Anaphylaxis Scot A Laurie MD Dallas Allergy and

Anaphylaxis Scot A. Laurie, MD Dallas Allergy and Asthma Center Clinical Assistant Professor, Division of Allergy & Immunology University of Texas Southwestern Medical Center

Historical Background • Discovered by Portier and Richet in 1902 – While attempting to immunize dogs to the venom of a sea anemone, they unknowingly sensitized the dogs • Dogs unexpectedly reacted to a previously nonlethal dose – Coined the term “anaphylaxie”, meaning without, or against, protection

DEFINITIONS • Anaphylaxis – Systemic, immediate hypersensitivity reaction caused by Ig. Emediated release of histamine and other mediators from mast cells and basophils – Clinical syndrome with multi-organ symptoms • • cutaneous respiratory cardiovascular gastrointestinal • Anaphylactoid – Identical symptoms as anaphylaxis – Non-Ig. E-mediated mechanism

EPIDEMIOLOGY • Hospitalization for Anaphylaxis – 13 yr retrospective review of anaphylactic shock from a hospital in Denmark • incidence of 3. 2 cases per 100, 000 inhabitants per year • mortality rate of these 20 cases was 5% – Sørensen H et al. Allergy 1989; 44: 288. • ER Visits for Anaphylaxis – Klein individually reviewed all 19, 122 ER records during a 4 month period from St. Mary’s Hospital in Rochester, MN – Incidence of anaphylaxis was 17 per 19, 122 emergency visits or 0. 09% – Only 4/17 had ICD-9 codes for anaphylaxis • most were simply classified as having an “allergic reaction” – Klein J, Yocum M. J Allergy Clin Immunol 1995; 95: 637 -8.

Epidemiology of Anaphylaxis • Retrospective review of • 1255 cases of “anaphylaxis” identified in Olmsted County from 1983 -1987 133 residents met criteria for anaphylaxis and had 154 reactions • 116 single episode • 13 had 2 episodes • 4 had 3 episodes • Anaphylaxis occurrence • • • rate 30/100, 000 person years Suspect allergen found 68% Allergy consultation in only 52% 1 patient died • 0. 65% fatality rate Yocum MW et al. J Allergy Clin Immunol 1999; 104: 452 -6.

Yocum MW et al. J Allergy Clin Immunol 1999; 104: 452 -6.

Anaphylaxis: Risk factors • Age – More common in adults • Atopy – Foods – Exercise – Latex – RCM – Idiopathic • Exposure route – Oral less likely • Gender – Males • Hymenoptera – Females • Latex • Muscle relaxant • Idiopathic

Mediators of Anaphylaxis

“SHOCK” ORGANS IN ANAPHYLAXIS • Skin • Respiratory tract • Cardiovascular system • Gastrointestinal tract

CUTANEOUS SYMPTOMS • Pruritus – initially palms, soles, groin, and axilla • Urticaria & Angioedema – – – most common finding usually resolves within 24 hours angioedema may persist for 2 -3 days • Warmth • Flushing • Erythema

RESPIRATORY SYMPTOMS • Lower respiratory symptoms – Dyspnea, wheezing, and chest tightness • Upper respiratory symptoms – – Nasal congestion, sneezing, rhinorrhea Laryngeal edema – often begin with a sensation of a “lump in the throat” – may progress to: vdysphonia vhoarseness vdrooling due to inability to swallow secretions vstridor vasphyxia

GASTROINTESTINAL SYMPTOMS • Abdominal cramping • Nausea • Vomiting • Diarrhea

CARDIOVASCULAR • Symptoms – – – lightheadedness tachycardia bradycardia hypotension vascular collapse • Signs – Arrhythmias • premature atrial contractions • atrial fibrillation • bundle branch block • peaked P waves and right axis deviation • ventricular premature contractions • ventricular fibrillation • asystole • myocardial infarction

FREQUENCY OF ANAPHYLACTIC SYMPTOMS

BIPHASIC & PROTRACTED ANAPHYLAXIS • Stark & Sullivan • Douglas et al. – Prospective study of 25 patients with anaphylaxis at PMH – 5 (20%) had " biphasic anaphylaxis" – 6 had "protracted anaphylaxis" – Risk Factors • oral agent • anaphylaxis began > 30 • minutes after exposure Stark B, Sullivan T. J Allergy Clin Immunol 1986; 78: 76 -83. – Biphasic anaphylaxis in only 5% of 44 inpatients • Douglas D et al. J Allergy Clin Immunol 1994; 93: 977 -85. • Both Studies – Glucocorticoid therapy did not prevent either recurrent or prolonged anaphylaxis – Patients without hypotension or laryngeal edema did not have biphasic reactions

Fatal Anaphylaxis Pumphrey RSH Clin Exp Allergy 2000: 30: 1144 -50.

