Allergy

POSITION PAPER

Skin test concentrations for systemically administered

drugs – an ENDA/EAACI Drug Allergy Interest Group
position paper
K. Brockow1, L. H. Garvey2, W. Aberer3, M. Atanaskovic-Markovic4, A. Barbaud5, M. B. Bilo6,
A. Bircher7, M. Blanca8, B. Bonadonna9, P. Campi10, E. Castro11, J. R. Cernadas11, A. M. Chiriac12,
P. Demoly12, M. Grosber1, J. Gooi13, C. Lombardo9, P. M. Mertes14, H. Mosbech2, S. Nasser15,
M. Pagani16, J. Ring1, A. Romano17, K. Scherer7, B. Schnyder18, S. Testi10, M. Torres8,
A. Trautmann19, I. Terreehorst20 on behalf of the ENDA/EAACI Drug Allergy Interest Group
1
Department of Dermatology und Allergology Biederstein, Division Environmental Dermatology and Allergology Helmholtz Zentrum
Mu €nchen/TUM, Technical University Munich, Munich, Germany; 2Allergy Clinic, Copenhagen University Hospital, Gentofte, Denmark;
3
Department of Dermatology, Medical University of Graz, Graz, Austria; 4University Children‘s Hospital, Medical Faculty University of
Belgrade, Belgrade, Serbia; 5Dermatology Department and EA 72-98 INGRES, Brabois Hospital, University Hospital of Nancy, Lorraine
University, Vandoeuvre les Nancy, France; 6Department of Immunology, Allergy and Respiratory Diseases, Allergy Unit, University Hospital
Ospedali Riuniti, Ancona, Italy; 7Dermatologische Universit€ atsklinik Kantonsspital, Basel, Switzerland; 8Allergy Service, Carlos Haya Hospital,
Malaga, Spain; 9Allergy Unit, Verona University Hospital, Verona, Italy; 10Allergy and Clinical Immunology Unit, San Giovanni di Dio Hospital,
Florence, Italy; 11Department of Allergy and Clinical Immunology, Medical University, H. S. Joao, Porto, Portugal; 12Allergy Department,
University Hospital of Montpellier and INSERM U657, Montpellier, France; 13Department of Immunology, Beaumont Hospital, Dublin,
sie-re
Ireland; 14Service d’anesthe animation chirurgicale, Ho
^pitaux Universitaires de Strasbourg, Strasbourg, France; 15Department of Allergy,
Addenbrooke’s Hospital, Cambridge, UK; Allergology and Oncology Service, Civil Hospital of Asola, Mantova; 17Allergy Unit, C. I.
16

Columbus, Rome and IRCCS Oasi Maria S. S., Troina, Italy; 18Department of Rheumatology, Clinical Immunology and Allergology, Bern,
Switzerland; 19Department of Dermatology and Allergology, University of Wu €rzburg, Wu €rzburg, Germany; 20Department of ENT and
Pediatrics, AMC, Amsterdam, The Netherlands

To cite this article: 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 on behalf of the ENDA/EAACI Drug Allergy Interest Group. Skin test concentrations for systemically administered
drugs – an ENDA/EAACI Drug Allergy Interest Group position paper. Allergy 2013; 68: 702–712.

Keywords Abstract
diagnosis; drug allergy; drug
hypersensitivity; intradermal test; skin test.
Skin tests are of paramount importance for the evaluation of drug hypersensitiv-
ity reactions. Drug skin tests are often not carried out because of lack of concise
Correspondence information on specific test concentrations. The diagnosis of drug allergy is often
Prof. Dr.med. Knut Brockow, Department of based on history alone, which is an unreliable indicator of true hypersensitiv-
Dermatology and Allergology Biederstein, ity.To promote and standardize reproducible skin testing with safe and nonirri-
Technische Universit€at Mu€nchen, tant drug concentrations in the clinical practice, the European Network and
Biedersteiner Str. 29, 80802 Mu€nchen, European Academy of Allergy and Clinical Immunology (EAACI) Interest
Germany. Group on Drug Allergy has performed a literature search on skin test drug con-
Tel.: 0049 89 4140 3182 centration in MEDLINE and EMBASE, reviewed and evaluated the literature in
Fax: 0049 89 4140 3127
five languages using the GRADE system for quality of evidence and strength of
E-mail: [email protected]
recommendation. Where the literature is poor, we have taken into consideration
Accepted for publication 7 February 2013
the collective experience of the group.We recommend drug concentration for skin
testing aiming to achieve a specificity of at least 95%. It has been possible to rec-
DOI:10.1111/all.12142 ommend specific drug concentration for betalactam antibiotics, perioperative
drugs, heparins, platinum salts and radiocontrast media. For many other drugs,
Edited by: Hans-Uwe Simon there is insufficient evidence to recommend appropriate drug concentration. There

Abbreviations
EAACI, European Academy of Allergy and Clinical Immunology; ENDA, European Network on Drug Allergy; GRADE, Grading of
Recommendations Assessment, Development and Evaluation; IDT, intradermal test; Im, intramuscular; Iv, intravenous; LA, local
anaesthetic; MDM, minor determinant mixture; NIHR, nonimmediate hypersensitivity reaction; NSAID, nonsteroidal anti-inflammatory drug;
Sc, subcutaneous; SPT, skin prick test.

702 Allergy 68 (2013) 702–712 © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Brockow et al. Skin test concentrations for drugs

is urgent need for multicentre studies designed to establish and validate drug skin
test concentration using standard protocols. For most drugs, sensitivity of skin
testing is higher in immediate hypersensitivity compared to nonimmediate hyper-
sensitivity.

