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
nuts, shellfish)
~35%
Drugs (e.g. antibiotics,
NSAIDs, radio contrast
media, anaesthetics)
Insect bites and stings
~15-20%
Latex
rare
Allergen vaccines
rare
Exercise induced
rare
Idiopathic
~30%
~5%
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)
1Kagan
et al., Ann Allergy Asthma Immunol. 2003 Jun;90(6):640-5 2003
2Sporik
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
100
probability of reaction
90
80
70
60
50
40
30
20
10
0
0
0.35
0.7
3.5
7
sIgE (kU/l)
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: 0.10.3 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 H2antagonist (Famotidine=Pepcid® 20mg IV)
– Children (2-12y): H1-antagonist (Diphenhydramine=Benadryl®1-1.25 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
angioedema
Food that can enhance allergic skin reactions:
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.
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)
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,
and sauerkraut.
5.Beer, wine and cider
6.Mushrooms.
7.Soy sauce.
8.Pickled and smoked meats and fish including sausages, bacon, ham, hot dogs,
corned beef, pastrami, and pickled tongue.
9.Lobster and shellfish.
10.Soured breads (e.g. pumpernickel, rye) fresh rolls, coffee cakes
11. Certain fruits such as melons, especially cantaloupe, mango, all tropical fruit
(pineapple, papaya etc.), grapes, strawberries
12.All dried and candied fruits including raisins, apricots, dates, prunes, and figs.
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
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
Histamine-releasing drugs (e.g. opioids, RCM),
pseudoallergens in food.
– Immediate or delayed onset of symptoms
– Mechanism not well understood
– Opiates, radio contrast media and
vancomycin are typical examples
– There is increasing data that certain food
can trigger histamine release in susceptible
individuals (e.g. chronic urticaria)
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
Leukotrienes
Angioedema
Bronchoconstriction and
vascular permeability
X
Cyclooxygenase-1
COX inhibitors (NSAID)
Prostaglandins
Bronchodilation
Mechanism of action of ACE inhibitor
ACE-inhibitor
NOSNO
Angioedema
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 antigenantibody 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, epsilonaminocaproic acid): inhibit plasminogen activation with
consequent “sparing” of C1 inh usage
Complement levels in C1 inhibitor deficiency
Angioedema
syndrome
Complement component levels
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
Allergen
Decision point
(spec. IgE kU/l)
PPV
Egg
7
98
Egg infant < 2y
2
95
15
95
Milk
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