upper dermis are visible, and direct immunofluorescence shows granular deposition of IgA in the papillary tips of the dermis.
-80% of patients with DH will have anti-endomysial antibodies (“GI transglutaminase”)

Question 24

Management of DH

Answer 24

-Gluten free diet, which reduces their requirements for medication and diminishes their increased risk of small bowel lymphoma.
-Dapsone: itching stopped within 48-72 hours the diagnosis was taken as confirmed.
=Note the occasional rare side effect of dapsone: agranulocytosis. More predictable is haemolytic anaemia. Patients need close monitoring for several months after starting the drug

Question 25

What is Erythema Multiforme?

Answer 25

-Usually a mild illness affecting the distal skin surfaces of young people, possibly with mild mucosal involvement.
-The classical clinical appearance is the ‘target’ lesion.
-Virtually all cases of erythema multiforme are an immunological response to an earlier infection (such as herpes simplex).

Question 26

What are the clinical features of EM?

Answer 26

-Target lesion: annular lesion with a red or dusky cyanotic centre, and a bright erythematous outer ring, separated by a slightly paler zone. There are therefore 3 colours to the target.
-Haemorrhage or blistering may occur in the central lesion.
-The lesion is initially macular, but then may become raised.
-The rash is most common on the extremities: acral (hand and soles), face, elbows, knees.
-Erythema multiforme is most common in young people (under the age of 40) with males suffering more commonly than females.

Question 27

What are the main causes of EM?

Answer 27

-Infections, commonly herpes simplex or mycoplasma.
-Other infections may cause it too
-Very rarely drugs might precipitate EM (emphasis on the word ‘rare’)
-In HSV caused EM you find expression of HSV DNA within the skin lesions (although you cannot cultivate the virus from the skin lesions)

Question 28

Describe a typical patient with EM

Answer 28

-18 year-old male who develops herpes simplex (often recurrent) and then a week to two weeks later, develops the characteristic target lesions of EM on his palms which then spread to other body sites and the mucosae. The initially macular lesions appear over the course of a day, and are fully developed at three days with bullae and haemorrhage in some cases. They subside over a few weeks, without any scarring of the skin

Question 29

Types of EM

Answer 29

-EM minor and EM major
-In the former, mucosal disease is mild or absent, whereas in EM major it is more severe.
-Fever and joint pains are a feature of EM major but are absent in EM minor

Question 30

Pathophysiology of EM

Answer 30

-Diagnosis is usually suspected clinically but biopsy confirmation is sometimes warranted.
-The classic features are of widespread epidermal cell death (keratinocyte death) with some dermal inflammation.
-You need to interpret the pathology with the clinical appearance, as the histology is not pathognomonic

Question 31

Management of EM

Answer 31

-If patients develop repeated episodes, it is almost certainly due to recurrent herpes simplex (even if herpes simplex is not clinically obvious)
=chronic antiviral treatment with aciclovir or a similar antiviral agent should be considered.
-In the acute phase, no treatment beyond basic skin care with antiseptics is usually necessary.
-If EM is markedly symptomatic some people use topical steroids.
-Some clinical experts in this group of disorders have used systemic steroids for severe EM although good evidence for efficacy is lacking.
-If mucosal involvement is severe, IV fluids might be needed (uncommon).
-Eye involvement with or without symptoms warrants an ophthalmology consult, because of the potential for late scarring

Question 32

What is Toxic Epidermal Necrolysis (TEN)?

Answer 32

-Catastrophic response to a drug, that picks out some people and not others on the basis of variation in drug metabolism and immunological reaction (peak risk from a drug is between 7 and 28 days after commencement, risk greater in immunosuppressed)
-It results in large sheets of epidermal / keratinocyte cell death, resembling a widespread burn, with mucosal involvement. It has a mortality of up to 50% in some contexts
-Most common in the elderly, but can occur (very rarely) in children, and is a potentially fatal skin and mucosal adverse drug reaction
-The main cause of death is infection and the hypercatabolic state

Question 33

Clinical presentation of TEN

Answer 33

-Sudden onset of diffuse erythema with sheets of skin undergoing necrosis (extreme pain)
-Wrinkling or blisters within those sheets may be seen.
-The epidermis lifts off the basement membrane due to widespread keratinocyte cell death. Rubbing normal apparent skin will cause the epidermis to come away — TEN is Nikolsky positive.
-Pyrexia, malaise, dysuria and sore eyes, may precede the onset of the rash.
-Macular deep red/blue areas with some similarities to target lesions may be seen, but classical target lesions are not seen.
-Whereas EM is acral and peripheral, TEN is often worst on the trunk, although any area can be affected.

