Determine When Skin Testing, Test Doses and Desensitization are Appropriate David A. Khan, MD Professor of Medicine Allergy & Immunology Program Director Division of Allergy & Immunology 1
Disclosures Research Grants NIH, Vanberg Family Fund Speaker Honoraria Merck, Genentech, Viropharma, Baxter Organizations: Joint Task Force on Practice Parameters
Objectives Be able to identify patients appropriate for drug skin testing Be able to identify patients appropriate for drug challenges Be able to identify patients appropriate for drug desensitization
Case 1 The Role of Drug Skin Testing
Drug Skin Testing Penicillin is only drug with well-validated outcomes Skin testing with platinum-based chemotherapeutics of value Skin testing for drug-induced anaphylaxis may be helpful Skin testing for most other drugs and other reaction types of unclear benefit 5
Penicillin Skin Testing Penicillin skin testing using PRE-PEN and PCN-G has good negative predictive value (96-99%) in excluding penicillin allergy Some of these studies may have excluded penicillin anaphylaxis Macy E et al. JACI In Practice 2013;1:258-63. Solensky R, Khan DA et al. Ann Allergy Asthma Immunol 2010;105:273e1-e78. delreal GA, et al. Ann Allergy Asthma Immunol 2007;98:355-9. Green GR, et al. J Allergy Clin Immunol1977;60:339-45. Brown BC, et al. JAMA1964;189:599-604.
PRE-PEN & PCN-G 500 patients with history of PCN allergy Rash (40%), hives/ae (34%), unknown (14%), other (8%), anaphylaxis (2.8%) Mean time since reaction 20 years 496 negative skin tests underwent amoxicillin challenge 15/496 had subjective symptoms (e.g. itching) with amoxicillin challenge 4/496 had urticaria within 1 hr with amoxicillin challenge NPV=96-99.1% Macy E et al. JACI In Practice 2013;1:258-63.
Drug-Induced Anaphylaxis Case 40 year old woman with history of recurrent urinary tract infection developed confusion, nausea, dyspnea, chest pain, sensation of throat closure, facial swelling, generalized erythema, pruritus, and collapse within 20 minutes after the first dose of cotrimoxazole and an energy drink. Treated with epinephrine 0.3mg IM x 2 at pediatric ED and transferred to a nearby adult emergency department where BP was 87/46 mmhg Resolution of hypotension after 3 rd dose of epinephrine and IV fluids
Drug-Induced Anaphylaxis Case Patient remains unconvinced that sulfonamide antibiotic was the cause of her anaphylaxis Skin testing to TMP/SMX performed using a nonirritating dose
Skin testing for Antibiotics There are no validated diagnostic tests for evaluation of IgE-mediated allergy to nonpenicillin antibiotics Skin testing with non-irritating concentrations of non-penicillin antibiotics established for 15 commonly used antibiotics A negative skin test result does not rule out the possibility of an immediate-type allergy Positive skin test results to a drug concentration known to be nonirritating suggests the presence of drug-specific IgE Empedrad R et al. J Allergy Clin Immunology 2003;112:629.
Antimicrobial drug Nonirritating concentration Full-strength concentration Dilution from full strength azithromycin 10 µg/ml 100 mg/ml 1:10,000 cefotaxime 10 mg/ml 100 mg/ml 1:10 cefuroxime 10 mg/ml 100 mg/ml 1:10 cefazolin 33 mg/ml 330 mg/ml 1:10 ceftazidime 10 mg/ml 100 mg/ml 1:10 ceftriaxone 10 mg/ml 100 mg/ml 1:10 clindamycin 15 mg/ml 150 mg/ml 1:10 cotrimoxazole 800 µg/ml 80 mg/ml 1:100 erythromycin 50 µg/ml 50 mg/ml 1:1000 gentamicin 4 mg/ml 40 mg/ml 1:10 levofloxacin 25 µg/ml 25 mg/ml 1:1000 imipenem/cilastin 0.5 mg/ml 500 mg/100 ml 1:10 meropenem 1 mg/ml 50 mg/ml 1: 50 nafcillin 25 µg/ml 250 mg/ml 1:10,000 ticarcillin 20 mg/ml 200 mg/ml 1:10 tobramycin 4 mg/ml 80 mg/2 ml 1:10 vancomycin 5 µg/ml 50 mg/ml 1:10,000 Khan DA. Drug Allergy. In Manual of Allergy & Immunology 5 th Ed. 2012
Positive Trimethoprim-Sulfamethoxazole Skin Test
Case 2 The Role of Drug Challenge
Terminology Drug Challenge Test dosing Drug provocation test Graded dose challenge Incremental challenge
Definition of Drug Challenge The intention of a drug challenge is to verify that a patient will not experience an adverse reaction to a given drug Intended for patients who are unlikely to be allergic to the given drug Graded challenge or test dosing describes administration of progressively increasing doses of a medication until a full dose is reached Some test doses may be full therapeutic doses Solensky R, Khan DA et al. Ann Allergy Asthma Immunol 2010;105:273e1-e78.
