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Acute Angioedema

Gabriele de Vos, M.D., M.Sc.

Division of Allergy and Immunology


Jacobi Medical Center
Albert Einstein College of Medicine
Differential diagnosis of acute
angioedema
IgE mediated allergic reactions to food, drugs, venoms
etc.
Histamine-releasing drugs (e.g. opioids, RCM),
pseudoallergens in food
Adverse reactions to certain medications: NSAIDs,
ACE-inhibitors
Chronic urticaria with angioedema
Idiopathic or exercise induced anaphylaxis
C1-Esterase Inhibitor deficiency (hereditary or
acquired)
Gleich syndrome: recurrent angioedema and high
eosinophil counts of unknown etiology
Angioedema in hypereosinophilic syndrome
Differential diagnosis of acute
angioedema
IgE mediated allergic reactions to food, drugs, venoms
etc.
Histamine-releasing drugs (e.g. opioids, RCM),
pseudoallergens in food
Adverse reactions to certain medications: NSAIDs,
ACE-inhibitors
Chronic urticaria with angioedema
Idiopathic or exercise induced anaphylaxis
C1-Esterase Inhibitor deficiency (hereditary or
acquired)
Gleich syndrome: recurrent angioedema and high
eosinophil counts of unknown etiology
Angioedema in hypereosinophilic syndrome
Differential diagnosis of acute
angioedema
IgE mediated allergic reactions to food, drugs,
venoms etc.
Immediate type (histamine)
Severe reactions (anaphylaxis) almost
always occur within 1-30 min
Anaphylaxis is accompanied by skin
symptoms in nearly 100%
Up to 20% late phase reaction 2-24 hours
(peak 8 hours)
How do mast cells release histamine?
Presentation of anaphylaxis
Cutaneous 90-100%
Urticaria and angioedema 85-90%
Flush 45-55%
Pruritus without rash 2-5%
Respiratory 50%
Dyspnea 50%
Throat tightness and wheezing 54%
Rhinitis 15-20%
Abdominal
Nausea, vomiting, diarrhea, cramping pain 25-30%
Other
Dizziness, syncope, hypotension 30-35%
Headache 7%
substernal pain 5%
seizure 1%
Causes of anaphylaxis
Food (e.g. peanuts, tree ~35%
nuts, shellfish)
Drugs (e.g. antibiotics, ~15-20%
NSAIDs, radio contrast
media, anaesthetics)
Insect bites and stings ~5%
Latex rare
Allergen vaccines rare
Exercise induced rare
Idiopathic ~30%
Work-up of IgE mediated allergic reactions

Skin-testing
Drugs: no standardized skin tests, except
penicillin
Food: best with fresh food
NPV thought to be generally >95%
PPV 50%1 95% (milk, egg, peanut, if wheal
>8mm)2
Refractory period up to 4 weeks after
anaphylaxis (data from venom anaphylaxis)
1
Kagan et al., Ann Allergy Asthma Immunol. 2003 Jun;90(6):640-5 2003
2
Sporik R, Hill DJ et al. Clin Exp Allergy. 2000 Nov;30(11):1540-6.
Work-up of IgE mediated allergic reactions

In vitro sIgE testing


RAST
(RadioAllergoSorbentTest)-
outdated test, but term still in use!
Newer tests: Radioactive signal
replaced by chemiluminescent
reaction (DPC Immulite 2000,
PharmaciaCap)
Limited sensitivity and specificity
Probability of reacting to egg

