IRISH DERM TUTOR

Erythroderma

Aetiology

Clinical

Psoriasis

Dermatitis

Drugs

CTCL

Investigations

Complications

Management

SJS/TEN

Pathogenesis

Causes

Clinical

Differential diagnosis

History

Exam

Investigations

Prognosis (SCORTEN)

Histology

Complications

Immediate management plan

Environment

Skin management

Monitoring and managing infection

Fluid replacement

Nutrition

Analgesia

Others (PPI, VTE, G-CSF)

Opthalmology management

Oral management

Urogenital management

Airway management

Treatment

Discharge and follow up

Drug rash (general information)

Aka Exfoliative dermatitis

Diffuse erythema and scaling of the skin involving more than 90% of the body surface area

regardless of the cause

Is a clinical sign and can be due to a number of underlying potential causes

More frequent in older adults (mean age approx 40 to 60) and men (2-4:1)

Most cases of erythroderma are due to a pre-existing condition like psoriasis or atopic dermatitis which spreads to involve 90% of the skin or more

Papulosquamous disorders:

• Psoriasis (approx 20% of cases)

• Pityriasis rubra pilaris

Dermatitis:

• Atopic dermatitis

• Allergic contact dermatitis

• Seborrhoeic dermatitis

• Autosensitization dermatitis (Id reaction)Chronic actinic dermatitis

Drug reactions:

• Simple drug reactions (eg exanthemaotus and urticarial)

• SJS/TEN

• DRESS

Malignancy:

• Lymphoma (Sezary syndrome, erythrodermic mycosis fungoides)

• Solid organ (paraneoplastic) erythroderma

Infections:

• Viral exanthems

• Norwegian scabies

• Staph scalded skin syndrome

Immune conditions:

• Lupus/Dermatomyositis

• Graft versus host disease

• Bullous blistering diseases (pemphigoid, pemphigus)

External conditions:

• Burns

Idiopathic (about 30% of cases)

Paediatric population considerations:

• Infections

• Inflammatory skin diseases

• Ichthyoses

• Immunodeficiencies

At least 50% of cases of erythroderma are caused by a pre-existing rash

Erythrodermic patients can be:

Stable - with a subacute or chronic course

Unstable - with acute or even life threatening onset

Can develop acutely over hours or days or evolve gradually over weeks to month:

• Drug - usually abrupt onset (with initial morbilliform/urticarial eruption which increase in size and coalesce)

• If develop from underlying disease can be more gradual, the initial rash may have charachteristics of the underlying disease but the specific features are lost when erythroderma fully develops (ask patient if they have any photos of when rash was developing)

Skin is red and warm to touch

• A violaceous colour suggests CTCL, salmon/orange colour PRP

Often pruritic (pronounced in atopic dermatitis, sezary syndrome)

Rash may be painful

Scaling common (particularly ≥ one week since onset of erythema)

Can get lichenification in chronic erythroderma (from chronic rubbing and scracthing)

Can feel indurated and leathery on palpation

Others:

Nail changes - paronychia, nail dystrophy, onychomadesis (nail shedding)

Hair affected - teleogen effluvium, scaling scalp

Eyelids - blepharitis, epiphora (excessive tearing), ectropion (eyelid eversion)

Clues to diagnosis on exam:

Colour - salmon pink/orange (PRP), violaceous colour (CTCL)

Palmoplantar keratoderma - PRP (waxy, orangey keratoderma), less commonly Sezary syndrome

Islands of sparing - PRP

Follicular plugging and papules on elbows, dorsal fingers, knees suggestive of PRP

Blistering - Autoimmune blistering (moist crusted leisons on face and upper trunk preceding erythroderma - pemphigus foilaceous), SJS/TEN

Facial oedema - DRESS (or other drug reaction)

Scale - fine scale (atopic dermatitis, general tinea), large areas peeling (acute cause: eg drug reaction), excessive scaling in psoriasis, scaling fingerwebs with burrows (scabies)

Nail pitting - Psoriasis

Joint pain - Psoriasis

Hair abnormalities - diffuse alopecia common in erythroderma but can be very severe in Sezary syndrome

Mucus membrane invovlement - SJS/TEN, pemihigus vulgaris, GVHD

Extracutaneous features:

Patients tend to feel shivery (poor temperature regulation) with malaise and fatigue

High output cardiac failure signs (peripheral oedema, tachycardia)

Peripheral oedema present 50% of cases

Hypoalbuminaemia

Lymphadenopathy

• Can be seen in any erythroderma patient (dermatopathic lymphadenopathy)

• May make you more suspicious for CTCL if prominent (LN biopsy can be diagnostic)

Hepatosplenomegaly

Clinical course:

Erythema can become generalized acutely (hours to days) or chronically (weeks to months)

Exfoliation typically occurs 2-6 days after onset of erythema

Over weeks to months hair and nail changes may occur

Erythroderma from drug reactions usually resolves in 2-6 weeks (may be longer in DRESS)

Can take longer if secondary to cutanaeous or systemic disease

Finding the correct diagnosis can be difficult and 30% of cases remain idiopathic

