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Drug ! Now What Drug is Safe? Speaker has no relationship to disclose. Prescribing Pearls for Primary Care

Amelie Hollier, DNP, FNP-BC, FAANP Lafayette, LA President, APEA

Objectives What is a Drug Allergy? • Identify symptoms of drug in • “Immunologic reaction to a drug” patients who exhibit possible allergic • Gell And Coombs Classification System is reactions. used • Develop a strategy for continuation of pharmacologic treatment after allergy is identified • Identify “culprit” drugs involved in reactions

Gell and Coombs Classification System Type I Mechanism Ty pe I IgE-mediated , Activation of mast cells, basophils, release of (occurs angioedema, Immediate-type vasoactive substances: , prostaglandins, within 1 , cytokines, and leukotrienes hour) bronchospasm Type II IgG antibodies and Hemolytic complement anemia Type III disease; IgG and IgM Type IV Cell mediated or Contact What we delayed dermatitis don’t see!! What we do see!! hypersensitivity

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Characteristics of Type I Reactions Type I Reactions Manifestations are due to ruptured mast cells MOST SEVERE: • Classic finding: Urticaria, pruritis, flushing, • Angioedema angioedema, wheezing, hypotension, GI • Anaphylaxis-involves at least 2 body systems symptoms • Classic wheal and flare hallmark signs of mast cell degranulation

True or False Anaphylaxis Epinephrine is the drug Epinephrine: • Drug of choice of choice to treat • Prevent or reverses airflow obstruction in upper and lower airways anaphylactic reactions. • Prevents or reverses cardiovascular collapse

Anaphylaxis Anaphylaxis

Bronchodilators: Histamines H1: • Given to relieve symptoms not relieved by • Relieve itch and hives epinephrine • DO NOT RELIEVE airway symptoms, shock, etc. • Adjunctive treatment • Onset of action is slow (even if given IV) • No effect on mucosal edema

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Anaphylaxis Anaphylaxis Histamines H2: Glucocorticoids: • Minimal evidence to support use • Onset of action takes several hours • Guidelines don’t include these • Given to prevent the biphasic reactions that • Ranitidine usually infused take place in 23% of adults with anaphylaxis • Cimetidine infusion can produce hypotension (11% of children) • Stop at 72 hours because all biphasic reactions take place by 72 hours

Take Home Point Type 1: When? • Anaphylaxis almost NEVER occurs • Rapidly! multiple days in to therapy IF doses • IV: seconds to minutes have been continuous • • If doses were skipped, then possible Oral on empty stomach: 3- 30 minutes • Oral with food: 10- 60 minutes

Type 1: When? Type I Reactions are COMMON!!!! Ty pe I IgE-mediated Anaphylaxis, • Urticarial rashes after multiple days of (within 1 Immediate-type angioedema, exposure are possible if drug is known to be hour) hypersensitivity hives, allergenic (beta-lactams) bronchospasm • Consider involvement if rash occurs Type II IgG antibodies and Hemolytic several days into treatment complement anemia Type III Immune complex Serum sickness disease; IgG and IgM

Type IV Cell mediated or Contact delayed dermatitis hypersensitivity

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Types II and III are Uncommon Type IV is Common Ty pe I IgE-mediated Anaphylaxis, Type I IgE-mediated Anaphylaxis, (within 1 Immediate-type angioedema, (within 1 Immediate-type angioedema, hour) hypersensitivity hives, hour) hypersensitivity hives, bronchospasm bronchospasm Type II IgG antibodies and Hemolytic Type II IgG antibodies and Hemolytic complement anemia complement anemia Type III Immune complex Serum sickness Type III Immune complex Serum sickness disease; IgG and IgM disease; IgG and IgM

Ty pe I V Cell mediated or Contact Ty pe I V T Cell mediated or Contact delayed dermatitis delayed dermatitis hypersensitivity hypersensitivity

Type IV Mechanism Type IV Cell Mediated Reaction T-cell mediated, delayed at least 24-48 hours but may begin weeks to months after treatment starts, not • Prominent skin findings (skin is a huge mediated by antibodies but involves activation of T repository for T cells) cells • Skin reacts rapidly if allergens penetrate skin or diffuse into the skin via circulation • Other organ involvement

What we don’t see!! What we do see!!