Sicherer et al. 2005


Treatment of severe allergic reactions
1. Epinephrine (Adrenaline) 1:1000 solution (=1mg/ml)
>12 years and adults: 0.3-0.5 mg IM anterolateral thigh; (IV must dilute: 0.1-0.3
mg (in 10ml) slowly over 10 minutes)
>6 months and <12 years: 0.01 mg/kg
2. Positioning: Keep patient lying flat with legs up unless respiratory distress
increases
3. Oxygen supplementation and beta-agonist inhalation (Albuterol)
4. IV access, intravenous fluids (normal saline) if still hypotensive after
epinephrine
Remember: 50% of the intravascular volume can be shifted to the extravascular
space within the first 10 min. of anaphylaxis
Normal Saline rapid infusion if epinephrine-resistant hypotension
5. If patient is on beta-blocker: Glucagon
Adult: 1-5 mg IV (IM,SC), followed by infusion 5-15 ug/min
6. Antihistamines
Adult: H1-antagonist (Diphenhydramine=Benadryl 25-50 mg IV) and H2-
antagonist (Famotidine=Pepcid 20mg IV)
Children (2-12y): H1-antagonist (Diphenhydramine=Benadryl1-1.25 mg/kg IV
q6h) and H2-antagonist (Famotidine=Pepcid 0.25-0.5 mg/kg IV q12h)
7. Steroids: do not help acutely but can prevent prolonged anaphylaxis
Liebermann et al. The diagnosis and management of anaphylaxis. An updated practice parameter, JACI 2005; 115
Differential diagnosis of acute
angioedema
IgE mediated allergic reactions to food, drugs, venoms
etc.
Histamine-releasing drugs (e.g. opioids, RCM),
pseudoallergens in food
Adverse reactions to certain medications: NSAIDs,
ACE-inhibitors
Chronic urticaria with angioedema
Idiopathic or exercise induced anaphylaxis
C1-Esterase Inhibitor deficiency (hereditary or
acquired)
Gleich syndrome: recurrent angioedema and high
eosinophil counts of unknown etiology
Angioedema in hypereosinophilic syndrome
Differential diagnosis of acute
Food that can enhance allergic skin reactions:

angioedema
1.Any spices and seasoning such as Sazon, Adobo, Vegeta, ginger, garlic, onion or
celery powder, any MSG containing food (e.g. Chinese food) etc.
Histamine-releasing drugs (e.g. opioids, RCM),
2.Premixed dressings for salads such as 1000 islands, blue cheese, French dressing
etc. (Only oil and a touch of vinegar or lemon juice should be used for salad dressing)
pseudoallergens in food.
3.Canned tomatoes, tomato sauce or paste, canned soups, other canned meals
4.Vinegar and vinegar-containing foods such as mayonnaise, ketchup, and mustard,
salad dressings, chili, shrimp sauce, pickles, pickled vegetables, relishes, green olives,
Immediate or delayed onset of symptoms
and sauerkraut.
5.Beer, wine and cider
Mechanism not well understood
6.Mushrooms.
7.Soy sauce.

Opiates, radio contrast media and


8.Pickled and smoked meats and fish including sausages, bacon, ham, hot dogs,
corned beef, pastrami, and pickled tongue.
9.Lobster and shellfish.
vancomycin are typical examples
10.Soured breads (e.g. pumpernickel, rye) fresh rolls, coffee cakes
11. Certain fruits such as melons, especially cantaloupe, mango, all tropical fruit
There is increasing data that certain food
(pineapple, papaya etc.), grapes, strawberries
12.All dried and candied fruits including raisins, apricots, dates, prunes, and figs.
can trigger histamine release in susceptible
13.Diet soda, sodas containing artificial coloring (in particular orange and grape,
mountain dew), ginger ale, Snapple, fruit punches of any kind, iced tea, any powdered
individuals (e.g. chronic urticaria)
drinks, health food preparations, any herbal teas (e.g. ginger or lemon or orange spice
tea), herbal medicines, vitamins or tonics unless prescribed.
14.Chocolate, nuts, peanut products, chewing gum, breath mints, candy
15. Milk and milk products; Cheeses, in particular aged cheeses, in some cases also
cottage cheese, sour cream, and buttermilk
Differential diagnosis of acute
angioedema
IgE mediated allergic reactions to food, drugs, venoms
etc.
Histamine-releasing drugs (e.g. opioids, RCM),
pseudoallergens in food
Adverse reactions to certain medications: NSAIDs,
ACE-inhibitors
Chronic urticaria with angioedema
Idiopathic or exercise induced anaphylaxis
C1-Esterase Inhibitor deficiency (hereditary or
acquired)
Gleich syndrome: recurrent angioedema and high
eosinophil counts of unknown etiology
Angioedema in hypereosinophilic syndrome
Mechanism of action of NSAIDs (non selective Cox-inhibitors)