Drug hypersensitivity affects about 5% of hospitalized mal test (IDT), patch test and scratch test. Additional articles
patients and is associated with significant morbidity and were found through archives or on the reference lists of the
mortality (1). Drug hypersensitivity reactions mediated by identified articles. Further data sources were textbooks, test
specific immune mechanisms are classified as drug allergy. concentrations recommended by national registries, existing
Based on the time between drug exposure and onset of symp- guideline articles and experiences by members of the task
toms/signs, reactions may be divided into immediate and force.
nonimmediate hypersensitivity reaction (NIHR). The mecha- We restricted the search to systemically administered drugs
nism underlying the former is thought to be IgE-mediated and excluded topically applied agents causing only contact or
and the latter is primarily T cell-mediated. There is some photocontact allergy. No prospective controlled studies were
overlap as early noneczematous NIHRs that become symp- found; thus, we included observational studies, case series,
tomatic over 1–6 h may show anaphylactic features and IgE- case reports and also the personal experience of members of
mediated mechanism. In drug allergy, skin testing is the most the group, when other reliable data were lacking. The litera-
widely used method to determine sensitization, as other tests ture reviewed contained minimal data on testing of healthy
(in vitro or drug provocation test) are less specific, less sensi- controls.
tive or potentially harmful (2). There is no international con-
sensus on how skin tests with drugs should be performed or
Data extraction
interpreted. There have been no multicentre studies to estab-
lish drug concentration, test protocol, specificity, sensitivity Our aim has been to provide data for all widely used drugs
and safety. Reliable skin test procedures including test con- or drug classes. Members of the task force were assigned
centrations for the diagnosis of drug hypersensitivity are not different drug classes (Appendix 1) who retrieved identified
available for most drugs (3). Consequently, many doctors do articles and assessed the data. The relevance of articles was
not investigate drug reactions and rely on the history alone evaluated by the responsible authors on the basis of title
to make a diagnosis of drug allergy and the unjustified use/ and abstract. The drug classes and responsible authors are
avoidance of indicated drugs. listed in Appendix 1. Selected articles were then retrieved
The European Network on Drug Allergy (ENDA) and and analysed. Detailed results of skin test concentrations
European Academy of Allergy and Clinical Immunology for all drugs were summarized in a master table, which is
(EAACI) Interest Group on Drug Allergy have already pub- available on our website http://eaaci.net/sections-a-igs/ig-on-
lished guidelines and position papers on procedures, such as drug-allergy/resources.html (see also Table S1 in the Sup-
history taking (4), general approach to skin testing (2), drug porting Information section of this paper). For drug groups
provocation tests (5), as well as recommendations for the where evidence was considered sufficient for recommenda-
management of betalactam hypersensitivity (6), perioperative tions to be made on skin concentrations, tables are included
anaphylaxis (7), radiocontrast media reactions (8), hypersen- in the following text (Tables 1–3). In addition, for each
sitivity to nonsteroidal anti-inflammatory drugs (NSAID) (9) drug or drug class, key statements on the quality of evi-
and on rapid desensitization (10). dence and recommendation (including strength) are made.
It is the primary purpose of this paper to present skin test The submission of the responsible author(s) was discussed
concentrations for practical use by the allergist. Suggested by the task force, confirmed or amended by consensus of
concentrations should be nonirritating aiming for the highest the group.
specificity, if possible exceeding 95%. By evaluating the liter-
ature, we developed additional key statements and recom-
mendations concerning methodology and clinical value of
skin testing for various drug classes. Table 1 Nonirritating test concentrations for betalactam antibiotics

DRUG SPT IDT PT

Methods
Penicilloyl-poly-L-lysine 5 9 10 mM5
5 9 10 mM5
NA
Data sources Minor determinant mixture 2 9 10 2 mM 2 9 10 2 mM NA
Benzylpenicillin 10.000 UI 10.000 UI 5%
In January 2010, articles in English, German, Italian, French
Amoxicillin 20 mg/ml 20 mg/ml 5%
and Spanish with data on skin test concentrations for drugs
Ampicillin 20 mg/ml 20 mg/ml 5%
were identified by searching the databases of MEDLINE
Cephalosporins 2 mg/ml 2 mg/ml 5%
(National Library of Medicine) and EMBASE (Elsevier Sci-
ence). Keywords were the names and synonyms of the For this and all following tables: SPT, skin prick test; IDT, intrader-
respective drugs and skin test, skin prick test (SPT), intrader- mal test; PT, patch test.

Allergy 68 (2013) 702–712 © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 703
Skin test concentrations for drugs Brockow et al.

Table 2 Nonirritating test concentrations for perioperative drugs

DRUG SPT IDT

Undiluted Maximum Maximum

Generic name concentration (mg/ml) Dilution concentration (mg/ml) Dilution concentration (mg/ml)

Thiopental 25 Undiluted 25 1/10 2.5

Propofol 10 Undiluted 10 1/10 1
Ketamine 10 Undiluted 10 1/10 1
Etomidate 2 Undiluted 2 1/10 0.2
Midazolam 5 Undiluted 5 1/10 0.5
Fentanyl 0.05 Undiluted 0.05 1/10 0.005
Alfentanil 0.5 Undiluted 0.5 1/10 0.05
Sufentanil 0.005 Undiluted 0.005 1/10 0.0005
Remifentanil 0.05 Undiluted 0.05 1/10 0.005
Morphine 10 1/10 1 1/1000 0.01
Atracurium 10 1/10 1 1/1000 0.01
Cis-atracurium 2 Undiluted 2 1/100 0.02
Mivacurium* 2 1/10 0.2 1/1000 0.002
Rocuronium 10 Undiluted 10 1/200 0.05
Vecuronium† 4 Undiluted 4 1/10 0.4
Pancuronium† 2 Undiluted 2 1/10 0.2
Suxamethonium* 50 1/5 10 1/500 0.1

IDT, intradermal test; SPT, skin prick test.

*Change to increase maximum concentrations on IDT has been proposed (mivacurium 1/200 = 0.01 mg/ml and suxamethonium
1/100 = 0.5 mg/ml) ref 9, 10 from the table of the e-appendix on the website (http://eaaci.net/sections-a-igs/ig-on-drug-allergy/resources.
html).
†Change to decrease maximum concentrations on IDT has been proposed (vecuronium 1/100 = 0.04 mg/ml and pancuronium
1/50 = 0.04 mg/ml) ref 9, 10 from the table of the e-appendix on the website.