Timing of Epinephrine in Fatal Anaphylaxis Pumphrey RSH Clin Exp Allergy 2000: 30: 1144 -50.

Self-injectable Epinephrine Use in Fatal Anaphylaxis Pumphrey RSH Clin Exp Allergy 2000: 30: 1144 -50.

Differential Diagnosis of Anaphylaxis and Anaphylactoid Reactions • Vasodepressor reactions • Flush syndromes- carcinoid • “Restaurant syndromes”- scombroidosis • Excessive endogenous production of histamine • • mastocytosis Nonorganic disease- panic disorder, vocal cord disorder, undifferentiated somatoform anaphylaxis Chronic idiopathic urticaria/angioedema

EVALUATION OF PATIENTS WITH ANAPHYLAXIS • Working definition of anaphylaxis – Either • Airway obstruction such as laryngeal, pharyngeal, or glossal edema or severe bronchospasm – Or • Documented hypotension or syncope – Plus • Symptoms of generalized mediator release – urticaria, angioedema, pruritus, or flushing • Review ER records for objective findings

DETERMINING THE ETIOLOGY OF ANAPHYLAXIS • Detailed History – – – Time of day Relationship to exercise, meals, and medications Prescribed medications • different formulations or lots of medications – Non-prescribed ingestants • vitamins, health food supplements, laxatives, and suppositories • specific ingredients of meals • within 4 hours of episode(s) – Women • menses or intercourse

SPECIFIC Ig. E in ANAPHYLAXIS • Skin testing – – – Accuracy > RAST Risk of fatal reactions Allergens • medications, anesthetics, • – – – venoms, foods, insulin, latex heterologous sera, vaccines, and other foreign proteins Specificity fairly good Sensitivity of many tests is ? Some drugs can cause direct histamine release – opiates, RCM , some muscle relaxants • RAST testing – Without risk – Limited applicability due to • lower accuracy • Few allergens available – venoms, foods, latex, and the major determinant of penicillin

FOOD SKIN TESTING IN ANAPHYLAXIS • Stricker et al – Panel of 79 antigens – Identified 7 food-induced anaphylaxis of 102 patients with IA • Stricker W et al. J Allergy Clin Immunol 1986; 77: 516 -519. • Patients frequently unaware of foods that caused reactions – Food allergic patients failed to identify causative food in 67% of positive DBPCFC • Atkins F. J Allergy Clin Immunol 1985; 75: 348 -355. – Most all patients with fatal food-induced anaphylaxis unknowingly ingested their fatal food • Skin testing with fresh foods – Commercial food extracts may lack antigenic epitopes

MEDIATOR MEASUREMENT IN ANAPHYLAXIS

TRYPTASE • Neutral protease in secretory granules of mast • cells Specific for mast cells • very minimal amounts in basophils • -tryptase • predominant form of tryptase in circulation in both normals and mastocytosis patients • -tryptase • released from secretory granules with systemic mast cell activation

TRYPTASE MEASUREMENTS • Total tryptase • • • measured with m. Ab B 12 measures both & -tryptase normal values < 15 ng/ml • increases detectable earlier than G 5 assay • available through commercial labs • -tryptase • measured with m. Ab G 5 • normal values < 1 ng/ml • undetectable within 30 minutes • peaks in 1 -2 hours • available through Dr. Schwartz’s lab at MCV

CLASSIFICATION OF ANAPHYLAXIS • Ig. E Mediated • Complement/Immune Complex Activation • Direct Histamine Release • Unknown Mechanisms

