Angioedema and Anaphylaxis

Angioedema - mucocutaneous swelling

Angioedema is the oedema of the deep layers of dermis and subcutaneous tissue. In comparison, urticaria involves the superficial dermis only. Angioedema is relatively common with 20% of the population ever experienced urticaria +/- angioedema during their lifetime.

2. Angioedema can occur with or without urticaria. It is classified into hereditary and acquired.

Hereditary angioedema is AD caused by C1 esterase inhibitor (C1-INH) defect (deficiency or mutation). The defect results in excessive protease accumulation which subsequently cleaves kininogen into bradykinin.

3. Acquired angioedema can be caused by a variety of aetiologies:
infection - HSV, Hep B, Coxsackie, Strep., parasites
Insect bites and stings
Physical, environmental and mental stress
CTS - SLE, HSP
Drugs - ACE inhibitors*, ARB (less), sulphur-containing drugs, aspirin, NSAID, phenytoin, rTPA
Food (antigen) - milk, egg, peanut, shellfish...

4. Mast cell activation and degranulation via type 1 hypersensitivity reaction or complement-mediated process results in the release of inflammatory mediators which leads to vascular leakage and oedema in deep layers of dermis and subcutaneous tissue.

5. Angioedema may be present as acute (<6w) or chronic (>6w).

The presentation of angioedema is non-pruritic, burning and not well dermacated. It can involve the eyelids, lips, tongue, extremities.

(To distinguish from urticaria - urticaria is pruritic, palpable, well dermacated and erythematous. It is smaller in size but multiple in number and usually fades 12-24 hours and frequently reappears at other sites.)

Further involvement may cause complications. Involvement of the upper airway (larynx) can cause respiratory distress while involvement of GIT system may lead to abdominal pain cyclic in nature and NVD.

It is often very DIFFICULT to determine the cause of angioedema. Patients should be asked regarding the aetiology exposure, drugs exposure, allergic history, as well as a family history of similar episodes (hereditary)

6. Diagnosis of angioedema is via detailed history and physical examination.

Laboratory testing is of limited value in diagnosis - it only helps in workup and evaluation. FBC, ESR and urinalysis may be ordered as initial evaluation of severity. C4 levels and C1-INH levels may be obtained if available in the hospital and would be reduced in hereditary form.

Stool ova and cyst, serology testing, skin prick tests may be done to determine the aetiology. Skin biopsy is reseved for chronic angioedema refractory to corticosteroid treatment.

7. The principle of management of angioedema is to eliminate the offending agent, avoid trigger factors and cold compression of affected areas. Since angioedema could present as emergency case of airway collapse, prompt actions must be taken.

8. Securing the ABC is of the upmost priority to ensure the airway remains patent.
High flow O2 is administered
IM/SC adrenaline 0.3-0.5 mg (1:1000 parts, care for risk of cardiac arrest).
IV fluid to be given if patient is hypotensive.
Antihistamine agents - H1 2nd gen (loratadine, cetrizine), H1 1st gen (diphenhydramine), H2 (cimetidine +/- ranitidine) given IV
Corticosteroids methylprednisolone given IV.

9. Hereditary angioedema may not respond to antihistamine agents. If cost is not an issue and C1-INH replacement therapy is available, it has been proven to be efficacious in treating acute attacks of hereditary angioedema.

10. Chronic angioedema is treated as per algorithm -
H1 second gen +/- H1 first gen +/- H2 +/- leukotrine receptor antagonist.
Prednisone is given at 1mg/kg/day for x5/7 then tapered down over few weeks.

11. Antihistamines usually provide symptomatic relief in 80% of patients with non-hereditary angioedema. Chronic angioedema may recur despite steroid treatment and can last for months and years.

12. The differential diagnosis include:
Urticaria
Anaphylaxis
Other skin disorders - cellulitis, dermatitis
Vasculitis

Steven-Johnson Syndrome and Toxic Epidermal Necrolysis

Steven-Johnson Syndrome (SJS) - the rare dermatological emergency with a prevalence of 1:100,000.

SJS is a vesiculobullous form of erythema multiforme affecting the skin, mouth, eyes and genitalia. Area of affected <10% - SJS; 10-30% - overlap syndrome; >30% Toxic Epidermal Necrolysis (TEN).

2. The aetiology is mainly drug reactions in supseptible HLA groups. The drugs mediate expression of various cytokines which trigger keratinocyte apoptosis and thus exfoliation of epidermis.

3. Some of the common medications known for causing SJS/TEN include:

anti-gout: allopurinol

antibiotics: cotrimoxazole, aminopenicillins, cephalosporins, quinolones, TMP-SFX

antiretrovirals

sulphur-containing drugs

phenytoin

phenobarbital

4. Patient presents with enlarging red-purple macules/papules/bullae at the conjunctiva, mucous membrane, nares and genital regions. The skin lesion enlarges within 2 days. There are flat, atypical target lesions or purpuric macules distributed on the trunk or widespread. The extent of involvement determines the classification of disease. Nikolsky sign (applying pressure on skin) may be positive with shearing off of epidermis.

5. Patient's history include cutaneous eruption that occurs within 8 weeks of drug initiation. Prior to the skin lesion, patient may complain of influenza-like symptoms (fever, cough, fatigue).

6. Delayed management may result in complications such as:

blindness due to corneal ulceration

haemorrhagic crusting at sites of stomatitis

dehydration due to poor oral intake (pain)

breathing difficulties due to thick mucopurulent sputum

difficulty urinating due to urethral involvement

7. Diagnosis is based on clinical presentation of the lesion. Laboratory tests are mainly to assess complications. A FBC and C+S may be ordered if suspected infection. Chest x-ray may show pulmonary involvement. If the diagnosis is uncertain, a skin biopsy may be performed. Serum electrolytes, urea, glucose, bicarbonate should be monitored to determine organ function and fluid balance.

8. The main principle of treatment is to WITHDRAW the drug and provide supportive care and management of secondary conditions. Referral should be made to ICU or burn unit. IVIG can be administered in severe cases. Recent studies by Paradisi A. et al (2014) suggest a role of TNF-a inhibitors (etanercept) to be efficacious in treating SJS/TEN. Other agents such as cyclosporine, cyclophosphamide and plasmapheresis may also be effective. Corticosteroids (prednisone) use is controversial due to risk of sepsis, but studies suggest that its usage is beneficial in early stages of disease.

9. Supportive treatments to improve QoL:

antihistamines to reduce pruritus

oral rinsing to relief oral lesions

provide soft diet and plenty of liquid for hydration

antibiotics cover if secondary infections

vitamin A to protect the eye against lacrimal hyposecretion

monitor the eyes for any worsening

catheterisation if urethral involvement

prophylactic anticoagulation

non-adhesive wound dressing

10. SCORETEN scale is used to predict the mortality risk and prognosis. The oral lesion may continue for several months. Permanent scarring and corneal abnormalities may occur in 20% of the patients. Late withdrawal of causative drug has a less favourable outcome.

11. The differential diagnosis include:

SJS-TEN spectrum

toxic erythema

pemphigus/pemphigoid

haemorrhagic fevers

staphylococcal scalded-skin syndrome