1. Anaphylaxis Jay Prochnau, MD Indiana University Health Arnett Allergy/Asthma Lafayette, IN

2. Disclosures Conduct research in COPD and asthma for GSK and Genentech/Roche No conflicts of interest

3. Anaphylaxis Definition Symptoms Mechanisms Causes Treatment Workup/prevention

4. Definitions “Ana” = against, “phylaxis” = protection Coin termed in 1902 by Portier and Richet Attempts to vaccinate dogs against the toxin of sea anemones led to death at much lower doses

5. Definitions “I know it when I see it” –Potter Stewart World Allergy Organization: “A severe, life threatening, generalized or systemic hypersensitivity reaction” NIAID/FAAN: “A serious allergic reaction that is rapid in onset and may cause death”

6. Criteria Criterion 1 – acute onset (minutes to hours) of an illness involving the skin, mucosal tissue or both (eg hives, pruritus, flushing, swollen tongue/lips/uvula) and at least one of the following: –Respiratory compromise (dyspnea, wheeze, stridor, hypoxemia, reduced peak flow) –Reduced blood pressure or associated signs/symptoms (hypotonia, syncope) Criterion 2 – 2 or more of the following that occur rapidly (minutes to hours) after exposure to a likely allergen: –Skin involvement –Respiratory compromise –Reduced BP –Persistent GI symptoms (abdominal cramping, vomiting) Criterion 3 – reduced BP after known allergen (minutes to hours) –Systolic <90mmHg (<70 in children), or 30% decrease is SBP

7. Working definition An potentially fatal reaction that involves more than one organ system

8. Definitions Anaphylaxis can be immunologic or non-immunologic, IgE mediated or non-IgE mediated Non-IgE mediated anaphylaxis used to be called “anaphylactoid”

9. Signs and symptoms Cutaneous>90% –Urticaria and angioedema85-90% –Flushing50% –Pruritus, no rash2-5% Respiratory40-60% –Dyspnea, wheeze45-50% –Upper airway swelling50-60% –Rhinitis15-20%

10. Signs and symptoms Circulatory –Dizziness, syncope, hypotension, tachycardia30-35% GI –Nausea, vomiting, diarrhea, cramping25-30% Miscellaneous –Headache5-8% –Chest pain4-6% –Seizures1-2%

11. Signs and symptoms

13. Mechanisms of anaphylaxis Main mediator of anaphylaxis is histamine Histamine released from mast cells Mast cell degranulation triggered by cross linking of IgE antibodies bound to IgE receptors

14. Mechanisms of anaphylaxis

15. Effects of histamine Activation of itch receptorsPruritus, urticaria VasodilationUrticaria, edema Smooth muscle contractionWheezing Increased vascular permeabilityedema, ↓ BP

16. Other mast cell mediators Neutral proteases –Tryptase, chymase, carboxypeptidase Proteoglycans –Heparin, chondroitin sulfate Leukotrienes Prostoglandins Platelet activating factor

17. Causes of anaphylaxis Medications –Most common cause of anaphylaxis (inpatient) –Drug reactions responsible for 230,000 hospital admissions in the US annually Foods –Food allergy affects 6-8% of children, 3-4% of adults –Most common cause of anaphylaxis at home Insect stings –40 deaths/year estimated due to Hymenoptera stings Blood products –Anti-IgA antibodies in an IgA deficient patient

18. Causes of anaphylaxis Exercise –May be food dependent Vaccines –Gelatin, ovalbumin Human seminal plasma anaphylaxis Aeroallergens –uncommon cause of anaphylaxis (horse)

19. Anaphylaxis to medications Antibiotics –Most common medication class associated with anaphylaxis –Penicillin, sulfonamides –Vancomycin – usually non IgE mediated/direct mast cell activation NSAIDs –Second most common –Most probably not IgE mediated Radiocontrast media –Usually not IgE mediated –Incidence appears to be diminishing

20. Anaphylaxis to medications Perioperative anaphylaxis –Most common neuromuscular blocking agents (62%) –Natural rubber latex (16%) –Intraoperative antibiotics –Protamine use to reverse heparin Opioid analgesics –Non IgE mediated –Directly activate mast cells

21. Anaphylaxis to foods

22. Any food can cause anaphylaxis Most common peanut and tree nuts “Big 6” foods –Peanut/tree nuts –Shellfish/fish –Cow’s milk –Egg –Soy –Wheat