Ig. E MEDIATED ANAPHYLAXIS • Antibiotics – Penicillin, Cephalosporins, Sulfamethoxazole • Proteins – Venoms, Heterologous sera, Latex, Seminal fluid – Hormones: ACTH, Insulin, PTH, Gn. RH – Enzymes: Chymopapain, Streptokinase • Foods – Peanut, Tree nuts, Crustaceans, Fish, Seeds, Spices – Milk, Egg, Soy, Many others • Therapeutics – Allergen extracts – Vaccines - including fillers (gelatin) – Intraoperative agents • Thiopental, Muscle relaxants, ? Protamine, Fentanyl – Chemotherapeutics, Ethylene oxide gas, Psyllium – Local anesthetics, ? Corticosteroids, ? NSAID’s

LOCAL ANESTHETIC ALLERGY • Allergy rare and anaphylaxis extremely rare – allergy to parabens also rare • Non-cross-reacting local anesthetic groups – defined based on patch testing for contact dermatitis – unclear if any relevance to anaphylaxis • Skin testing & incremental challenge – validated method – recommended for evaluation of possible allergy

IMMUNE COMPLEX/COMPLEMENT ACTIVATION • ? Radiocontrast Media • Blood/Blood products – Plasma, Serum, cryoprecipitate – Ig. E mediated anaphylaxis • passive sensitization • Ig. E anti-Ig. A in Ig. A deficient patients • FVIII • Hemodialysis membranes • IVIG

THE MYTH OF SEAFOOD ALLERGY & RCM REACTIONS • Despite the common belief that individuals with seafood allergy have a higher risk of RCM reactions, there is no data to support this and it has no theoretical basis – Shellfish allergic patients are allergic to muscle proteins, not iodide – RCM reactions are not caused by iodide – Low-ionic RCM have a lower incidence of anaphylactoid reactions despite containing more iodide per particle than traditional RCM

DIRECT HISTAMINE RELEASE • Hypertonic Solutions – RCM, Mannitol • Plasma Expanders – Dextran, Hydroxyethyl starch • Drugs – Opiates, Vancomycin, Curare, Fluoroscein

Anaphylaxis with Unknown Mechanism • Exercise Induced Anaphylaxis • Idiopathic Anaphylaxis • Progesterone Anaphylaxis

ACUTE TREATMENT OF ANAPHYLAXIS • Early recognition and treatment – delays in therapy are associated with fatalities • Assessing the nature and severity of the • reaction Brief history – identify allergen if possible • initiate steps to reduce further absorption – medications (especially -blockers) • General Therapy – supplemental oxygen, IVF, vital signs, cardiac monitoring • Goals of therapy – ABC’s

EPINEPHRINE • First-line drug of choice in anaphylaxis • Mechanisms of action – agonist • increase BP by peripheral vasoconstriction – -agonist • reverse bronchoconstriction • positive ionotropic and chronotropic activity • increases cyclic AMP levels – inhibit further mediator release from mast cells and basophils • Subcutaneous administration – dose: 0. 3 to 0. 5 mg of a 1: 1, 000 dilution prn q 1015 min – IV epinephrine for cardiovascular collapse • Side effects – severe hypertension, arrhythmias, myocardial ischemia and infarction • DO NOT WITHHOLD EPINEPHRINE BECAUSE OF CARDIAC HISTORY

Epinephrine Absorption: SQ vs. IM Simons FER et al. J Allergy Clin Immunol 1998; 101: 33 -7.

Epinephrine Subcutaneous Epinephrine Intramuscular Simons FER et al. J Allergy Clin Immunol 1998; 101: 33 -7.

Epinephrine Subcutaneous Epinephrine Intramuscular Simons FER et al. J Allergy Clin Immunol 1998; 101: 33 -7.

Outdated Epi. Pens Simons FER et al. J Allergy Clin Immunol 1998; 101: 33 -7.

Simons FER et al. J Allergy Clin Immunol 2000; 105: 1025 -30.

Use of Epi. Pen in Children with Anaphylaxis • Retrospective survey of children with anaphylaxis • who attended an allergy clinic in North Adelaide Australia 45 episodes of anaphylaxis • Epi. Pen given • Epi. Pen not given 13 (29%) 32 (71%) • Epi. Pen given • Epi. Pen not given 2 (14%) p<. 05 15 (47%) • Hospitalization for anaphylaxis Gold MS, Sainsbury R. J Allergy Clin Immunol 2000; 106: 171 -6.