Type IV Cell Mediated Reaction Type IV Cell Mediated Reaction Common Skin Reactions: MOST SEVERE: • Contact dermatitis • Stevens-Johnson syndrome (SJS) • Morbilliform eruptions (other mechanisms can produce morbilliform rashes) • Toxic epidermal necrolysis (TEN) • Others • Drug-induced hypersensitivity syndrome (DIHS) or drug rash with eosinophilia and systemic symptoms (DRESS)

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When? Type IV Reactions When? Type IV Reactions • Delayed by at least 48-72 hours • SJS, DRESS can occur after weeks • Could even occur 1-3 days after 10 of unremarkable treatment day course of antibiotic • Usually days to weeks • Very impressive!!!! • Reaction depends on how many T cells are stimulated by the drug (a lotà quickly) (fewà slowly)

Type IV Reaction are COMMON!!!! “Other” Reactions Ty pe I IgE-mediated Anaphylaxis, Ty pe I IgE-mediated Anaphylaxis, (within 1 angioedema, (within 1 angioedema, Immediate-type Immediate-type hour) hives, hour) hives, hypersensitivity hypersensitivity bronchospasm bronchospasm Type II IgG antibodies and Hemolytic Type II IgG antibodies and Hemolytic complement anemia complement anemia Type III Immune complex Serum sickness Type III Immune complex Serum sickness disease; IgG and IgM disease; IgG and Ty pe I V Cell mediated or Contact IgM delayed dermatitis Ty pe I V Cell mediated or Contact hypersensitivity delayed dermatitis Other Various Various hypersensitivity

“Other” Types of Reactions are Pretty Common Example 1: Opiates Pseudoallergic Reactions Pseudoallergic Reactions • Don’t be fooled by the name!!!!! • Range from mild to fatal • Opiate analgesics: • Uncertain how these reactions occur Morphine and codeine • Probably mast cell degranulation by a cause direct mast cell non-IgE mediated mechanism activation • Don’t worsen with repeated exposure

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Common Culprits Case: “John” Pseudoallergic Reactions John has taken guafenesin with • Radiocontrast medium • Opiates dextromethorphan. He • NSAIDs develops urticaria. • Muscle relaxants (atracurium, vecuronium, succinylcholine, curare) • Chemo agents Etiology? • Vancomycin: “Red man” syndrome

Case: “John” Other Common Culprits Dextromethorphan PseudoallergicReactions in Children • To m at o e s Codiene • Strawberries

Viral Infections Case “Emma” Can predispose patients to reactions Emma is a college student who to certain drugs presents with cough, fever, and • Epstein-Barr plus amoxicillin feeling “lousy” after studying for 24 • Amoxicillin in children can produce hours for a “big” exam. She receives exanthematous reactions a Rx for azithromycin. She returns • CMV plus antibiotics the next day with acute urticaria. • HHV 6 Etiology? • HIV (sulfa drugs)

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Allergic Reaction Allergic Reaction Penicillins • Most common allergies are to • 5.1/1000 patients is antibiotics allergic (0.5%) • 5-10% of patients report PCN allergy • PCN can cause all 4 types of reactionsbut Type 1 is most common

The truth is……. The problem is……. Self reported “PCN allergic” Most (85-90%) patients are more likely to patients who receive broad spectrum state PCN allergy antibiotics: DO NOT have a true allergy to FQs, clindamycin, vancomycin, rd PCN 3 gen cephalosporins. Macy E, Contreras R. Healthcare use and serious infection prevalence associated with penicillin “allergy” in hos pitaliz ed patients : a cohort s tudy. J Allergy Clin Immunol. 2014; 133:790-796.

