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Immune System Disorders - Anaphylaxis, Angioedema, Drug Allergies

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Presented at #EMconf on 3/16/2016 at Denver Health Medical Center

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Immune System Disorders - Anaphylaxis, Angioedema, Drug Allergies

  1. 1. IMMUNE SYSTEM DISORDERS Zach Jarou, MD | @zachjarou @DenverEMed Denver Health Residency in Emergency Medicine
  2. 2. 9.1 COLLAGEN VASCULAR DISEASE 9.1.1 Reynaud’s disease 9.1.2 Reiter’s syndrome 9.1.3 Rheumatoid arthritis 9.1.4 Scleroderma 9.1.5 Systemic lupus erythematosus 9.1.6 Vasculitis 9.3 TRANSPLANT-RELATED PROBLEMS 9.3.1 Immunosuppression 9.3.2 Rejection 9.2 HYPERSENSITIVITY 9.2.1 Allergic reaction 9.2.2 Anaphylaxis 9.2.3 Angioedema 9.2.4 Drug allergies 9.4 IMMUNE COMPLEX DISORDERS 9.4.1 Kawasaki syndrome 9.4.2 Rheumatic fever 9.4.3 Sarcoidosis 9.4.4 Poststreptococcal glomerulonephritis THE EM MODEL 16 IMMUNE SYSTEM DISORDERS IN 4 CATEGORIES abem.org/public/publications/em-model
  3. 3. THE EM MODEL ROUGHLY CORRELATES TO GELL AND COOMBS’ CLASSIFICATION • developed nearly 50 years ago to classify drug hypersensitivity reactions • does not account for pseudo-allergic reactions (ie: direct histamine release from hyperosmolarity of contrast media or red-man syndrome) • allergies may be caused by more than one mechanism (ie: contrast medium may also cause IgE-mediated mast cell degranulation)
  4. 4. ANAPHYLAXIS DEFINITION, MECHANISM, COMMON ALLERGENS, TREATMENT, BIPHASIC REACTIONS, DO STEROIDS HELP?, WILDERNESS BONUS EPI
  5. 5. ANAPHYLAXIS TYPE I HYPERSENSITIVITY DIAGNOSIS TWO OR MORE ORGAN SYSTEMS MECHANISM TWO SEPARATE EXPOSURES *ANAPHYLACTOID = NON-IgE MEDIATED, TREATED SIMILARLY absent 20% cases
  6. 6. ANAPHYLAXIS COMMON ALLERGENS
  7. 7. ANAPHYLAXIS TREATMENT
  8. 8. THE GOOD alpha-1 • vasoconstriction, increased PVR/BP • decreased mucosal/upper airway edema beta-1 • increased chronotropy • increased inotropy beta-2 • decreased release of inflammatory mediators from mast cells/basophils • increased bronchodilation/vasodilation THE BAD common anxiety, palpitations, pallor, tremor, fear, restlessness, dizziness, headache uncommon ventricular arrythmias, angina, MI, pulmonary edema, hypertensive urgency/emergency, ICH ANAPHYLAXIS EFFECTS OF EPI non-selective alpha/beta agonist
  9. 9. ANAPHYLAXIS WHEN IM EPI FAILS Step 1: Take your code-cart epinephrine. It doesn’t matter if it is 1:1,000 or 1:10,000! Step 2: Inject the full 1 mg into a 1,000 mL normal saline bag (final concentration 1 mcg/mL). Step 3: Run wide open until hemodynamics stabilize. • temporizing measure only, always call your pharmacist! • desired infusion rate 2- 10 mcg/min • carefully titrate using roller clamp based upon response PHARMACY INFUSION VS. DIRTY EPI DRIP
  10. 10. ANAPHYLAXIS ADJUNCTIVE AGENTS • Epi is 1st line, there is no equivalent substitute & no absolute contraindications • H1 blockers – relieve cutaneous symptoms only – no RCTs to support use during anaphylaxis • H2 blockers – in combination with H1 blockers, may help with cutaneous symptoms (up to 10% of cutaneous histamine receptors are H2), though no RCT for this or for use in anaphylaxis • Bronchodilators • Steroids • Glucagon for beta-blocked patients (1-2mg q5min IM/IV – may cause N/V/hyperglycemia)
  11. 11. ANAPHYLAXIS BIPHASIC REACTIONS Biphasic Anaphylaxis: Review of Incidence, Clinical Predictors, and Observation Recommendations Immunology and Allergy Clinics of North America, 2007. PMID 17493505 Study # Biphasic # Total % Biphasic Notes Popa & Lerner, 1984 3 N/A N/A coined term biphasic anaphylaxis Stark & Sullivan, 1986 5 25 20% epinephrine was given SQ Douglas et al, 1994 6 103 5.8% Brady et al, 1997 2 67 3% first to include return ED visits Brazil & MacNamara, 1998 6 34 18% range 4.5 - 29.5 hours, biphasic group initially required mean 1.2mg vs 0.6mg epinephrine Lee & Greenes, 2000 6 105 6% first study of children Forrest-Hay et al, 2003 9 91 9% 8 within 6 hours, 1 at 35 hours Ellis & Day, 2004 20 103 19.4% 40% occurred 10+ hours later, 55% biphasic never received epi (compared to 82% uniphasic) Smit et al, 2005 15 282 5.3% Hong Kong, mean 7.6 hours (range of 1.2 - 22.5 hours)