Skin prick test (SPT) and IDT with immediate readings

Grading quality of evidence and strength of recommendation
are used for investigation of immediate hypersensitivity reac-
Grading of the quality of evidence and the strength of tions. These tend to occur within 1 h after drug administra-
recommendation for key statements and skin test concentra- tion, but may develop after 1–6 h (and exceptionally later).
tions were performed using the Grading of Recommenda- Symptoms are often confined to the skin and mucous mem-
tions Assessment, Development and Evaluation (GRADE) branes, for example, generalized rash/urticaria or angio-
system (11). Evidence was graded as high quality, if further oedema and may progress in some cases to more severe
research is very unlikely to change our confidence in the symptoms of bronchospasm, hypotension and anaphylactic
estimate of effect; moderate, if further research is likely to shock. Investigations of NIHR should include IDT with late
have an important impact on our confidence in the estimate readings as well as patch tests (2). Nonimmediate hypersensi-
of effect and may change the estimate; low, if further tivity reactions develop within hours to days but in highly
research is very likely to have an important impact on our sensitized individuals may manifest within 24 h. Symptoms
confidence in the estimate of effect that is likely to change of NIHR show a diversity of clinical manifestations with ma-
the estimate; and very low, if any estimate of effect is very culopapular exanthema being the most common presentation
uncertain. The strength of recommendation is strong, if cli- (high/strong).
nicians are very certain that the benefits outweigh the risks. A validated protocol should be used, and guidelines have
A recommendation is weak if the benefits and risks are been published (high/strong) (2, 12). Scratch tests are poorly
finely balanced, or appreciable uncertainty exists about the standardized and are not recommended (moderate/strong).
magnitude of the risk. The grading of high/strong in the For children, the tools used for management established in
text denotes a high quality of evidence and strong strength adults are applicable even though there is insufficient evi-
of recommendation. dence of their suitability. A separate position paper on paedi-
atric drug hypersensitivity is in progress.
The sensitivity of skin tests appears to be moderate to high
Results for immediate hypersensitivity reactions to betalactam antibiot-
ics, perioperative drugs, heparins, platinum salts, radiocontrast
General aspects
media, but low for many other drugs (moderate/weak).
Skin test is the most commonly used procedure to confirm a The parenteral preparation of the suspected drug, prefera-
sensitization in drug hypersensitivity; for many drugs, in vitro bly the intravenous form at the recommended concentration,
tests are not available or sufficiently validated (high/strong). should be used for SPT and IDT. For drugs suspected of

704 Allergy 68 (2013) 702–712 © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Brockow et al. Skin test concentrations for drugs

Table 3 Nonirritating test concentrations for selected other drugs able to make the test as sensitive as possible (12). Most drugs
and drug classes are poorly soluble in water, and it is often the saturated sus-
pension that is used. It is important to make an accurate
Drug or drug class SPT IDT Patch
record of the method used (e.g. suspension prepared by dis-
Anticoagulants solving ground up 500 mg tablet in 10 ml 0.9% saline at
Heparins* Undiluted 1/10 diluted Undiluted room temperature for ‘X’ min/h/overnight). This will facili-
Heparinoids† Undiluted 1/10 diluted Undiluted tate comparative/standardize studies (high/strong). A univer-
Platinum salts sally accepted recommendation regarding solvents and
Carboplatin 10 mg/ml 1 mg/ml NA concentrations is currently impossible (low/strong).
Oxaliplatin 1 mg/ml 0.1 mg/ml NA The vehicle providing optimal skin penetration for drug
Cisplatin 1 mg/ml 0.1 mg/ml NA patch test has not been formally evaluated. The most com-
NSAIDs mon method is to use finely ground tablet of liquid drug to
Pyrazolones‡ Powder 0.1 mg/ml 10% make different test concentration of 5–30% in petrolatum. It
Coxibs§ Powder 10% is important to mix well to obtain a homogenous preparation
Other NSAIDs¶ Powder 0.1 mg/ml 10%
(high/strong) (12). Drugs may be irritant to the skin, and it
Biologicals
is necessary to establish in healthy controls (ideally  20) the
Adalimumab 50 mg/ml 50 mg/ml Undiluted
nonirritant concentration (13).
Etanercept 25 mg/ml 5 mg/ml NA
A positive skin test to nonirritating drug concentrations is
Infliximab 10 mg/ml 10 mg/ml NA
consistent with an allergic mechanism, although the precise
Omalizumab 1.25 µg/ml 1.25 µg/ml NA
Others
test accuracy (sensitivity/specificity) remains unknown (high/
Local anaesthetics Undiluted 1/10 diluted Undiluted strong). Test accuracy cannot be determined without the num-
Iodinated contrast media Undiluted 1/10 diluted Undiluted bers of true positive and negative test results, which would
Gadolinium che lates Undiluted 1/10 diluted NA require provocation tests in all patients including those with
Patent blue Undiluted 1/10 diluted NA positive skin tests. The negative predictive value is dependent
Methylene blue 1/100 diluted on the pretest probability and is not helpful without this infor-
Fluorescein Undiluted 1/10 diluted Undiluted mation in selected patient groups. ST is not helpful in situa-
Proton pump inhibitors** Undiluted 40 mg/ml 10% tions where the sensitivity is very low, because of the increased
Anticonvulsants†† NA NA 10% risk of false-negative reactions. In the absence of this informa-
Chlorhexidine digluconate 5 mg/ml 0.002 mg/ml 1% tion, we have aimed for nonirritating skin test concentrations,
with the highest possible test specificity (if possible exceeding
IDT, intradermal test; NSAID, nonsteroidal anti-inflammatory drug;
95%). Because of limited sensitivity, a negative skin test
SPT, skin prick test.
does not rule out drug hypersensitivity (high/strong). Before
*Heparins: heparin sodium, nadroparin, dalteparin and enoxaparin;
re-administration, a drug provocation test following ENDA
testing contraindicated in HIT.
†Heparinoids: danaparoid and fondaparinux.
recommendations is necessary (high/strong) (5).
‡Pyrazolones: metamizol, paracetamol, propyphenazone, aminopy-
rine, phenazone and phenylbutazone. Antibiotics
§Coxibs: celecoxib, etoricoxib and valdecoxib.
¶Other NSAIDs: for example, aspirin, ibuprofen, naproxen, indo- Recommendations for the diagnosis of betalactam hypersen-
methacin, diclofenac, fenoprofen, meloxicam, mefenamic acid and sitivity have recently been updated, and nonirritant skin test
nimesulide. concentrations are shown in Table 1 (moderate/strong) (6).
**For lansoprazole and rabeprazole, no intravenous solution is avail- However, several studies indicate that for cefuroxime, ceftri-
able: SPT with powder, IDT not possible. axone, cefotaxime, cefazidime, cefozolin, cephalexin, cefaclor
††In case of history with severe reaction, test first 1%; NA, not and cefatrizine, but not cefepime, concentrations up to
applicable or no test concentration recommended. 20 mg/ml are probably also not irritant and might improve
the sensitivity without affecting the specificity (14, 15).
causing severe reactions or where literature/experience is The diagnosis of penicillin hypersensitivity is only con-
lacking, skin tests should use nonirritant concentrations of firmed in a fraction of patients claiming such reactions, espe-
the drug. This can be established using different dilutions of cially when parents report their children’s history (high/
increasing drug concentration. The nonirritant drug concen- weak) (16). Initially, specific IgE is determined for confirma-
tration should ideally be established in healthy controls tion. However, skin testing remains the most important
[reviewed in (2)]. Where the drug is available only in tablet, method for confirming betalactam allergy. Immediate hyper-
capsule or topical form, only SPT and/or patch test can be sensitivity reactions to betalactam can be due to reactivity to
performed (moderate/strong). the betalactam moiety or the side chain. Testing with the
There are no standardized protocols or data on the opti- penicillin polylysine and minor determinant mixture (MDM)
mal drug concentration available for skin testing using drug appears adequate to establish the diagnosis, when benzyl
solution prepared from an oral formulation (moderate/weak). penicillin is the suspected antibiotic and the reactivity is
The common practice is to dissolve the tablet/capsule content against the betalactam moiety. However, the reactivity could
in 0.9% saline and use the maximum concentration achiev- be against the side chain (e.g. aminopenicillin side chain in