Approx 20% of erythroderma cases

Often have pre existing psoriasis that flares

Triggers for flare:

• Withdrawal of immunosuppressive treatments such as oral steroids, ciclosporin or methotrexate

• Alcohol

• Smoking/stress

• Infection (eg streptococcus, or other infection causing generalised pustular psoriasis)

• Hypocalcaemia (can lead to pustular psoriasis)

• Sun burn or phototherapy burns

• Medications: Lithium, anti-malarials, ACEi, beta blackers, NSAIDs, terbinafine, paradoxical psoriasis from TNFa inhibitors

• HIV

Atopic dermatitis makes up around 9% of cases

(ACD around 6%, Seb derm 4%, CAD 3%)

Rarely a stasis dermatitis can cause a profound ID reaction leading to erythroderma

Atopic dermatitis:

Often have history of one or more features of atopic triad

Also usually have more severe itch than in other forms of erythroderma

IgE and eosinophilia can be raised

Erythroderma can occur due to withdrawal of systemic treatments (eg steroids) or on exposure to triggers such as stress, smoking, fragrances, fabrics (wool), food allergens, pet dander, dry environments

Allergic contact dermatitis:

Reports to parthenium plant in India

Seborrhoeic dermatitis:

Can be more severe in patient’s with neurologic disease (parkinson’s) or HIV

Chronic actinic dermatitis:

Classically in men over 50 and can occur due to combination of UVA, UVB and visible light

Patients have increased ratio of CD8:CD4 cells (Opposite of Sezary syncrome)

Approx 20% of cases

My initially present as morbilliform, lichenoid or urticarial and eventually progress to erythroderma

Can get different types of drug rashes leading to erythroderma:

• Standard morbilliform eruption (commonest)

• Stephen Johnson syndrome/TEN

• DRESS

Huge amount of culprits but commonest are similar to SJS culprits

Allopurinol, sulfonamides, anti seizure medications (carbamazepine, phenytoin)

HIV paitents more likely to have drugs as a cause of erythroderma (can also be due to anti-retrovirals)

8% of cases

Sezary syndrome:

Leukaemic variant of MF

Triad:

Erythroderma

Diffuse Lymphadenopathy

Malignant T cells (Sezary cells) in blood/skin/lymph nodes

• Atypical lymphocytes with cerebriform/convulted appearing nucleus

• For diagnosis need at least 1000 sezary cell per microlitre or one of following

1. Increased CD4:CD8 ratio > 10

2. Increased amounts of abnormal CD4 cells that are either CD7 negative or CD26 negative

Clinically the patients tend to be erythrodermic from the start

Often have severe itching (much like atopic dermatitis)

Other features:

• Alopecia

• Nail dystrophy

• Leonine facies

(Ddx leonine facies - PALMS - Paget’s disease of bone, amyloidosis, lepromatous leprosy, lymphoma/leishmaniasis, MF, Sarcoidosis/Scleromyxoedema]

Also prone to viral and bacterial infections due to immune dysfunction

Important not to miss Sezary syndrome diagnosis

Erythrodermic MF:

Have pre-existing patches or plaques of MF that then progress to erythroderma without meeting the criteria for Sezary syndrome

If atypical lymphocytes are seen on biopsy then immunohistochemistry and T cell receptor gene rearrangement studies should be performed

Supportive of Sezary:

• Immunophenotype of T cells lacking mature T cell antigens (CD7 or CD26 negative)

• Clonality seen in TCR studies

• Expression of PD-1 on CD4+ T cells seen more in neoplastic T cells in Sezary then in T cells seen in erythroderma associated with inflammatory skin disease

Sezary syndrome:

Triad of:

1.Erythroderma,

2.Generalized lymphadenopathy

3. Neoplastic T cells (Sezary cells) in skin, lymph nodes and peripheral blood

Criteria for diagnosis: one or more of following

1. Absolute Sezary cell count > 1000 cells/mm3

2. Deomstration of immunophenotypical abnormalities

A. An expanded CD4+ T-cell populaiton resultingin CD4/CD8 ratio of more than 10

B. Loss of any or all of T-cell antigens: CD2, CD3, CD4 and CD5

3. Demonstration of a T cell clone in the peripheral blood by molecular or cytogenetic methods

Lymphadenopathy, alopecia, onychodystrophy and palmoplantar hyperkeratosis are common findings

Lab investigtions:

Non-specific abnormalities may be seen (leucocytosis, anaemia, high ESR)

FBC - eosinophilia (drug/AD)

U&E - monitor electrolyte imbalance

LFT - deranged in DRESS

Glucose

LDH

IgE - ? AD

ANA - ? Lupus or other autoimmune conditions if high titre (20% healthy people 1:40 ANA, 10% 1:80, 5% 1:160)

ENA/CK/Myositis specific antibodies - if dermatomyositis suspected

Blood film:

Looking for Sezary cells (atypical lymphocytes with cerebriform nuclei) - counts of atypical cells >20% of examined cells suggest Sezary. <10% can be found in erythrodermas of different causes

