Anaphylaxis

1. Anaphylaxis David Sloane, MD Brigham and Women’s Hospital 3/30/12

2. Scheme • Why do you care? • Definitions • Manifestations • Differential Diagnosis • Triggers • Mechanisms • Treatment and Prevention

3. Why do you care? • Incidence (totally) unclear, but under-reporting is proven; Estimate = 10-100/105 pt years • Often caused by us (drugs) • Potentially fatal • Asthma is a component of the presentation and a risk factor for fatality • Early intervention is often life-saving while delay in treatment increases the risk of fatality

4. History and Definitions • Portier and Richet, 1902 • During attempts to immunize them, dogs accidentally sensitized to previously sub-lethal doses of sea anemone venom died in ana(≠pro)-phylactic reactions. • Definitions and consciousness. • “The hardest part about an ethical dilemma is knowing when you are in one.” (Ed Hundert, MD)

5. Definitions “A systemic, immediate hypersensitivity reaction caused by immunoglobulin E (IgE) mediated immunologic release of mediators from mast cells and basophils.” (Lieberman, 2003) Anaphylaxis = “a severe , potentially fatal systemic allergic reaction that occurs suddenly after contact with an allergy-causing substance.” (Second Symposium, JACI 2006;117:391-397) “A serious allergic reaction that is rapid in onset and might cause death” (Simons, 2010)

6. Definition

7. The Drama of Anaphylaxis • Patient: “The history is the most important tool to establish the cause of anaphylaxis and takes precedence over diagnostic tests.” (Liberman et al, Practice Parameter, JACI 2005) • Dr. Sheffer: Impending Sense of Doom • Dr. Castells: Western Medicine – risk and rescue

8. “Anaphylactoid”? • Anaphylactoid reactions seem to be clinically identical, but do not result from the same molecular mechanism. It is dubious whether this makes a difference in the acute setting, because anaphylaxis may be considered a clinical syndrome caused by no fewer than two mechanisms (IgE-mediated and direct mast cell activation) but it might make a difference in the long term treatment and prevention (e.g. the efficacy of anti-IgE; preventability with steroids and antihistamines). • “The terms anaphylactoid or pseudoanaphylaxis are no longer recommended for use.” (Simons 2010)

9. A Modern Disease The death of Pharaoh Menes in 2,600 BCE by anaphylaxis to a wasp or hornet sting has been debunked as an interpretation of fragmentary hieroglyphs unsupported by hard data

10. Clinical Manifestations • Acute onset of an illness (min to hrs) with involvement of the skin and/or mucosae (hives, pruritus, flushing) and at least one of the following • Respiratory compromise (dyspnea, wheeze, bronchospasm, stridor, reduced PEF, hypoxemia) • Reduced BP or symptoms (syncope) • Two or more of the following that occur rapidly after exposure to a likely allergen for that patient (min to hrs) • Skin and/or mucosae • Respiratory compromise • Reduced BP • GI symptoms (colic, diarrhea) • Reduced BP after exposure to a known allergen for that patient (min to hrs) Table I from Sampson et al JACI 2006 117:391-397.

11. Frequency of Manifestations • Cutaneous 90% • Urticaria and Angioedema 85-90% • Flushing 45-55% • Pruritus 2-5% • Respiratory 40-60% • Dyspnea and Wheeze 45-50% • Laryngeal Angioedema 50-60% • Rhinitis 25-20% • Dizziness, syncope, hypotension 30-35% • Abdominal (n, v, colic, diarrhea) 25-30% • Misc (HA 5-8%, SSCP 4-6%, Sz 1-2%) Liberman P et al JACI 2005;115(3):S483-S523

12. Grading of Severity • Brown performed a retrospective analysis of 1149 hypersensitivity reactions treated in an Australian Hospital ED (Brown JACI 2004;114:371-376) • Statistical relationships between symptoms and hypotension and hypoxemia were determined in order to grade reaction severity.

