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

Speaker Honoraria

NIH, Vanberg Family Fund

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 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 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
azithromycin
cefotaxime
cefuroxime
cefazolin
ceftazidime
ceftriaxone
clindamycin
cotrimoxazole
erythromycin
gentamicin
levofloxacin
imipenem/cilastin
meropenem
nafcillin
ticarcillin
tobramycin
vancomycin

Nonirritating
concentration
10 g/ml
10 mg/ml
10 mg/ml
33 mg/ml
10 mg/ml
10 mg/ml
15 mg/ml
800 g/ml
50 g/ml
4 mg/ml
25 g/ml
0.5 mg/ml
1 mg/ml
25 g/ml
20 mg/ml
4 mg/ml
5 g/ml

Full-strength
concentration
100 mg/ml
100 mg/ml
100 mg/ml
330 mg/ml
100 mg/ml
100 mg/ml
150 mg/ml
80 mg/ml
50 mg/ml
40 mg/ml
25 mg/ml
500 mg/100 ml
50 mg/ml
250 mg/ml
200 mg/ml
80 mg/2 ml
50 mg/ml

Dilution from full

strength
1:10,000
1:10
1:10
1:10
1:10
1:10
1:10
1:100
1:1000
1:10
1:1000
1:10
1: 50
1:10,000
1:10
1:10
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

Over next 5 minutes symptoms more severe,

with worsening throat tightness

BP 133/83, P 132

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
# steps
Dosing increments
Diagnostic test
Induces drug
tolerance
Must be repeated
prior to drug
readministration
Reactions with
procedure

Challenge
low

Desensitization
high

1-3
10-fold
yes
no

> 12
2-fold
no
yes

no

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 1/10,000th 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