Question 34

Pathology of TEN

Answer 34

Full thickness epidermal death due to Fas mediated cell apoptosis

Question 35

Management of TEN

Answer 35

-Stop relevant drugs ASAP!
=All drugs except absolutely essential drugs should be stopped (drugs have a slow half life or the immunological reaction that underpins this disorder may be to drug metabolites that may have a prolonged half-life)
=allopurinol, carbamazepine, sulphonamides are high risk/ AAA (antibiotics such as beta lactams, anti-epileptics, allopurinol)

-General:
= HDU / ITU
=monitor fluid balance, ensure adequate analgesia and to advise.
=A controlled pressure thermoregulated bed and aluminium survival sheet
=Skilled dermatological nursing
=Ophthalmological input is required to assess ocular involvement

-Specific
=IV immunoglobulin (IVIG)
=anti-TNF drugs (infliximab or thalidomide), as has ciclosporin in the past

Question 36

Prognosis in TEN

Answer 36

Clinical scoring system called the SCORTEN, which provides some prognostic information, and is based on age, extent of rash, heart rate, glucose, bicarbonate level etc. TEN has an overall mortality of ~40%, with a SCORTEN score of over 5 predicting death in 90% of cases

Question 37

What is Stevens-Johnson Syndrome (SJS)?

Answer 37

-Milder variant of TEN with a body area involvement of <10%, but with mucosal involvement.
-The pathophysiology and cause of SJS is similar to that of TEN, but morbidity and mortality is lower, with a mortality rate for SJS of <5%

Question 38

What is Staphylococcal Scalded Skin Syndrome (SSSS)?

Answer 38

-Result of a circulating toxin produced by particular subtypes of staphylococci.
-The toxin is a serum protease that cleaves desmoglein 1 (Dsg1) (a key component of the desmosome high up in the epidermis and this target antigen is the same as in pemphigus foliaceous).
- In SSSS the toxin is circulating, whereas in bullous (staphylococcal) impetigo the toxin is localised to (a) particular area(s) of the skin

Question 39

Clinical features of SSSS

Answer 39

-Dsg1 is not a component of the mucosal desmosomes so mucosae are not affected (contrast with pemphigus vulgaris, and TEN)
-Children under 5/ immunosuppressed or have renal failure (the toxin is cleared by the kidney)
-The site of the staph infection is not usually the skin, and skin swabs will usually be negative (contrast with impetigo)
-In children, common sites of infection are the nasopharynx or the conjunctivae
-Onset is with a scarlet fever like rash, often around the mouth and nappy area, with perioral crusting and furrowing.
-The erythema first appears on the face, with or without oedema, and then generalises particularly to intertriginous sites
-The child is pyrexial but often looks reasonably well (at least initially)
-There is intense pain, with separation of the skin in sheets on a red base
-Over 48 hours widespread flaccid blisters develop. The Nikolsky sign may be positive. The child looks as though it has been scalded (hence the clinical epithet, ‘scalded skin’).

Question 40

Diagnosis of SSSS

Answer 40

-Clinical suspicion. The child may not be very ill (initially).
-A superficial biopsy will support the diagnosis, and differentiate SSSS from TEN
-Culture swabs from the throat, and eyes. =negative

Question 41

Management of SSSS

Answer 41

-IV anti-staphylococcal drugs (flucloxacillin, vancomycin, or as advised by microbiology).
-Supportive care is important as is barrier nursing.
-Mortality with treatment is very low.
-SSSS rarely occurs in adults, but can occur in the chronically immunosuppressed adults and in sick patients on ITU

Question 42

Describe the urticarial response to drugs

Answer 42

-Urticarial rash with or without angioedema (IgE mediated reaction causing degranulation of mast cells)
=allergies to penicillins
=Anaphylaxis is rare but possible - especially after iv injections

Question 43

Overview of maculopapular exanthema (drug reaction)

Answer 43

-Classic and most common cutaneous reaction to a drug.
-Exanthematous reaction that mimics the rash seen in a variety of infections such as measles, rubella, roseola, erythema infectiosum, glandular fever etc.)
-Erythematous, in places macular and in others papular, usually with minimal scale, and is sometimes itchy.
-The rash typically starts somewhere between 4 days and 21 days after taking the medication, but sooner if the medication has been taken previously. T
-he rash seen with penicillin and glandular fever normally occurs quicker (within days).
-The frequent clinical problem is distinguishing between drugs as the cause of the rash, and a rash directly caused by an infectious agent (e.g. virus).