13. Grading of Severity (cont.) GradeDefined by 1=Mild (skin and SC only) Gen erythema, urticaria periorbital edema, angioedema 2=Moderate (Resp, CV, GI) Dysp, Stridor, Wheeze Naus, Vom, Dizziness, Diaphoresis, CT/Throat tight, Abd pain 3=Severe (↓O2,↓BP, Neuro) Cyanosis, Sat <92%, SBP <90mmHg in adults Confusion, syncope, incontinence Brown JACI 2004;114:371-376

14. Grading of Severity (cont.) • Careful observation indicated that almost all patients with anaphylaxis had some skin involvement • While univariate analysis indicated that age, ACE-I’s, b-antagonists, known lung disease, and etiology influenced severity, multinomial logistic regression confirmed only the influence of age, insect venom (OR 2.7), and iatrogenic causes (OR 2.3). • Preexisting lung disease was associated with hypoxia, but not reaction severity. Brown JACI 2004;114:371-376

15. Differential Diagnosis • Flush syndromes (e.g. carcinoid) • Postprandial/“restaurant” syndromes (e.g. scrombroid fish poisoning) • Systemic Mastocytosis • Pheochromocytoma • Vasovagal reaction • Panic attack, Undifferentiated Somatoform Idiopathic Anaphylaxis, and other psychiatric conditions • Hypoglycemia • Shock (Septic or Cardiogenic [MI, PE]) • Menopausal hot flashes • SIDS

16. Mechanisms • Cells • Mast cells • ? Basophils • Mediators and Biomarkers • Histamine, cysLTs • Mast Cell Tryptases • PAF • Mechanisms • Cross-linking of FceRI-bound cell surface IgE by antigen (e.g. Ara h1, PCN) • Auto-antibodies (e.g., against IgE or FceRI) • IgG (?) • Direct mast cell releasers (e.g., Opioids, RCM) • The nervous system

17. Broadcast vs. Network Hypotheses Ag Ag

18. Broadcast hypothesis: Let’s do some arithmetic • Presume a subject with peanut anaphylaxis has a mass of 70kg. Total body water is approximately 60% of total body mass, thus 42L. • Let the pt eat one gram of defatted dry roasted peanut flour, which is 50% protein by mass. • Let this patient be hypersensitive to peanuts based on reactivity to Ara h1 (vinculin) alone. Ara h1 has a mol wt of 64kD (64,000 gm/mol). Determine the number of molecules in the volume occupied by one mast cell at equilibrium if Ara h1 is a) 100%, b) 10%, or b) 1% of the protein content. • Recall that a basophil (which admittedly is not a surrogate for a mast cell) has 5x103 – 1x106 FceRI per cell and activation by antigen requires anywhere from 200-30,000 of these receptors to be cross-linked. Presume each molecule of Ara h1 has 2-10 IgE binding epitopes. Then the minimum number of Ara h1 molecules required for activation would be 20-15,000.

19. Broadcast hypothesis: Let’s do some arithmetic • Presume there is rapid diffusion of peanut proteins throughout the total body water volume. If you argue that only the extracellular compartment (33% of TBW) is available, compensate for that by allowing 67% of the ingested material to be catabolized. The patient ingests a) 0.5 gm, b) 0.05gm, or c) 0.005gm Ara h1. • Thus, the equilibrium concentrations of Ara h1 will be a) 11.9 mcg/mL, b) 1.19 mcg/mL, or c) 0.119 mcg/mL. • Mast cells have a mean diameter of 12.8microns. Thus, a reasonable estimate of the volume of a mast cell is a sphere of radius 6.5 microns (V = (4/3)pr3 = 1.15 x 10-15 m3 = 1.15 x 10-9mL) • Given the molecular mass of 64000gm/mol and Avogadro's number is 6.022x1023 molecules per mol, we have: • (Xgm/mL)(6.022x1023 molecules/64,000 gm)(1.15x10-9 mL/mast cell) where x = 11.9x10-6, 1.19x10-6, or 0.119 x 10-6, respectively. • a) 128,767 molecules per mast cell • b) 12,877 molecules per mast cell • c) 1,288 molecules per mast cell

