Anaphylaxis

1. Anaphylaxis

2. Objectives • Definitions • Pathophysiology • Etiologies • Signs and Symptoms • Differential Diagnosis • Acute Management • Referrals

3. Definitions • Anaphylaxis • Severe, systemic allergic reaction • Involves 2 or more systems: • Skin, respiratory, cardiovascular, GI tract • Often life threatening • IgE mediated reaction • Anaphylactoid reaction (AKA Non-IgE Anaphylaxis) • Identical clinical syndrome • NOT IgE mediated

4. Pathophysiology First exposure to allergen TH2 activation, IgE class switching IgE production IgE binding to mast cells Repeat exposure to allergen Activation of mast cells

5. Pathophysiology cont. Anaphylaxis is an acute, life-threatening systemic reaction with varied mechanisms, clinical presentations, and severity that results from the sudden systemic release of mediators from mast cells and basophils.

6. Pathophysiology cont.

7. Allergic Reaction: Time Course Late Phase Cytokines Immediate Histamine Leukotrienes Prostaglandins Thromboxanes Bradykinins

8. Time Course • Immediate • Within seconds to minutes of exposure • Late phase • Similar symptoms occur 1 to 8-12 hr after onset • Prolonged • Protracted sx up to 32 hours • May not be affected by corticosteroids Kemp SF. J Allergy Clin Immunol 2002;110:341-8. Wade JP, et al. Proc Clin Biol Res 1989;297:175-82. Brazil E, MacNamara AF. J Accid Emerg Med 1998;15:252-3.

9. Signs and Symptoms • 2 or more body systems involved • Cutaneous (90%) • Pruritus, urticaria, angioedema, flushing • Respiratory (40-60%) • Upper airway edema → Stridor, angioedema • Lower airway edema → Dyspnea, wheezing • Rhinitis • Dizziness, syncope (30-35%) The diagnosis and Management of Anaphylaxis: An Updated Practice Parameter. J Allergy Clin Immunol 2010.

10. Signs and Symptoms cont. • Cardiovascular (30-35%) • Vasodilation → Relative hypovolemia • Increased capillary permeability → intravascular volume loss • 50% of intravascular fluid transfers into extravascular space within 10 minutes • Hypotension 2005 AHA Guidelines for CPR and ECC. The diagnosis and Management of Anaphylaxis: An Updated Practice Parameter. J Allergy Clin Immunol 2005;115:S483-523.

11. Signs and Symptoms cont. • Gastrointestinal 25-30% • Abdominal pain, emesis, diarrhea • Miscellaneous • Headache 5-8% • Substernal pain 4-6% • Seizure 1-2% • Sense of “impending doom” • Metallic taste The diagnosis and Management of Anaphylaxis: An Updated Practice Parameter. J Allergy Clin Immunol 2005;115:S483-523.

12. Etiologies • Drugs • Latex • Stinging insects • Foods • Exercise • Seminal Fluid • Idiopathic

13. Risk Factors Related to Anaphylaxis • Prior hx of anaphylaxis • Beta-blocker use • Atopic background • Latex • Venom • RCM - anaphylactoid • Not risk factor for anaphylaxis to medications

14. Penicillins and beta-lactam family • Penicillin is most commonly reported drug allergy • Up to 0.04% of PCN treated subjects • Anaphylaxis - 0.001% PCN treated pt • Cross-reactivity • Cephalosporins – Unknown but LOW • Some Carbapenems are cross-reactive* • Meropenum may be tolerated by some PCN allergic patients • Aztreonam does not cross-react with other beta-lactams except ceftAzadime Idsoe O, et al. Bull World Health Organ 1968;38:159-88.

15. Aspirin and NSAIDs • Second most common cause • Anaphylactic reactions • Drug specific • Aspirin exacerbated respiratory disease (AERD) • Class specific (Due to inhibition of COX-1 and shunting to AA metabolites to produce increased amounts of Leukotrienes)

16. Latex • Prevalence < 1% general population • High risk populations • Health care workers (5-15%) • Pts with spina bifida (24-60%) • Workers with occupational latex exposure • Most important factor is degree of exposure • Up to 17% cases of intraoperative anaphylaxis • No commercially avail skin test reagents in US • Diagnosis: Hx + IgE Latex Alenius H, et al. J Lab Clin Med 1994;123:712-20. Poley G, Slater J. J Allergy Clin Immunol 2000;105:1054-62.

17. Stinging Insects • 40-50 reported deaths per year in US • 3% of adults, up to1% of children • Bees, yellow jackets, hornets, wasps • Fire ants • 25-70% chance of systemic rxn if re-stung • Maintenance Venom IT reduces this risk to 1-2% if re-stung.

18. Natural History: Systemic reaction Golden et.al. JACI 2000;105:385-90

19. Foods • Food is the most common cause of anaphylaxis in the outpatient setting, and food allergens account for 30% of fatal cases of anaphylaxis. • Most common offenders: - peanuts, tree nuts, fish, shellfish, cow’s milk, soy, and egg (Sesame Seeds) • Common themes associated with fatal food anaphylaxis include the following: • Reactions commonly involve peanuts and tree nuts • Victims are typically teenagers and young adults; • Patients have a previous history of food allergy and asthma • Failure to administer epinephrine promptly

20. Oral Allergy Syndrome (Food-Pollen Allergy) • Seen in patients with seasonal allergic rhinitis • Itching and swelling in mouth and oropharynx • Associated with ingestion of fresh fruits, vegetables, or nuts • Basically the immune system mistakenly confused certain epitopes on the fruit for a tree, grass or weed pollen (aeroallergens). • Birch - apples, pears, hazelnut, carrot, potato, kiwi • Ragweed – melons, banana • Mugwort – celery, carrot, fennel, parsley • Tolerate cooked or processed fruits, vegetables • Cooking denatures the 3-D shape of the proteins such that they no longer resemble to aeroallergen.

21. Exercise Induced Anaphylaxis • Associated factors: foods and meds • Within 2-4 hours after ingestion • Eating the same foods without exercising does not cause symptoms • Exercise changes absorption of antigen • Implicated foods: celery, shrimp, apples, and wheat • Avoidance of exercise 4-6 hr after eating

22. Seminal Fluid Induced Anaphylaxis • Coital anaphylaxis caused by human seminal fluid has been shown to be a result of IgE-mediated sensitization to seminal plasma proteins. • Prostate-specific antigen (PSA) has been demonstrated to be a relevant allergen in some cases. • It is essential to exclude other underlying causes such as allergens in natural rubber latex condoms or in drugs or foods passively transferred via seminal plasma. • Patients with seminal plasma allergy may be able to conceive without undergoing desensitization, by artificial insemination with washed spermatozoa.

23. Idiopathic Anaphylaxis • The symptoms of idiopathic anaphylaxis are identical to those of episodes related to known causes. • Patients with idiopathic anaphylaxis should receive an intensive evaluation, including a meticulous history to rule out a definite cause of the events. • specific laboratory studies to exclude systemic disorders such as indolent systemic mastocytosis are often utilized.

24. Differential Diagnosis • Scombroid poisoning • Rxn within 30 min of eating spoiled fish • Tuna, mackerel, mahi-mahi • Urticaria, nausea, vomiting, diarrhea, headache • Histidine → Histamine • Angioedema • Asthma exacerbation • Psychiatric conditions – panic attacks, conversion d/o • Vocal cord dysfunction • Vasovagal reactions • Flushing syndromes • Systemic mastocytosis • Cardiogenic shock • Other cardiovascular or respiratory events

25. What is Red Man Syndrome? Anaphylactic reaction Anaphylactoid reaction Neither

26. Red Man Syndrome • Associated with rapid infusion of vancomycin • Flushing, tingling, pruritus, erythema, maculopapular rash, hypotension • Onset 15-45 min after start of infusion • Resolves 10-60 min after d/c infusion • Tx: Pretreat pt with antihistamines prior to infusion, infuse dose over 2 hr Susla G, et al. Critical Care Medicine. 2nd Ed., 2002, 335.

27. Anaphylactoid Reactions • Nonspecific mast cell release • May occur with first exposure • Opioids • Anesthetics • Vancomycin • ASA, NSAIDs • Radiocontrast media Individuals with a hx of anaphylactoid reactions are at increased risk of having another with future exposures. i.e. Pre-treatment protocols for RCM etc….

28. Anaphylactic Reaction in the operating room • Incidence is 1 in 4000 to 1 in 25,000 anesthetic procedures. • Mortality as high as 5% • NMBA are the most common cause during anesthesia. Succinylcholine is the most common offender. • Latex(23%) and Antibiotics (15%) • Less common: Local anesthetics, Opioidanalgesics (anaphylactoid) • Presents as CV collapse, airway obstruction, flushing, and/or edema

29. Radiocontrast Media • Overall frequency of adverse rxn 5-8% • Life threatening rxn < 0.1% • Prevalence greatest in 20-50 yo • 16-44% risk if hx of previous reaction • Risk reduced to 1% if lower osmolarity agent and pretreatment used • No reliable data showing a link between RCM and Iodine or shellfish.

30. RCM Pretreatment Regimen • Prednisone 50 mg po • 13, 7, and 1 hr prior to RCM administration • Diphenhydramine 50 mg po or IM • 1 hr prior • If emergency procedure • Hydrocortisone 200 mg IV every 4 hr • Diphenhydramine 50 IM 1 hr prior • LOW OSMOLARITY CONTRAST IS BEST (and more expensive – so you will need to beg for this)

31. Acute Management of Anaphylactic Reaction Epinephrine Epinephrine Epinephrine Epinephrine Epinephrine Epinephrine Epinephrine Epinephrine Epinephrine Epinephrine

32. Epinephrine IM injection in thigh (vastus lateralis) All patients with S/S of systemic reaction 0.3 – 0.5 mg (1:1000), repeat every 5 min, as necessary There is no contraindication to the use of epinephrine in a life threatening situation Acute Management 2005 AHA Guidelines for CPR and ECC.

33. Epinephrine • Alpha-adrenergic effects • Vasoconstriction • Increase coronary and cerebral perfusion pressure • Beta-adrenergic effects • May increase myocardial work • Reduce subendocardial perfusion

34. Epipen in the Thigh!

35. Acute Management cont. • Antihistamines • Second line treatment after administration of epi • H1 antagonists • Diphenhydramine 25 to 50 mg slow IV or IM • H2 antagonists • Ranitidine 1 mg/kg IV, cimetidine 4 mg/kg IV • Inhaled beta-adrenergic agents • Albuterol 2.5 – 5 mg in 3 ml saline • Bronchospasm refractory to epi • Ipratropium use if patient on beta-blocker 2005 AHA Guidelines for CPR and ECC.

36. Acute Management cont. • Corticosteroids • High dose IV corticosteroids • Methylprednisolone 1-2 mg/kg/d divided q6h • Effects delayed at least 4-6 hours X

37. Acute Management cont. • Aggressive fluid resuscitation • Isotonic crystalloid • 1-2L, possibly 4L may be needed • Oxygen • Monitors • Removal of venom sac

38. Patients on Beta-Blockers • More likely to experience more severe anaphylactic reactions. • Epinephrine may be ineffective • Unopposed alpha-adrenergic effects • Reflex vagotonic effects • Profound hypotension, bradycardia, bronchospasm • Consider glucagon • Activating adenylcyclase directly and bypassing beta-adrenergic receptor

39. Potential Therapies • Glucagon • If patient on beta-blocker • 1 - 5 mg IV every 5 minutes • Side effects – nausea, vomiting, hyperglycemia • Vasopressin • Nonadrenergic peripheral vasoconstrictor • May benefit severely hypotensive pts • Dopamine • Stimulates alpha and beta adrenergic receptors • Atropine • Reverses cholinergic-mediated decrease in HR, BP • Relative or severe bradycardia

40. Airway Obstruction • Early elective intubation recommended • Hoarseness, lingual edema, stridor, oropharyngeal swelling • Pts can deteriorate within ½ to 3 hours 2005 AHA Guidelines for CPR and ECC.

41. Cardiac Arrest • Cardiopulmonary resuscitation • Aggressive volume expansion • 2 large bore IVs with pressure bags 4-8 L of isotonic crystalloid • High dose epinephrine IV • 1-3 mg IV (3 min), 3-5 mg IV (3 min), 4-10ug/min infusion • Antihistamine IV • Corticosteroids • ACLS algorithms 2005 AHA Guidelines for CPR and ECC.

42. IV Epinephrine • Risk for potentially lethal arrhythmias • Not the preferred method. • Administer epinephrine IV only • During cardiac arrest (ACLS protocols) • Profoundly hypotensive subjects unresponsive to volume replacement and several IM injections

43. Labs in Acute Setting • Serum tryptase level • Peak 60-90 min after onset of sx • Persist for 6 hrs • Ideal measurement time 1-2 hr after onset • Serum tryptase level may be normal in the setting of food allergy induced anaphylaxis • Plasma histamine level • Increase within 5-10 min after onset • Persist 30-60 min

44. Observation • Biphasic reaction in up to 20% pts • Symptoms recur within 1-8 hours • Observe until asymptomatic ≥ 4 hours • Longer observation if severe reaction

45. Discharge • EpiPen • Corticosteroids • Antihistamines • Beta-agonist • Buddy care • Allergy consult

46. Allergy Evaluation • Detailed allergy history • Labs and allergy testing • Avoidance measures • Therapeutic options • Graded dose challenge • Drug desensitization • Medical warning tags/ Red Dog Tags

47. Testing for Specific IgE • Allergen-specific IgE • In vivo testing • Prick and ID skin tests • Venom • Foods • In vitro testing • RAST • Latex • Venom • Foods

48. Clinical Scenario • 25 yo AD male OIF air evac’ed from Iraq after IED explosion • ICU for Acinetobacter sepsis • Childhood hx rash with amoxicillin • ICU team initially starts imipenem • ID recommends Unasyn (amp/sulbactam)

49. PCN Cross Reactivity • Carbapenems are cross-reactive • Ampicillin is a beta-lactam antibiotic • Patient requires drug desensitization

50. Drug Desensitization • Conversion from highly sensitive state to a tolerant state • Mast cells unresponsive to specific drug • Temporary, lasting as long as therapy is uninterrupted • Administration of gradually increasing doses of drug over several hours or days • Sensitivity returns within 48 hr of d/c drug