Flow cytometry and TCR rearrangement studies (pointers to Sezary syndrome):

• Elevated CD4:CD8 ratio > 10:1 in Sezary (normal ratio is 1:1). [note: elevated CD8:CD4 seen in CAD]

• Absolute Sezary cell count > 1000/microL

• Aberrant expression of pan-T cell markers including CD2, CD3, CD7

• Deficient expression of CD26 and CD7

• Evidence of circulating T cell clone

Biopsy:

Multiple punch biopsies maybe required for diagnosis- often remain non-specific in 1/3 of patients

Histopathology:

Non-specific findings often seen in erythroderma:

• Hyperkeratosis

• Acanthosis

• Spongiosis

• Perivascular inflammatory infiltrate

More specific histopathologic changes may become more apparent later in the course of the disease:

Sezary syndrome - with time the atypical lymphocytes may becomes more numerous and pleomorphic

• If see atypical lymphocytes may perform immunophenotyping and TCR gene rearragnement studies to further investigate

Direct immunoflourescence:

Perform if suspect a possible immunobullouse disease (ie blistering present or rash has urticarial apperance of pre-bullous pemphigoid)

Microbiology studies if superinfection suspected:

• Bacterial swabs

• Viral swabs (HSV/VZV)

• Fungal scrapings

• +/- Blood cultures

If lymphadenopathy present:

Could consider referral for LN biopsy (rule out lymphoma) or consider PET CT

Imaging:

If erythroderma is suspected to be the manifestation of occult malignancy could consider:

• CXR

• CT, MRI, PET CT imaging

Haemodynamic/metabolic disturbance:

• Fluid and electrolyte imbalance

• Thermoregulatory issues (heat loss and hypothermia which can cause compensatory hypermetabolism with hyperthermia)

• High-output cardiac failure (blood shunted to skin due to peripheral vasodilation)

• Significant protein loss through exfoliation

◦ Hypoalbuminaemia, oedema, muscle wasting

Secondary infections:

• Erythrodermic skin susceptible to bacteria colonisation

• Can get sepsis from Staph aureus (particularly HIV patients)

• Also can get widespread herpes simplex virus superinfection (Kaposi varicelliform eruption)

ARDs

Acute supportive therapy and when possible early diagnosis are important to correct underlying cause and improve morbidity and mortality

Acute or symptomatic patients and who are in any way unstable may require admission for investigation and treatment

Regardless of cause management involves:

Keep patient warm: put in a warm (30-32C) and humid environment to prevent hypothermia

Monitor and replace any electrolyte imbalance

Monitor haemodynamic status and look out for signs of high output cardiac failure

Nutritional support

Intensive skin care:

• Regular emollients (eg 50:50) +/- wet dressings

• Wash with antibacterial wash (eg dermol 500)

• Topical steroids (if any suspicion of psoriasis could consider commencing with moderate steroid such as eumovate instead of more potent steroid to prevent possibility of pustular psoriasis but practice differs) +/- addition of topical antibiotic if weepy (depends clinicans practice)

• Sedating anti-histamines may help (eg hydroxyzine 25mg tds-qds)

Monitor for infection and treat appropriately

Infection from S. Aureus is common and should be treated promptly with systemic antibiotics

Monitor for herpes superfinection and treat if identified

Look for mucous membrane invovlement;

Eyes - may need opthalmology review

Oral - assess oral intake and insert NG tube if required

Genitourinary - consider urinary catheterisation (also may help with assessing haemodynamic status)

Treat underlying condition:

Psoriasis:

May require systemic therapy (MTX, Ciclosporin, Acitretin, Biologic)

PRP:

Systemic retinoids, MTX, Ciclosporin, Azathioprine, TNFa inihibitors

Atopic dermatitis:

Intensive topical treatments

May require systemic agetn: MTX, Ciclosporin, Azathioprine

Drug:

Stop culprit drug or all non essential medications if drug not known

If appropriate short course of oral steroids may be beneficial (1-2mg/kg/day)

SJS/TEN:

Supportive care

Sezary:

Extracorporeal photochemotherapy, systemic retinoids, methotrexate, interferon, brentuximab, vedotin

Idiopathic:

No specific measures

Many respond to topical treatments

May need to consider systemic steroids or steroid sparing agents but evidence in these cases is very limited and using treatment in the absence of a diagnosis remains controversial

Need to reevaluate at least every 6 months to try find underlying diagnosis (may do repeated lab invetigations, biopsies +/- imaging)

Up to date recommendation:

• Systemic corticosteroids: 0.5-1mg/kg/day (max 60mg) for 7-10 days slowly tapered over several weeks to minimise risk of rebound

• During this time other immunosuppression could be introduced (MTX, Azathioprine, MMF)

• Difficulty with this regime is it can be very difficulty to wean patients due to high chance of rebound with interruption of treatment

Otherwise could consider MTX or Ciclosporin first but may take longer to take effect

Rare but possibly fatal mucocutaneous reactions, usually due to drugs, that leads to keratinocyte death (incidence 2-7/million cases per year)

Get full thickness necrosis of the epidermis causing severe desquamation of the epidermis of the skin and mucosal surfaces.

