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 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 Nonirritating Full-strength Dilution from full
drug concentration concentration strength
azithromycin 10 g/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 g/ml 80 mg/ml 1:100
erythromycin 50 g/ml 50 mg/ml 1:1000
gentamicin 4 mg/ml 40 mg/ml 1:10
levofloxacin 25 g/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 g/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 g/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 low high
allergy
# steps 1-3 > 12
Dosing increments 10-fold 2-fold
Diagnostic test yes no
Induces drug no yes
tolerance
Must be repeated no yes
prior to drug
readministration
Reactions with < 10% ~ 30%
procedure 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.

Intravenous Desensitization Protocol

Castells MC. Curr Opin Allergy Clin Immunol 2006;6:476481.

 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