ANTIHISTAMINES IN ANAPHYLAXIS • Not a substitute for epinephrine • H 1 -antagonists – useful for cutaneous symptoms • H 2 -antagonists – somewhat controversial – combination of H 1 and H 2 antagonists was required for optimal prevention of hypotension in studies of histamine infusions – overall evidence favors the addition of H 2 antagonists • especially in the presence of hypotension

-BLOCKED ANAPHYLAXIS • Beta blockade – increase release of mediators – enhance the responsiveness of pulmonary, cardiovascular, and cutaneous systems to mediators – paradoxical responses to epinephrine • bronchoconstriction and bradycardia – unopposed adrenergic and reflex vagotonic effects • May be especially refractory to therapy • Treatment – high doses of isoproterenol or dopamine – atropine – glucagon • increases c-AMP • independent of receptor nausea and vomiting common

PREVENTION OF ANAPHYLAXIS • Referral to BC/BE allergist – Determine an etiology • skin testing • challenges • desensitization. – Educate the patient on avoidance • proper use and indications of injectable epinephrine • when to seek medical attention • obtain a Medic-Alert® bracelet – Develop a management plan • prevent and reduce further anaphylactic episodes • Select an alternative drug if on -blocker

ACUTE DESENSITIZATION • Indications – Patients allergic to an essential therapeutic agent – Systemic reactions to venoms (optional) • Technique – Escalating doses of antigen administered over a brief period – Oral route preferred when possible • Desensitization procedures are dangerous • Mechanism of desensitization – Unknown – Desensitized state is antigen specific • not due to tachyphylaxis to mediators, mast cell depletion, or unresponsiveness to any Ig. E signal

CASE REPORT • LB is a 62 yo WM who presented with • recurrent syncopal episodes. These episodes were associated with pruritus, urticaria, lightheadedness, and syncope with urinary & fecal incontinence and occurred after playing basketball or ping-pong. However, he has performed more vigorous exercise without reactions. An echocardiogram, Holter monitor and head CT were all normal. Physical examination was unremarkable

EXERCISE-INDUCED ANAPHYLAXIS • Classification – Food dependent EIA • Specific food dependent EIA – occurs only if exercise after eating specific food(s) – implicated foods v shellfish, wheat, celery, tomato, apple, grapes, litchi, hazlenut, chestnut, peanut, milk, rice, potato • Non-specific food dependent EIA – occurs if exercising after eating any food – Food independent EIA

POSSIBLE MECHANISMS OF EIA • Subthreshold amount of mast cell associated Ig. E cross- linking – Endogenous opioid stimulus can trigger primed mast cells to degranulate – Increases in codeine skin test reactivity after exercise – Increased wheal response to compound 48/80 in individuals with food-dependent EIA, but only after challenges with specific foods and exercise. – Gastrin can stimulate mediator release from mast • cells Abnormal responses of the autonomic nervous system – Increases in parasympathetic responses – Decreases in sympathetic activity

CLINICAL FEATURES OF EIA • 7% of anaphylaxis due to • EIA Symptoms & signs of EIA similar to other forms of anaphylaxis – premonitory symptoms • generalized warmth, pruritus • urticaria are usually 10 -15 mm in diameter • angioedema of face, palms, and soles – reactions occur while exercising or shortly thereafter – duration of 0. 5 to 4 hours • Exercise triggers – Tennis, warmups, dancing, soccer, basketball, running – vaginal delivery • Predisposing factors – personal or family history of atopy • familial EIA has been reported – aspirin ingestion prior to exercise may trigger 30% – exercising in warm or humid weather – menses

THERAPY OF EIA • Acute treatment – epinephrine • available while exercising • Prevention – exercise with a partner – limiting or discontinuing exercise at the first sign of prodromal symptoms – avoid NSAID’s – avoiding foods for 4 -5 hours prior to exercise – antihistamines - unable to totally prevent attacks – oral disodium cromoglycate – “exercise desensitization”

Natural History of EIA • 279 EIA patients completed mailed survey • Clinical course – – Attacks/yr decreased from 14. 5 to 8. 3 47% decrease in attacks 46% same 7% increased • Food Associated EIA – 37% patients – Shellfish, alcohol, tomato most common triggers • Avoidance behaviors – Avoid exercise in extreme hot/cold or allergy season – Avoid eating before exercise Shadick NA et al. J Allergy Clin Immunol 1999; 104: 123 -7.