Exist on spectrum:

• SJS < 10% BSA skin detachment

• SJS-TEN overlap syndrome 10-30%

• TEN > 30% BSA involved

In severe cases the acute phase may be accompanied by a variety of systemic complications, including multiorgan failure

Pathophysiology still not fully understood

It is a T-cell mediated, type IV hypersensitivity reaction

There are a few differing hypotheses about how the drug generates an immune response to cause SJS/TEN

Despite the uncertainty regarding the mechanism of how it begins the end results is activation of T-cells in response to a drug or infection and downstream epidermal necrosis

Get widespread epithelial keratinocyte apoptosis and necrosis

1. Cytoxic T cells and NK cells become activated after exposure to a drug

2. In patients with certain predispositions (see below) they may infiltrate the skin and target keratinocytes

3. These immune cells then release cytotoxic proteins such as granulysin (key mediator), soluble fas ligand, perforin and granzyme b which contribute to keratinocyte death

   Of these granulysin appears to be the most important and can be found in blister fliud

   Granulysin levels have been reported in some studies to correlate with disease activity

   Granulysin enters the kertatinocyte, disrupts the cell and causes apoptosis

4. During the process other mediators including IL-15, TNFa and IFNy are released which further exacerbate the inflammatory response

   IL-15 has also been reported to be correlated to disease activity in some studies

Predispositions:

Patients who are slow acetylators of certain medications

Patients with certain HLA sub-types including:

• HLA-B*15:02 seen in 7-10% of patients of Asian/South Asian ancestry are at increased risk after exposure to carbamazepine (and ther aromatic anticonvulsants)

• HLA-B*58:01 seen in Hans Chinese patients are at incrased risk after exposure to allopurinol

Patients with HIV or AIDs (x 100 times greater risk)

Patients with active cancer (particulalry haematological)

On over 1/3 of cases no cause is found

When found medications account for the vast majority of causes in adults

Infection plays a more prominent role in children so consider viruses like Mycoplasma, HSV, Coxsackie

Medications: over 100 reported but main culprits:

• Sulfa drugs (Trimethoprixm-sulfamethoxazole is commonest cause, sulfasalizine can also cause it)

• Antibiotics - others such as beta lactams

• Allopurinol

• Anti-convulsants - aromatic (eg carbamazepine, phenytoin) and lamotrigine

• Anti-inflammatories - Oxicam NSAIDs

• Anti-retrovirals - Abacavir, Nevirapine

• Anti-cancer drugs - checkpoint inhibitors (pembrolizumab, nivolumab) and others

Tricky medications:

Patracetamol, ibuprofen:

Weak association may exist

But it is often taken for management of prodromal symptoms

It is often likely confounders

A history of previous tolerated use makes their association less likely

Similarly penicillins (eg amox/ampicillin) are often given to treat prodromal symptoms so good history is key

Infections (children > adults):

• Mycoplasma pneumonia

• EBV

• HSV

Drug timing:

5-28 days is the usual length since taking first dose of causative medications

Can be in days- particularly if had drug before

It can be longer for the anti-convulsants

Prodrome of fever and flu-like symptoms

Around 1-3 days get muco-cutaneous lesions - may appear as erythema and erosions

(Nearly all patients with SJS/TEN have mucosal involvement so is key to ask about and examine)

May initially complain of discomfort in cutaneous and mucosal areas before there is any clinical evidence of rash on exam

SJS/TEN in skin usually begins on the trunk, proximal limbs or face with erythematous macules and ‘atypical target lesions’ with a dusky or purpuric centre

The scalp is typically spared

Skin is tender to touch

The lesion then spread elsewhere on the body and coalesce in hours to days

Affected areas can progress to flaccid blisters and sheets of skin that start to desquamate

Exposed dermis exudes serum, readily bleeds and can become easily secondarily infected

Skin fragility can be displayed by:

• Nikolsky’s sign: positive when tangential pressure put on unblistered skin causes skin sloughing

Mucosal surfaces:

>90% of patients will have mucosal involvement

Oral, ocular and genital sites are most frequently involved

Can get respiratory tract involvement (bronchial obstruction and ventilatory compromise) and gastrointestinal involvement (diarrhoea)

Once active blistering and epidermal detachement ceases, re-epithelialization commences

Healing can occur within a few days or may be protracted taking weeks

• SJS/TEN

• Erythema multiforme major

• Staph scalded skin syndrome

• Toxic shock syndrome

• DRESS

• Purpura fulminans

• Acute GVHD

• Pemphigus vulgaris

SJS/TEN vs Erythema multiforme major (EMM):

In EMM you also get mucous membrane involvement and can get cutaneous blistering with epidermal detachment which typically affects < 10% BSA

Other differences:

Distribution: The lesions in EMM tends to be predominantly localised on the limbs and extremities

SJS has atypical targets:

• Macular and not raised or palpable as in erythema multiforme

• Only two zones of colour seen compared to the three zones seen in erythema multiforme - central dusky/necrotic area, pale erythematous zone, outer red halo

EMM tends to be more likely related to herpes infection rather then medications

Reactive Infectious Mucocutaneous Eruption:

Relatively newly described entity which has gone through a few variations of names including Mycoplasma-induced rash and mucositis (MIRM)

Causes include: mycoplasma, flu, covid-19

Usually seen in paediatric populations

Get predominant mucous membrane involvement with little or no cutaneous lesions

Due to its infectious nature is more likely to be recurrent

Determine the index date of symptoms (ie first symptom or sign of disorder)

Any prodromal symptoms prior to the rash beginning (fever, flu-like symptoms)?