Allergy 68 (2013) 702–712 © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 705
Skin test concentrations for drugs Brockow et al.

amoxicillin) in which case tests for penicillin polylysine and mediated mechanism, but are thought to be related to an
MDM are negative, but the suspected betalactam positive aberrant arachidonic acid metabolism (high/strong) (9). In
(17). Amoxicillin has replaced penicillin polylysine and these cases, SPT and IDT are usually negative (high/strong).
MDM as the most important determinant of penicillin Therefore, it is not recommended in routine clinical practice
allergy (18, 19). For optimal sensitivity, we recommend SPT to skin test nonpyrazolone NSAID (moderate/strong).
and IDT with penicillin polylysine, MDM, benzyl penicillin, Instead, drug provocation test with the suspected NSAID is
amoxicillin and the suspected betalactam (high/strong) (6). the recommended diagnostic test and this is in line with
Betalactam may be used in combination with a betalactam- ENDA recommendation (5, 9). The irritating potential of all
ase, for example, Amoclav/Augmentin (amoxicillin and clavul- NSAIDs appears to be low in SPT, and the specificity is thus
anic acid). A reported reaction to Augmentin could therefore high (≫95%). For IDT, 0.1 mg/ml appears to be not irritat-
be due to an allergy to clavulanic acid and not amoxicillin ing to the skin (moderate/weak; Table 3). Higher concentra-
(20). Skin testing should be carried out against the original tions of NSAID appear irritant (low/weak).
drug and individual component of the antibiotic combination. Positive skin and/or laboratory tests may be seen in up to
As with penicillins, skin tests with nonirritant concentra- 40% of patients with immediate hypersensitivity reactions to
tion of cephalosporins have a higher sensitivity compared pyrazolones (high/strong) (28). IgE-mediated anaphylactic
with NIHR (high/weak). For the investigation of adverse reactions are exceptional with nonpyrazolone NSAID such
reaction to cephalosporin, it is recommended that the sus- as diclofenac or ibuprofen.
pected cephalosporin, PPl, MDM and betalactams with simi- All NSAIDs can cause NIHR, and these can be detected
lar side chains are used (moderate/strong) (6). by positive patch tests (high/strong) (29). The relative inci-
In severe reactions (anaphylaxis, severe systemic symp- dence of allergic and nonallergic reactions is not well studied
toms) to antibiotics, it is strongly advised that SPT is initially (moderate/weak). Patch tests with up to 10% NSAID in pet-
performed after IgE testing. If negative, IDT should start rolatum do not seem to be irritant to the skin (Table 3)
antibiotic at dilutions of 1/1000 or 1/100. This is to reduce (moderate/strong). Concentrations up to 30% may be toler-
the risk provoking systemic symptoms (high/strong) (6). ated (low/weak), although the additional value of using the
In NIHR, skin testing with penicillin polylysine and MDM higher concentration is questionable (moderate/weak). Undi-
is scarcely useful (moderate/strong). IDT with delayed read- luted celecoxib appears irritant, and this may be the case for
ings generally has a higher sensitivity than patch test with other NSAIDs (moderate/weak) (30).
similar specificity (low/weak) (21). The value of patch test in
addition to IDT remains controversial. Negative IDT but
positive patch test has been observed by some members of Opioids
the group, and in NIHR to betalactam, most of the group
Opioids induce nonspecific direct histamine release, leading
recommend additional patch test (low/weak).
to false-positive SPT and IDT (strong). To minimize errone-
The sensitivity of betalactam skin tests differs between
ous reading due to histamine release or irritant reaction, it is
studies (high) and may be as high as 70% in immediate and
proposed that increasing dilutions of the suspect opioid (end
10–30% in NIHR (low/weak) (22, 23). When the skin test is
point titration) are used when investigating immediate hyper-
negative, a diagnosis cannot be established without a drug
sensitivity reactions (high/strong).
provocation test (strong).
The value of skin tests with opioids remains unproven, and
For most nonbetalactam antibiotics, the value of skin tests
optimal skin test concentrations are unknown (moderate/
appears to be uncertain (moderate/weak) and false-positive
strong) (31). For fentanyl and its derivatives, the undiluted
reactions may occur when the antibiotic is tested at high con-
solution is recommended (Table 2) (moderate/strong), and
centrations.
for morphine SPT, 1 mg/ml is proposed (low/weak). In an
Skin prick tests and IDTs with undiluted intravenous solu-
unpublished study of 16 normal controls, 0.1 µg/ml mor-
tions for the majority of nonbetalactam antibiotics may be irri-
phine, 0.01 µg/ml codeine, 0.5 µg/ml pethidine and 1.7 µg/ml
tant, and lower dilutions should be used (high/strong) (24, 25).
tramadol were found to be nonirritant to the skin (AB per-
In the literature, reports on the highest nonirritant dilutions
sonal communication; low/weak).
vary greatly and sensitivity appears to be low (moderate/strong)
Positive patch tests to opioids in NIHR have been
(24, 26). Recommendations on concentrations are currently not
described. There is no universal agreement on the optimal
possible, and concentrations used in the literature are given in
vehicle (aqua, petrolatum, ethanol) or test concentration
Table S1 (26, 27). Nonimmediate hypersensitivity reactions to
(high). 3% and 5% diacetylmorphine in petrolatum have
nonbetalactam antibiotics, studied using patch tests with differ-
been shown to be nonirritant (low/weak) (32). 5% morphine
ent concentrations of crushed tablets in petrolatum, have been
in petrolatum is nonirritant and elicited positive reactions
reported to be nonirritating (moderate/strong) (27).
(low/weak) (33). There appears to be skin test cross-reactivity
between morphine and 5% codeine phosphate but not with
Nonsteroidal anti-inflammatory drugs 5% pentazocine and 5% tramadol (low/weak). No
The vast majority of immediate hypersensitivity reactions recommendation can be given for optimal conditions for
to NSAIDs (excluding pyrazolones) are not due to an IgE- codeine or buprenorphine (high).