Case Report • CW is a 14 yo WF with a history of large local reactions to “bees”. 3 weeks prior to evaluation she was bit in the forehead by an ant and within 5 minutes developed facial urticaria, chest tightness, and throat tightness which improved with H 1 & H 2 antagonists administered by her father a cardiologist. – Prick testing to imported fire ants was positive

IMPORTED FIRE ANTS • IFA most common cause of anaphylaxis to • stinging insects in this area Imported fire ant species – Solenopsis richteri • introduced from Uruguay or Argentina accidentally into the USA through the port of Mobile, Alabama in 1918 • localized to northeastern Mississippi and northwestern Alabama – Solenopsis invicta • Brazilian species introduced later between 1933 -1941

Fire Ant Anaphylaxis • • 0. 6% to 2% of patients requiring medical treatment for stings Texas has the 2 nd highest number of IFA sting fatalities Diagnosis – anaphylaxis history after sting with development of a pustule – fire ant-specific Ig. E by skin tests • 25% of nonallergic individuals in endemic areas have IFA specific Ig. E Immunotherapy – Indicated for patients with systemic reactions, especially anaphylaxis – IFA whole body immunotherapy efficacy • field re-stings – 2. 1% risk of anaphylaxis • intentional sting challenge – 0/30 reactions • Optimal duration of immunotherapy unknown

CASE REPORT • 34 yo BF with recurrent episodes of pruritus, • • urticaria, angioedema, chest tightness, and syncope. One episode required ER treatment and hypotension was documented. All episodes occurred shortly after sexual intercourse. She was seen initially by a neurologist who thought she was having hypoglycemic attacks and recommended eating prior to intercourse which did not help. She also had an ETT performed and the cardiologist thought she “was crazy”. Skin testing with her partners semen at 1: 1, 000 dilution was markedly positive while her partner was skin test negative Condom use was recommended and prevented the attacks

HUMAN SEMINAL PLASMA ANAPHYLAXIS • First reported by Specken in 1958 • Pathogenesis – Halpern et al. (1967) • Evaluated a woman with anaphylaxis occurring 15 -30 minutes after coitus • Scratch tests were positive to – husband’s whole sperm & seminal fluid devoid of spermatozoa – donor seminal fluid devoid of spermatozoa • Scratch tests negative to – – husband’s serum semen from rabbit, guinea-pig, horse and bull • Passive transfer (Prausnitz-Küstner reaction) – positive in 5 female controls as well as in monkeys • Chromatography and electrophoresis of seminal fluid identified basic protein fractions that were the most antigenic

HUMAN SEMINAL PLASMA ANAPHYLAXIS • Antigens – Isolated to seminal plasma • reactions can occur with vasectomized partners • only one case reported of a women reactive to spermatozoa and HSP • canine sperm can also induce anaphylaxis due to bestiality – Antigenic fraction of seminal fluid • MW of 20, 000 to 30, 000 daltons • heat stable • prostatic origin • prostate specific antigen (PSA) may be a major allergen

THERAPY OF HSP ANAPHYLAXIS • Condoms – – universally successful may induce remission if used for prolonged periods • Prophylactic antihistamines – may control local HSP reactions – ineffective for systemic reactions • Pregnancy – successful impregnation may be achieved using artificial insemination with isolated spermatozoa • Immunotherapy – extracts of antigenic fractions of HSP most successful • Immunologic changes variable – decrease in Ig. E – progressive rise in Ig. G – rapid desensitization • parenteral and local (intravaginal) – long term success • up to 8 years after immunotherapy • maintaining sexual activity 2 -3 times per week

Idiopathic Anaphylaxis • Diagnosis of exclusion – Careful evaluation for known causes should be performed • Mechanism is unknown • Patients present with the same constellation of • symptoms as others with anaphylaxis Treatment approach is the same – Preventative therapy with qd or qod prednisone may be required • Patients require education and support as part of their disease management

CONCLUSIONS • Anaphylaxis is the most dramatic and potentially fatal • • manifestation of immediate hypersensitivity Majority of reactions are due to medications, insect stings, radiocontrast media and food, however many are idiopathic Most anaphylactic reactions respond to aggressive therapy, but fatalities still occur, especially if treatment is delayed Epinephrine is still underutilized in many patients Almost all cases of anaphylaxis should be referred to an allergist