What date did the rash begin and where exactly?

Is there skin pain?

Is there mucous membrane invovlement?

• Eyes - photophobia, vision change

• Nose - nose bleeds

• Mouth - sore throat, painful swallowing

• Genital - dysuria, discomfort

Is there respiratory tract involvement

• Cough, dyspnoea, bronchial hypersecretion, haemoptysis

Is there bowel involvement

• Nausea , vomiting, diarrhoea, abdominal distension

Most crucial part of history is drug history:

• Record all medicines taken over prior 2 months

• Use multiple sources if possible

• Include prescribed medications, supplements, herbals, over the counter medications, eye drops, dose increases, brand switches

• Ask about prior drug allergies

• Risk stratify medications in to: ‘likely culprits’, ‘possible culprits’, ‘unlikely culprits’ based on the type of medications and when it was started

• Prior or ongoing medical problems:

? Any recent hospitalisations/infections - may of taken antibiotics for them

? Recent chest infection (mycoplasma)

? Recent or recurrent HSV infections

Mucous membrane: looks for mucositis, blisters or erosions of eye, nose, mouth, genital and anal mucosa

Rash: Look for atypical targets, purpuric macules, blisters and areas of epidermal detachment. A dusky, purple colour is suggestive of necrosis

Test for nikolsky’s sign by putting pressure on several erytehmatous , non-blistered areas - if there is dermal-epidermal cleavage this is a positive nikosky’s sign

Record the body surface area extent of both erythema and epidermal detachment

When calculating detachment include ‘detachable epidermis’ (ie Nikolsky positive skin)

Check for lymph nodes

To calculate body surface area:

Rule of 9s:

• 9% each arm

• 9% head

• 18% front of torso

• 18% back

• 18% each leg

Using palm:

• Palm of hand including fingers is 1% BSA only include detached and detachable areas but not area that is

FBC

U&E, calcium, magnesium, phosphate, bicarbonate

LFT (albumin)

CRP/ESR

Glucose

Coagulation studies

Mycoplasma serology

HIV

Immunoglobulins

ANA

CXR

Bacterial swabs from lesional skin

Biopsies:

1 biopsy from lesional skin adjacent to blister for H&E

1 biopsy from periblister lesional skin for DIF (rule out blistering disorder: pemphigus vulgaris)

Level of split is very important so could consider sending additional biopsy for frozen section to see the level of the split ASAP (may need to run this by pathology first)

If see very superficial split near granular layer - more likely toxin mediated eruption (eg Staph scalded skin syndrome)

If see deeper sub-epidermal blister with overlying confluent epidermal necrosis and sparse infiltrate you are more likely dealing with SJS/TEN

Early SJS/TEN:

Scattered apoptotic keratinocytes in epidermis with unimpressive perivascular lymphohistiocytic infiltrate with eosinophils

As progress:

Full thickness epidermal necrosis with subepidermal blister formation

Findings can look identical to that seen in erythema multiforme (particularly at the centre of a EM lesion) so need to differentiate lesions clinically and not histologically

Moratlity rate continues to increase up to one year after disease onset

Overall mortality rate SJS/TEN is approximately 30%

Approx 10% SJS

Approx 50% TEN

Check the SCORTEN at presentation in hospital and 48 hours later

Can use mnemoic TAMEBUG:

Tachycardia > 120bpm

Age > 40

Malignancy

Epidermal loss > 10%

Bicarbonate <20mmol/l

Urea > 10mmol/l

Glucose > 14mmol/l

Predicted mortality in adults

(although this probably overestimtes mortality due to improvement in supportive care since first published)

0-1: 3%

2: 12%

3: 35%

4: 58%

≥5: 90%

Most accurate on day 3 of hospital presentation so usually calculated at day 1 and day 3

(New prognostic score ABCD10 but SCORTEN still more accurate)

Other lab abnormalities to consider:

Neutropaenia - present in 1/3 of patientss, correlated with poor prognosis

Hypoalbuminaemia

LFT derangement: mild elevations AST/ALT common, overt hepatitis in 10%

Acute phase tends to last 8-12 days

-Persistent fever, severe mucus membrane invovlement, epidermal sloughing

Re-epithelialization may begin after several days and typically requires 2-4 weeks

Skin that remained attached during acute process may peel gradually and nails may be shed

Acute complications:

Thermoregulatory dysfuction

Large insensible fluid loss - electrolyte abnormalities, hypovolaemic shock, multi-organ dysfunction

Haemodynamic instability

Systemic sepsis - most frequent cause of death (sloughed skin puts patients at high risk of infections secondary to staphylococcus and pseudomonas which can lead to septic shock)

Anaemia, leucopaenia

Renal impairment

Liver dysfunction

Pulmonary complications - pneumonia, ARDs

Chronic complications:

• Poor healing in affected areas:

• Dyspigmentation

• Scarring - hair loss, nail changes, contractures around geniitals, eyes (ectropion)

The commonest complictions following SJS/TEN are ocular:

• Chronic dry eyes

• Symblepharon - adhesion of inner eyelid to eyeball itself

• Blindness

It is essential to discontinue any potential culprit drugs

All evidence suggests the importance of good supportive care

Skin care and mucous membrane care is key and also managing the complications of acute skin dysfunction and failure

In acute skin failure you get skin dysfunciton which may lead to fluid loss, heat loss, protein loss, sepsis, bone marrow paresis, so management involves:

• Early IV access and IV fluids if indicated (non-lesional skin ideally)

• Close monitoring of fluid balance

• Monitoring of nutrition (NG tube insertion if can’t maintain hydration/nutrition)

• +/- Insertion of a urinary catheter (assists monitoring fluid input/output and also helps keep urethra open if concern of urogenital involvement with dysuria or retention)

BSA >10% epidermal loss should be admitted without delay to burn centre or ICU with experience of treating patients with SJS/TEN (BAD guidelines)

Decision of most approrpiate care setting may be influenced by other factors such as SCORTEN and the existence of co-morbidities

• Delayed transfer to an appropriate unit has been shown to increase mortality

Nurse in side room to facilitate barrier nursing

Room should be controlled for humidity

Raise ambient temperature to 25-28C (reduces energy consumptions and metabolic stress which increases with epidermal loss)

(Franze article - 30-32C)

Pressure relieving mattress

Up to date guidelines suggest:

Decision to refer patient to intensive care or burn unit should be made on a case-by-cae basis taking into account:

Extent of skin invovlement

Presence of comorbidities

SCORTEN

Patients with limited skin invovlement, a SCORTEN of 0 or 1 and disease that is not rapidly progressing may be treated in nonspecialissed wards

Patients with more severe disease (> 30% detachment) or SCORTEN ≥ 2 should be transferred to ICU, burns unit or specialised dermtology unit if avaialble

Strict barrier nursing (reduce nosocomial infections)

Careful antishear handling of skin (when moving and positioning patients) prefrably undertaken by specialist nurses with experience in dealing with such patients)

Limit epidermal trauma where possible (avoid BP cuffs, adhesive ECG leads, wrist tags, adhesive dressings)

Do conservative approach initially:

Leave detached,lesional epidermis in situ to act as biologic dressing to underlying dermis

If bullae are prominent aspirate or express the fluid and leave blister roof on

Regularly cleanse wounds and skin by irrigating gently (warm sterile water, saline or chlorhexidine 1/5000)

Regular greasy emollient over whole epidermis and denuded areas

• Supports barrier function, decreases water loss, encourages re-epithelialization

• 50:50 emollin spray or dermamist spray (spray can minmize shearing forces)

Topical antimicrobial agent to sloughy areas only

Apply non-adherent dressings to denuded dermis

• Soft silicon: Mepitel, Atrauman, Urgotul

• With silver: Mepitel with flamazine cream (avoid if sulfa drug implicated), Atrauman Ag, Urgotul Siver, Urgotul SSD (avoid if sulfa drug implicated)

Examples for fixation of lines: mepitac (soft silicone tape), mepitel if no mepitac

Apply secondary foam or burn dressing to collect exudate (eg Exu-Dry sheets, Eclypse absorbent pads, Askina foam, Lyofoam sheets)

Consider supplemental surgical approach and transfer to burns unit in certain situations

Debride detached epidermis to remove potentially infected material and close wound using biosynthetic dressings, xenograft or allograft

Situations where may consider approach:

• Clinical deterioration

• Extension of epidermal detachment

• Subepidermal pus

• Local sepsis

• Wound conversion progression of superficial skin loss to deeper defect)

• Delayed healing

Denuded dermis and haemorrhagic crust act as substrate for microbial colonisation

First Staphyloccus aureus, then Gram-negative rods from digestive flora (especially P Aeriginosa)

Infection impairs re-epithelialization and can cause sepsis (commonest cause of death)

Prophylactic systemic antibiotics can increase skin colonisation (particularly candida albicans)

Should only give systemic antibiotics if there are clinical signs of infection

Can be difficult to detect as fever can be caused by SJS/TEN process

Monitor for other signs of infection/sepsis:

• Confusion

• Hypotension

• Decreased urine output

• Decreased oxygen saturation

• Increased skin pain indicating cutaneous infection

• Increased CRP, neutrophiilia

• Skin cultures:

  If monoculture detected on culture of swabs from multiple sites which had previously been mixed growth indicates one strain of organism becoming predominant indicating likelihoood of invasive infection

• Consider activation of HSV in eroded or vesicular area that are slow to heal (particularly oral and genital)

Other considerations:

In immobile patients with diarrhoea consider faecal management system

Monitor fluid balance carefully and catheterise if appropriate

If estimation of fluid balance is challenging in severely affected patients may need central venous monitoring and serial serum lactate measurements

Oral administration should be progressively increased if tolerated

Replacement volumes required to give can be estimated by the formula 2ml/kg body weight/%BSA epidermal detachment

(Franze article: fluid replacement should be driven by urine output with goal of 0.5-1ml/kg/hour)

Get hypermetabolic response with energy expenditure approx twice predicted resting values

Get loss of large amounts of albumin and protein from blister fluids

Nutritional regimen key to support metabolic disturbance, minimize protein loss and promote healing

Enteral nutrition prefarable to parenteral (reduces peptic ulceration and limits translocation of gut bacteria)

Give NG feed

Give 20-25kcal/kg daily during early, catabolic phase of SJS/TEN

During anabolic, recovery phase increase to 25-30 kcal/kg daily

Involve the acute pain team early

Start with paracetamol

Avoid NSAIDs (renal and gastric injury)

Moderate to severe pain uncontrolled by simple analgesia use opiate—based regimen

Additional analgesia often needed for pain associated with handling, repositioning, dressing changes, physiotherapy

Entonox may help if cutaneous involvement is small for procedures such as dressing changes

PPI:

• If enteral feeding not established my benefit from PPI (protect against stress ulceration)

VTE prophylaxis:

• Low molecular weight heparin for immobile patients

Recombinant G-CSF:

• Neutropaenia increases the risk of life-threatening sepsis so G-CSF can be used to resist infectious complications in neutropaenic patients

• It may also be helpful in TEN by enhancing re-epithelialization

Requires daily opthalmology review

Two-hourly application of lubricant (eg carmellose eye drops, nonpreserved hyaluronate)

Ocular hygiene:

• To remove inflammatory debris anc break down adhesions daily by opthalmology doctor or nurse

• Done with saline irrigation, a squint hook, forceps +/- scissors

Unconscious patients should have moisture chamber attached (to prevent risk of ulceration and infection with corneal exposure)

Anti-microbials:

Broad-spectrum topical antibiotic prophylaxis in presence of fluoroscein staining or frank ulceration when microbial keratitis excluded (In UK use quinolone such as moxifloxacin/levofloxacin qid)

If suspect corneal infection (often manifests as stromal loss):

• Initially give hourly broad spectrum topical antibiotics

• Take cultures for bacteria and fungus (candida keratitis)

• Treat to results

Topical corticosteroids (eg dexamethasone 0.1%):

May reduce ocular surface damage in SJS/TEN but can mask signs of corneal infection

Use nonpreserved eye drops

Use should be guided by ophtalmologist

Amntiotic membrane transplantation:

In patients who ocular hygiene is impossible without GA and in those with extensive loss of ocular surface epithelia unresponsive to conservative measures can consider this

Aim is to reduce inflammation, enhance re-epithelialization , reduce scarring and reduce symblepharon formation

Can be sutured on or kept attached using symblepharon rings or conformers only

Daily oral review required

White soft paraffin to lips every 2 hours

Protect ulcerated mucosal surfaces with mucoprotectant mouthwash three times daily (eg Gelclair)

Clean mouth daily with warm saline mouthwashes or oral sponge

Antiseptic oral rinse twice daily eg 0.2% corsodyl mouthwash ‘chlorhexidine digluconate’ 10ml bd)

Anti-inflammatory oral rinse or spray (with benzdyamine) every 3 hours particularly before eating

If pain still not controlled use topical anaesthetic preparation as alternative:

• Viscous lidocaine 2%: 15ml per application

• If severe: cocaine mouthwashes 2-5% tds

Oral and lip swabs regularly for bacteria and candida

For candida:

• Nystatin oral suspension 100,000 units four times daily x 1 week or Daktarin oral gel 5-10ml in mouth after food qid x 1 week

Slow healing of oral mucosa may reflect secondary infection or reactivation by HSV

Consider topical steroid:

Bethamethasone sodium phosphate 0.5mg qid in 10ml water as 3-min rinse and spit preparation

More potent preparaaton is dermovate mixed in equal amounts with orobase applied daily

Get mucosal erythema, blistering, erosions

During acute phase urinary dysfunction (dysuria/retention) is common

Secondary infection (bacteria/candida/HSV common)

Erosions may persist for weeks and heal with scarring

In long term get risk of:

• Strictures and stenosis of urethra

• Phimosis males

• Vaginal synechiae females

Requires daily urogenital review during acute illness

Alll patients should be catheterized to prevent strictures forming in urethra

One study of female TEN patients showed up to 70% had vulvo-vaginal lesions of which 30% had long term issues from the involvement

Early assessment by vulval specialist (eg Obs-gynae team) is recommended in all women to perform speculum exam and consider prophylactic dilators to prevent vaginal synechiae and topical corticostroids

