This document discusses skin testing for the diagnosis of immediate drug hypersensitivity reactions. It provides guidelines for selecting the appropriate diagnostic tests, performing skin prick and intradermal tests, and determining maximum non-reactive drug concentrations. Skin testing is recommended as the most common method for confirming drug sensitization, though sensitivity and predictive values vary by drug. Proper technique and use of non-irritating concentrations are important. Guidelines provide dilution thresholds for common drugs to avoid inducing reactions.

1. Prick and intradermal skin tests in
immediate type drug induced
hypersensitivity reactions
Author: Nadia Gherman,MD,PhD
Allergology and Clinical Immunology consultant physician, Clinical
Emergency County Hospital Cluj
University Teaching Assistant, Dept. of Allergology and Immunology
“Iuliu Ha ieganuț ” University of Medicine and Pharmacy Cluj-Napoca
nadiaghermanionica@yahoo.com

2. Classification of drug allergies
P. Demoly, N. F. Adkinson, K. Brockow et al, International Consensus on drug allergy. Allergy. 2014 Apr;69(4):420-37.

3. Grade of severity of the immediate HSR (and clinical features)
.. Mertes PM1
, Malinovsky JM, Jouffroy L; Working Group of the SFAR and SFA, Aberer W, Terreehorst I, Brockow K, Demoly P; ENDA;
EAACI Interest Group on Drug Allergy. Reducing the risk of anaphylaxis during anesthesia: 2011 updated guidelines for clinical practice.
J Investig Allergol Clin Immunol. 2011;21(6):442-53.

4. Selecting diagnostic tests in the immediate type HSR to drugs
Romano A1
, Torres MJ, Castells M, Sanz ML, Blanca M Diagnosis and management of drug hypersensitivity reactions. J Allergy Clin Immunol.
2011 Mar;127(3 Suppl):S67-73

5. The skin tests in the diagnosis of drug allergy
Skin test is the most commonly used procedure to confirm a sensitization in drug
hypersensitivity; for many drugs, in vitro tests are not available or sufficiently
validated
Their diagnostic value has not been fully evaluated for all drugs
The tests should follow standard procedures and should be performed by trained staff
Skin tests have to be applied depending on the suspected pathomechanism of the DHR
Sensitivity and predictive values vary, depending on the culprit drug and the clinical
presentation
They appear to be ‘good’ for immediate DHRs to β-lactam antibiotics, NMBA, platin
salts, and heparins, but moderate to low for most other drugs.
P. Demoly, N. F. Adkinson, K. Brockow et al, International Consensus on drug allergy. Allergy. 2014 Apr;69(4):420-37
Brockow K, Garvey LH, Aberer W,et al. Skin test concentrations for systemically administered drugs -- an ENDA/EAACI DrugAllergy Interest Group
position paper. Allergy. 2013 Jun;68(6):702-12
.

6. The skin tests in the diagnosis of immediate type drug allergy
P. Demoly, N. F. Adkinson, K. Brockow et al, International Consensus on drug allergy. Allergy. 2014 Apr;69(4):420-37
Brockow K, Garvey LH, Aberer W,et al. Skin test concentrations for systemically administered drugs --
an ENDA/EAACI DrugAllergy Interest Group position paper. Allergy. 2013 Jun;68(6):702-12
PM Mertes,1 JM Malinovsky,2 L Jouffroy,3 and the Working Group of the SFAR* and SFA* and W Aberer,4 I Terreehorst,5 K Brockow,6 P Demoly,7 for
ENDA** and the EAACI Interest Group on Drug Allergy. Reducing the Risk of Anaphylaxis During Anesthesia: 2011 Updated Guidelines for Clinical Practice .
J Investig Allergol Clin Immunol 2011; Vol. 21(6): 442-453
.
Skin prick tests (SPT) and intradermal tests (IDT) with immediate readings are used
for investigation of immediate hypersensitivity reactions
Intradermal tests are undertaken when skin prick tests are negative
Intradermal testing begins with 1/1000 dilution of the non-reactive concentration to
avoid a test-induced anaphylaxis (severe history)
Compared to skin prick tests, intradermal tests provide an enhanced sensitivity for
drug-specific IgE
The parenteral preparation of the suspected drug, preferably the intravenous form at
the recommended concentration, should be used for SPT and IDT
Tests should be performed 4–6 weeks after the reaction