Another problem is……. Most Common PCN Reaction Self reported “PCN allergic” IgE Mediated patients are: Presents with intense 30% more likely to have VRE itching, urticaria, angioedema, wheezing, 23% more likely to have C diff abdominal distress 14% more likely to have MRSA (emesis or diarrhea),

Reddy V, Baman NS, Whitener C, Ishmael FT. Drug resistant infections with methicillin resistant Staphylococcus aureus, Clostridium difficile, and vancomycin resistant Enterococcus are associated with a hypotension higher prevalence of penicillin allergy. J Allergy Clin Immunol. 2013;131(Suppl):AB1 70.

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IgE Mediated Symptoms Risk Factors for PCN Allergy • Symptoms appear within minutes to 4 • Age: 20-49 years at greatest risk for hours of exposure to the IgE, especially anaphylactic allergen • Frequent repeated courses • It can happen on the • Route: IV, IM more associated with second exposure or the anaphylaxis 22nd exposure

Hereditary Factors A 24 year old receiving amoxicillin-clavulanate • Children of parents with for acute sinusitis antibiotic allergy 15 develops raised rash and times more likely to be nd antibiotic allergic (by urticaria on 2 day of history) treatment. What now?

J Allergy Clin Immunol. 2000;105(1 Pt 1):184.

Clinical Action Clinical Action • Bring her into the office for evaluation • If a true reaction: Treat it! (Epinephrine, of the symptoms! antihistamines, steroids, etc.) • Patients tend to be poor historians • Get detailed history from patient about skin rashes • Skin testing is available • Able to test for PCN allergy; and allergy to clavulanate

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Clinical Action Suppose this happened 3 years ago? • Strongly consider referral to allergist for confirmatory testing 24 year old receiving amoxicillin- • Complete test could take 2 hours (Skin test; if clavulanate for acute sinusitis negative, then oral amoxicillin challenge with nd 1 hour observation) develops urticaria on 2 day of treatment. What now?

Clinical Action Common Clinical Scenario Get a Good History if possible “my mama told me I had a • What kind of reaction was it? reaction to PCN when I was a • Timing of the onset of the reaction • Exact agent child” • Dose, route • What other meds on board • Treatment and response to treatment • Similar history with other drugs?

Clinical Facts Consequences of NOT Testing

• 50% of patients with IgE mediated PCN • Patients avoid beta lactams for future allergy lose sensitivity 5 years after last infections reaction • Treated with more broad spectrum • 80% of patients with IgE mediated PCN antibiotics allergy lose sensitivity 10 years after last • Antibiotic resistance develops reaction

• Referral to allergist if available

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Allergy Referral Strongly consider referral to allergist if: • PCN allergy plus one other antibiotic allergy Can PCN allergic patients • Patients with frequent sinusitis, other infections safely receive • Performed using skin testing, results in less cephalosporins? than an hour

2 Issues True Allergic Reaction There MUST be a PCN •IgE mediated allergic reaction!!! (type 1 hypersensitivity reaction)

Morbilliform Rash Morbilliform Rash • Rash is macular or Usually T-cell mediated maculopapular, lesions • Concurrent viral infections are fixed, area expands predispose patients to over several days morbilliform rash • May itch • Unknown mechanism by • More prevalent in children which this occurs • More common with aminopenicillins (amox and ampicillin)

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The rash is Not IgE-mediated if neither urticarial nor pruritic!!! Second Issue How And there is NO increased risk of significant is the same rash recurring with the cross- repeated courses of the same sensitivity antibiotic. reaction?

