1

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

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 co-trimoxazole 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 3rd 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 non-penicillin 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 5th 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

Symptoms with Drug Reactions

  RhoGAM   After 15 minutes, urticaria, throat tightness, BP

90/50 mm Hg, dyspnea, sense of impending doom

  Subsequent drug reactions:   Usually within minutes of 1st 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 structurally-unrelated 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

Challenge Desensitization Likelihood of drug allergy

low high

# steps 1-3 > 12 Dosing increments ≥10-fold 2-fold Diagnostic test yes no Induces drug tolerance

no yes

Must be repeated prior to drug readministration

no yes

Reactions with procedure

< 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 1/10,000th 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.

Castells MC. Curr Opin Allergy Clin Immunol 2006;6:476–481.

Intravenous Desensitization Protocol

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