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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
y o
f re
acti
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