-no severe systemic involvement (as in, not DRESS)
- no blisters
- no mucosal involvement
- no target lesions of erythema multiforme
- no necrolysis / widespread epidermal necrosis (TEN)
-If there is a candidate drug, and it is safe to do so, stop the drug. If the drug cannot be safely stopped (usually based on discussion with other medical staff), wait and see, as the cutaneous disease alone will not kill the patient. (This assumes all the ‘negatives’ listed above apply).

Question 44

Overview of DRESS

Answer 44

-Drug Reaction with Eosinophilia and Systemic Symptoms.
-Widespread rash (possibly erythrodermic), that may be eczematous with or without facial oedema.
-There may be purpura especially on the lower legs.
-The rash normally occurs over 2 weeks after the drug was started, and therefore the rash may appear after the drug has been stopped.
-Other clinical features include:- lymphadenopathy- pyrexia- hepatitis- nephritis.

-Well known precipitants include carbamazepine, phenytoin, dapsone and allopurinol.
-Much of there action seems to be an immunological response to reactivation of latent viral infections, such as herpesvirus 6 and cytomegalovirus virus infection.
-The reaction may persist for several weeks or more, and there is an overall mortality rate of 10%, usually from hepatitis.

-Supportive care is important, as is stopping any causative drugs as early as possible.
-Systemic steroids are frequently used

Question 45

Describe a fixed drug reaction

Answer 45

-Red, round, plaques with erythema and even blistering, that resolve leaving marked hyperpigmentation.
-Frequently the original inflammation has not been noticed, it’s only the resulting pigmentation that causes the patient to consult.
-They are associated with a variety of drugs, including NSAIDs and penicillins and occur on a particular single body site, or multiple body sites, and reoccur at the same site if the drug is used on a further occasion (hence, the ‘fixed’ epithet).
-They are most common on the genitalia, lips, or acral skin.
-Each time the drug is taken, the physical signs return — in the same site (although further new sites may develop)

Question 46

What is Acute generalised exanthematous pustulosis (AGEP)?

Answer 46

-Characterised by fever, and a widespread pustular rash that resembles pustular psoriasis.
-Systemic steroids are said to help.
-Biopsy, skin folds

Question 47

What is erythroderma?

Answer 47

-Widespread erythema, or papulo squamous rash.
-Particular diagnostic break off points such as 90% involvement are rather unrealistic, as by and large, people are not very good at estimating body surface area accurately.
-Essentially we mean most / virtually all of the skin

Question 48

Common causes of erythroderma

Answer 48

1. Psoriasis
2. Atopic dermatitis or other forms of eczema
3. Drug reactions
4. Cutaneous T-cell lymphoma

Question 49

Management of erythroderma

Answer 49

-Patients require supportive care, as their skin will feel uncomfortable and itchy.
-They can become seriously ill, particularly if there are co-morbidities.

-The main issues to consider:
=Fluid loss from the skin is greatly increased, and thermoregulation is markedly impaired. Sweat gland duct occlusion (blockage) may occur, leading to an inability to lose heat from sweating, leading to hyperthermia. Conversely, the large volume of blood circulating through the skin may result in hypothermia. These patients are therefore at risk of both hypothermia and hyperthermia. The former is more likely.
=The hypothermia is said to be concealed because the patients look as though they are hot (high skin blood flow, with warm peripheries), but in reality the core temperature is reduced. =Thermoregulatory abnormalities may precipitate rigours, shivers and significant malaise.

-Admission and skilled nursing support.
-Emollients, topical corticosteroids, systemic corticosteroids, ciclosporin, retinoids or watchful waiting.
-Such patients feel sick, and their skin is ‘uncomfortable’

Question 50

Presentation and management of generalised pustular psoriasis

Answer 50

-Characterised by recurrent flares of widespread sterile pustules with erythematous, painful skin.
-GPP can be associated with systemic inflammation including fevers and/or hepatic, gastrointestinal, musculoskeletal, renal, or pulmonary involvement.

Management:
=Emollients, IV fluids and electrolytes, analgesia
=Topical: calcipotriol/ tacrolimus/ steroids
=Ciclosporin/ methotrexate/ retinoids/ mycophenolate
=Biologics