Acute AngioedemaAcute Angioedema

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

Division of Allergy and ImmunologyDivision of Allergy and ImmunologyJacobi Medical CenterJacobi Medical Center

Albert Einstein College of MedicineAlbert Einstein College of Medicine

Differential diagnosis of acute Differential diagnosis of acute angioedemaangioedema

IgE mediated allergic reactions to food, drugs, venoms IgE mediated allergic reactions to food, drugs, venoms etc.etc.Histamine-releasing drugs (e.g. opioids, RCM), Histamine-releasing drugs (e.g. opioids, RCM), pseudoallergens in foodpseudoallergens in foodAdverse reactions to certain medications: NSAIDs, Adverse reactions to certain medications: NSAIDs, ACE-inhibitors ACE-inhibitors Chronic urticaria with angioedemaChronic urticaria with angioedemaIdiopathic or exercise induced anaphylaxisIdiopathic or exercise induced anaphylaxisC1-Esterase Inhibitor deficiency (hereditary or C1-Esterase Inhibitor deficiency (hereditary or acquired)acquired)Gleich syndrome: recurrent angioedema and high Gleich syndrome: recurrent angioedema and high eosinophil counts of unknown etiologyeosinophil counts of unknown etiologyAngioedema in hypereosinophilic syndromeAngioedema in hypereosinophilic syndrome

Differential diagnosis of acute Differential diagnosis of acute angioedemaangioedema

IgE mediated allergic reactions to food, drugs, venoms IgE mediated allergic reactions to food, drugs, venoms etc.etc.Histamine-releasing drugs (e.g. opioids, RCM), Histamine-releasing drugs (e.g. opioids, RCM), pseudoallergens in foodpseudoallergens in foodAdverse reactions to certain medications: NSAIDs, Adverse reactions to certain medications: NSAIDs, ACE-inhibitors ACE-inhibitors Chronic urticaria with angioedemaChronic urticaria with angioedemaIdiopathic or exercise induced anaphylaxisIdiopathic or exercise induced anaphylaxisC1-Esterase Inhibitor deficiency (hereditary or C1-Esterase Inhibitor deficiency (hereditary or acquired)acquired)Gleich syndrome: recurrent angioedema and high Gleich syndrome: recurrent angioedema and high eosinophil counts of unknown etiologyeosinophil counts of unknown etiologyAngioedema in hypereosinophilic syndromeAngioedema in hypereosinophilic syndrome

Differential diagnosis of acute Differential diagnosis of acute angioedemaangioedema

IgE mediated allergic reactions to food, drugs, IgE mediated allergic reactions to food, drugs, venoms etc. venoms etc.

– Immediate type (histamine)Immediate type (histamine)– Severe reactions (anaphylaxis) almost Severe reactions (anaphylaxis) almost

always occur within 1-30 minalways occur within 1-30 min– Anaphylaxis is accompanied by skin Anaphylaxis is accompanied by skin

symptoms in nearly 100%symptoms in nearly 100%– Up to 20% late phase reaction 2-24 hours Up to 20% late phase reaction 2-24 hours

(peak 8 hours)(peak 8 hours)

How do mast cells release histamine?How do mast cells release histamine?

Presentation of anaphylaxisPresentation of anaphylaxisCutaneous 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 anaphylaxisCauses of anaphylaxisFood (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%

Work-up of IgE mediated allergic reactions Work-up of IgE mediated allergic reactions

Skin-testingSkin-testing– Drugs: no standardized skin tests, except Drugs: no standardized skin tests, except

penicillin penicillin – Food: best with fresh foodFood: best with fresh food

NPV thought to be generally >95% NPV thought to be generally >95% PPV 50%PPV 50%11 – 95% (milk, egg, peanut, if wheal – 95% (milk, egg, peanut, if wheal >8mm)>8mm)22

– Refractory period up to 4 weeks after Refractory period up to 4 weeks after anaphylaxis (data from venom anaphylaxis)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 Work-up of IgE mediated allergic reactions

In vitro sIgE testingIn vitro sIgE testing– ““RAST” RAST”

((RRadioadioAAllergollergoSSorbentorbentTTest)-est)-outdated test, but term still in use!outdated test, but term still in use!

– Newer tests: Radioactive signal Newer tests: Radioactive signal replaced by chemiluminescent replaced by chemiluminescent reaction (DPC Immulite 2000, reaction (DPC Immulite 2000, PharmaciaCap)PharmaciaCap)

– Limited sensitivity and specificityLimited sensitivity and specificity

Probability of reacting to eggProbability of reacting to egg

Sicherer et al. 2005

0

10

20

30

40

50

60

70

80

90

100

0 0.35 0.7 3.5 7

sIgE (kU/l)

pro

bab

ilit

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f re

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on

Treatment of severe allergic reactionsTreatment of severe allergic reactions1. Epinephrine (Adrenaline) 1:1000 solution (=1mg/ml)1. Epinephrine (Adrenaline) 1:1000 solution (=1mg/ml)– >12 years and adults:>12 years and adults: 0.3-0.5 mg IM anterolateral thigh; (IV must dilute: 0.1-0.3 0.3-0.5 mg IM anterolateral thigh; (IV must dilute: 0.1-0.3

mg (in 10ml) slowly over 10 minutes)mg (in 10ml) slowly over 10 minutes)– >6 months and <12 years>6 months and <12 years: 0.01 mg/kg: 0.01 mg/kg