Journal of Family Practice, Feb. 2006

Likely Allergy to Likely Allergy to

Cephalosporins after allergy to PCN Cephalosporins after allergy to PCN Ver y likely to have SAME allergic reaction with these drugs because they share a similar • Cephalexin (1st gen) R side chain • Cefadroxil (1st gen) • Cefaclor (2nd gen) Pen G Cefaclor Cefadroxil • Cefprozil (2nd gen) • Ceftriaxone (3rd gen IM) (Rocephin) Amoxicillin Cephalexin Ceftriaxone • Cefpodoxime (3rd gen ) (Vantin) Ampicillin Cefprozil Cefpodoxime Journal of Family Practice, Feb. 2006

UNLIKELY Allergy to UNLIKELY Allergy to Cephalosporins Cephalosporins after allergy to PCN after allergy to PCN NOT likely to have SAME allergic reaction with these drugs because they are dissimilar • Cefazolin (1st gen IM) in structure • Cefuroxime (2nd gen) Cefazolin Cefuroxime Ceftibuten • Cefdinir (3rd gen ) (Omnicef) Cefdinir • Cefixime (3rd gen ) (Suprax) • Ceftibuten (3rd gen ) (Cedax) Cefixime

Journal of Family Practice, Feb. 2006

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RECOMMENDATION Low Risk

The risk of an allergic reaction is very low or non-existent if the IF PCN reaction > 10 years ago and side chains of the drugs are not reaction did not include IgE mediated features, similar. THEN Consider giving cephalosporin if there is no sharing of the side chain. Reaction within 24 hours may occur in < 1% of

Journal of Family Practice, Feb. 2006 patients. Anaphylaxis possible but unlikely!

Figure 1 in Ann Allergy Immunol1999; 83: Suppl.

Moderate Risk Graded Challenge • This is used to exclude allergy to the medication in question IF PCN reaction < 10 years and • Used when the patient is UNLIKELY to be reaction DID include IgE mediated features, allergic to med in question THEN cephalosporin (with dissimilar side • Never used if known allergy to drug in chain) by graded challenge by allergist. question! Reaction within 24 hours may occur in < 1% of patients. Risk of anaphylaxis possible but not likely! Figure 1 in Ann Allergy Asthma Immunol1999; 83: Suppl.

Graded Challenge • Starting dose is 1/100 or 1/10 of full dose • Increase by 10-fold increments every 30-60 Can cephalosporin allergic minutes until therapeutic dose reached • Must plan for a possible anaphylactic patients safely receive reaction PCN?

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FYI Multiple Drug Allergy Syndrome There is a three-fold People who have allergic reactions increased coincidental risk (IgE or non-IgE) to 2 or more non- of adverse reactions to cross-reacting medications UNRELATED drugs among PCN allergic patients!

Allergic Reaction Sulfonamide Allergies AKA “Sulfa allergies” • Second most frequent cause • 3.4% of patients are “sulfa allergic” of allergic drug reactions are • They are NOT allergic to sulphur, “Sulfa drugs” sulphates, or sulphites!!!!!!!!

Sulfonamide Allergies HIV 2 Distinct Chemical Groups • Patients with HIV infection are 100 times more likely to have drug • Antimicrobial Sulfonamides: TMP- sensitivity than non-infected patients SMX • Marked increase in hypersensitivity to sulfonamides • Non-antimicrobial Sulfonamides: Diuretics, hypoglycemics, antiinflammatories

Curr Opin Allergy Clin Immunol. 2007;7(4):324.

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Sulfonamide Allergies Take Home Point Non-antimicrobial sulfonamides • Diuretics, hypoglycemics, anti- Avoid the term “Sulfa allergy”. inflammatories and anti-hypertensive agents Document allergy to specific • Do not contain arylamine group or medication and the reaction substituted aromatic ring that occurred.

Sulfonamide Allergies Sulfonamide Allergies AKA Sulfa alle rgie s AKA Sulfa allergies What’s the most common Skin Manifestations: clinical sign of a sulfonamide • Erythema, maculopapular or morbilliform rash, urticaria, pruritis allergy? • Appear within 72 hours of first dose • Resolve with discontinuing the sulfonamide

Sulfonamide Allergies Take Home Point AKA Sulfa allergies Fever + skin rash = Trouble • Fever is the second most If fever accompanies (precedes or common clinical sign immediately follows) a skin rash • An enormous cause of after ingestion of sulfonamide, clinical confusion! then assume (and prepare for) a systemic reaction!!!