7. The skin tests in the diagnosis of immediate type drug allergy
Brockow K, Romano A. Skin tests in the diagnosis of drug hypersensitivity reactions. Curr Pharm Des. 2008;14(27):2778-91
. Mirakian R1
, Leech SC, Krishna MT, Richter AG, Huber PA, Farooque S, Khan N, Pirmohamed M, Clark AT, Nasser SM. Management of allergy to
penicillins and other beta-lactams. Clin Exp Allergy. 2015 Feb;45(2):300-27.
.
Only 20–30% of patients positive on a penicillin skin test remain positive after 10
years
Five years after a positive skin test, 100% of amoxicillinallergic patients lost skin
test reactivity compared to 40% of patients who reacted to a beta-lactam determinant
More than half of patients with both penicillin- and cephalosporin-positive allergy
tests (non-selective reactors) remain positive after 5 years
Optimally, a time interval between the reaction and the skin test of 1 and 6 months
has been suggested
It is not known whether the loss of skin test reactivity corresponds to a loss of
allergy

8. The skin tests in the diagnosis of immediate type drug allergy
Brockow K, Romano A. Skin tests in the diagnosis of drug hypersensitivity reactions. Curr Pharm Des. 2008;14(27):2778-91.
Leysen J1
, Uyttebroek A, Sabato V, Bridts CH, De Clerck LS, Ebo DG. Predictive value of allergy tests for neuromuscular blocking agents: tackling an
unmet need. Clin Exp Allergy. 2014 Aug;44(8).
.
The specificity of skin tests with all β-lactam drugs is very good, reaching
97% to 100%
The sensitivity of skin testing was 22% for PPL, 21% for MDM, 43% for
amoxicillin, and 33% for ampicillin, and the combination of all four haptens
gave a sensitivity of 70%.
NMBA skin test and BAT have an excellent negative predictive value;
negative skin test and negative BAT assisted the selection of
alternative NMBA, which were well tolerated .

9. The skin tests in the diagnosis of immediate type drug allergy
P. Demoly, N. F. Adkinson, K. Brockow et al, International Consensus on drug allergy. Allergy. 2014 Apr;69(4):420-37
Brockow K, Garvey LH, Aberer W,et al. Skin test concentrations for systemically administered drugs -- an ENDA/EAACI DrugAllergy Interest
Group position paper. Allergy. 2013 Jun;68(6):702-12
.
Skin tests should use nonirritant concentrations of the drug
The non-reactive concentrations can be established using different dilutions of
increasing drug concentration
The nonirritant drug concentration should ideally be established in healthy
controls
A positive skin test to nonirritating drug concentrations is consistent with an
allergic mechanism, although the precise test accuracy (sensitivity/specificity)
remains unknown
Where the drug is available only in tablet, capsule or topical form, only SPT
and/or patch test can be performed

10. The skin tests in the diagnosis of immediate type drug allergy- determination of
the maximum non reactive concentrations
.
For skin testing, the criteria for positivity are based on dilutions of drugs
that do not cause wheal and flare in people with no history of reaction
Fisher MM, Doig GS. Prevention of anaphylactic reactions to anaesthetic drugs. Drug Saf. 2004;27(6):393-410.
Interpretation of skin tests requires verification of the patient‘s normal skin reactivity with
negative (normal saline solution) and positive controls (1% histamine, 9% codeine
phosphate solutions)
The criteria of a positive prick test are the appearance after 20 min of a wheal with a
diameter at least 3 mm greater than the negative control, and equal or larger than half the
diameter of the positive control
The criteria for positivity of an intradermal test are the appearance after 20 min of a
wheal with a diameter at least double the diameter of the injecting bleb (8 mm for an
injecting bleb of 4 mm).
Mertes PM, Laxenaire MC, Lienhart A, Aberer W, Ring J, Pichler WJ, Demoly P; Working Group for the SFAR; ENDA; EAACI Interest Group
on Drug Hypersensitivity. Reducing the risk of anaphylaxis during anaesthesia: guidelines for clinical practice.
J Investig Allergol Clin Immunol. 2005;15(2):91-101.
An increase in weal size of more than 3 mm from the initial bleb with flare is considered
positive.
P. Demoly, N. F. Adkinson, K. Brockow et al, International Consensus on drug allergy. Allergy. 2014 Apr;69(4):420-37.
Mirakian R1
, Leech SC, Krishna MT, Richter AG, Huber PA, Farooque S, Khan N, Pirmohamed M, Clark AT, Nasser SM. Management of
allergy to penicillins and other beta-lactams. Clin Exp Allergy. 2015 Feb;45(2):300-27.

11. The skin tests in the diagnosis of immediate type drug allergy- determination of
the maximum non reactive concentrations
NMBAs
.
Skin reactions to intradermal neuromuscular blocking agent injections: a random
Mertes PM, Moneret-Vautrin DA, Leynadier F, Laxenaire MC.
Anesthesiology. 2007 Aug;107(2):245-52. (!accept 5% positivities with
maximal non-reactive concentations)
Weal and flare responses to intradermal rocuronium and cisatracurium
in humans.
Levy JH, Gottge M, Szlam F, Zaffer R, McCall C.
Br J Anaesth. 2000 Dec;85(6):844-9.
Rocuronium and cisatracurium-positive skin tests in non-allergic
volunteers: determination of drug concentration thresholds using a
dilution titration technique.
Berg CM, Heier T, Wilhelmsen V, Florvaag E.
Acta Anaesthesiol Scand. 2003 May;47(5):576-82

12. The skin tests in the diagnosis of immediate type drug allergy- determination of
the maximum non reactive concentrations
midazolam, ketamine, metamizol
.
Maximum non-reactive concentration of midazolam and ketamine for
skin testing study in non-allergic healthy volunteers.
Hagau N, Bologa RO, Indrei CL, Longrois D, Dirzu DS, Gherman-Ionica N.
Anaesth Intensive Care. 2010 May;38(3):513-8
Proposal for use of two reading concentrations for metamizol to
intradermal testing.
Gherman-Ionică N, Bologa R, Cocu S, Cristea C, Dîrzu D, Hagău N.
Farmacia 2011; 59(4): 578-589

13. Recommended maximum non-reactive drug concentrations for prick and intradermal
testing
Skin test concentrations for systemically administered drugs -- an
ENDA/EAACI Drug Allergy Interest Group position paper.
Brockow K, Garvey LH, Aberer W, Atanaskovic-Markovic M, Barbaud A, Bilo MB,
Bircher A, Blanca M, Bonadonna B, Campi P, Castro E, Cernadas JR, Chiriac AM,
Demoly P, Grosber M, Gooi J, Lombardo C, Mertes PM, Mosbech H, Nasser S, Pagani M
, Ring J, Romano A, Scherer K, Schnyder B, Testi S, Torres M,Trautmann A,
Terreehorst I; ENDA/EAACI Drug Allergy Interest Group.
Allergy. 2013 Jun;68(6):702-12

14. Recommended maximum non-reactive drug concentrations for prick and intradermal
testing
Brockow K, Garvey LH, Aberer W,et al. Skin test concentrations for systemically administered drugs -- an
ENDA/EAACI DrugAllergy Interest Group position paper. Allergy. 2013 Jun;68(6):702-12

15. Recommended maximum non-reactive drug concentrations for prick and
intradermal testing
Brockow K, Garvey LH, Aberer W,et al. Skin test concentrations for systemically administered drugs -- an ENDA/EAACI DrugAllergy Interest Group
position paper. Allergy. 2013 Jun;68(6):702-12

16. Recommended maximum non-reactive drug concentrations for prick and
intradermal testing
Brockow K, Garvey LH, Aberer W,et al. Skin test concentrations for
systemically administered drugs -- an ENDA/EAACI DrugAllergy
Interest Group position paper. Allergy. 2013 Jun;68(6):702-12

17. Skin tests in immediate type drug allergy
Brockow K, Garvey LH, Aberer W,et al. Skin test concentrations for systemically administered drugs -- an ENDA/EAACI
DrugAllergy Interest Group position paper. Allergy. 2013 Jun;68(6):702-12

18. Skin tests in immediate type drug allergy-concentrations controversies
For midazolam intradermal test, a concentration of 0.25 mg/ml does not produce
the doubling of the diameter of the injecting bleb, so does not produce positive
results, and at a concentration of 0.1 mg/ml were no changes (wheal and flare) in
the test area at 20 min interval; for the recommended concentration (0.5 mg/ml),
50% of controls presented positive reactions.
For ketamine intradermal test, at the recommended concentration of 1 mg/ml,
85% of controls developped positive reaction; at 0.25 mg/ml the test does not
produce positive results (bleb diameter doubling), and at 0.1 mg/ml the test area
does not present any wheal and flare reactions at the reading time.
Hagau N1
, Bologa RO, Indrei CL, Longrois D, Dirzu DS, Gherman-Ionica N. Maximum non-reactive concentration of midazolam and ketamine for skin testing
study in non-allergic healthy volunteers. Anaesth Intensive Care. 2010 May;38(3):513-8
In our population, the recommended concentrations for midazolam and ketamine
seems to be to high, leading to false positive results.

19. Skin tests in immediate type drug allergy-concentrations controversies
Guyer AC, Saff RR, Conroy M, Blumenthal KG, Camargo CA Jr, Long AA, Banerji A. Comprehensive allergy evaluation
is useful in the subsequent care of patients with drughypersensitivity reactions during anesthesia. J Allergy Clin Immunol Pract.
2015 Jan-Feb;3(1):94-100
Ketamine 0.25 mg/ml

20. Skin tests in immediate type drug allergy-concentrations controversies
For intradermal testing with metamizol a concentration of 50 mg/ml does not
produce positive results (bleb doubling), and at a concentration of 5 mg/ml no
wheal and flare are observed a 20 min.
The concentration of 5 mg/ml respect the definition of the maximal non-reactive
concentration, beeing the greatest concentration that does not produce wheal and
flare in controls.
Gherman-Ionică N, Bologa R, Cocu S, Cristea C, Dîrzu D, Hagău N. Proposal for use of two reading concentrations for metamizol to intradermal testing. Farmacia
2011; 59(4): 578-589.
In our population, the recommended concentration of 0.1 mg/ml is to low,
increasing the risk of a false negative test.
Of 130 intradermal tests to metamizol, only 4 (3%) were positive at 5 mg/ml.
(CAATI II database)

21. Skin tests in immediate type drug allergy
cross-reactivities: NMBAs (QAI epitope)
Cross-reactivity has been reported between neuromuscular blocking agents in up to 60–70%
of cases
It is recommended that in the investigation of the suspected drug, also other available
neuromuscular blocking agents should be tested simultaneously to rule out cross-reactivity
and to identify a safe alternative
Brockow K, Garvey LH, Aberer W,et al. Skin test concentrations for systemically administered drugs -- an ENDA/EAACI DrugAllergy Interest Group position paper.
Allergy. 2013 Jun;68(6):702-12
Multiple sensitizations are observed in the majority of patients
Monosensitization is more common with succinylcholine
Sensitization to all NMBAs are uncommon
Dong SW, Mertes PM, Petitpain N, Hasdenteufel F, Malinovsky JM; GERAP. Hypersensitivity reactions during anesthesia. Results from
the ninth French survey (2005-2007). Minerva Anestesiol. 2012 Aug;78(8):868-78.
A positive result to more than one NMBA (crossreactivity) was observed in 56% of patients
with positive prick and intradermal tests, in 42% with positive BAT and in 63% with
positive specific IgEs.
Nadia Gherman-Ionica, Erika Susana Brezoszki, Manuela Sfichi, Ramona Bologa, Natalia Hagau. Perianaesthetic anaphylaxis. Initial results of the first Romanian
allergo-anaesthesia center.Romanian Journal of Anaesthesia and Intensive Care , 2011 Vol.18 Nr.2, 87-94

22. Skin tests in immediate type drug allergy
cross-reactivities: β-lactams
Mirakian R1
, Leech SC, Krishna MT, Richter AG, Huber PA, Farooque S, Khan N, Pirmohamed M, Clark AT, Nasser SM. Management of
allergy to penicillins and other beta-lactams. Clin Exp Allergy. 2015 Feb;45(2):300-27.
Allergenic epitopes: The beta-lactam ring, the thiazolidine/dihydrothiazine rings
and the side group are all potentially immunogenic.

23. Skin tests in immediate type drug allergy
cross-reactivities: β-lactams side chains
Kim MH, Lee JM.
Diagnosis and management of immediate hypersensitivity reactions to cephalosporins.
Allergy Asthma Immunol Res. 2014 Nov;6(6):485-95

24. Skin tests in immediate type drug allergy
cross-reactivities: β-lactams side chains
Kim MH, Lee JM.
Diagnosis and management of immediate
hypersensitivity reactions to cephalosporins. Allergy Asthma Immunol Res. 2014
Nov;6(6):485-95

25. Particular situation
Skin tests in penicillin allergy-role in the diagnosis algorithm
Mirakian R1
, Leech SC, Krishna MT, Richter AG, Huber PA, Farooque S, Khan N, Pirmohamed M, Clark AT, Nasser SM.
Management of allergy to penicillins and other beta-lactams. Clin Exp Allergy. 2015 Feb;45(2):300-27.

26. Skin tests in perioperative allergy-role in the diagnosis algorithm
PM Mertes,1 JM Malinovsky,2 L Jouffroy,3 and the Working Group of the SFAR* and SFA* and W Aberer,4 I Terreehorst,5 K Brockow,6 P
Demoly,7 for ENDA** and the EAACI Interest Group on Drug Allergy. Reducing the Risk of Anaphylaxis During Anesthesia: 2011 Updated
Guidelines for Clinical Practice . J Investig Allergol Clin Immunol 2011; Vol. 21(6): 442-453

27. Skin tests in immediate type drug allergy
Conclusions
The skin test is the most commonly used procedure to confirm a sensitization in drug
hypersensitivity
Skin tests have to be applied depending on the suspected pathomechanism of the DHR
Skin prick tests (SPT) and intradermal tests (IDT) with immediate readings are used
for investigation of immediate hypersensitivity reactions
The sensitivity of skin tests decrease with time, and it is not known whether the loss of
skin test reactivity corresponds to a loss of allergy
Skin tests should use nonirritant concentrations of the drug, determined in healthy
controls; for many drugs the non-reactive concentration is still debatable
Specificity, sensitivity, predictive value is not well established for all drugs
All in all, skin testing represent an important step in the diagnostic algorithm of drug
allergy, mainly when the drug provocation test is not advisable (NMBAs), or in vitro
tests are not available or sufficiently validated