Mepitel dressings can be used to eroded areas

The vulval scarring can continue up to one year after the initial event so need close follow up after admisison

Uncircumscribed males should be checked for preputial retractability

Can get early pulmonary manifestations with dyspnoea, increased resp rate with CXRs developing diffuse pulmonary infiltrates

These patients can get bronchial hypersecretion

Bronchoscopy can show diffuse loss of bronchial epithelium in the proximal airways

Mechanical ventilation is required in these patients and they have a high mortality rate

Airway sloughing can occur and cause obstruction and death

If they survive bronchial mucosa begins to recover at same time as skin recovery

May have long term complications: bronchiolotis obliterans, bronchiectasis, chronic bronchitis

Therefore respiratory symptoms and hypoxaemia on admission should prompt urgent transfer to ICU or burns centre as deterioration requiring mechanical ventilation is likely

Bronchoscopy should be undertaken to identify bronchial involvement and take bacterial samples to outrule infection

It may also help prevent atelectasis and obstruction by allowing mechanical removal of sloughed bronchial epithelium

Patiens with ongoin respiratory symmptoms should be closely monitored with pulmonary function testing and hrCT

Can get delayed pulmonary manifestations including atelectasis, bacterial pneumonia and fluid overload which tend to recover

Currently no active treatments have been to be unequivocally of benefit

Many of the studies regarding this have been relatively small, uncontrolled series

Treatments that have been considered:

• IVIG

◦ Fas-fas ligand interaction plays a role in TEN keratinocyte apoptosis

◦ Thought that high levels of immunoglobulin may inhibit this interaction

• Systemic corticosteroids

• Ciclosporin

IVIG:

A systematic review and meta-analysis (Huang et al) of relatively small numbers (n < 374) overall didn’t show a significant change in mortality compared to supportive care alone

In study, paediatric patients treated with IVIG had a significantly lower mortality compared to parents and adults treated with high-dose IVIG had lower mortality then those treated with low-dose IVIG

Felt that there may have been major methodological limitations to the original cohorts so results should be interpreted with caution

Further smaller studies demonstrated no improvement in survival with IVIG vs supportive care alone and no difference in mortallity with regards to dose of IVIG

Corticosteroids:

In favour: if given early may inhibit inflammation

Opponents: increases risk of sepsis

Only small studies have been done to date

Some small studies may suggest a slight decrease in mortality but these were very small studies

Ciclosporin:

Again studies very small

Overall, the guideline development group for the BJD guidelines did not think there was good enough quality studies to make a recommendation for or against the use of active interventions and that further research is required for this

Withdrawal of the culprit drug and meticulous attention to high-quality, multi-disciplonary supportive care remains the priority

Ideally any interventions should be practice under the supervision of a specialist skin failure MDT in the context of a clinical study or case registry

Make sure information on culprit drug is documented and relayed to patient and all relevant parties

Adverse drug reaction should be reported to MHRA in the UK

Explanatory letter should be sent to GP stating culprit drug and potential complications to look out for

Encourage patient to wear MedicAlert bracelet regarding drug allergy

Should be followed up in the appropriate clinic (eg dermatology unit with subspecialty interest) within a few weeks of discharge

Look out for:

• Fatigue, lethargy - in initial stages may be profound

• Depression

• Complications in skin, mouth, urogenital, respiratory and GI tract

Ocular damage from corneal scarring is the most disabling complication and can develop for a varibale period after the acute disease - if had eye invovlement in acute phase ensure opthalmology follow up within weeks of discharge

Skin is one of the commonest targets for an adverse drug reaction

Commenest type of drug eruptions are exanthematous and urticarial type of drug eruption

2% of all drug induced skin reactions are serious (ie hospitalization, prolongation of hospitalization, significant disability, death)

Therefore prompt identification of a Severe Cutaneous Adverse Reaction (SCAR) is key so the offending agent can be stopped

Drug reactions are often immunlogically mediated:

Type 1 hypersensitivity reaction – Urticaria, angioedema, anaphylaxis

Type 3  (immune complex) – Vasculitic, urticarial vasculitis

Type 4  (delayed type hypersensitivity) – Exanthematous, DRESS, SJS/TEN

SCARs:

Anaphylaxis

DRESS

AGEP

SJS/TEN

Others: Anticoagulant induced skin necrosis, generalised fixed drug eruption

Identifying a SCAR:

Try to identify between a ‘simple’ drug eruption versus the more severe ‘complex’ drug eruption

Shear’s diagnostic triangle:

Appearance of the rash

Systemic symptoms (fever!!!)

Histology 

Simple reaction (no fever/systemic involvement):

Exanthematous - Exanthematous drug rash

Urticarial - Urticarial drug rash

Blistering – fixed drug eruption (usually localised blisters)

Pustular – acneiform rash

Complex drug reaction (fever/systemic invovlement)

Exanthematous: DRESS 

Urticarial: Serum sickness like rash

Blistering: SJS/Ten

Pustular: AGEP