Acute Angioedema

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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

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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

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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

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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)

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How do mast cells release histamine?
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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
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Causes of anaphylaxis
Food (e.g. peanuts, tree nuts, shellfish) 35
Drugs (e.g. antibiotics, NSAIDs, radio contrast media, anaesthetics) 15-20
Insect bites and stings 5
Latex rare
Allergen vaccines rare
Exercise induced rare
Idiopathic 30
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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 gt95
• PPV 501 95 (milk, egg, peanut, if wheal
  gt8mm)2
• Refractory period up to 4 weeks after anaphylaxis
  (data from venom anaphylaxis)

1Kagan et al., Ann Allergy Asthma Immunol. 2003
Jun90(6)640-5 2003 2Sporik R, Hill DJ et al.
Clin Exp Allergy. 2000 Nov30(11)1540-6.
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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

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Probability of reacting to egg
Sicherer et al. 2005
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Treatment of severe allergic reactions

• 1. Epinephrine (Adrenaline) 11000 solution
  (1mg/ml)
• gt12 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)
• gt6 months and lt12 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 (DiphenhydramineBenadryl
  25-50 mg IV) and H2-antagonist (FamotidinePepcid
  20mg IV)
• Children (2-12y) H1-antagonist
  (DiphenhydramineBenadryl1-1.25 mg/kg IV q6h)
  and H2-antagonist (FamotidinePepcid 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

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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

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Differential diagnosis of acute angioedema

• Food that can enhance allergic skin reactions
• Any spices and seasoning such as Sazon, Adobo,
  Vegeta, ginger, garlic, onion or celery powder,
  any MSG containing food (e.g. Chinese food) etc.
• 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)
• Canned tomatoes, tomato sauce or paste, canned
  soups, other canned meals
• Vinegar and vinegar-containing foods such as
  mayonnaise, ketchup, and mustard, salad
  dressings, chili, shrimp sauce, pickles, pickled
  vegetables, relishes, green olives, and
  sauerkraut.
• Beer, wine and cider
• Mushrooms.
• Soy sauce.
• Pickled and smoked meats and fish including
  sausages, bacon, ham, hot dogs, corned beef,
  pastrami, and pickled tongue.
• Lobster and shellfish.
• Soured breads (e.g. pumpernickel, rye) fresh
  rolls, coffee cakes
• Certain fruits such as melons, especially
  cantaloupe, mango, all tropical fruit (pineapple,
  papaya etc.), grapes, strawberries
• All dried and candied fruits including raisins,
  apricots, dates, prunes, and figs.
• 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.
• Chocolate, nuts, peanut products, chewing gum,
  breath mints, candy
• 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)

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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

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Mechanism of action of NSAIDs (non selective
Cox-inhibitors)
Angioedema
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Mechanism of action of ACE inhibitor
ACE-inhibitor
Angioedema
NOS?NO
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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

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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

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• C1 inhibitor deficiency (hereditary or acquired)
• Hereditary
• au.-dom.,can begin in childhood, 130.000
• 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.

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The role of C1 inhibitor and available treatments
Morgan, NEJM 2010
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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

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Complement levels in C1 inhibitor deficiency
Angioedema syndrome Complement component levels Complement component levels Complement component levels Complement component levels
Angioedema syndrome C1q C4 C2 C1-inhibitor functional/antigenic
HAE type 1 normal low low low/low
HAE type 2 normal low low low/normal
Aquired low low low low/variable
during attack
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• Questions ?

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In vitro sIgE-testing
Allergen Decision point (spec. IgE kU/l) PPV
Egg 7 98
Egg infant lt 2y 2 95
Milk 15 95
Milk infant lt 2y 5  
Peanut 14 100
Fish 20 100
Soybean 30 73
Wheat 26 74
tree nuts 15 95
Sampson et al. JACI 2003.111S542