706 Allergy 68 (2013) 702–712 © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Brockow et al. Skin test concentrations for drugs

strong). Skin prick test and IDT should not be performed

Perioperative drugs
with LA containing vasoconstrictors like adrenaline, as they
The perioperative drug skin test concentration recommended mask a local wheal and flare reaction (high/strong). Excipi-
is listed in Table 2, which is derived from literature published ents in LA, such as bisulphites, have been reported to
in 2002–2009 and is probably the maximum nonirritant drug exceptionally cause anaphylaxis and delayed-type reactions.
concentration. There have been numerous multicentre studies To diagnose these reactions, bisulphite skin tests are of no
from France under the auspices of Societe Francaise d’anes- diagnostic value and oral provocation test with metab-
thesia et de Reanimation (34), whose recommendations have isulphite is necessary to confirm/exclude the diagnosis
been updated recently (7) and these have been endorsed by (moderate/strong).
ENDA. However, their skin test criteria differ, and further Cross-reactivity has been reported between ester-type LA
studies, preferably multicentre studies, are needed to harmo- but not between amide LA. In confirmed LA allergy, other
nize and standardize the test criteria (moderate/strong). LAs should be tested to identify an alternative (moderate/
There are few studies in healthy volunteers but these differ strong). A drug provocation test with the alternative LA is
in test methods and diagnostic criteria, making comparison necessary (high/strong). In NIHRs to LAs, it is recom-
of data difficult (high/strong). Geographical differences exist mended that IDT is performed with 1/10 dilution LA and
in the incidence of reactions to neuromuscular blocking patch test with neat LA (high/strong).
agents, probably partly due to pholcodine exposure, which
may increase risk of sensitization (35).
Heparins, heparinoids and other anticoagulant drugs
Neuromuscular blocking agents can induce nonspecific
direct histamine release in the skin, increasing the possibility Neat heparins appear nonirritant and can be used as such for
of false-positive tests, especially in IDT (high/strong). Preop- SPT (high/strong). Intradermal test using 1/10 dilution
erative screening or testing in patients without prior reactions appears irritant (41). If 1/10 dilution has been used, it is
may lead to false-positive tests/conclusions and should not be advised that further tests be carried out with 1/100 and 1/
carried out routinely (high/strong). 1000 dilution to exclude an irritant reaction (moderate/weak).
Cross-reactivity has been reported between neuromuscular Immediate-type IDT reactions may also be caused by chon-
blocking agents in up to 60–70% of cases (moderate/strong) droitin sulphate that may present due to incomplete purifica-
(36). It is recommended that in the investigation of the sus- tion of heparins (low/weak).
pected drug, also other available neuromuscular blocking Nonimmediate hypersensitivity reactions to subcutaneous
agents should be tested simultaneously to rule out cross-reac- (sc) injection of heparins present as erythematous or eczema-
tivity (high/strong) and to identify a safe alternative (moder- tous plaques at the injection sites (high/strong). If heparin
ate/weak). Chlorhexidine is an integral part of the treatment is continued, there is a risk of a generalized eczema
perioperative test panel in some centres. Validated nonirritant or exanthema (high/weak).
chlorhexidine concentration is listed in Table 3 (high/strong) For skin testing, it is recommended that a panel of differ-
(37, 38). ent heparin and heparinoid preparations, including an
The investigation of adverse reaction to perioperative unfractionated heparin, low molecular weight heparins and
drugs should be in specialist centres and in close collabora- heparinoids, are used (moderate/weak). Patch tests can be
tion with anaesthetists (moderate/strong). Investigations performed using undiluted heparin or heparinoids sc or iv
should include SPT  IDT with all substances the patient solutions (high/strong). A 1/10 dilution is recommended for
was exposed to including antibiotics, colloids, latex, disinfec- heparin and heparinoid IDT (Table 3) (moderate/strong).
tants (e.g. chlorhexidine), opioids, patent blue, etc. (high/ Lower concentrations decrease the sensitivity of IDT (high/
strong). strong) (41). Heparin skin testing is contraindicated in
Specific IgE to latex, chlorhexidine, penicillin determinants, patients with heparin-induced thrombocytopenia (high/
pholcodine and muscle relaxants are well-validated widely strong).
available tests and should be an integral part of the investiga- The literature is poor on skin testing with vitamin K
tions. antagonists, and it is not possible to make any specific rec-
As perioperative reactions are almost exclusively immediate ommendation. Because of low specificity, IDTs are not useful
hypersensitivity reactions, there are no recommendations for for screening patients with protamine-associated anaphylaxis
the investigation of apparent NIHR to perioperative drugs. (low/weak) (42).