2. Positioning: Keep patient lying flat with legs up unless respiratory distress 2. Positioning: Keep patient lying flat with legs up unless respiratory distress increasesincreases3. Oxygen supplementation and beta-agonist inhalation (Albuterol)3. Oxygen supplementation and beta-agonist inhalation (Albuterol)4. IV access, intravenous fluids (normal saline) if still hypotensive after 4. IV access, intravenous fluids (normal saline) if still hypotensive after epinephrineepinephrine– Remember: 50% of the intravascular volume can be shifted to the Remember: 50% of the intravascular volume can be shifted to the

extravascular space within the first 10 min. of anaphylaxisextravascular space within the first 10 min. of anaphylaxis– Normal Saline rapid infusion if epinephrine-resistant hypotensionNormal Saline rapid infusion if epinephrine-resistant hypotension

5. If patient is on beta-blocker: Glucagon 5. If patient is on beta-blocker: Glucagon – Adult:Adult: 1-5 mg IV (IM,SC), followed by infusion 5-15 ug/min 1-5 mg IV (IM,SC), followed by infusion 5-15 ug/min

6. Antihistamines6. Antihistamines– Adult: H1-antagonist (Diphenhydramine=Benadryl® 25-50 mg IV) Adult: H1-antagonist (Diphenhydramine=Benadryl® 25-50 mg IV) andand H2- H2-

antagonist (Famotidine=Pepcid® 20mg IV)antagonist (Famotidine=Pepcid® 20mg IV)– Children (2-12y): H1-antagonist (Diphenhydramine=Benadryl®1-1.25 mg/kg IV Children (2-12y): H1-antagonist (Diphenhydramine=Benadryl®1-1.25 mg/kg IV

q6h) q6h) andand H2-antagonist (Famotidine=Pepcid® 0.25-0.5 mg/kg IV q12h) H2-antagonist (Famotidine=Pepcid® 0.25-0.5 mg/kg IV q12h) 7. Steroids: 7. Steroids: do not help acutely but can prevent prolonged anaphylaxisdo not help acutely but can prevent prolonged anaphylaxis

Liebermann et al. “The diagnosis and management of anaphylaxis. An updated practice parameter”, JACI 2005; 115Liebermann et al. “The diagnosis and management of anaphylaxis. An updated practice parameter”, JACI 2005; 115

Differential diagnosis of acute Differential diagnosis of acute angioedemaangioedema

IgE mediated allergic reactions to food, drugs, venoms IgE mediated allergic reactions to food, drugs, venoms etc.etc.Histamine-releasing drugs (e.g. opioids, RCM), Histamine-releasing drugs (e.g. opioids, RCM), pseudoallergens in foodpseudoallergens in foodAdverse reactions to certain medications: NSAIDs, Adverse reactions to certain medications: NSAIDs, ACE-inhibitors ACE-inhibitors Chronic urticaria with angioedemaChronic urticaria with angioedemaIdiopathic or exercise induced anaphylaxisIdiopathic or exercise induced anaphylaxisC1-Esterase Inhibitor deficiency (hereditary or C1-Esterase Inhibitor deficiency (hereditary or acquired)acquired)Gleich syndrome: recurrent angioedema and high Gleich syndrome: recurrent angioedema and high eosinophil counts of unknown etiologyeosinophil counts of unknown etiologyAngioedema in hypereosinophilic syndromeAngioedema in hypereosinophilic syndrome

Differential diagnosis of acute Differential diagnosis of acute angioedemaangioedema

Histamine-releasing drugs (e.g. opioids, RCM), Histamine-releasing drugs (e.g. opioids, RCM), pseudoallergens in food.pseudoallergens in food.

– Immediate or delayed onset of symptomsImmediate or delayed onset of symptoms– Mechanism not well understoodMechanism not well understood– Opiates, radio contrast media and Opiates, radio contrast media and

vancomycin are typical examplesvancomycin are typical examples– There is increasing data that certain food There is increasing data that certain food

can trigger histamine release in susceptible can trigger histamine release in susceptible individuals (e.g. chronic urticaria)individuals (e.g. chronic urticaria)

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 meals4.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 cider6.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

Differential diagnosis of acute Differential diagnosis of acute angioedemaangioedema