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Types of Reactions Types of Reactions Hypersensitivity Reactions Hypersensitivity Reactions MOST COMMON with Sulfonamides Cutaneous Reaction Can Progress • Morbilliform/maculopapular rash with • Morbilliform/maculopapular rash with fever and systemic symptoms (malaise, fever and systemic symptoms pharyngitis) • Can progress to multi-system organ • Starts 1-2 weeks after start of treatment involvement (hepatitis, nephritis, others) • Peripheral smear: atypical lymphs, • Starts 1-2 weeks after start of treatment eosinophils • Re-exposure produces symptoms in 1-3 • Symptoms resolve with d/c’ing of drug days

Hypersensitivity Reactions Types of Reactions Stevens Johnson Syndrome (SJS) Hypersensitivity Reactions Toxic Epidermal Necrolysis (TEN) • Type I (IgE mediated) reactions • SJS: Malaise, fever, macules, plaques, are rare and blistering of mucous membranes • May involve the aromatic ring, • TEN: Similar symptoms but involves a not the arylamine ring larger body surface area • Not associated with non-antimicrobial sulfonamides

Hypersensitivity Reactions Erythema multiforme Cross-Reactivity • EM: cutaneous reaction involving mucus FDA information for most non- membranes and vesiculobullous lesions with propensity for extremities antimicrobial sulfonamide drugs • Palms of hands, soles of feet with contains warnings about possible lesions cross-reactions--- but these are rarely observed

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Management Patient: “Drew” Past Reactions to TMP-SMX 67 year old male who needs diuresis • History: Assess type of reaction with furosemide • Referral to Allergist?: there is no currently valid, reliable test for past Allergies: TMP-SMX allergy (rash and sulfonamide reactions fever, no other allergies) • Allergist is able to test for trimethoprim allergy or can rule this out (20% of TMP-SMX allergic HIV Can you safely give furosemide? patients are allergic to trimethoprim)

Patient: “Nancy” Patient: “Nancy” 70 year old female who needs Hhhhmmmm………. diuresis with furosemide Consult an allergist who can perform Allergies: TMP-SMX allergy (rash and test doses of the furosemide. fever), seafood, penicillin A patient with multiple drug allergies is at higher risk for allergic reaction to Can you safely give furosemide? ANY drug!

Sulfonamide Diuretic Allergy Patient: Mr. Boudreaux Patient Needs Diuresis 77 year old male who needs diuresis. • Ethacrynic acid (Edecrine) is Allergies: Hydrochlorothiazide preferred agent-no cross reactivity • Consult allergist if other diuretic is Can you safely give furosemide? desired (HCTZ, furosemide, What diuretic can you safely give? bumetanide, torsemide, carbonic anhydrase inhibitors).

Montanaro, A. Sulfonamide allergy in non-HIV infected patients. In: UpToDate, Bas ow, DS (Ed) Waltham, MA,2012

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IF Past Reaction to Sulfonamide ACE Inhibitor related was SJS or TEN Angioedema

• 20-30% of angioedema presenting to ER • 0.1 – 0.7% of patients on ACE-I will develop angioedema AVOID • More common in older, African Americans • Class effect • No commercial test to identify who is at risk

Montanaro, A. Sulfonamide allergy in non-HIV infected patients. In: UpToDate, Bas ow, DS (Ed) Waltham, MA,2012

Angioedema ACE Inhibitor related Angioedema 3 Types: 1. Mast cell-mediated angioedema • 50% occurs within the first week of (urticaria, pruritis, bronchospasm, etc.) administration, 66% within the first 3 months, but…….can occur years later 2. Bradykinin-induced angioedema • Visceral angioedema: diffuse abdominal pain NOT associated with urticaria, and diarrhea bronchospasm, pruritis, etc • Diagnosis delayed by months, years 3. Hereditary angioedema: rare form

ACE Inhibitor related ACE Inhibitor related Angioedema Angioedema • Switch to an ARB: 8% will be allergic to ARBs • Discontinue drug!!!! • Edema resolves in 24-48 hours • May have continued attacks in the first months following discontinuation (suggests mechanism unrelated to ACE inhibitor use)