Local anaesthetics Iodinated contrast media, gadolinium chelates and dyes

Confirmed immediate hypersensitivity reactions to local Skin testing is recommended in the work-up of iodinated
anaesthetic (LA) are rare. Undiluted LA appears nonirri- contrast media hypersensitivity (high/strong). It is advisable
tant in SPT. Undiluted LA was reported to give negative to use a panel of ICM so as to identify cross-reactivity and
IDTs in 90–95% of patients and in >90% of controls (39, safe alternatives (high/strong) (8).
40). Intradermal test with 1/10 diluted LA has been shown Skin prick tests and patch tests should be performed using
to be nonirritant. It is recommended that neat LA is used undiluted solutions (high/strong). For IDT, a 1/10 dilution of
for SPT and 1/10 dilution LA for IDT (Table 3) (high/ ICM is recommended, as undiluted contrast media may be

Allergy 68 (2013) 702–712 © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 707
Skin test concentrations for drugs Brockow et al.

irritating (weak/high; Table 3). In delayed reactions, both due to toxicity concerns, a general recommendation cannot
delayed reading IDT and patch test should be carried out to be given.
enhance sensitivity (moderate/high). False-negative skin tests For IDT, a 1/10 dilution of most chemotherapeutic drugs
in NIHRs do occur (43). is nonirritant and may be used in clinical practice (moderate/
It is not possible to recommend firm test concentration for strong), whereas higher concentrations appear to be irritant
gadolinium chelates. For SPT, a neat solution appears nonir- (MP, personal communication; low/weak). Patch tests are
ritant (moderate/weak). For IDT, neat gadolinium has been almost always negative in NIHRs and are not recommended
reported to cause false-positive reactions in normal controls; in clinical practice (low/weak).
thus, a 1/10 dilution has been used (44). There are no reports
of NIHR to gadolinium chelates.
Biological agents
Experience with blue dyes is limited (45). Skin prick test
has been performed using undiluted solutions (Table 3) and The literature on skin testing for biological agents is poor.
IDT using up to 1/10 dilution for patent blue dye and 1/100 However, there are satisfactory data on nonirritant test con-
for methylene blue dye (moderate/weak). Cross-sensitivity centrations for the TNFa antagonists adalimumab, etaner-
has been described, and we therefore recommend testing cept and infliximab and omalizumab.
other dyes (low/strong). The highest published nonirritant concentrations for ada-
Literature on skin test to fluorescein is poor. Fluorescein limumab (SPT 50 mg/ml, IDT 5 mg/ml) (51), etanercept
has been used neat for SPT and 1/10 for IDT in the diagno- (SPT 25 mg/ml, IDT 5 mg/ml) (51), infliximab (10 mg/ml)
sis of allergy (low/weak) (46). (52) and omalizumab (12.5 µg/ml) (53) can be used for skin
testing (moderate/weak). Patch test has been performed using
undiluted adalimumab and is recommended for NIHRs (low/
Anticonvulsants
weak).
IgE-mediated immediate hypersensitivity reactions to anticon-
vulsant drugs do probably not exist. For NIHR, patch test
Hormones
with a concentration of up to 10% of the pure substance
appears to be nonirritating to the skin (moderate/strong) Glucocorticoids rarely cause immediate hypersensitivity reac-
(Table 3). In severe anticonvulsant hypersensitivity reactions, tions, and a general recommendation for all glucocorticoids
patch test may result in a flare-up. In such cases, the initial test is currently not possible. Glucocorticoids may be formulated
concentration should be diluted to 1% (moderate/strong). The with other drugs, for example, LAs and contain excipients
sensitivity appears highest for carbamazepine and phenytoin like macrogol. Skin test must include the additional drug(s)
and lower for phenobarbital and lamotrigine (moderate/ and excipient in the panel. Skin test with methylprednisolone
weak). Clinical cases suggesting cross-reactivity between anti- (SPT 2 mg/ml and 20 mg/ml, IDT 0.2 mg/ml and 2 mg/ml)
convulsants have been reported (47), but it has been discussed and triamcinolone (SPT 4 mg/ml and 40 mg/ml, IDT
that those may rather represent flare-up reactions (48). The 0.4 mg/ml and 4 mg/ml) has been reported.
sensitivity of patch test seems unaffected by the vehicle used Hypersensitivity reactions to glucocorticosteroids tend to be
(petrolatum, normal saline, water or ethanol; moderate/weak). NIHRs (high/strong). Glucocorticoids may suppress skin reac-
tivity (54) and give paradoxical reading of greater reactivity at
lower test concentration and at later time points (moderate/
Abacavir
strong) (55). Thus, the patient should be instructed to come for
Patch testing with 10% abacavir revealed a specificity of a repeat visit, if test reactions do develop after 4–7 days. The
100% and sensitivity of 79% for patients with confirmed significance of dose, vehicle, occlusion time and reading time is
HLA-B*5701 genotype (49). only partially evaluated (moderate/strong) (55). Two steroids
(budesonide and tixocortol) have been well studied and used at
0.1 mg/ml in the standard patch test panel (high/strong). There
Chemotherapeutic drugs
is cross-reactivity between the different glucocorticoids, and in
Except for platinum salts, an IgE-mediated hypersensitivity NIHR, 4 cross-reactive groups have been proposed (high/
to chemotherapeutic drugs has not been demonstrated (mod- strong) (54). Glucocorticoids’ cross-reactivity has also been
erate/strong). described for immediate hypersensitivity reactions (56).
Skin tests are useful for platinum salt-related immediate Up to 28% of asymptomatic insulin users may be IDT
hypersensitivity reactions (moderate/strong) (50), while for positive in IDT to 1/10 insulin (57). The clinical significance
other chemotherapeutic drugs, experience is limited and test of positive insulin skin test should be confirmed by drug
results often negative (low/weak). provocation test (moderate/weak). Insulin additives such as
The irritant potential of chemotherapeutic drugs appears protamine have to be considered and tested. The literature is
to be low. For platinum salts, the use of undiluted drugs is scanty on skin test for other therapeutic hormones. It is not
recommended (high/strong). For other chemotherapeutic possible to make any specific recommendation (low/weak),
drugs, SPT with undiluted agents is probably nonirritant, but and skin testing remains experimental (low/weak).