  12. 12. ANAPHYLAXIS BIPHASIC REACTIONS BACKGROUND •biphasic anaphylactic reactions have been reported to occur in as many as 20% of anaphylactic reactions from 1 – 72 hours after resolution of primary event METHODS •retrospective chart review of ~260k presentations to ED of a tertiary care hospital in Switzerland – 1334 (0.5%) for allergic reactions – 532 (0.2%) were for anaphylaxis •outcomes – clinically important biphasic reactions – number of ICU transfers – number of deaths within 10 days Biphasic anaphylactic reactions: occurrence and mortality Allergy, 2014. PMID 24725226 RESULTS •of 532 cases of anaphylaxis – 507 uniphasic – 25 (4.6%) biphasic, of which 12 (2.3%) were clinically important •no identifiable risk factors for biphasic CONCLUSIONS •biphasic reactions, especially clinically important ones, are rare •no mortality difference whether monitored for >8 hours compared to less •consider discharging patients after complete resolution of anaphylactic reaction & dispense with prolonged monitoring 532 cases, 2.3% rate of clinically important biphasic reactions
  13. 13. ANAPHYLAXIS BIPHASIC REACTIONS BACKGROUND •allergic reactions are common presentations to the ED •patients are often monitored for prolonged periods to manage potential biphasic reactions METHODS •retrospective cohort of 2800 adults presenting to two urban academic emergency departments in Canada •primary outcome = clinically important biphasic reaction •secondary outcome = mortality Incidence of Clinically Important Biphasic Reactions in Emergency Department Patients With Allergic Reactions or Anaphylaxis Annals of Emergency Medicine, June 2014. PMID 24239340 RESULTS •of 428k visits, 2800 (0.66%) were reviewed (496 anaphylaxis, 2323 allergic reactions) •185 (6.6%) had subsequent visit for allergic symptoms •5 (0.18%) had clinically important biphasic reactions (2 during ED visit, 3 post-discharge) •no fatalities CONCLUSIONS •clinically important biphasic reactions/fatalities are rare •prolonged routine monitoring of patients whose symptoms have resolved is likely unnecessary 2800 cases, 0.18% rate of clinically important biphasic reactions
  14. 14. ANAPHYLAXIS DO STEROIDS HELP? BACKGROUND •use of corticosteroids for allergic reactions in ED has doubled in the past decade METHODS •retrospective cohort of 2700 adults presenting to two urban academic emergency departments in Canada (473 anaphylactic) •half got steroids (either in ED and/or 5 day course), the other half received none •primary outcome = repeat allergy-related ED visit within 7 days •secondary outcomes = mortality, clinically important biphasic reactions Emergency Department Corticosteroid Use For Allergy Or Anaphylaxis Is Not Associated With Decreased Relapses Annals of Emergency Medicine, March 2015. PMID 25820033 RESULTS •no difference in repeat ED visits (n=170) – 5.8% steroid group – 6.7% non-steroid group •no difference between subgroups initially presenting with allergy vs. anaphylaxis •5 clinically important biphasic reactions – 4 steroid group (0.31% ) – 1 non-steroid group (0.071%) •no deaths CONCLUSIONS •steroids do not reduce the risk of relapse for patients presenting with allergic reactions or anaphylaxis 2700 cases, steroids do not change rate outcomes
  15. 15. ANAPHYLAXIS READY FOR DISCHARGE • EpiPen, the Kleenex of epinephrine autoinjectors • only comes in two-packs • $1 worth of drug in a $415 package (after insurance discounts) • shelf-life 18 months • Mylan Pharmaceuticals bought EpiPen from German company in 2007, revenue has increased from $2 million to more than $1 billion • in France, 2x EpiPens cost $85 September 23, 2015
  16. 16. ANAPHYLAXIS WILDERNESS BONUS EPI
  17. 17. ANGIOEDEMA ACE INHIBITOR INDUCED, HEREDITARY/ACQUIRED, PATHOPHYSIOLOGY, TREATMENT OPTIONS
  18. 18. ANGIOEDEMA PRESENTATION • consider fiberoptic naso-pharyngo-laryng-oscopy • lip/tongue swelling may not accurately reflect degree of airway edema • localized swelling of subcutaneous layer of skin OR submucosal layers of respiratory/GI tracts (+/- hives)
  19. 19. ANGIOEDEMA TYPES • allergic (with hives = mast cell/IgE-mediated) • non-allergic (no hives = bradykinin-mediated) – RAS blocker-induced (1/3 of all cases in the ED) • renin-angiotensin-aldosterone system blockers (ie: ACEi) • more than half of cases within 90 days but may take years – hereditary (HAE): 3 types • type I = low levels of C1 esterase inhibitor (80-85%) • type II = normal level, decreased function C1-INH (15-20%) • type III = estrogen induced – acquired (AAE) • rare, auto-antibodies against C1-INH • a/w lympho-proliferative disease – pseudoallergic • NSAIDs, contrast, opioids – idiopathic • chronic, a/w chronic urticaria • triggered by emotional/physical stress
  20. 20. ANGIOEDEMA PATHOPHYSIOLOGY • HAE/AAE = uninhibited conversion of kininogen to bradykinin • ACEi-AE = in some individuals, defect in other peptidases leads to BK accumulation (as well as substance P)
  21. 21. ANGIOEDEMA TREATMENT OPTIONS • HAE/AAE = FFP, recombinant C1-INH, ecallantide • ACEi-AE = stop ACEi, icatibant for severe presentations
  22. 22. ANGIOEDEMA TREATMENT OPTIONS A Randomized Trial of Icatibant in ACE-Inhibitor-Induced Angioedema New England Journal of Medicine, January 2015. PMID 25629740 BACKGROUND •ACE-inhibitor angioedema accounts for 1/3 of angioedema cases seen in ED •life-threatening, no approved treatment METHODS •multicenter, double-blind, randomized phase 2 study •30mg SQ icatibant, selective B2 antagonist (compared to standard therapy of IV prednisolone 500mg, plus clemastine 2mg – an anti-histamine) •primary end point = median time to complete resolution of edema RESULTS •27 patients •median hours to complete resolution – icatibant = 8 hours (IQR, 3-16) – control = 27 hours (IQR 20-48) •median hours to onset of relief – icatibant = 2.0 hours – control = 11.7 hours CONCLUSIONS •time to onset of relief & complete resolution of symptoms significantly shorter with icatibant compared to glucocorticoid & antihistamine it works but with only 27 patients not powered for adverse effects, major side effect: pain at injection site, debate: cost/indication
  23. 23. DRUG ALLERGIES PENICILLIN-CEPHALOSPORIN CROSS-REACTIVITY, CONTRAST MEDIA, LOCAL ANESTHETICS
  24. 24. DRUG ALLERGIES PENICILLINS-CEPHALOSPRINS The use of cephalosporins in penicillin-allergic patients: a literature review Journal of Emergency Medicine, May 2012. PMID 21742459 BACKGROUND •articles from the 1960s-70s report cross reactivity rates of 8-18% •the practice of avoiding cephalosporin administration to PCN-allergic patients persists despite low rate of cross reaction METHODS •literature review of all MEDLINE articles from 1950-2012 matching “penicillin$,” “cephalosporin$,” “allerg$,” “hypersensitivity,” “cross-react$” yielded 406 articles, 27 of which were reviewed RESULTS •little cross reactivity between B-lactam rings themselves, instead related to R1 side chain (amoxicillin/ampicillin) •cross-allergy w/1st -gen cephalosporins (OR 4.8) exists, negligible with 2nd -gen CONCLUSIONS •even when using 1st -gen cephalosporins or those with similar R1 side chains, rate of cross-reactivity is approximately 1% •use of 3rd /4th generation cephalosporins or those with dissimilar side chains has negligible risk of cross allergy PCN = most commonly reported medication allergy Up to 90% of patients with reported allergy don’t have it.
  25. 25. DRUG ALLERGIES LOCAL ANESTHETICS Diphenhydramine as an Alternative Local Anesthetic Agent Journal of Clinical and Aesthetic Dermatology, October 2009. PMID 2923931 • anaphylaxis from local anesthetics is extremely rare, most reactions are localized type 4 hypersensitivity • when anaphylaxis does occur, usually esters, rarely amides • no cross-reactivity between classes, however if patient reports true anaphylaxis and you don’t know the class… • or you don’t have access to lidocaine... or you’re near the toxic dose of local anesthetic...
  26. 26. DRUG ALLERGIES CONTRAST MEDIA The Relationship of Radiocontrast, Iodine, and Seafood Allergies: A Medical Myth Exposed Journal of Emergency Medicine, November 2010. PMID 20045605 • risk of reaction to contrast media ranges from 0.2% to 17%, low-osmolality contrast available since 1988 w/less effects • risk of reaction similar between those reporting allergy to seafood/shellfish and other food allergies/asthma • “iodine allergy” does not exist; no evidence that premedication works
  27. 27. IMMUNE SYSTEM DISORDERS Zach Jarou, MD | @zachjarou @DenverEMed Denver Health Residency in Emergency Medicine

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