Ann Allergy Asthma Immunol. 2007;98(1):57

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Allergy to NSAIDs Background on COX

• ASA is a strong inhibitor of COX-1 • Pseudoallergic: related to COX-1 • NSAIDs that inhibit both COX-1 inhibiting properties of the NSAID and COX-2 are called non- (induced by multiple NSAIDs including selective NSAIDs ASA) • NSAIDs that inhibit only COX-2 are called COX-2 selective • Allergic: IgE mediated (induced by a single NSAID in a susceptible person)

Pseudoallergic NSAID Allergy: IgE Mediated reactions • Due to a SINGLE NSAID • Any NSAID that inhibits COX-1 • Most common is ibuprofen but common with will produce symptoms in any COX-1 inhibitor susceptible patients • No commercial allergy tests for this • Usually seen in patients with asthma, allergies, or chronic urticaria

Patient: “Bonnie” Patient: “Bonnie” 44 year old female who is allergic to 44 year old female who is allergic to aspirin, naproxen, and ibuprofen. aspirin, naproxen, and ibuprofen. Is this more likely to be a pseudoallergy or IgE mediated What’s likely to happen if she takes allergy? celecoxib?

Pseudoallergy Probably OK

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Patient: “Harry” Patient: “Allison” 44 year old male who is allergic to 44 year old female who is allergic to celecoxib. celecoxib, ibuprofen, and naproxen. Is this more likely to be a pseudoallergy or IgE mediated Is this more likely to be a pseudoallergy allergy? or IgE mediated allergy?

IgE mediated Hmmmm……

NSAID Reported Allergy NSAID Reported Allergy • If reaction was severe or life- threatening, referral to allergist and AVOID NSAIDs, History VERY Important ASA

• Single NSAID or multiple? • Care with OTC combo meds • History of allergy, asthma, urticaria • Care with bismuth • IF only one event and patient has avoided all subsalicylate: metabolized to NSAIDs since then, then…….difficult salicylic acid • No problem with dietary salicylates

ASA Exacerbated AERD Respiratory Disease Clinical Presentation (AERD) • 30 mins – 3 hours after exposure to ASA, asthma exacerbation symptoms • Pseudoallergy (because • Nasal and ophthalmic symptoms it is not IgE mediated) • Flushing, erythema • Precipitated by meds • 15% have hives that can inhibit COX-1 • Less than 5% of asthma patients exhibit enzyme • Pathophysiology not well understood

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Thank you! References

• References used for developing this educational activity: • Reddy V, Baman NS, Whitener C, Ishmael FT. Drug resistant infections with methicillin resistant Staphylococcus aureus, Clostridium difficile, an d vancomycin resistant Enterococcus are associated with a higher prevalence of penicillin allergy. J Allergy Clin Immunol. 2013;131(Su p p l ):AB170. For questions or to contact me: • • UpToDate, NSAIDs (including aspirin): Allergic and pseudoallergic reactions. Accessed: August 2 6 , 2 0 1 5 . • • UpToDate, Anaphylaxis: Rapid recognition and treatment. Accessed: August 2 6 , 2 0 1 5 . • Amelie Hollier • UpToDate, Drug Allergy: Classification and Clinical Features. Accessed: August 2 6 , 2 0 1 5 . • • UpToDate, Approach to the patient with drug allergy. Accessed: August 2 6 , 2 0 1 5 . • [email protected] • J Allergy Clin Immunol. 2000;105(1 Pt 1):184. • • Journal of Family P ractice, Feb. 2 0 0 6 • • Curr Op in Allergy Clin Immunol. 2007;7(4):324. • • Dailymed.gov (drug package inserts); retrieved August, 2015 • • Joint Task Force on P ractice P arameters, American Academy of Allergy, Asthma and Immunology, Joint Council of Allergy, Asthma an d Immunology. Advanced Practice Education Associates Drug allergy: an updated practice parameter. Ann Allergy Asthma Immunol 2012; 105:259. • Lafayette, LA

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