IgE mediated allergic reactions to food, drugs, venoms IgE mediated allergic reactions to food, drugs, venoms etc.etc.Histamine-releasing drugs (e.g. opioids, RCM), Histamine-releasing drugs (e.g. opioids, RCM), pseudoallergens in foodpseudoallergens in foodAdverse reactions to certain medications: NSAIDs, Adverse reactions to certain medications: NSAIDs, ACE-inhibitors ACE-inhibitors Chronic urticaria with angioedemaChronic urticaria with angioedemaIdiopathic or exercise induced anaphylaxisIdiopathic or exercise induced anaphylaxisC1-Esterase Inhibitor deficiency (hereditary or C1-Esterase Inhibitor deficiency (hereditary or acquired)acquired)Gleich syndrome: recurrent angioedema and high Gleich syndrome: recurrent angioedema and high eosinophil counts of unknown etiologyeosinophil counts of unknown etiologyAngioedema in hypereosinophilic syndromeAngioedema in hypereosinophilic syndrome

Leukotrienes

lipoxygenase

Release of arachidonic acid

Prostaglandins

Cyclooxygenase-1

Cell stimulation

Phospholipase A2 activation

Bronchodilation Bronchoconstriction and vascular permeability

COX inhibitors (NSAID)COX inhibitors (NSAID)

X

Angioedema

Mechanism of action of NSAIDs (non selective Cox-inhibitors)

ACE-inhibitor

NOSNO

Mechanism of action of ACE inhibitor

Angioedema

Differential diagnosis of acute Differential diagnosis of acute angioedemaangioedema

IgE mediated allergic reactions to food, drugs, venoms IgE mediated allergic reactions to food, drugs, venoms etc.etc.Histamine-releasing drugs (e.g. opioids, RCM), Histamine-releasing drugs (e.g. opioids, RCM), pseudoallergens in foodpseudoallergens in foodAdverse reactions to certain medications: NSAIDs, Adverse reactions to certain medications: NSAIDs, ACE-inhibitorsACE-inhibitors Chronic urticaria with angioedemaChronic urticaria with angioedemaIdiopathic or exercise induced anaphylaxisIdiopathic or exercise induced anaphylaxisC1-Esterase Inhibitor deficiency (hereditary or C1-Esterase Inhibitor deficiency (hereditary or acquired)acquired)Gleich syndrome: recurrent angioedema and high Gleich syndrome: recurrent angioedema and high eosinophil counts of unknown etiologyeosinophil counts of unknown etiologyAngioedema in hypereosinophilic syndromeAngioedema in hypereosinophilic syndrome

Differential diagnosis of acute Differential diagnosis of acute angioedemaangioedema

IgE mediated allergic reactions to food, drugs, venoms IgE mediated allergic reactions to food, drugs, venoms etc.etc.Histamine-releasing drugs (e.g. opioids, RCM), Histamine-releasing drugs (e.g. opioids, RCM), pseudoallergens in foodpseudoallergens in foodAdverse reactions to certain medications: NSAIDs, Adverse reactions to certain medications: NSAIDs, ACE-inhibitorsACE-inhibitors Chronic urticaria with angioedemaChronic urticaria with angioedemaIdiopathic or exercise induced anaphylaxisIdiopathic or exercise induced anaphylaxisC1-Esterase Inhibitor deficiency (hereditary or C1-Esterase Inhibitor deficiency (hereditary or acquired)acquired)Gleich syndrome: recurrent angioedema and high Gleich syndrome: recurrent angioedema and high eosinophil counts of unknown etiologyeosinophil counts of unknown etiologyAngioedema in hypereosinophilic syndromeAngioedema in hypereosinophilic syndrome

C1 inhibitor deficiency (hereditary or acquired)C1 inhibitor deficiency (hereditary or acquired)– Hereditary: Hereditary:

au.-dom.,can begin in childhood, ~1:30.000au.-dom.,can begin in childhood, ~1:30.00030% new mutations30% new mutationsDepending on gene defect either type I (deficient quantitative Depending on gene defect either type I (deficient quantitative production) or type II (deficient qualitative production); type III with production) or type II (deficient qualitative production); type III with nl C1 inh recently described in women, still poorly understoodnl C1 inh recently described in women, still poorly understood

– Acquired: Acquired: over utilization of the normal C1 inhibitor by high levels of antigen-over utilization of the normal C1 inhibitor by high levels of antigen-antibody complexes antibody complexes factors formed by lymphoid tumors that destroy C1-INH activity factors formed by lymphoid tumors that destroy C1-INH activity autoantibody to the C1-INH that prevents its functionautoantibody to the C1-INH that prevents its function

Attacks are typically triggered by trauma (e.g. dental surgery), Attacks are typically triggered by trauma (e.g. dental surgery), infection, stress, ACE inhibitors, etc.infection, stress, ACE inhibitors, etc.

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

The role of C1 inhibitor and available treatments

Complement levels in C1 inhibitor deficiencyComplement levels in C1 inhibitor deficiency

Angioedema syndrome

Complement component levels

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

Questions ?Questions ?

In vitro sIgE-testingIn vitro sIgE-testing

AllergenDecision point

(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