Cell stimulation

Phospholipase A2 activation

Release of arachidonic acid


lipoxygenase
X Cyclooxygenase-1
COX inhibitors (NSAID)
Leukotrienes Prostaglandins

Angioedema
Bronchoconstriction and Bronchodilation
vascular permeability
Mechanism of action of ACE inhibitor

ACE-inhibitor

Angioedema
NOSNO
Differential diagnosis of acute
angioedema
IgE mediated allergic reactions to food, drugs, venoms
etc.
Histamine-releasing drugs (e.g. opioids, RCM),
pseudoallergens in food
Adverse reactions to certain medications: NSAIDs,
ACE-inhibitors
Chronic urticaria with angioedema
Idiopathic or exercise induced anaphylaxis
C1-Esterase Inhibitor deficiency (hereditary or
acquired)
Gleich syndrome: recurrent angioedema and high
eosinophil counts of unknown etiology
Angioedema in hypereosinophilic syndrome
Differential diagnosis of acute
angioedema
IgE mediated allergic reactions to food, drugs, venoms
etc.
Histamine-releasing drugs (e.g. opioids, RCM),
pseudoallergens in food
Adverse reactions to certain medications: NSAIDs,
ACE-inhibitors
Chronic urticaria with angioedema
Idiopathic or exercise induced anaphylaxis
C1-Esterase Inhibitor deficiency (hereditary or
acquired)
Gleich syndrome: recurrent angioedema and high
eosinophil counts of unknown etiology
Angioedema in hypereosinophilic syndrome
C1 inhibitor deficiency (hereditary or acquired)
Hereditary:
au.-dom.,can begin in childhood, ~1:30.000
30% new mutations
Depending on gene defect either type I (deficient quantitative
production) or type II (deficient qualitative production); type III with
nl C1 inh recently described in women, still poorly understood
Acquired:
over utilization of the normal C1 inhibitor by high levels of antigen-
antibody complexes
factors formed by lymphoid tumors that destroy C1-INH activity
autoantibody to the C1-INH that prevents its function

Attacks are typically triggered by trauma (e.g. dental surgery),


infection, stress, ACE inhibitors, etc.
The role of C1 inhibitor and available treatments

Morgan, NEJM 2010


The role of C1 inhibitor and available treatments

C1 inhibitor concentrates: Cinryze (pateurized,


nanofiltered C1 inh concentrate approved for prophylaxis
of attacks; studies showed 50% reduction in severity and
frequency of attackes (50%) if infused twice weekly
Attenuated Androgens (danazol, stanazol): increase C1
inh production in liver
Antifibrinolytic agents (tranexamic acid, epsilon-
aminocaproic acid): inhibit plasminogen activation with
consequent sparing of C1 inh usage
Complement levels in C1 inhibitor deficiency

Angioedema Complement component levels


syndrome
C1q C4* C2* C1-inhibitor
functional/antige
nic
HAE type 1 normal low low low/low

HAE type 2 normal low low low/normal

Aquired low low low low/variable

*during attack
Questions ?
In vitro sIgE-testing
Decision point
Allergen (spec. IgE kU/l) PPV

Egg 7 98

Egg infant < 2y 2 95

Milk 15 95

Milk infant < 2y 5

Peanut 14 100

Fish 20 100

Soybean 30 73

Wheat 26 74

tree nuts 15 95

Sampson et al. JACI 2003.111:S542