23. Anaphylaxis to insect stings Hymenoptera venoms most common Hymenoptera = “membrane winged” insects –Yellow jacket, yellow hornet, white faced hornet, paper wasp, honeybee, imported fire ant (in the south) Anaphylaxis reported to multicolored asian lady beetles

24. Causes of anaphylaxis Up to 60% of cases of anaphylaxis referred to allergy specialty clinics have no apparent trigger = “idiopathic anaphylaxis”

25. Differential diagnosis of anaphylaxis ACE inhibitor mediated angioedema –Mediated by bradykinin, not histamine –May affect up to 2.2% of patients on ACE inhibitors Restaurant syndromes –Scombroid fish poisoning –Anisakiasis –MSG –Sulfites Mastocytosis –Systemic mastocytosis, mast cell activation syndrome

26. Differential diagnosis of anaphylaxis Nonorganic disease –Vocal cord dysfunction, globus hystericus, panic attack Vasovagal syncope –Pallor as opposed to flushing –Bradycardia as opposed to tachycardia Myocardial infarction or stroke Flushing disorders –Menopause –Medications that cause flushing (niacin) –Alcohol

27. Differential diagnosis of anaphylaxis Tumors –Carcinoid –Pheochromocytoma –GI tumors: VIPoma –Medullary carinoma of the thyroid Idiopathic capillary leak syndrome –Rare, can be fatal Undifferentiated somatoform anaphylaxis

28. Diagnosis of anaphylaxis Diagnosis of anaphylaxis is primarily clinical Laboratory workup may be helpful –Histamine Stays elevated for 30-60 minutes Urinary metabolites may stay elevated for 24 hours –Tryptase Stays elevated for 4-6 hours May not be elevated in anaphylaxis due to food allergy –Platelet activating factor (PAF) “BNP” of anaphylaxis Increasing levels of PAF may indicate greater severity

29. Tryptase in anaphylaxis

30. PAF in anaphylaxis N Engl J Med 2008 Jan 3;358(1):28-35 N

31. Treatment of anaphylaxis ABCs Protection of airway crucial, early intubation if necessary –Laryngeal edema most common cause of death from anaphylaxis –Supplemental oxygen Pressure support –Place patient in recumbent position, elevate lower extremities –IV fluids, pressors if necessary

32. Treatment of anaphylaxis “EASI” Epinephrine 1:1000 –First line therapy for anaphylaxis –Should be given IM (as opposed to SC or IV), lateral thigh (vastus lateralis muscle) for optimal absorption –Dose 0.3 to 0.5ml for adults, 0.01ml/kg for children –Can be repeated every 5-15 minutes as needed Antihistamines –Diphenhydramine or hydroxyzine 50mg every 6 hours Steroids –Methylprednisolone or prednisone to prevent biphasic reaction Inhaled beta-agonists (e.g., albuterol)

33. Absorption by administration site

34. Prevention of anaphylaxis Allergy referral Careful history and directed testing to identify trigger of anaphylaxis –Skin testing vs RAST testing –Skin testing to medications is of limited utility with the exception of penicillin Patients should have access to an epinephrine autoinjector

35. Prevention of anaphylaxis

37. Medication allergy –Avoidance –Desensitization if necessary Food allergy –Avoidance –Trials with oral immunotherapy look promising Hymenoptera allergy –Venom immunotherapy 98% curative, 100% effective

38. Prevention of anaphylaxis Radiocontrast media allergy –Use of lower osmolar or nonionic contrast media –Pretreatment with steroids and antihistamines Prednisone 50mg 12h, 6h and 1h and diphenhydramine 50mg 1h prior to RCM administration Hydrocortisone 200mg and diphenhydramine 50mg pre-procedure –Risk of reaction 60% if high osmolar contrast is used again, 6% with either low osmolar contrast media or with pretreatment, 0.6% with low osmolar contrast media and pretreatment

39. Mast cell activation disorders Primary mast cell disorders –Mastocytosis –Monoconal mast cell activation disorder (MMAD) Secondary mast cell disorders –Allergic disorders (IgE mediated urticaria/anaphylaxis) –Chronic autoimmune urticaria/angioedema Idiopathic mast cell disorders –Idiopathic anaphylaxis –Idiopathic urticaria/angioedema –Idiopathic mast cell activation syndrome (MCAS)

40. Questions