708 Allergy 68 (2013) 702–712 © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Brockow et al. Skin test concentrations for drugs

found to be nonirritant (61). However, IDT with methylcellu-

Blood products including immunoglobulins
lose and macrogol may be complicated by severe systemic
Blood products including immunoglobulins may induce reactions (62). Skin prick test up to undiluted macrogol/poly-
immediate hypersensitivity reactions. They result from pre- ethylene glycol 4000 have been reported (61). At present, it is
existing IgG antibodies to human proteins and complement not possible to recommend optimal skin test concentration
activation and manifest as haemolytic anaemia/shock (blood for these additives.
group antibodies, anti-IgA), fever (cytotoxic antibodies).
There are limited data on skin testing with sera and immuno-
Proton pump inhibitors and H2 antihistamines
globulins, and definite recommendations on the value and
test concentrations are not possible. Most reported reactions to proton pumps inhibitors and H2
antagonists are immediate hypersensitivity reactions (63).
However, the specificity of skin tests has to be determined
Vaccines
(low/weak). Undiluted and 1/10 parenteral proton pump
Adverse reactions to vaccines may be due hypersensitivity to inhibitors appear nonirritant (moderate/weak) (63). There are
the vaccine itself, excipients (e.g. gelatin), added antibacterial inadequate data on H2 antagonist skin test concentration
(neomycin) or proteins resulting from culture methods (oval- (low/weak): 1/100 appears nonirritant but not 1/10 dilution,
bumin from yolk sacs in influenza, herpes simplex and yellow especially for nizatidine. Currently, it is not possible to make
fever, but not in measles, mumps, rubella or rabies vaccines) specific recommendations for these drugs (low/weak). Patch
and may manifest as acute urticaria, angio-oedema and ana- test with proton pump inhibitors at 10–50% of the drug in
phylaxis (58). Although very rare, vaccine components, that petrolatum is nonirritant (moderate/weak).
is, immunizing agents, egg proteins, gelatin and other poten-
tial allergens may induce immediate hypersensitivity reac-
Antihypertensive drugs
tions, such as immediate urticaria, angio-oedema and
anaphylaxis (58). Antihypertensives rarely cause immediate hypersensitivity
Skin prick test with neat vaccine and IDT with 1/100 dilu- reactions, and skin tests with calcium channel blockers and
tion have been shown to be nonirritant, and it is recom- beta-blockers appear not to be useful in the investigation of
mended that these concentrations are used (low/weak) (59). hypersensitivity to these drugs (moderate/weak). Most con-
Skin prick test  IDT with immediate reading should be firmed hypersensitivity reactions to antihypertensive drugs
performed in suspected reactions using the suspected vac- (beta-blockers and calcium channel blockers) are NIHRs pre-
cines, excipients such as gelatin, and neomycin when indi- senting with exanthemas (high/strong), and positive patch
cated. In individuals with a history of serious systemic tests have been described in some case reports. Patch tests
reaction to egg and the vaccine needed by the patient is with calcium channels blockers and beta-blockers of 1–30%
derived by yolk sac culture (e.g. influence, yellow fever, her- drug in petrolatum appear nonirritant (moderate/weak).
pes simplex), the investigation would need to include a risk Reports about hypersensitivity reactions to other anti-hyper-
assessment of ovalbumin allergy (low/weak). tensive drugs (such us diuretics, alpha-blockers, ACE inhibi-
Vaccine excipients have been reported to induce eczema- tors and angiotensin receptor blockers) are scarce or
tous or indurated NIHR (aluminium hydroxide, thimerosal, nonexistent and do not allow any recommendations to be
phenoxyethanol and formaldehyde). The pathogenesis of made (high/strong).
late-onset urticaria, angio-oedema and nonurticarial rashes is
not known.
Discussion
Skin tests have the potential to locally reproduce in vivo an
Additives
IgE-mediated or T-cell-mediated drug allergy. Interpreted in
Several cases of anaphylaxis to additives such as polysorbate the clinical context, skin tests using nonirritant drug concen-
80, carboxymethylcellulose and macrogols/polyethylene gly- trations can confirm or exclude the diagnosis of drug allergy.
cols have been described. Although uncommon, hypersensi- In vitro laboratory tests may not be available, restricted in
tivity should be considered, if a patient shows reaction to repertoire, not well validated or of research nature. Drug
different unrelated drugs containing the same additive (high/ provocation tests are time-consuming, associated with appre-
strong). In such cases, skin testing with the active drugs as ciable risk to the patient and not standardized for NIHR. In
well as the additive is recommended (moderate/strong). our review, we note the paucity of literature on skin drug test
0.5–1.0 mg/ml polysorbate 80 in SPT and IDT and 5– concentration and method protocols. However, we have by
10 mg/ml carboxymethylcellulose have been reported to be consensus been able to agree and recommend test concentra-
nonirritant (weak/low). In carboxymethylcellulose NIHR, tion for many drugs that are listed in Tables 1–3 (moderate/
1 mg/ml carboxymethylcellulose was reported to elicit a posi- strong). In addition, structured and detailed information
tive delayed reading IDT and to be nonirritant in 6 normal on all relevant studies from the literature is available on
controls (60). the website http://eaaci.net/sections-a-igs/ig-on-drug-allergy/
Undiluted PEG 400 has been used in the investigation of resources.html on the homepage of the Drug Allergy Interest
immediate hypersensitivity reactions to macrogol/PEG and Group of the EAACI (Table S1).