20. Mast Cell Mediators

21. a tryptase is not a reliable biomarker of mast cell degranulation or of mast cell numbers b tryptase seems to be the important molecule The kinetics of tryptase elevations in anaphylaxis trail those of symptoms and histamine release While there are tantalizing hypothetical reasons to suspect that tryptases may contribute to the pathobiology of anaphylaxis, there are no hard data to support such a hypothesis yet. Mast Cell Tryptase Genetics Caughey GH Tryptase genetics and anaphylaxis. JACI 2006;117:1411-1414

22. Platelet Activating Factor • PAF can recapitulate symptoms and signs of anaphylaxis in mice • PAF receptor antagonists protect mice from fatal anaphylaxis • PAF receptor KO mice have attenuated anaphylaxis • In humans, serum PAF acetylhydrolase activity was significantly decreased in those with fatal peanut-induced anaphylaxis compared to all control groups. Vadas P et al. PAF Acetylhydrolase Deficiency Predisposes to Fatal Anaphylaxis. J Allergy Clin Immunol 2003;111:S206.

23. PAF and Severe Anaphylaxis Vadas P et al. NEJM 2008;358:28-35

24. ? Basophils • Simons FER et al. Risk assessment in anaphylaxis: Current and future approaches. J Allergy Clin Immunol 2007;120:S2-24.

25. Basophils • Pathobiologic role in anaphylaxis is unclear • (+) FceRI, histamine, LTC4, and PAF (but not the biologically active form of PAF!) • Mostly in the blood stream, not as well endowed with mediators as most MCs. • Useful biomarkers? Gober et al studied 35 patients with confirmed Hymenoptera venom induced reactions and assessed changes in peripheral blood basophil activation markers after both in vitro and in vivo exposure to venom. (Gober LM et al JACI 2007;119:1181-1188)

26. Basophils Higher baseline CD63 was observed in patients with a history of systemic reaction despite immunotherapy. Greater increases in CD69 and CD203c were seen in patients with a history of systemic reactions Similar patterns after in vitro challenge as in in vivo. There was no correlation between marker expression changes and mediator release. Gober LM et al JACI 2007; 119:1181-1188

27. Basophils Gober LM et al JACI 2007; 119:1181-1188

28. Role of the Nervous System? MacQueen G et al. Science 1989;243:83-85

29. Murine Models

30. MCs and Basos in Murine Anaphylaxis Basos Removed M-phages Removed Basos Removed NKs Removed MCs, Basos Removed PMNs Removed Tsujimura Y Immunity, 2008;28:581

31. Galli SJ Immunity 2008;28:495

32. Antigens Drugs (PCN = #1, ASA/NSAIDs = #2, RCM, Anaesthetics) Foods Venoms Exercise and other physical agents Triggers Simons FER. Anaphylaxis, killer allergy: Long-term management in the community. J All Clin Immun 2006;117:367-377.

33. Triggers: Leviticus 18:23 Holden TE and Sherline DM. Obstet Gynecol 1973;42:138-140

34. Acute Treatment • ABCs • Epinephrine: 1:1000 = 1mg/mL, 0.3-0.5mg in adults, 0.01mg/kg in children up to a max of 0.3mg. • Consensus (primacy; route and location of administration = IM in anterolateral thigh (Simons FER et al. JACI 2001;108:871-873)) • Ignorance (dose, frequency, pharmacokinetics and pharmacodynamics in real patients) • Future Sublingual? (Rawas-Qalaji MM et al JACI 2006;117:398-403) • Side effects = Pallour, tremor, heart pounding, headache, shivers, dizziness (Simons FER et al. JACI 2001;108:871-873).

35. Epi: Take the Right Route

36. Acute Treatment (cont.) • O2 via NRB for hypoxemia • Inhaled b2 agonists for bronchospasm refractory to Epi • IV Fluids for hypotension refractory to Epi • Vasopressin (case reports) = 40 units IV • H1 and H2 antagonists = second line • Corticosteroids are untested and have delayed onset of action; they may help prevent a late phase recrudescence (biphasic reaction). • Glucagon = bolus of 1-5mg (20-30mcg/kg in children) given in 5 minutes and followed by an infusion of 5-15mcg/min titrated to clinical response.

37. Seconds, anyone? • It is difficult to predict which patients will require a second dose of Epi. • In various studies, anywhere from 16% to 36% required at least one additional dose of Epi. • Variables include route of Epi administration (SC vs. IM), precipitating allergen (aeroallergen extract, venom, food), patient co-morbidities (asthma), patient medications (b antagonists) and anxiety (patient and practitioners). • Therefore, be guided by clinical status: talk to and examine the patient.

38. Labs to Obtain:Acute Setting • Serum Histamine • Difficult at best, rapidly returns to baseline • 24 Urine Histamine metabolites, PGs LTs • Serum Tryptase • Total and mature b within 1-6 hours of the onset of symptoms. • Beware false negative in food induced anaphylaxis • gut MCs contain less tryptase than other MCs • Tryptase may enter the gut lumen • Basophils, which possess less tryptase than MCs, may play a more prominent role in food induced anaphylaxis than in other types of anaphylaxis. • Mast cell carboxypeptidase, chymase, PAF, Bradykinin, CRP, IL-2, IL-6, IL-10, TNFaRI have all been proposed but none is ready for prime time.

39. Observation: GOMER or SIMER? • Biphasic reactions occur in 3-20% • They are more likely in patients who present with severe symptoms • They can occur anywhere from 1-72 hours after the initial symptoms • A reasonable observation period is 4-6 hours. • Tailor observation times to the severity of the presentation and the risk of severity if a recrudescence occurs (e.g., if bronchospasm is a prominent symptom, the risk is higher)

40. Fatal Anaphylaxis Pumphrey RSH Clin Exper All 2000;30:1144-1150

41. Long Term Management • Risk Assessment • Confirmation of the diagnosis (History) • Lab Tests (acute = tryptase (total and mature); long term = skin tests, CAP, DBPCFC; ? Baso in vitro activation test, ? serum peptide microarrays) • Comorbidities and Concurrent Meds (asthma, b antagonists, ACEi’s) • Verification of trigger(s) • Novel Triggers • Mechanisms

42. Simons FER et al. Risk assessment in anaphylaxis: Current and future approaches. J Allergy Clin Immunol 2007;120:S2-24.

43. Simons FER et al. Risk assessment in anaphylaxis: Current and future approaches. J Allergy Clin Immunol 2007;120:S2-24.

44. Notae • Skin test reaction size does not necessarily correlate with reaction risk or severity • Levels of allergen specific IgE measured in vitro may help determine risk of systemic reaction (e.g. foods), but this is generally unproven or untrue for other allergens at this time. • Levels of allergen specific IgE do not reliably predict the severity of the next reaction. • However, many patients do seem to have individual, stereotypical, stable reaction patterns (e.g., Hymenoptera venom hypersensitivity)

45. Long Term Treatment: Risk Assessment Simons FER JACI 2006;117:367-377

46. Long Term Treatment: Prevention • Long Term Risk Reduction • Avoidance of specific triggers • Education: Unconsciousness → Vigilance← Paranoia • Preventive treatment, including trigger specific treatment • separation of exercise and food; • meds for idiopathic = H1/H2 antagonists, Steroids, LT modifiers • allergen desensitization for abx, ASA/NSAIDs, semen, venom • ? Anti-IgE, ? Anti-CD63 • Self-injectable Epi and an Action Plan • Education in the general public

47. Simons FER. Anaphylaxis, killer allergy: Long-term management in the community. J All Clin Immun 2006;117:367-377.

48. Anaphylaxis Management Plans (AMPs) Nurmatov U et al. JACI 2008;122:353-361

49. Should CAD patients with anaphylaxis have b blockers? • Using available literature, TenBrook et al constructed a Markov model for patients with heart disease (post MI or CHF) at risk for peanut-induced anaphylaxis to compare life expectancy with and without b antagonist treatment. The benefit of b antagonists outweighed the risk of death from anaphylaxis. Thus according to their model, CAD patients should receive these drugs. (TenBrook JA et al. Should b blockers be given to patients with heart disease and peanut-induced anaphylaxis? A decision analysis. JACI 2004;113:977-982)

50. Guidelines • History is the most important data source • Patients should wear Medicalert bracelets and/or carry other information about hypersensitivity. • Dr. Sheffer’s sage advice about what to say in restaurants.