Multiple Drug Allergy Case 38 yo woman with multiple drug-induced anaphylaxis Listed Drug Allergies RhoGAM Ciprofloxacin Ceftriaxone Amoxicillin Also reports episodes of crawling skin, nasal congestion, few non-pruritic skin lesions, throat tightness Treated with prednisone (up to 400 mg/d) for months at a time
RhoGAM Symptoms with Drug Reactions After 15 minutes, urticaria, throat tightness, BP 90/50 mm Hg, dyspnea, sense of impending doom Subsequent drug reactions: Usually within minutes of 1 st dose Itching, tingling lips, throat tightness, dysphonia, cough Other triggers Certain toothpastes, perfumes
Multiple Drug Allergy Case Skin testing with non-irritating concentration of ceftriaxone negative Penicillin skin tests negative What would you recommend now? A. Continued avoidance of all listed drugs due to anaphylactic history B. Drug desensitization if listed antibiotic required C. Graded challenge D. Full therapeutic dose challenge
Drug Anaphylaxis Case Due to doubtful reaction history patient given full therapeutic dose of ciprofloxacin 12 minutes later had itching of palms, lip numbness, and mild throat tightness BP 133/83, P 132 Over next 5 minutes symptoms more severe, with worsening throat tightness BP 142/96, P 142 Laryngoscopy performed and revealed VCD with arytenoids completely adducting with inspiration Symptoms resolved with reassurance and relaxation
Drug-Induced Vocal Cord Dysfunction (VCD) Often mistaken for anaphylaxis Primary and most severe symptom is isolated throat tightness Often have histories of multiple drug anaphylaxis from structurallyunrelated drugs Lack objective angioedema elsewhere Khan DA. Ann Allergy Asthma Immunol 110 (2013) 2-6.
Role of Drug Challenges Drug challenges are an important tool in diagnosis and management of drug allergic patients With careful assessment of patients and appropriately designed protocols, drug challenges can be safely performed in your office Patients with > 10 listed allergies and subjective symptoms at higher risk for subjective symptoms with drug challenge Kao L et al. Ann Allergy Asthma Immunol 110 (2013) 86e91.
Benefit of Drug Challenges The real benefit of drug challenges is that it answers the question (Is the patient allergic to the drug?) Avoids unnecessary repeated empiric desensitizations Great service the practicing allergist can provide to patients and referring physicians
New Code for Oral Challenge 95076 Ingestion Challenge Higher RVUs Minimum of 61 minutes required Likely requires a graded challenge Stay tuned on this No E&M should be billed in conjunction with this code
Case 3 Drug Desensitization
Case of Macrolide Allergy A 68-year-old woman developed urticaria and shortness of breath six days into a course of clarithromycin for Mycobacterium avium intracellulare infection Her pulmonologist advised her to take a test dose of azithromycin 250 mg. Within an hour she developed urticaria, shortness of breath, and throat tightness resulting in an emergency department visit. Swamy N et al. Ann Allergy Asthma Immunol 2010;105:489-90.
Macrolide Allergy Case: Confirmed with Skin Tests Swamy N et al. Ann Allergy Asthma Immunol 2010;105:489-90.
Role of Drug Desensitization Penicillin and chemotherapy desensitization protocols have been studied the most Similar desensitization principles can be used for other drugs Most drug desensitizations associated with ~ 1/3 risk of reactions during desensitizations severe anaphylactic reactions are rare Choice of location depends on treatment facilities, experience, drug, and patient factors
Drug Challenge vs Drug Desensitization Likelihood of drug allergy Challenge low Desensitization high # steps 1-3 > 12 Dosing increments 10-fold 2-fold Diagnostic test yes no Induces drug tolerance Must be repeated prior to drug readministration Reactions with procedure no no yes yes < 10% ~ 30% 28
Drug Desensitizations Indicated for patients with: High likelihood or confirmed drug allergy e.g. + skin test In need of culprit drug where no therapeutic alternative exists
Basic Template of Drug Desensitization Protocols Typical starting dose is 1/10,000 th of target therapeutic dose Can also use calculated dose from skin test as starting point Further dosage increases are typically double the previous dose Administered at 15-20 minute intervals until therapeutic dosage achieved
Oral Penicillin Desensitization Wendel GD et al. New Engl J Med 1985;312:1229-32.
Intravenous Desensitization Protocol Castells MC. Curr Opin Allergy Clin Immunol 2006;6:476 481.
Oral Clarithromycin Desensitization Protocol Swamy N et al. Ann Allergy Asthma Immunol 2010;105:489-90.
Back to the Case Clarithromycin desensitization performed in the office No adverse reactions developed during the desensitization After the desensitization she began routine administration of clarithromycin 500 mg twice a day and received this dose over the following three months She tolerated the treatment course without any adverse effects, and had resolution of her respiratory symptoms
Conclusions Other than penicillin skin testing, drug skin testing has a limited utility when negative, but when positive can be helpful Drug challenges are an underutilized tool and with careful selection of patients, can be done safely in the office Drug desensitizations are effective when used appropriately but are often over utilized instead of performing a drug challenge