Allergy 68 (2013) 702–712 © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 709
Skin test concentrations for drugs Brockow et al.

Table 4 Drugs for which the value of skin tests has not adequately skin tests, drug allergy cannot be excluded and a drug provo-
been demonstrated cation test has to be considered. In drug skin test, it is best
Antihypertensive drugs that the skin test concentration achieves higher specificity,
Biologicals other than anti-TNF preparations and omalizumab which may be at the expense of sensitivity (high).
Hormones, corticosteroids and insulins In addition to standardizing skin test concentration, there
Nonbetalactam antibiotics is a need to be able to reproduce test results not only in a
Nonplatinum chemotherapeutics single but amongst different centres. A study of the test pro-
NSAIDs other than pyrazolones for immediate reactions tocol in different centres in Europe showed that there are
Opioids substantial differences in performance and interpretation of
Sera, immunoglobulins and vaccines skin tests (65). The ENDA group has developed a generic
skin test protocol for performing, reading and interpreting
NSAID, nonsteroidal anti-inflammatory drug.
the results (2), and this has been adopted by several centres.
Tables 1–4 and recommendations in this paper are based on
this method. Other published techniques and protocols are
For many drugs, where the literature is confined to small
available in the online Table S1, for example, the multicentre
case series, case reports, personal experience or nonexistent,
French study on perioperative drugs (34). Studies are in pro-
no specific recommendation is made or should be regarded
gress in Europe to validate and further standardize the
as tentative until further review. For some drugs, the value
ENDA/EAACI skin test protocol in particular IDT. Such
of skin tests has not been sufficiently demonstrated (Table 4).
studies will enable results to be scientifically compared and
The optimal vehicles for skin test reagents and data on sta-
exchanged. Skin testing in healthy volunteers is essential to
bility remain unknown. Drug reactions may be due to its
establish nonirritant test concentration and determine test
metabolites, and testing using drug metabolites should be an
sensitivity and specificity.
area for further research.
In conclusion, it has only been possible to obtain a high to
For most drugs, particularly for betalactam antibiotics, the
moderate level quality of evidence and strong (strength of)
sensitivity of skin testing (SPT, IDT, patch test) is signifi-
recommendation for specific skin test concentrations for a
cantly higher for immediate hypersensitivity reactions pre-
few drugs. For most other drugs, there is a definite need for
senting as anaphylaxis or urticaria compared to NIHRs such
multicentre studies on skin test concentrations in patients
as exanthemas (high/strong).
and in unexposed controls. The recommendations will need
Skin prick test is relatively simple to perform and shows
regular review and standardization. In specialized centres, we
acceptable specificity for most of the reviewed drugs with the
recommend testing all patients with a suggestive history of
exception of drugs with irritant or histamine-releasing prop-
drug allergy with the concentrations listed in Tables 1–3 as
erties such as quinolones and opioids (high/strong). It is
well as in Table S1 on the website to gain further experience.
usual and advisable to exclude specific IgE first, if available,
then do SPT especially in individuals presenting with severe
systemic reactions, and only if negative, proceed to IDT. Conflict of interest
Fatal systemic anaphylaxis has been reported after IDT with- There has been no conflict of interest for any author.
out preceding SPT (64). Intradermal test has a high sensitiv-
ity, but also a higher risk of inducing irritant reactions and
Author contributions
false-positive results. For NIHRs, the patch test has an equal
or slightly lower sensitivity than IDT with delayed readings. See Appendix 1.
Patch test is especially helpful as an additional test method
when no intravenous drug solutions are available for an
Supporting Information
IDT.
When nonirritant concentrations are used, skin tests in Additional Supporting Information may be found in the
drug hypersensitivity are generally characterized by a rela- online version of this article:
tively low sensitivity and a high specificity (high/strong). In Table S1. Relevant literature data on reported skin test
this review, we aimed to select skin test concentrations with concentrations to systemically applied drugs with information
the highest possible specificity (>95%) and thus a high posi- on the test preparation, number of patients and controls, test
tive predictive value. Unfortunately, the sensitivity of skin details and type of study.
tests to most drugs is low. Therefore, in cases of negative

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Appendix 1. Author responsibility

Analgesics, NSAID: Brockow K
Antacids, cardiovascular, Bonadonna P, Lombardo C
Anticoagulants, protamine: Trautmann A
Anticonvulsants, Schnyder B
Biologicals: Campi P, Testi S
Betalactam antibiotics: Torres M, Blanca M
Chemotherapeutics: Pagani M
Contrast media, dyes, gadolinium, fluorescein: Demoly P, Chiriac AM
Hormones: Aberer W
Local anaesthetics: Ring J, Grosber M
Nonbetalactam antibiotics: Cernadas JR, Castro E
Opioids:Scherer K, Bircher A
Perioperative drugs, muscle relaxants: Garvey LH, Mosbech H, Nasser S, Mertes M
Antiseptics, additives: Grosber M, Garvey LH
Sera, vaccines, immunoglobulins: Bilo B
Overall control of integrity: Barbaud A, Terreehorst I, Atanaskovic-Markovic M, Romano A, Garvey LH, Gooi J
Acknowledgement for further help: Hausmann O (omalizumab), Zanoni G (vaccines), Pichler W (overall).

712 Allergy 68 (2013) 702–712 © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd