Allergy
POSITION PAPER
In vitro tests for drug hypersensitivity reactions: an ENDA/
EAACI Drug Allergy Interest Group position paper
C. Mayorga1,2, G. Celik3, P. Rouzaire4, P. Whitaker5, P. Bonadonna6, J. Rodrigues-Cernadas7, A.
Vultaggio8, K. Brockow9, J. C. Caubet10, J. Makowska11, A. Nakonechna12, A. Romano13, M. I. Mon~ ez14, J. J. Laguna15, G. Zanoni16, J. L. Gueant17, H. Oude Elberink18, J. Fernandez19, S. Viel20,
tan
P. Demoly21 & M. J. Torres2 on behalf of In vitro tests for Drug Allergy Task Force of EAACI Drug
Interest Group
1
Research Laboratory, IBIMA-Regional University Hospital of Malaga-UMA; 2Allergy Unit, IBIMA-Regional University Hospital of MalagaUMA, Malaga, Spain; 3Division of Immunology and Allergy, Department of Chest Diseases, Ankara University School of Medicine, Ankara,
Turkey; 4Department of Immunology and ERTICa Research Group, University Hospital of Clermont-Ferrand and Auvergne University,
Clermont-Ferrand, France; 5Regional Adult Cystic Fibrosis Unit, St James’s Hospital, Leeds, UK; 6Allergy Unit, Azienda Ospedaliera
Universitaria Intergata of Verona, Verona, Italy; 7Immunoallergology Department, Faculty of Medicine, Centro Hospitalar S~
ao Jo~
ao, Porto,
Portugal; 8Immunoallergology Unit, Department of Biomedicine, Careggi Hospital, Florence, Italy; 9Department of Dermatology and
€nchen, Munich, Germany; 10Pediatric Allergy Unit, Department of Child and Adolescent,
Allergology Biederstein, Technische Universit€at Mu
University Hospitals of Geneva, Geneva, Switzerland; 11Department of Immunology, Rheumatology and Allergy, Healthy Ageing Research
dz, Poland; 12Allergy and Immunology Clinic, Royal Liverpool and Broadgreen University Hospital,
Center, Medical University of Łodz, Ło
13
Liverpool, UK; Allergy Unit Complesso Integrato Columbus, Rome and IRCCS Oasi Maria S.S., Troina, Italy; 14BIONAND-Andalusian Centre
for Nanomedicine and Biotechnology, Malaga; 15Allergy Unit, Hospital de la Cruz Roja, Madrid, Spain; 16Section of Immunology, Department
of Pathology and Diagnostics, University of Verona, Verona, Italy; 17Department of Molecular Medicine and Personalized Therapeutics and
Inserm UMRS 954N-GERE (Nutrition-Genetics-Environmental Risks), University Hospital of Nancy and University of Lorraine, Nancy, France;
18
Department of Allergology, GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, The
Netherlands; 19Allergy Section, Alicante University Hospital, UMH, Alicante, Spain; 20Laboratory of Immunology, Centre Hospitalier Lyon
^pital Arnaud de Villeneuve, University Hospital of Montpellier, and Sorbonne Universite
s,
Sud, Hospices Civils de Lyon, Lyon, France; 21Ho
UPMC Paris 06, UMR-S 1136, IPLESP, Equipe EPAR, Paris, France
To cite this article: Mayorga C, Celik G, Rouzaire P, Whitaker P, Bonadonna P, Cernadas JR, Vultaggio A, Brockow K, Caubet JC, Makowska J, Nakonechna A, Romano
~ez MI, Laguna JJ, Zanoni G, Gueant JL, Oude Elberink H, Fernandez J, S Viel, Demoly P, Torres MJ, on behalf of In vitro tests for Drug Allergy Task Force of
A, Montan
EAACI Drug Interest Group. In vitro tests for drug hypersensitivity reactions: an ENDA/EAACI Drug Allergy Interest Group position paper. Allergy 2016; 71: 1103–1134.
Keywords
diagnosis; drug hypersensitivity; IgE;
in vitro; T cells.
Correspondence
Maria Jose Torres, MD, PhD, Allergy
Service, IBIMA-Regional University Hospital
of Malaga (Pavilion C), Plaza del Hospital
Civil. 29009 Malaga, Spain.
Tel.: +34-951290224
Fax: +34-951290302
E-mail: mjtorresj@ibima.eu
Accepted for publication 12 March 2016
DOI:10.1111/all.12886
Edited by: Werner Aberer
Abstract
Drug hypersensitivity reactions (DHRs) are a matter of great concern, both for outpatient and in hospital care. The evaluation of these patients is complex, because
in vivo tests have a suboptimal sensitivity and can be time-consuming, expensive and
potentially risky, especially drug provocation tests. There are several currently available in vitro methods that can be classified into two main groups: those that help to
characterize the active phase of the reaction and those that help to identify the culprit
drug. The utility of these in vitro methods depends on the mechanisms involved,
meaning that they cannot be used for the evaluation of all types of DHRs. Moreover,
their effectiveness has not been defined by a consensus agreement between experts in
the field. Thus, the European Network on Drug Allergy and Drug Allergy Interest
Group of the European Academy of Allergy and Clinical Immunology has organized
a task force to provide data and recommendations regarding the available in vitro
methods for DHR diagnosis. We have found that although there are many in vitro
tests, few of them can be given a recommendation of grade B or above mainly
because there is a lack of well-controlled studies, most information comes from small
studies with few subjects and results are not always confirmed in later studies. Therefore, it is necessary to validate the currently available in vitro tests in a large series of
well-characterized patients with DHR and to develop new tests for diagnosis.
Allergy 71 (2016) 1103–1134 © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
1103
Mayorga et al.
Drug hypersensitivity reactions (DHRs) are frequently
encountered and can lead to serious outcomes, making them
of great concern both in outpatient and in hospital care. It is
not only the acute DHRs that cause problems, but also the
issues related to patient reporting can also lead to uncertainty
for doctors in terms of what drugs to prescribe. Alternative
drugs may be more expensive and less effective than the original drug to which the patient reacted. To avoid the negative
social and economic impact caused by alternative treatments,
it is important to establish simple tests to help clinicians
choose the correct medication.
Diagnosis of DHRs is primarily based on a detailed clinical history and in vivo procedures, such as skin testing (ST)
and drug provocation tests (DPT). The Interest Group on
Drug Allergy from the European Academy of Allergy and
Clinical Immunology (EAACI) has made position statements
on general procedures for collecting clinical history and performing ST and DPT (1–4); as well as specific procedures for
the most frequent DHR-inducing drugs such as beta-lactams
(BLs), nonsteroidal anti-inflammatory drugs (NSAIDs) and
radio-contrast media (RCM) (5–9). In the recent International Consensus on drug allergy (10), the need for biological
tests to establish the nature of culprit agents and to predict
immunogenicity was highlighted. This would be particularly
helpful for those patients who received several drugs simultaneously and for severe life-threatening DHRs where skin tests
are not possible or appropriate, and DPT is contraindicated.
However, expert consensus has not been reached on the value
of in vitro methods for DHR diagnosis. The aim of this
review was to provide data and recommendations regarding
in vitro methods currently available for the diagnosis of
DHR based on published studies.
Abbreviations
15-HETE, 15-hydroxyeicosatetraenoic acid; AGEP, acute
generalized exanthematic pustulosis; BA, biological agents; BAT,
basophil activation test; BLs, beta-lactams; CAST, cellular antigen
stimulation test; CFSE, carboxyfluorescein diacetate succinimidyl
ester; COX-1, cyclooxygenase-1; CysLTs, cysteinyl leukotrienes;
DHR, drug hypersensitivity reaction; DPT, drug provocation tests;
DRESS, drug reaction with eosinophilia and systemic symptoms;
EAACI, European Academy of Allergy and Clinical Immunology;
ELISA, Enzyme-linked immunosorbent assay; ELISpot, enzymelinked immunosorbent spot; FDE, fixed drug eruption; FEIA,
fluoroimmunoassay; GR, grade of recommendation; HSA, human
serum albumin; IR, immediate reactions; LE, level of evidence;
LTC, leukotriene; LTT, lymphocyte transformation test; MPE,
maculopapular exanthema; NECD, NSAID-exacerbated cutaneous
diseases; NERD, NSAID-exacerbated respiratory diseases; NIR,
nonimmediate reactions; NIUA, NSAID-induced urticaria
angioedema; NSAIDs, nonsteroidal anti-inflammatory drugs; PG,
prostaglandins; PLL, poly-L-lysine; RAST, in-house
radioallergosorbent test; RCM, radio-contrast media; RIA,
radioimmunoassay; sIgE, specific IgE; SJS/TEN, Stevens–Johnson
syndrome/toxic epidermal necrolysis; ST, skin testing; a-gal,
galactose-1,3-galactose.
1104
Methods
A bibliographic search was performed using electronic databases
(MEDLINE and PubMed), electronic libraries (Science Direct,
OVID) and a systematic review database (Cochrane library).
Publications were selected from the 1983–2015. Keywords were
DHR, allergy, intolerance, idiosyncrasy, in vitro tests, IgE and
specific reactions, drugs, cells and mediators. In total, 228 publications were reviewed and evaluated on the basis of title and
abstract; of these, 150 were selected because they met the selection criteria (observational studies or case series larger than five
subjects) and analysed, discussed, confirmed or amended by
group consensus. Key statements were provided with a level of
evidence (LE) and grade of recommendation (GR) according to
the SIGN statement (11). Where evidence was lacking, a consensus was reached among the experts of the task force.
DHR classification
From a mechanistic point of view, DHRs are classified as
allergic or nonallergic reactions.
Allergic DHR
These comprise 5–10% of adverse drug reactions (12) and
can belong to any of the four types proposed in the Coombs
and Gell classification (13), with types I and IV being the
most frequent (Table 1). While drugs can also induce type II
and III reactions, these are somewhat uncommon and discussion of their in vitro evaluation is beyond the scope of this
position paper.
Type I (immediate) reactions (IR) are induced by specific
IgE (sIgE) antibodies, which are produced against a hapten–
carrier conjugate during a sensitization phase (usually asymptomatic) and subsequently attached to high-affinity IgE
receptors on mast cells or basophils. Re-exposure and crosslinking of sIgE lead to the cell activation and the release of
several mediators, resulting in the symptoms (13).
Type IV (nonimmediate) reactions (NIR) are mediated by
T cells, and due to the involvement of different cytokines,
cytotoxic mediators and cell subtypes, it can induce wellcharacterized clinical entities (14).
Nonallergic DHR
This group includes all other DHRs without a demonstrated
immune mechanism (9). Although many drugs could induce
these reactions, for example NSAIDs, RCM or opioids, the
former are the most frequent elicitors and the pathogenesis
involves cyclooxygenase-1 (COX-1) inhibition (9). This
produces an increase in cysteinyl leukotrienes (CysLTs),
prostaglandins (PG) D2, 15-hydroxyeicosatetraenoic acid
(15-HETE) with an overexpression of leukotriene (LTC4)
synthase and a decrease in PGE2 (9).
Nonallergic DHRs to NSAIDs have been classified as (9)
NSAID-exacerbated respiratory disease (NERD), NSAIDexacerbated cutaneous disease (NECD) and NSAID-induced
urticaria/angioedema (NIUA).
Allergy 71 (2016) 1103–1134 © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
13989995, 2016, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/all.12886 by Albania Hinari NPL, Wiley Online Library on [29/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
In vitro tests for drug hypersensitivity
Table 1 Classification and mechanisms involved in drug allergy
Types
of
reaction
Immune response
Pathomechanism
Clinical features
Chronology of the reaction
I
IgE mediated
Mast cell and basophil
degranulation
1–6 h after the last intake
of the drug
II
IgG/IgM and complement
III
IgG/IgM and complement
or FcR
IgG/IgM and complementdependent cytotoxicity
Deposition of immune
complexes
IVa
Th1 monocyte/macrophages
via IFN-c/TNF-a
Th2 via IL-4, IL-5, IL-13,
eotaxin
Monocytic inflammation
Urticaria, angioedema,
bronchospasm,
anaphylactic shock
Cytopenia, anaemia,
Thrombocytopenia
Serum sickness, urticaria,
lymphadenopathy, fever,
arthropathy, vasculitis
Eczema, contact dermatitis,
bullous exanthema
Maculopapular exanthema,
DRESS
IVc
CD4 + /CD8 + cytotoxic T
cells via perforin,
granzyme B, FasL
Keratinocyte death
Maculopapular exanthema,
SJS/TEN, pustular exanthema,
fixed drug eruption
IVd
T cells via IL-8/CXCL8 and GM-CSF
Neutrophilic inflammation
Acute generalized
exanthematous pustulosis
IVb
Eosinophilic inflammation
Diagnosis
Clinical history is the first approach for diagnosis; however,
it is often unreliable and can lead to either over- or underdiagnosis. This results in a restriction of therapeutic options
for the patient.
Skin testing has been standardized and can be useful for
diagnosing allergic reactions, especially in IR and for some
drugs, such as BLs (7). However, with NIR, the rate of positive
responses, even with BLs, is rather low (15). This means that in
a large number of cases, DPT is the only test that can confirm
the reaction (4, 9). DPT are not risk-free, and they are timeconsuming and must be performed in a specialized setting by
trained personnel. They can also be inappropriate for some
types of reactions. Thus, in vitro tests represent a potentially
safer procedure for diagnosing DHRs; however, DPT results
should be used whenever possible to validate in vitro tests.
Although many tests are available, there is currently no consensus on their diagnostic value in routine clinical care.
In vitro diagnostic tests
In vitro diagnostic tests can be useful for the evaluation of cells
involved and mediators released during the acute phase of the
reaction and for the identification of the culprit drug after resolution. The methods used for the diagnosis of a DHR depend
on the mechanism involved and reaction kinetics.
Tests to characterize the active phase of the reaction
Several mediators including tryptase, histamine (and metabolites), PG, LTC4, LTD4, pro-inflammatory cytokines and
5–15 days after starting the
eliciting drug
1–8 days for serum sickness/
urticaria
7–21 days for vasculitis
1–21 days after starting the
eliciting drug
1-several days after starting
the eliciting drug for MPE
2–6 weeks after starting the
eliciting drug for DRESS
1–2 days after starting the
eliciting drug for fixed drug
eruption;
4–28 days after starting the
eliciting drug for SJS/TEN
1–2 days after starting the
eliciting drug
chemokines determined in serum, plasma, urine or the
involved tissue during the active phase of the reaction may
be useful for the diagnosis of DHR (9, 16). For IR, tryptase
and histamine are the two most studied mediators, and for
NIR, the cellular analysis, including studies in skin biopsies
and peripheral blood, has been also used (Table 2).
Tryptase determination
Tryptase is a serine protease and an important prestored proinflammatory mast cell mediator. Total tryptase is composed
of an immature monomer isoform (continuously, but weakly
released in serum by mast cells) and a heterotetramer mature
isoform (suddenly and rapidly released upon mast cell
degranulation), and it is mainly determined by immunoassay
(17).
Clinical studies.
Mature tryptase is better related to mast cell activation.
However, there are no commercial tests for the specific
determination of mature tryptase only (18).
Twenty-two percentage of cases with perioperative DHRs
had tryptase levels >11.4 ng/ml with median levels being
higher in IgE-mediated (9.0 ng/ml) compared to non-IgEmediated DHR (4.0 ng/ml) (19).
In severe perioperative DHR (anaphylactic shock), tryptase levels >13.5 ng/ml were found in 66.6% of patients
(20).
•
•
•
Technical recommendations.
Total tryptase level can be measured in serum using a
widely available commercial assay, and its measurement
•
Allergy 71 (2016) 1103–1134 © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
1105
13989995, 2016, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/all.12886 by Albania Hinari NPL, Wiley Online Library on [29/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
In vitro tests for drug hypersensitivity
Mayorga et al.
1106
N.D.
518 ANAPH
271 Contr
48
37 ANAPH
Contr N.I.
34
49.8
75 ANAPH
25 Contr
66 ANAPH
Contr N.I.
47.4
N.D.
518 ANAPH
271 Contr
102 ANAPH
Contr N.I.
36.8
18 ANAPH
20 Contr
36
34
66 ANAPH
Contr N.I.
76 ANAPH
20 Contr
41
17 ANAPH
13 Contr
n
362F
156M
N.D.
17F
20M
55F
20M
39F
63M
38F
38M
362F
56M
12F
6M
N.D.
9F
8M
Sex (F/M)
CH/ST
CH
CH/ST
CH
CH
CH
CH/ST
CH/ST
CH
CH
Methods
(CH/ST/DPT)
NMBA, latex, antibiotics,
hypnotics, opioids, colloids
N.D.
AX, GEL, ATR, META,
AX-CLV, LEVO, PROT,
POV, CEFAZ, LAT
Drug, latex
Drug, food, inhalant
Drug, food, insect
ALC, ATR, BUP, CLORH,
DIAZ, DROP, FENT, GLYC,
METRO, MIDA, OXA,
PANC, PETH, PROPY,
SUXA, THIO, VEC
NMBA, latex, antibiotics,
hypnotics, opioids, colloids
N.D.
ATR, META, AX, CEF,
Food, Idiopathic
Drugs analysed
RIA (yes)
His>9 nM
Immunotech
ELISA (yes)
His>10 nm/ml
CAP-FEIA (yes)
Tryp>11.4 ng/ml
<2
<12
CAP-FEIA (yes)
Tryp>12.3 lg/l
CAP-FEIA (yes)
Tryp>11.4 ng/ml
<2
2/6/24
CAP-FEIA (yes)
Tryp>2 ng/ml
<2
CAP-FEIA (yes)
Tryp>13.5 ng/ml
3/6/24
CAP-FEIA (yes)
Tryp>25 lg/l
CAP-FEIA (yes)
Tryp>13.5 ng/ml
<12
N.D.
CAP-FEIA (yes)
Tryp>8.23 ng/ml
Commercialized
in vitro test
(Yes/No)
<6
Time
study
(hours)
75
64
37 in ST
+ 6 in ST-
82.7
61.8
75 severe
55 moderate
64
66.6
30
94.1
Sens (%)
51
N.D.
94.4
96
N.D.
N.D.
89.3
100
N.D.
92.3
Spec (%)
75
N.D.
N.D.
N.D.
N.D.
N.D.
92.6
N.D.
N.D.
N.D.
NPV (%)
51
N.D.
N.D.
N.D.
N.D.
N.D.
54.3
N.D.
N.D.
N.D.
PPV (%)
† Drug
ANAPH
in 31/66
With a
cut-off
Trypt >
8.23 ng/ml,
Sens =
58%
† Drug
ANAPH
in 51/102
† Drug
ANAPH
in 26/76
† Drug
ANAPH
in 31/66
Controls
patients
with URT
Comments
Mayorga et al.
Allergy 71 (2016) 1103–1134 © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
13989995, 2016, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/all.12886 by Albania Hinari NPL, Wiley Online Library on [29/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Histamine*
Lin
et al. (25)
(PMID:
10887307)
Mertes
et al.
(PMID:
12960536)
Mertes
et al. (2003)
(PMID:
12960536)
Stone
et al. (26)
(PMID:
19767073)
Sala-Cunill
et al. (27)
(PMID:
23018683)
Laroche
et al. (30)
(PMID:
24787350)
Berroa
et al. (19)
(PMID:
24237068)
Tryptase
Enrique
et al. (24)
(PMID:
10435474)
Lin et al. (25)
(PMID:
10887307)
Dybendal
et al. (20)
(PMID:
14616317)
Paper
Mean age
(years)
Table 2 In vitro tests to characterize the active phase of the reaction
In vitro tests for drug hypersensitivity
n
Mean age
(years)
Sex (F/M)
Methods
(CH/ST/DPT)
50.1
55.9
N.D.
44.1
9 Pats
9 Contrs
21 Pats
Contrs: N.I.
8 Pats
5 Contrs
16 Pats
Contrs: N.I.
Hari
et al. (37)
(PMID:
11591190)
Allergy 71 (2016) 1103–1134 © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Homey
et al. (2002)
(PMID:
11821900)
Tapia
et al. (2004)
(PMID:
15316512)
11F
5M
N.D.
13F
9M
5F
4M
CH
CH/ST
CH
CH/ST
SULFAM, DILT, CLIND, AX,
SULFAS, META, HYDANT,
ACETAM, PHENY, TEICO, IBU,
SPIRA, METRO, ERYT
PRED, VERA, VITB, SULFAM,
TRIM, INDA, ACETAM,
DORZ, SIMV, LOSAR, TORA,
METOL, TICLO, PG, AX,
CEPH, ALLO, CARBA
Nickel
AX-CLV, CEFAZ, PRED,
CARBA, INDA, METOL, VITB
No
Methods: FC, IHQ
Markers: CCL27
No
Methods: PCR, IHQ
Markers: CCL27
<24
<24
<24
<24
<24
AX, DICL, META, AMI, IBU,
AMP, PG, CARBA, HYDANT,
CEFT
No
Methods: FC
Markers: CLA,
HLA-DR
No
Methods: PCR,
ELISA
Markers: IFN-c,
TNF-a, IL-2, IL-4
No
Methods: IHQ
Markers: Eosinophils,
IL-5, eotaxin, IL-8,
RANTES, MCP-3
No
Methods: FC
Markers: HLA-DR
in CD8+
Fluorometric (No)
His>28 ng/ml
<2
AX, GEL, ATR, META,
AX-CLV, LEVO, PROT,
POV, CEFAZ, LAT
<24
RIA (yes)
> 6 nmol/l
<2
Drug, latex
PROPY, AX, PHENY, CLOX,
SPIRA, METRO, CAPTO,
TIAZ, AX-CLV, PV
IBL ELISA (yes)
His>1.2 ng/ml
<2
N.D.
Drugs analysed
Commercialized
in vitro test
(Yes/No)
Time
study
(hours)
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
92
90.7
61 severe
35 moderate
Sens (%)
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
1.7
N.D.
Spec (%)
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
NPV (%)
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
PPV (%)
Peripheral
blood and
skin
Peripheral
blood and
skin
Peripheral
blood
and skin
Peripheral
blood
and skin
Peripheral
blood
Peripheral
blood
† Drug
ANAPH
in 26/76
Comments
In vitro tests for drug hypersensitivity
1107
13989995, 2016, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/all.12886 by Albania Hinari NPL, Wiley Online Library on [29/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Yawalkar
et al. (73)
(PMID:
11112902)
76 ANAPH
36
38F
CH
Stone
34 Contr
38M
et al. (26)
(PMID:
19767073)
75 ANAPH
49.8
55F
CH
Laroche
25 Contr
20M
et al. (30)
(PMID:
24787350)
37 ANAPH
48
17F
CH/ST
Berroa
Contr N.I.
20M
et al. (19)
(PMID:
24237068)
Cellular phenotypical analysis in skin biopsies and/or peripheral blood
9 Pats
49
6F
CH/ST/DPT
Blanca
et al. (49)
18 Contrs
3M
(PMID:
11097307)
19 Pats
44.8
9F
CH/ST/DPT
Posadas
9 Contrs
10M
et al. (151)
(PMID:
11031349)
Paper
Table 2 (continued)
Mayorga et al.
1108
73.1
9F
14M
17F
10M
21F
4M
35F
15M
N.D.
Sex (F/M)
CH
CH/ST/DPT
CH/ST/DPT
CH/ST/DPT
CH
Methods
(CH/ST/DPT)
CEF, ALLO, MEFE, DICLX,
DICL, CLORH, TETRAC, ACETAM,
IBU, KETO, AX, ICM, COTRI
AX, CEF, AX-CLV, META, PARA,
CEFAC, CEPH, IBU, SPIRA,
TETRAZ, EBAST
AX, CEF, AX-CLV, META, PARA,
CEFAC, CEPH, IBU, SPIRA,
TETRAZ, EBAST, CEF, DIPH,
PHENOB, CARBA, ACEC, ALLO,
METRO, NIMO
AX, CEF, META, PARA, ALLO,
CEPH, DIPH, CARBA, PHENOB,
SPIRA
COTRI, CARBA, TETRAZ, PIRO
Drugs analysed
<24
<24
<24
<24
<24
Time
study
(hours)
No
Methods: PCR
Markers: IFN-c,
TNF-a, TNF-beta
No
Methods: PCR, IHQ
Markers: TNF-a,
IFN-c, IL-4, perforin,
granzyme B, CXCR3,
CXCL9, CXCL10
No
Methods: IHQ
Markers: granulysin,
FasL, granzyme B,
perforin, FoxP3
No
Methods: FC
Markers: HLA-DR,
granzyme B
No
Methods: FC, IHQ
Markers: CLA, CD69,
CD25, HLA-DR
Commercialized
in vitro test
(Yes/No)
N.D.
N.D.
N.D.
N.D.
N.D.
Sens (%)
N.D.
N.D.
N.D.
N.D.
N.D.
Spec (%)
N.D.
N.D.
N.D.
N.D.
N.D.
NPV (%)
N.D.
N.D.
N.D.
N.D.
N.D.
PPV (%)
Skin
Peripheral
blood
and skin
Peripheral
blood
Peripheral
blood
and skin
Blister fluid
Comments
Mayorga et al.
Allergy 71 (2016) 1103–1134 © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
13989995, 2016, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/all.12886 by Albania Hinari NPL, Wiley Online Library on [29/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Sensitivity, Specificity, NPV and PPV values are calculated based on all drugs tested. Data for individual drugs are not always available.
F, female; M, male; CH, clinical history; ST, skin test; DPT, drug provocation test; ANAPH, anaphylaxis; URT, urticaria; CMH, contrast media hypersensitivity; N.I., not included; N.D., no
data; Sens, sensitivity, Spec, specificity, NPV, negative predictive value and PPV, positive predictive value; ACEC, aceclofenac; ACETM, acetaminophen; ALCU, alcuronium; ALLO, allopurinol; AMLO, amlodipine; AMP, ampicillin; ATRA, atracurium; AX, amoxicillin; AX-CLV, amoxicillin–clavulanic acid; BUP, bupivacaine; CAPTO, captopril; CARBA, carbamazepin; CEF, cefuroxime; CEFAC, cefaclor; CEFAD, cefadroxil; CEFAZ, cefazolin; CEFT, ceftriaxone; CEPH, cephalosporin; CLIND, clindamycin; CLORH, chlorhexidine; CLOX, cloxacillin; COTRI, cotrimoxazole;
DIAZ, diazepam; DICLO, diclofenac; DICLX, dicloxacillin; DILT, diltiazem; DIPH, diphenylidantoin; DORZ, dorzolamide; DROP, droperidol; EBAST, ebastine; ERYT, erythromycin; FENTA, fentanyl; GLYC, glycopyrronium bromide; HYDANT, hydantoin; IBU, ibuprofen; INDA, indapamide; KETO, ketoprofen; LAT, latex; LEVO, levofloxacin; LOSAR, losartan; MEFE, mefenamic acid;
META, metamizole; METOL, metolazone; METRO, metronidazol; MIDA, midazolam; NIMO, nimodipine; NMBA, neuromuscular-blocking agents; OXA, oxazepam; PANC, pancuronium;
PARA, paracetamol; PETH, pethidine; PG, penicillin G; PHENOB, phenobarbital; PHENY, phenytoin; PIRO, piroxicam; POV, povidone; PRED, prednisolone; PROPY, propyphenazone; PROT,
protamine; PV, penicillin V; SIMV, simvastatin; SPIRA, spiramycin; SULFAM, sulphamethoxazole; SULFAS, sulfasalazine; SUXA, suxamethonium; TEICO, teicoplanin; TETRA, tetracaine;
THIO, thiopentone; TIAZ, thiazide; TICLO, ticlopidine; TORA, torasemide; TRIM, trimethoprim; VEC, vecuronium; VERA, verapamil; VITB, Vitamin B complex.
*For histamine metabolites, different cut-off levels have been used and sensitivity and specificity cannot be reliably given for anaphylaxis. Studies measuring only beta-tryptase, which is no
longer available, and not total tryptase were excluded. Cell subsets, cytokines or activation markers in the skin biopsy or blood of patients have been analysed semiquantitatively only and
are not included.
†Study not specific for drug anaphylaxis.
Cho
et al. (53)
(PMID:
24388722)
23 Pats
Contrs: N.I.
25 Pats
14 Contrs
37.7
43.24
50 Pats
56 Contrs
27 Pats
26 Contrs
40.3
6 Pats
0 Contrs
Nassif
et al. (44)
(PMID:
15536433)
Torres et al. (48)
(PMID:
16569350)
Cornejo
et al. (52)
(PMID:
17983377)
Fernandez
et al. (50)
(PMID:
18384452)
N.D.
n
Mean age
(years)
Paper
Table 2 (continued)
In vitro tests for drug hypersensitivity
•
•
•
is robust and the mediator is stable at room temperature
(18, 21) (LE 2+) (GR B).
Because the half-life of tryptase is 90–120 min, its measurement should ideally be taken between 30–120 min
after the onset of symptoms and be compared to basal
levels, measured at least 24 h after the resolution of anaphylactic symptoms (17, 21, 22) (LE 2+) (GR B).
The minimal clinically significant elevation of the acute
total tryptase level has been suggested to be ≥20% above
baseline level plus 2 lg/l, within 4 h after a symptomatic
period (23) (LE 2) (GR B).
The presence of mast cell disease influences basal tryptase
levels (23) (LE 2+) (GR B).
Clinical recommendations.
Tryptase determination during the acute phase is an useful method for confirming mast cell-mediated reactions
with a sensitivity ranging from 30% to 94.1% and with a
specificity from 92.3% to 94.4% depending on the cut-off
point (19, 20, 24–27), with higher tryptase values
obtained in more severe clinical drug reactions (19, 28)
(LE 2) (GR B).
•
Determination of histamine and its metabolites
Histamine is a mediator of allergic inflammation derived
from the enzymatic processing of histidine by L-histidine
decarboxylase, and large amounts of this compound are
stored in basophils and mast cell granules, and it is mainly
determined by immunoassay (29).
Clinical studies.
Histamine is probably the most abundant and important
mediator for acute anaphylaxis, and the sensitivity of tests
using this mediator has been reported to be higher than that
of tests using tryptase in nonsevere reactions (20, 30).
•
Technical recommendations.
Because of its short half-life (20 min), blood should be
collected within the first hour (19) and histamine level
must be compared to baseline level (LE 2) (GR B).
Histamine must be assessed in nonhaemolysed plasma
that should be cooled and processed immediately (31)
(LE 3) (GR B).
Measurements of histamine metabolites, N-methylhistamine and N-methylimidazoleacetic acid, in urine during a
24-h period have been used as indirect methods for the
determination of histamines (29) (LE 3) (GR B).
Bacteria in the digestive or urinary tract and histaminerich food have been reported to increase histamine
metabolite levels (32, 33) (LE 3) (GR C).
•
•
•
•
Clinical recommendations.
Plasma histamine has a sensitivity from 61% to 92%,
and as baseline levels have high interindividual variability and intraindividual variability, this has limited its
specificity from 51% to 91% (19, 25, 26, 30, 34–36). It
was the reference laboratory tool to confirm anaphy-
•
laxis until tryptase determination became available (37)
(LE 3) (GR B).
Cellular analysis
The clinical assessment of NIR patients can be difficult, and
possible differential diagnoses must be considered. Cellular
tests can be useful to assess the immunopathological
response.
Skin biopsies
These consist of the detection and quantification of specific
cell surface markers and mediators in affected skin using histology, immunohistochemistry and/or molecular biology
methods.
Clinical studies.
In maculopapular exanthema (MPE), CD4+T cells predominate, with variable degrees of neutrophils and eosinophils (38, 39).
In acute generalized exanthematic pustulosis (AGEP), histology shows spongiform subcorneal, intradermal pustule,
papillary oedema and/or perivascular infiltrate with activated neutrophils by IL-8 (CXCL8), which is produced by
T cells (40, 41). The histological observations in drug reaction with eosinophilia and systemic symptoms (DRESS)
can be accompanied by dermal oedema. Superficial
lymphocytic infiltrate formed by both CD4+ and CD8+T
cells is found with a perivascular involvement, which
produce IL-5 responsible for the eosinophil recruitment
(42–44).
Severe bullous drug reactions such as Stevens–Johnson
syndrome/toxic epidermal necrolysis (SJS/TEN) are characterized by necrotic keratinocytes and vacuolization of
the basement membrane zone that result in subepidermal
blistering. The dermis usually shows a perivascular lymphohistiocytic infiltrate (45). Cytotoxic CD8+T cells producing high amounts of granzyme B, perforin, Fas-L and
granulysin are detected (46).
•
•
•
Technical recommendations.
Skin biopsy is a simple procedure; tissue can be stored
for a long period and can be used to study different cell
subsets and inflammatory mediators (42, 47, 48) (LE 3)
(GR B).
•
Clinical recommendations.
Although skin biopsies may not differentiate DHRs
from other cutaneous diseases such as viral infections
and generalized pustular psoriasis (42, 47), they are
essential to differentiate from the wide spectrum of cutaneous DHRs and are especially recommended where
there is a significant skin involvement, for example, in
SJS/TEN, DRESS and AGEP (38, 39, 41, 43–45) (LE 2)
(GR B).
•
Peripheral blood. Peripheral blood samples consist of the
detection and quantification of different cell subsets and
Allergy 71 (2016) 1103–1134 © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
1109
13989995, 2016, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/all.12886 by Albania Hinari NPL, Wiley Online Library on [29/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
In vitro tests for drug hypersensitivity
Mayorga et al.
Mayorga et al.
inflammatory markers (cytokines, chemokines and adhesion
molecules) by flow cytometry and/or molecular biology
methods.
Clinical studies.
T-cell activation markers, such as HLA-DR (49), skinhoming receptors (CLA, CCR6 and CCR10) (50–52),
IFN-c and TNF-a expression (53, 54), as well as cytotoxic markers (49, 55) have been shown to be elevated
during the acute phase of NIR.
The involvement of different cell subpopulations and
inflammatory mediators depends on the clinical symptoms (49–51, 53–55).
•
•
Technical recommendations
Due to the interindividual variability, the different markers
determined in sequential peripheral blood samples collected
during the active phase and after resolution of the reaction
should be compared intraindividually (48).
Clinical recommendations.
These studies can provide an indirect information about
the mechanisms involved and cell trafficking when combined with the results of skin biopsies (39, 44, 49, 51, 56)
(LE 3) (GR C).
•
Tests to identify the culprit drug
These methods are based on the analysis of specific markers
after the stimulation with the culprit drug or their metabolites at the resolution of the reaction. They depend on the
underlying mechanism whether IgE or T cell mediated.
IgE-mediated drug allergy
Methods determining IgE, either soluble or bound to basophil surfaces as well as mediators released upon IgE-mediated
cell activation, are used (Table 3).
Specific IgE determination. This is based on the detection of
drug-sIgE in serum using a solid phase functionalized with
drug–carrier conjugates by immunoassay (57). The most
widely used commercial method is the fluoroimmunoassay
(FEIA) (ImmunoCAP Thermo-Fisher, Uppsala, Sweden),
where the drug is covalently bound to poly-L-lysine (PLL).
In-house radioimmunoassay (RIA) or enzymoimmunoassay
(ELISA) using different carriers [human serum albumin
(HSA), PLL, amino-aliphatic spacers and dendrimer structures)] (58, 59) as well as using different solid phases (cellulose, Sepharose, zeolites or silica particles) has also been used
(60–63).
Clinical studies.
ImmunoCAP sensitivity depends on the drug involved,
but is rather low and variable (0–50%) for BLs allergy
(64–67) and heterogeneous for NMBA, ranging from
83% to 92% for rocuronium, 78% to 84% for morphine
and 44% for suxamethonium (68–70). Moreover in
•
1110
•
•
•
•
•
•
chlorhexidine allergy, it showed a sensitivity of 91.6% in
patients with a positive ST and 100% specificity (71).
ImmunoCAP to penicillin V can lead to false allergy
diagnoses (72).
In-house RIA has mainly been carried out with BLs. Sensitivity ranges from 42.9% to 75% and specificity from
67.7% to 83.3% for both penicillins and cephalosporins
(64, 73, 74).
In-house Sepharose-RIA has shown a good sensitivity for
cephalosporins (74.3%) (60) and NMBA (86–88%) (75,
76) and low sensitivity for fluoroquinolones (31.6–54.5%).
Sensitivity of in-house Sepharose-RIA depends on the drugs
involved, clinical manifestations and total IgE levels (61, 62).
False-positive results may occur through the presence of nonspecific cross-reactivity of hydrophobic IgE (77).
In-house ELISA to NSAID has demonstrated sIgE to
pyrazolones in 60% of patients (78), but not for diclofenac metabolites (79).
The majority of these in vitro tests show high specificity,
although this depends on the drugs studied and the methods used.
Technical recommendations.
All immunoassays have the advantages that serum samples can be stored and easily transported, and analysis
can be automated although showing low sensitivity that
could depend on (i) drug binding to the solid phase,
(ii) carrier as part of the antigenic determinant, (iii) the
density of haptens in the conjugate, (iv) the metabolites
involved in the reaction, (v) time interval and (vi) the lack
of positive controls availability for many drugs.
In vitro drug-sIgE decreases with time (80); for this, it is
recommended that the assay should not be performed
after longer than 3 years following the reactions (LE
2++) (GR B).
In BLs allergy, sensitivity correlates with the severity of
the clinical symptoms (64) (LE 2 ).
In BLs allergy, lowering the threshold from 0.35 to
0.1 kUA/l increases the sensitivity, although it also
reduces specificity, particularly for cases with total
IgE>200 kU/l (81, 82), and the ratio of sIgE to total IgE
increases the specificity (82) (LE 3) (GR C).
•
•
•
•
Clinical recommendations.
ImmunoCAP is recommended for diagnosing BLs,
NMBA and chlorhexidine DHR, after ST in order to
avoid DPT (64–71) (LE 2+) (GR B).
As ImmunoCAP is only available for a limited number
of drugs, in-house tests could be used especially for some
BLs and fluoroquinolones (60–62, 64, 73, 74) (LE 2)
(GR C).
Immunoassays, when available, should be performed
before in vivo tests including ST in life-threatening reactions or in high-risk patients (7) (LE 2) (GR B).
•
•
•
Detection of sIgE to biological agents (BA). This is based on
the detection of circulating BA-sIgE antibodies in serum
using ImmunoCAP and in-house methods.
Allergy 71 (2016) 1103–1134 © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
13989995, 2016, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/all.12886 by Albania Hinari NPL, Wiley Online Library on [29/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
In vitro tests for drug hypersensitivity
Allergy 71 (2016) 1103–1134 © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
19F
11M
77F
52M
N.D.
54F
34M
33F
20M
54F
22M
N.D.
40
41.3
N.D.
51.8
31.3
44
45.22
38.9
74 Pats
55
Contrs
290
Pats
120
Contrs
58 Pats
30
Contrs
53 Pats
20
Contrs
55 Pats
32
Contrs
76 Pats
Contrs
N.I.
51 Pats
Contrs
N.I.
44F
11M
28F
3M
N.D.
CH/ST/DPT
CH/ST
CH
ST
CH/ST
CH/ST/DPT
CH/ST/DPT
ST
CH/ST
CH
Methods
(CH/ST/
DPT)
CEFAC, CEFON,
CEFO, CEFTA,
CEFT, CEFU
PIP, RUFL,
PEFL, NALI,
CINOX, LOME,
CIPRO, NORF,
OFLO
CEFT, CEFO,
CEFTA
PROPY
PG, AX, CEFU,
CEFAZ
PG, AX, AMP
CEPHAL,
CEFAM,
CEFTA,
CEFT, CEFU,
CEFO
PG, AX, CLV
MORPH, TMA,
TEA, SUCCI,
ALCU
SUXA, VEC,
ALCU, PANCU,
GALL
Analysed
drugs
CAP-FEIA (yes)
Seph-RIA (no)
RAST (no)
401.2
Seph-RIA (no)
371
725.4
ELISA
(no)
CAP-FEIA
(yes)
CAP-FEIA (yes)
CAP-FEIA
(yes)
RAST (yes)
PAPPC RIA
(no) Seph-RIA
(no)
RAST (no)
Seph-RIA (no)
RAST (no)
Commercialized
in vitro test
(Yes/No)
652.39
N.D.
3670
252
371
N.D.
Mean
Time
study
(days)
47
74.3
54.5
58
38
BPO: 10–68;
AXO: 41–53
BPO: 32;
AXO: 43;
BPO+AXO: 50
N.D.
N.D.
100
N.D.
87
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
BPO: 98;
AXO: 98;
BPO+AXO: 96
BPO: 95
AXO: 95
N.D.
PAPPC
RIA:94
N.D.
N.D.
PAPPC
RIA: 97
PAPPC RIA: 97
Seph-RIA: 86
RAST SUCCI:70
RAST-ALCU:39
CEPH: 30
PENI: 10
N.D.
PPV (%)
N.D.
N.D.
NPV (%)
N.D.
Spec (%)
Seph: 88
RAST-SUCC: 67
RAST-ALCU: 41
Sens (%)
Sensitivity with
ST + 96%
Positive
results in
ST-patients
Comments
In vitro tests for drug hypersensitivity
1111
13989995, 2016, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/all.12886 by Albania Hinari NPL, Wiley Online Library on [29/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Romano
et al. (57)
(PMID:
16164453)
Antunez
2006 (71)
(PMID:
16461141)
Blanca
et al. (62)
(PMID:
11551251)
Torres
et al. (63)
(PMID:
11551249)
Sanz
et al. (64)
(PMID:
11929494)
Himly
et al. (75)
(PMID:
12704373)
Manfredi
et al. (58)
(PMID:
14713922)
N.D.
Sex
(F/M)
N.D.
Immunoassays
n = 83
Gueant
et al. (73)
(PMID:
1957994)
31 Pats
Guilloux
34 Contrs
et al. (72)
(PMID:
1500622)
30 Pats
Romano
et al. (70)
Contrs N.I.
(PMID:
11112903)
Paper
No. of
pats
Mean
age
(years)
Table 3 In vitro tests to identify the culprit drug in IgE-mediated drug allergy
Mayorga et al.
1112
N.D.
27 Pats
513
Contrs
N.D.
N.D.
N.D.
106F
65M
73F
41M
49.5
114
Pats
54
Contrs
11 Pats
20
Contrs
N.D.
24F
14M
43.5
38 Pats
35
Contrs
171 Pats
122 Contrs
23F
11M
N.D.
N.D.
25 Pats
55
Contrs
N.D.
1F
11M
63.6
12 Pats
10
Contrs
61 Pats
115
Contrs
30F
15M
38.5
Sex
(F/M)
30 Pats
15
Contrs
Mean
age
(years)
CH/DPT
CH/ST
CH/ST
CH/ST
CH/DPT
CH/ST
CH/ST
ST
ST/DPT
Methods
(CH/ST/
DPT)
CETUX
PG, PV, AX,
AMP
SUXA, ROCU,
MORPH
MORPH
MOXI, CIPRO,
LEVO
PG, PV,
AX, AMP
ROCU
CHLOR
PG, AX, AMP,
CEPH
Analysed
drugs
N.D.
89.1
N.D.
N.D.
120
95.85
N.D.
n.d
999
Mean
Time
study
(days)
CAP-FEIA (yes)
CAP-FEIA (yes)
CAP-FEIA (yes)
PAPPC
RIA (no)
CAP-FEIA (yes)
Seph-RIA (no)
CAP-FEIA (yes)
CAP-FEIA (yes)
CAP-FEIA (yes)
CAP-FEIA (yes)
RAST (no)
Commercialized
in vitro test
(Yes/No)
68 Severe 92
SUXA:44;
ROCU:83;
MORPH: 78
PAPPC: 85
66 sIgE/tIgE:43
84
31,5
ROCU:92
SUXA: 72
MORPH: 88
PHOL: 86
85
91.6
CAP: 0–25
RAST: 43–75
Sens (%)
N.D.
N.D.
SUXA: 100
ROCU: 71
MORPH: 82
PAPPC: 93
66 sIgE/
tIgE:93
SUXA: 67;
ROCU: 81;
MORPH:81
PAPPC: 82
52 sIgE/
tIgE:55
SUXA: 100
ROCU: 68
MORPH: 85
PAPPC: 95
52 sIgE/tIgE:95
98 Severe 90
82.7
N.D.
77.4
N.D.
90.7
100
N.D.
N.D.
N.D.
ROCU:93
SUXA: 100
MORPH: 100
PHOL: 100
54
N.D.
N.D.
CAP: 45
RAST: 38
PPV (%)
N.D.
CAP: 77
RAST: 81
NPV (%)
100
CAP: 83–100
RAST: 67–83
Spec (%)
Pre-existing
IgE specific
for
Gal1-3Gal
Total IgE has
an influence
on the
detection of
sIgE to BL
Comments
Mayorga et al.
Allergy 71 (2016) 1103–1134 © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
13989995, 2016, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/all.12886 by Albania Hinari NPL, Wiley Online Library on [29/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Aranda
et al. (59)
(PMID:
20722637)
Laroche
et al. (66)
(PMID:
21169794)
Rouzaire
et al. (105)
(PMID:
22091673)
Vultaggio
et al. (79)
(PMID:
4399843)
Chung
et al. (80)
(PMID:
2361129)
Fontaine
et al. (61)
(PMID:
17156341)
Garvey
et al. (68)
(PMID:
17559915)
Ebo
et al. (67)
(PMID:
17667569)
Vultaggio
et al. (78)
(PMID:
19400911)
Paper
No. of
pats
Table 3 (continued)
In vitro tests for drug hypersensitivity
3F
11M
16F/14M
37F
21M
20F
6M
58
50.6
51.5
41
39
39
43.27
54.5
54.5
14 Pats
195
Contrs
30 Pats
50
Contrs
58 Pats
30
Contrs
26 Pats
30
Contrs
70 Pats
40 Contrs
51 Pats
56 Contrs
Allergy 71 (2016) 1103–1134 © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
55 Pats
30 Contrs
26 Pats
43 Contrs
8 Pats
20 Contrs
5F
3M
16F
10M
23 F
32 M
35F
16M
38F
32M
5F
6M
50.6
Sex
(F/M)
11 Pats
20
Contrs
Mean
age
(years)
ST/DPT
CH/ST
ST/DPT
CH/ST/DPT
ST/DPT
ST/DPT
ST
ST
CH
CH
Methods
(CH/ST/
DPT)
IOD, IOH, IOM,
IOB
IOXIT, IOPR,
IOPA, IOH,
IOB
PG, AX, AXCLV, CLV
PG, AX, AMP,
MDM, PPL,
CEFU, CEFAZ,
CEFAC
META
META
PG, AX, AMP,
MDM, PPL,
CEFU, CEFAZ
INFLIX
CETUX
INFLIX
Analysed
drugs
6882.5
808.8
No
Flow2-CAST (yes)
No
No
Orpegen (yes)
233.6
383,5
No
No
N.D.
510
CAP-FEIA (yes)
ELISA (no)
CAP-FEIA (yes)
Commercialized
in vitro test
(Yes/No)
N.D.
1
N.D.
Mean
Time
study
(days)
62.5
46.2 - 61.5
G BP:60
G AX:52.9
G CLV: 50
54.9
48.6
42.3
50
26
71.4
27.2
Sens (%)
100
N.D.
50 - 54.5
N.D.
90
88.4 - 100
67.6
N.D.
99.4
N.D.
89
98.5
N.D.
NPV (%)
85.7
93
100
93.3
90
82.1
N.D.
Spec (%)
N.D.
88.9 - 100
N.D.
77.7
N.D.
100
N.D.
26
33.3
N.D.
PPV (%)
Potential for
predicting
reactions
at first therapy
Correlation
with ST
Reaction
after first
therapy
Comments
In vitro tests for drug hypersensitivity
1113
13989995, 2016, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/all.12886 by Albania Hinari NPL, Wiley Online Library on [29/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Vultaggio
et al. (82)
(PMID:
19951375)
Mariotte
et al. (81)
(PMID:
21654207)
Matucci
et al. (83)
(PMID:
23711128)
BAT
Sanz
et al. (64)
(PMID:
11929494).
Gamboa
et al. (101)
(PMID:
12708979)
Torres
et al. (94)
(PMID:
15544603)
Gomez
et al. (102)
(PMID:
19400910)
Torres
et al. (95)
(PMID:
20159266)
Pinnobphun
et al. (106)
(PMID:
21530870)
Salas
et al. (107)
(PMID:
23991759).
Paper
No. of
pats
Table 3 (continued)
Mayorga et al.
1114
N.D.
46
50
22 Pats
34 Contrs
28 Pats
20 Contrs
8 Pats
7 Contrs
Mean
age
(years)
7F
1M
N.D.
16F 6M
Sex
(F/M)
ST
CH/DPT
ST
Methods
(CH/ST/
DPT)
ATRA
CIPRO, MOXI
ATRA, ROCU,
SUXA, PANCU
Analysed
drugs
1072.5
191,8
N.D.
Mean
Time
study
(days)
No
No
Flow2-CAST (yes)
Commercialized
in vitro test
(Yes/No)
63
Light: 46.4
Dark: 57.1
68.18
Sens (%)
100
Light: 90
Dark: 90
100
Spec (%)
70
N.D.
N.D.
NPV (%)
100
N.D.
N.D.
PPV (%)
Comments
Mayorga et al.
Allergy 71 (2016) 1103–1134 © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
13989995, 2016, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/all.12886 by Albania Hinari NPL, Wiley Online Library on [29/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Sensitivity, Specificity, NPV and PPV values are calculated based on all drugs tested. Data for individual drugs are not always available.
CH, clinical history; ST, skin test; DPT, drug provocation test; Seph, Sepharose; N.I., not included; Sens, sensitivity, Spec, specificity, NPV, negative predictive value; and PPV, positive predictive value. ALCU, alcuronium; AMP, ampicillin; ATRA, atracurium; AX, amoxicillin; AX-CLV, amoxicillin–clavulanic acid; CEFAC, cefaclor; CEFAM, cefamandole; CEFAZ, cefazolin; CEFO,
cefotaxime; CEFON, cefonicid; CEFT, ceftriaxone; CEFTA, ceftazidime; CEFU, cefuroxime; CEPH, cephalexin; CEPHAL, cephalothin; CETUX, cetuximab; CHLOR, chlorhexidine; CINOX,
cinoxacin acid; CIPRO, ciprofloxacin; CLV, clavulanic acid; INFLIX, infliximab; IOB, iobitrol; IOD, iodixanol; IOH, iohexol; IOM, iomeprol; IOPA, iopamidol; IOPR, iopromide; IOXIT, ioxithalamate; LEVO, levofloxacin; LOME, lomefloxacin; MDM, minor determinants mixture; META, metamizole; MORPH, morphine; MOXI, moxifloxacin; NALI, nalidixic acid; NORF, norfloxacin;
OFLO, ofloxacin; PANCU, pancuronium; PEFL, pefloxacin; PG, penicillin G, PIP, pipemidic acid; PPL, benzylpenicilloyl-polylysine; PROPY, propyphenazone; PV, penicillin V; ROCU, rocuronium; RUFL, rufloxacin; SUCCI, succinyl choline; SUXA, suxamethonium; TEA, triethylamine; TMA, trimethylamine; VEC, vecuronium.
Hagau et al.
(2013)
(PMID:
24499278)
Mayorga
et al. (109)
(PMID:
23183272)
Uyttebroek
et al. (2014)
(PMID:
24961660)
Paper
No. of
pats
Table 3 (continued)
In vitro tests for drug hypersensitivity
Clinical studies.
Cetuximab-sIgE directed against galactose-a-1,3-galactose
residues (a-gal) present in the Fab portion of this antibody has been detected. Pre-existing cetuximab-sIgE,
directed against a-gal, has been detected, possibly related
to tick bites or other sources (83).
ImmunoCAP sensitivity to cetuximab ranges from 68%
to 92% and specificity from 90% to 92% depending on
DHR severity (83).
ELISA is useful for predicting high-grade reactions to
cetuximab at first infusion (sensitivity 71.4% and specificity 82.1%) (84).
Anti-infliximab IgE in ImmunoCAP has a sensitivity of
26% and a specificity of 90% (85, 86).
Acute infusion reactions can co-occur with the presence
of sIgE to cetuximab, rituximab, tocilizumab, natalizumab, infliximab and muromonab (83, 87–90).
•
•
Basophil activation test. This test is based on flow cytometry with different strategies to identify basophils (antiIgE, CCR3, CRTH2 and CD203c) and to measure their
activation (CD63 and CD203c) after the stimulation with
the culprit drug or their metabolites.
Clinical studies.
•
•
•
•
Technical recommendations.
High levels of IgG as well as BA in serum can interfere
with the identification of BA-sIgE by ImmunoCAP (91).
•
•
•
•
Clinical recommendations.
BA-sIgE determination may be useful with high sensitivity and specificity (LE 2) (GR B).
•
Cellular tests
Several functional assays try to mimic in vivo IgE-mediated
cell activation and mediator release. They have the
advantage that they can be performed with any
injectable drug without preparing hapten–carrier conjugates;
however, they require fresh blood and it is currently
unclear how other medicines/treatments may affect the
results.
Mediator release assays (Histamine and CysLTs). These tests
measure the mediator released (histamine or LTC4) in
supernatant upon the cell activation with the suspected drug
(92).
Clinical studies.
•
•
Histamine release assays display a poor sensitivity (50%)
and PPV (30%) in BLs allergy (93), being higher for
NMBA (65%) (94).
Sulphidoleukotriene release assay by cellular antigen stimulation test (CAST) to BLs has a sensitivity and specificity of 47.7% and 83.3%, respectively, in patients with
positive ST and 22.7% and 83.3% (95) in those with negative ST (96).
Technical recommendations.
•
The in vitro stability of released mediators could affect
the results.
Clinical recommendations.
•
Histamine and sulphidoleukotriene release assays have
too low sensitivity and specificity to be recommended for
diagnosis (93–96) (LE 2 ) (GR C).
•
Sensitivity of basophil activation test (BAT) for penicillins ranges from 22% to 55% (67, 97) and for clavulanic acid up to 52.7%. It shows a good specificity,
ranging from 79% to 96% (67, 93–99).
Sensitivity of BAT to NMBA ranges from 64% to 85.7%
and specificity from 93% to 100% (100–105), being especially higher for rocuronium (91.7%) (70).
In IgE-mediated allergy to pyrazolones, the sensitivity
ranges from 42% to 55% and specificity from 86% to
100% (106, 107).
BAT to fluoroquinolones has a sensitivity ranging from
36% to 71%, depending on the drug tested, with a specificity of 90% (62, 108, 109), and a high negative predictive value (NPV) that helps to decide whether to perform
DPT (110).
In RCM, BAT sensitivity varies from 46% to 62%, with
high specificity (88–100%), although the results do not
correlate with symptom severity (111, 112).
Technical recommendations.
•
•
•
•
Although commercially available tests exist, BAT protocols are not standardized between different laboratories
in terms of markers, procedures and drug concentrations
(113).
In vitro drug-sIgE decreases with time (80, 101, 107), and
therefore, the assay should be performed within 3 years
of the reaction (LE 2++) (GR B).
Up to 10% of patients can be ‘nonresponders’, and in
these cases, BAT results cannot be interpreted (113) (LE
2) (GR B).
In fluoroquinolones, photodegradation may influence
BAT results, especially for moxifloxacin (114) (LE 3).
Clinical recommendations.
•
•
•
BAT is recommended for diagnosing BLs and NMBA
DHR and can be complementary to other in vitro tests
(67, 70, 97–103) (LE 2) (GR B).
BAT can be recommended for diagnosing IgEmediated allergy to pyrazolones (106, 107), fluoroquinolones (62, 108–110) and RCM (111, 112) (LE
2 ) (GR C).
In life-threatening reactions or in high-risk patients,
BAT, when available, should be performed before in vivo
tests including ST (7) (LE 2) (GR B).
T-cell-mediated drug allergy
There are some in vitro assays that allow determining the
individual risk of DHR before drug administration
although most of them are used for identifying the drug
involved after the reaction has already occurred. Most
in vitro tests for diagnosing NIR are not commercially
Allergy 71 (2016) 1103–1134 © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
1115
13989995, 2016, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/all.12886 by Albania Hinari NPL, Wiley Online Library on [29/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
In vitro tests for drug hypersensitivity
Mayorga et al.
Mayorga et al.
available, and therefore, standardization has not been possible (Table 4).
HLA allele determination. The HLA genotyping is based on
reverse sequence-specific oligonucleotide-polymerase chain
reaction using DNA from the peripheral blood.
Clinical studies.
HLAB*57:01 has been found to be associated with abacavir hypersensitivity in most ethnic populations (115),
and its determination has a sensitivity of 45.5–80%, a
specificity of 97.6–99%, a NPV of 100% and a PPV of
55–58% (116–118).
For carbamazepine-induced DHR, the most powerful
association has been established with HLA-B*15:02 and
SJS/TEN in Han Chinese (119), Thai (120), Indian (121)
and Malaysian (122) populations. HLA-A*31:01 has also
been associated with MPE/DRESS in Japanese, Han Chinese and Europeans (123, 124).
HLA-B*58:01 allele is associated with relatively high risk
of allopurinol-induced DRESS and SJS/TEN in Han Chinese and other ethnic populations such as Thai, Japanese,
Korean and Europeans (125–130).
HLA associations do not explain all cases and their screening has a low PPV, suggesting the involvement of additional factors in the mechanisms of DHR (131, 132).
•
•
Some drugs (vancomycin, NSAIDs, RCM) may slightly
enhance the proliferation even in nonsensitized individuals (143). Also, positive results do not necessarily imply
an effector response because this could be due to Treg
cell proliferation (144).
Sensitivity and specificity depend on the clinical manifestations of the reaction, being higher in MPE, FDE,
AGEP and DRESS than in SJS/TEN (145, 146).
Sensitivity of lymphocyte transformation test (LTT) is
higher than that of ST for diagnosing NIR (38, 139,
147).
•
•
•
Technical recommendations.
Controversy exists regarding the optimal phase of the
reaction to perform LTT: for SJS/TEN, higher sensitivity
has been found in the acute phase and for DRESS in the
resolution phase, while other studies found no differences
(148, 149).
Modifications to the LTT can increase its sensitivity by
the use of professional antigen-presenting cells (140, 150,
151), the inclusion of drug metabolites (152), the depletion of FoxP3+ regulatory T cells (153) or the evaluation
in effector cells (146, 154) (LE 3).
•
•
Technical recommendations.
To avoid DNA fragmentation that will make difficult the
HLA allele determination, it is not recommended to
extract the DNA kept for a long period of time.
•
Clinical recommendations.
HLA-B*57:01 screening is recommended for abacavirinduced DHR. Its use has demonstrated a reduction in
the prevalence from 12–7.5% to 3–0% in several countries (133–135) (LE 2 + +) (GR B).
The Food and Drug Administration recommends screening for HLA-B*15:02 before starting the treatment with
carbamazepine in at-risk patients (136) (LE 2++) (GR
B).
Screening for the presence of the HLA-B*58:01 allele is
recommended by the American College of Rheumatology
in individuals considered to be at high risk of developing
allopurinol DHR (137) (LE 2++) (GR B).
•
•
•
Lymphocyte transformation test. Proliferation of drug-specific T cells from patients with DHR upon the stimulation
with the suspected drug(s) is measured by the
incorporation of [3H] or carboxyfluorescein diacetate succinimidyl ester (CFSE) content using flow cytometry. The
latter technique enables the identification of the effector
cell(s) involved.
Clinical studies.
The most widely studied drugs are BLs with a sensitivity
and specificity ranging from 58% to 88.8% and 85% to
100%, respectively (138–142).
•
1116
•
•
Clinical recommendations.
Sensitivity and specificity are highly variable, from 27%
to 88.8% and 63% to 100%, respectively, depending on
the culprit drug, being higher for BLs and anticonvulsants (38, 138–142, 146–148, 155–161), and on the clinical
symptoms, being higher for MPE, FDE, AGEP and
DRESS (145), but of little value in SJS/TEN (146) (LE
2 ) (GR C).
•
Enzyme-linked immunosorbent spot assay. Enzyme-linked
immunosorbent spot (ELISpot) determines the number of
cells that release relevant cytokines and cytotoxic markers
after their activation by the culprit drug or their metabolites
(162, 163).
Clinical studies.
IFN-c ELISpot has been used to diagnose NIR to BLs
with the sensitivity ranging from 13% to 91% (141, 142,
149, 164).
Granzyme B and granulysin ELISpot assays have been
used for evaluating severe cutaneous reactions (146, 154).
•
•
Technical recommendations.
Drug-reactive T cells remain detectable several years after
the reaction (160, 165).
This test could be appropriate for high-throughput
screening and is able to detect <25 secreting cells per
million peripheral blood mononuclear cells.
•
•
Clinical recommendations.
IFN-c ELISpot can be used for evaluating NIR to BLs
(141, 142, 149, 164) (LE 3) (GR C).
•
Allergy 71 (2016) 1103–1134 © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
13989995, 2016, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/all.12886 by Albania Hinari NPL, Wiley Online Library on [29/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
In vitro tests for drug hypersensitivity
Allergy 71 (2016) 1103–1134 © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
12F
15M
65
51 Pats
135
Contrs
27 SJS
Pats
54
Contrs
27F
24M
66
15 Pats
33
Contrs
Niihara
et al. (118)
(PMID:
22211527)
Hung
et al. (120)
(PMID:
554812)
Tassaneeyakul
et al. (123)
(PMID:
19696695)
10F
5M
50.7
8 SJS
Pats
10
Contrs
Mehta
et al. (116)
(PMID:
19915237)
13F
18M
4F
4M
22.9
10 SJS
Pats
50
Contrs
55.3
3F
7M
21.8
25 Pats
175
Contrs
Colombo
and Gell
(113)
(PMID:
18256392)
Locharernkul
et al. (115)
(PMID:
18637831)
31 SJS
Pats
1822
Contrs
N.D.
N.D.
803
Pats
847
Contrs
HLA allele
Mallal
et al. (111)
(PMID:
18256392)
CH
CH
CH
CH/ST/DPT
CH
CH
CH
CH/ST/DPT
Methods
(CH/ST/DPT)
ALLO
ALLO
ALLO
CARBA
CARBA
CARBA
ABAC
ABAC
Drugs analysed
NI
NI
NI
NI
NI
NI
NI
NI
Time
reaction
(I/NI)
N.D.
N.D.
660
N.D.
N.D.
N.D.
N.D.
N.D.
Mean
time
study
until
(days)
100
55
100
In MPE
66.6
75
100
80
45.5
Sens (%)
87.1
98.5
85.2
In MPE
87.9
100
75
99
97.6
Spec (%)
1.52
N.D.
N.D.
N.D.
N.D.
43
94
95.5
NPV (%)
100
N.D.
N.D.
N.D.
N.D.
100
100
61.2
PPV (%)
Allele: HLAB*57:01
Main ethnics
groups:
Caucasian
82.8%
Black 12%
Allele: HLAB*57:01
Main ethnics
groups:
Caucasian
Allele: HLAB*1502
Main ethnics
groups:
Thai
Allele: HLAB*1502
Main ethnics
groups:
Indian
Allele: HLA-A31
Main ethnics
groups:
Japanese
Allele: HLAB*5801
Main ethnics
groups:
Han Chinese
Allele: HLAB*5801
Main ethnics
groups:
Caucasian
Allele: HLAB*5801
Main ethnics
groups:
Tai
Comments
In vitro tests for drug hypersensitivity
1117
13989995, 2016, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/all.12886 by Albania Hinari NPL, Wiley Online Library on [29/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Lonjou
et al. (121)
(PMID:
18192896)
208F
595M
42
n
Sex
(F/M)
Paper
Mean
age
(years)
Table 4 In vitro tests to identify the culprit drug in T-cell-mediated drug allergy
Mayorga et al.
1118
40.26
19 Pats
28
Contrs
N.D.
44.9
16F
3M
7F
5M
N.D.
N.D.
923
Pats
102
Contrs
10 Pats
6
Contrs
45.08
N.D.
N.D.
20 Pats
Contrs
N.I.
12 Pats
6
Contrs
9F
3M
38
12 Pats
8
Contrs
11F
14M
56
25 Pats
57
Contrs
Kang
et al. (125)
(PMID:
21301380)
ST/DPT
CH/ST
CH/ST
CH/DPT
CH
CH
CH
CH
Methods
(CH/ST/DPT)
PG, AX
PG, AX
LID, MEP, ART,
BUP, PRI, PRO,
OXI, TETRA
PG, COTRI, META
OXYP, COTRI, PIRO,
CARBA, FENB,
FLUR, NORAM,
SULFAD
SULFAM, PHENY,
CARBA
ALLO
ALLO
Drugs analysed
NI
1836
955
N.D.
NI
NI
N.D.
30
25
N.D.
N.D.
N.D.
NI
NI
NI
NI
Time
reaction
(I/NI)
Mean
time
study
until
(days)
57.9
83
60
78
N.D.
44
92
64
Sens (%)
92.8
100
100
85
N.D.
63
89.5
96
Spec (%)
N.D.
75
N.D.
N.D.
N.D.
N.D.
2.06
N.D.
NPV (%)
N.D.
100
N.D.
N.D.
N.D.
N.D.
99.98
N.D.
PPV (%)
Allele: HLAB*5801
Main ethnics
groups:
Caucasian
Allele: HLAB*5801
Main ethnics
groups:
Koreans
Comments
Mayorga et al.
Allergy 71 (2016) 1103–1134 © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
13989995, 2016, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/all.12886 by Albania Hinari NPL, Wiley Online Library on [29/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
LTT
Roujeau
et al. (151)
(PMID:
3875565)
Mauri-Hellweg
et al. (152)
(PMID:
7602118)
Nyfeler and
Pichler (142)
(PMID:
9061217)
Orasch
et al. (153)
(PMID:
10520085)
Schnyder
and Pichler
(133) (PMID:
10718859)
Luque
et al. (134)
(PMID:
11421918)
14F
11M
67.4
25 Pats
23
Contrs
Goncalo
et al. (124)
(PMID:
23600531)
Sex
(F/M)
n
Mean
age
(years)
Paper
Table 4 (continued)
In vitro tests for drug hypersensitivity
Allergy 71 (2016) 1103–1134 © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
8F
1M
11F
16M
43
49.44
48
47
70
N.D.
5 Pats
3 Contrs
9 Pats
8
Contrs
27 Pats
10
Contrs
15 Pats
12 Contrs
69 Pats
22 Pats
11
Contrs
N.D.
36F
33M
12F
3M
7F
3M
ST
CH, DPT
ST
CH
CH/ST
ST
CH/ST
CH
Methods
(CH/ST/DPT)
AX
INH, RIF,
ETHAM, PZA
ACET, CARBA,
AX, MINO, PHENOB,
SCOP, BROM,
PHENY, TIAP,
LCARBO, MEXI,
LOXO, DAP,
MEROP, SULT
AX
AX
VANC, AX, CARBA,
SULFAM
PRED, VERA, VITB,
SULFAM, TRIM,
INDA, ACET,
DORZ, SIMV,
LOSAR, TORA,
METOL, TICLO, PG,
AX, CEPH, ALLO,
CARBA
AX, CHLORA, FENO,
PHENY, CARBA,
PHENOB
Drugs analysed
NI
NI
NI
4150
N.D.
N.D.
75.8
NI
I/NI
4700
1140
NI
NI
N.D.
N.D.
Time
reaction
(I/NI)
NI
Mean
time
study
until
(days)
68
14.9
N.D.
N.D.
88.8
N.D.
75
67
Sens (%)
85
90.7
N.D.
N.D.
100
N.D.
100
100
Spec (%)
N.D.
9.3
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
NPV (%)
N.D.
85.1
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
PPV (%)
Comments
In vitro tests for drug hypersensitivity
1119
13989995, 2016, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/all.12886 by Albania Hinari NPL, Wiley Online Library on [29/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Khalil
et al. (136)
(PMID:
18775806)
Suzuki
et al. (2008)
(PMID:
18583516)
Rozieres
et al. (137)
(PMID:
19154548)
2F
3M
32.3
10 Pats
10
Contrs
Sachs
et al. (154)
(PMID:
11994099)
Beeler
et al. (155)
(PMID:
16461148)
Rodriguez
et al.
(PMID:
17030251)
Kano
et al. (143)
(PMID:
17983378)
13F
9M
55.9
21 Pats
Contrs
N.I.
Hari
et al. (37)
(PMID:
23957338)
Sex
(F/M)
n
Mean
age
(years)
Paper
Table 4 (continued)
Mayorga et al.
1120
2F
3M
43
47
5 Pats
3
Contrs
15 Pats
12 Contrs
6F
6M
25F
18M
8F
7M
4F
13M
55.3
52.1
44.7
49
37.1
56
12 Pats
16
Contrs
43 Pats
14
Contrs
14 Pats
Contrs
N.I.
17 Pats
42
Contrs
15 Pats
18
Contrs
25 Pats
20
Contrs
ST
CH
CH/ST
CH
CH
ST
ST
ST
ST
CH
Methods
(CH/ST/DPT)
CEPH
CARBA, SULPHO,
LAMO, ALLO,
OXIP, MEFE
ABAC
AX, NIME, ACETAM,
HIDROX, ALLO,
CARBA, PG, CEFAZ
ALLO, AX, CARBA,
CEF, MEROP,
PG, VANC
AX, CIPRO, CARBA
AX
AX
VANC, AX, CARBA,
SULFAM
CARBA, SULPHO,
LAMO, ALLO,
OXIP, MEFE
Drugs analysed
NI
NI
NI
602.9
150
4890
420
NI
N.D.
211.5
1140.6
4150
N.D.
NI
I/NI
I/NI
I/NI
1140
150
Time
reaction
(I/NI)
NI
Mean
time
study
until
(days)
40
33
N.D.
92
82
N.D.
91
N.D.
N.D.
27
Sens (%)
N/A
98
N.D.
N.D.
IFN-c: 83
IL-4: 92
N.D.
95
N.D.
N.D.
100
Spec (%)
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
NPV (%)
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
PPV (%)
Comments
Mayorga et al.
Allergy 71 (2016) 1103–1134 © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
13989995, 2016, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/all.12886 by Albania Hinari NPL, Wiley Online Library on [29/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
14F
11M
7F
8M
N.D.
N.D.
38 Pats
11 Contrs
12F
3M
7F
8M
37.1
15 Pats
18
Contrs
Porebski
et al. (141)
(PMID:
23957338)
ELISPOT
Beeler
et al. (155)
(PMID:
16461148)
Khalil
et al. (136)
(PMID:
18775806)
Rozieres
et al. (137)
(PMID:
19154548)
Zawodniak
et al. (149)
(PMID:
19793058)
Polak
et al. (2012)
(PMID:
23106791)
Fu et al.
(158)
(PMID:
23029066)
Esser
et al. (2012)
(PMID:
22338581)
Porebski
et al. (141)
(PMID:
23957338)
Tanvarasethee
et al. (157)
(PMID:
22722755)
Sex
(F/M)
n
Mean
age
(years)
Paper
Table 4 (continued)
In vitro tests for drug hypersensitivity
Allergy 71 (2016) 1103–1134 © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
8F
7M
12F
3M
6F
6M
4F
6M
32.3
48
47
49.2
47
15 Pats
5
Contrs
15 Pats
12
Contrs
12 Pats
11
Contrs
10 Pats
5
Contrs
7F
3M
Sex
(F/M)
10 Pats
10
Contrs
n
Mean
age
(years)
CH
CH
ST
CH
CH/ST
Methods
(CH/ST/DPT)
ASA, AMLO, AX, ATEN,
AX-CLV, BUP, CEF,
CLIND, COD, DICLO,
FELO, FENTA,
Histafedâ, IBU, LIGNO,
LORAT, META, MINO,
NAPRO, PARA, PRAVA,
PROPRA, Rafathricinâ,
Resprimâ, Rokal â, WARF
AX, SULFAM, SULFAP
AX
AX, AMP, VANC, CARBA,
SULFAP, CEF, SULFAM,
PHENY, CLV, MOXI
AX, CHLORA, FENO,
PHENY, CARBA,
PHENOB
Drugs analysed
NI
NI
I/NI
NI
NI
Time
reaction
(I/NI)
672
N.D.
N.D.
538
N.D.
Mean
time
study
until
(days)
N.D.
80
80
N.D.
IL-5: 92
IFN-c:
36
IL-10:
50
Sens (%)
N.D.
62
100
IL-5:
100
IFN-c:
60
IL-10:
100
N.D.
Spec (%)
N.D.
44
N.D.
N.D.
N.D.
NPV (%)
N.D.
89
N.D.
N.D.
N.D.
PPV (%)
Methods: BEADS
Markers:
IL-2, IL-5, IL-13,
IFN-c
Methods:
ELISA
Markers:
IFN-c
Methods: ELISA
Markers:
IL-2, IL-5, IFN-c
Methods: FC
Markers: CD69
Methods:
ELISA
Comments
In vitro tests for drug hypersensitivity
1121
13989995, 2016, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/all.12886 by Albania Hinari NPL, Wiley Online Library on [29/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Lochmatter
et al.
(161) (PMID:
19254289)
Beeler
et al. (159)
(PMID:
18005225)
Khalil et al.
(136)
(PMID:
18775806)
Halevy
and Grossman
(162)
(PMID:
19160944)
Cell markers
and cytokine
release
Sachs
et al. (154)
(PMID:
11994099)
Paper
Table 4 (continued)
Mayorga et al.
1122
37.1
53
Mean
age
(years)
7F
8M
15F
4M
Sex
(F/M)
CH
CH
Methods
(CH/ST/DPT)
AX, CARBA, IBU, PG,
VALP, AMP, CLIND,
COTRI, DOXY, META,
CEF, CLARI, NADR,
METRO, OME,
PANTO, PERCH,
IODX, LAMO
CARBA, SULPHO,
LAMO, ALLO, OXIP,
MEFE
Drugs analysed
NI
150
805.36
Time
reaction
(I/NI)
NI
Mean
time
study
until
(days)
Granul:
60
IFN-c:
55
IL-5:
43
IL-2:
38
100
Sens (%)
Granul:
96
IFN-c:
95
IL-5:
100
IL-2:
98
100
Spec (%)
N.D.
N.D.
NPV (%)
N.D.
N.D.
PPV (%)
Methods: FC,
BEADS
Markers:
granulysin,
IL-2, IL-5,
IFN-c
Methods: FC,
ELISA
Markers: IL-5,
IFN-c, IL-10
Comments
Mayorga et al.
Allergy 71 (2016) 1103–1134 © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
13989995, 2016, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/all.12886 by Albania Hinari NPL, Wiley Online Library on [29/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Sensitivity, Specificity, NPV and PPV values are calculated based on all drugs tested. Data for individual drugs are not always available.
F, female; M, male; CH, clinical history; ST, skin test; DPT, drug provocation test; FC, flow cytometry; IHQ, immunohistochemistry; Sens, sensitivity, Spec, specificity, NPV, negative predictive value and PPV, positive predictive value; ABAC, abacavir; ACETM, acetaminophen; ALLO, allopurinol; AMLO, amlodipine; AMP, ampicillin; ART, articaine; ASA, acetylsalicylic acid;
ATEN, atenolol; AX, amoxicillin; AX-CLV, amoxicillin–clavulanic acid; BROM, bromhexine; BUP, bupivacaine; CARBA, carbamazepin; CEF, cefuroxime; CEFAZ, cefazolin; CEPH, cephalosporin; CHLORA, clorazepate; CIPRO, ciprofloxacin; CLARI, clarithromycin; CLIND, clindamycin; CLV, clavulanic acid; COD, codeine phosphate; COTRI, cotrimoxazole; DAP, dapsone; DICLO,
diclofenac; DORZ, dorzolamide; DOXY, doxycycline; ETHAM, ethambutol; FELO, felodipine; FENB, fenbufen; FENO, fenoterol; FENTA, fentanyl; FLUR, flurbiprofen; IBU, ibuprofen; INDA,
indapamide; INH, isoniazid; IODX, iodixanol; LAMO, lamotrigine; LCARBO, L-carbocisteine; LID, lidocaine; LIGNO, lignocaine HCl; LORAT, loratadine; LOSAR, losartan; LOXO, loxoprofen
sodium; MEFE, mefenamic acid; MEP, mepivacaine; MEROP, meropenem; META, metamizole; METOL, metolazone; METRO, metronidazol; MEXI, mexiletine; MINO, minocycline; MOXI,
moxifloxacin; NAPRO, naproxen; NORAM, noramidopyrine; OMEP, omeprazole; OXI, oxybuprocaine; OXIP, oxipurinol; PANTO, pantoprazole; PARA, paracetamol; PERCH, Na-perchlorate;
PG, penicillin G; PHENOB, phenobarbital; PHENY, phenytoin; PIRO, piroxicam; PRAVA, pravastatin; PRED, prednisolone; PRI, prilocaine; PRO, procaine; PROPRA, propranolol; PZA, pyrazinamide; RIF, rifampin; SCOP, scopolamine butylbromide; SIMV, simvastatin; SULFAD, sulfadiazine; SULFAM, sulfamethoxazole; SULFAP, sulfapyridine; SULFAS, sulfasalazine; SULPHO,
sulphonamides; SULT, sultamicillin; TETRA, tetracaine; TIAP, tiaprofenic acid; TICLO, ticlopidine; TORA, torasemide; TRIM, trimethoprim; VALP, valproic acid; VANC, vancomycin; VERA,
verapamil; VITB, Vitamin B complex; WARF, warfarin sodium.
*No available commercialized tests.
15 Pats
18
Contrs
19 Pats
10
Contrs
Martin
et al. (160)
(PMID:
19796221)
Porebski
et al. (141)
(PMID: 23957338)
n
Paper
Table 4 (continued)
In vitro tests for drug hypersensitivity
44
45
52
44
44.1
141 Pats
136
Contrs
43 Pats
35
Contrs
8 Pats
18
Contrs
Allergy 71 (2016) 1103–1134 © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
60 Pats
30
Contrs
60 Pats
30
Contrs
37F
23M
33F
27M
18F
8M
32F
11M
81F
71M
N.D.
34F
21M
38
N.D.
21F
17M
39.25
40 Pats
39
Contr
38 Pat
50
Contr
55 Pats
64
Contrs
No. of pats
Sex
(F/M)
ASA, PARA,
META, DICL,
NAPRO
ASA, PARA,
META, DICL,
NAPRO
42 CH
18 DPT
43 CH
17 DPT
ASA
ASA
ASA, PARA,
DICL,
NAPRO,
META
ASA
ASA, BL,
ACETAM
ASA, DICL,
IBU, INDO
Drugs
analysed
3 CH
5 DPT
25CH
18 DPTNPT-BPT
DPT
10 CH
29 DPT
30 ST
25 DPT
CH
Methods
(CH/ST/
DPT/NPT)
N.D.
N.D.
N.D.
N.D.
<4
<4
N.D.
N.D.
<24
N.D.
N.D.
308
<1
N.D.
204.6
Time
study
(days)
N.D.
Time
reaction
(hours)
No
No
Assay Designs
(yes)
Assay Designs
(yes)
CAST-ELISA
(yes)
CAST (yes)
CAST-ELISA
(yes)
CAST-ELISA
(yes)
Commercialized
in vitro test
(Yes/No)
66.7
43.3
63%
83%
24
25
34.5
NERD: 72.7
NIUA: 100
Sens (%)
93.3
100
50%
82%
89
92.3
NERD: 96.7
NIUA:
96.7
86
Spec (%)
N.D.
100
N.D.
0.79
N.D.
28.7
N.D.
N.D.
NPV (%)
N.D.
99.4
N.D.
0.86
N.D.
90.7
N.D.
N.D.
PPV (%)
NIUA/NERD
NIUA/NERD
NERD
NERD
NERD/NECD/
NIUA
NERD
N.D.
NERD/NIUA
Comments
In vitro tests for drug hypersensitivity
1123
13989995, 2016, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/all.12886 by Albania Hinari NPL, Wiley Online Library on [29/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
CysLT
May (167)
(PMID:
10520062)
Lebel
et al.
(166)
(PMID:
11421930)
Bavbek
et al. (173)
(PMID:
19033733)
De Weck
et al. (164)
(PMID:
19862935)
15-HETE
Kowalski
et al. (168)
(PMID:
16076298)
Korosec
et al. (169)
(PMID:
22015094)
BAT
Gamboa
et al. (171)
(PMID:
15347380)
Sanz
et al. (170)
(PMID:
15608437)
Paper
Median
age
(y.o.)
Table 5 In vitro tests to identify the culprit drug in nonallergic hypersensitivity to NSAIDs
Mayorga et al.
1124
46.8
44
43.2
19 Pats
40
Contrs
60 Pat
20
Contrs
30 Pats
15
Contrs
18 Pats
24
Contrs
44
36
10 Pats
10 Contrs
152 Pats
165
Contrs
55
43 Pats
29
Contrs
RodrıguezTrabado
et al. (174)
(PMID:
18534081)
Celik
et al. (172)
(PMID:
19486029)
Bavbek
et al. (173)
(PMID:
19494523)
27F
3M
45F
15M
24F
35M
81F
71M
14F
4M
4F
6M
24F
19M
Sex
(F/M)
CH
CH
12 CH
7 DPT
CH/DPT
16 DPT
2 CH
CH
33 CH
10 DPT
Methods
(CH/ST/
DPT/NPT)
ASA, DICL,
KETO,
CELEC,
ACETAM
ASA
ASA
ASA, PARA,
DICL, NAPRO,
METAM
ASA, DICL
ASA
ASA, PARA,
META, DICL
Drugs
analysed
N.D.
<2
N.D.
N.D.
<1
N.D.
N.D.
N.D.
305
N.D.
<1
N.D.
<365
>365
Time
study
(days)
<1
Time
reaction
(hours)
No
No
FastImmune
(yes)
Flow-CAST
(Yes)
CD63: Flow-CAST
(yes)
CD203c: Cellular
Analysis of
Allergy (yes)
No
Orpegen (yes)
Commercialized
in vitro test
(Yes/No)
60–76.7
ASA: 37
DICLO: 33
78–80
CD63:
ASA: 33.3
DICLO:
16.7
CD203c:
ASA: 16.7
DICLO:
22.2
Both:
ASA: 33.3
DICLO:
22.2
ASA/DICLO/
NAPRO
70–75%
CD63: 30
CD203c:70
42.8
Sens (%)
80
ASA: 90
50–83
CD63:
ASA: 75
DICLO:
83.3
CD203c:
ASA: 100
DICLO:
100
Both:
ASA: 75
DICLO:
83.3
ASA/DICLO/
NAPRO
47–91%
CD63: 40
CD203c:45
100
Spec (%)
N.D.
64
N.D.
N.D.
CD63 15
CD203c
100
N.D.
100
NPV (%)
N.D.
79
N.D.
N.D.
CD63 90
CD203c
90
N.D.
53.84
PPV (%)
NERD/NECD
NECD/NIUA
NERD
NERD/NIUA
AERD
AERD
NIUA/NERD/
SNIUAA
Comments
Mayorga et al.
Allergy 71 (2016) 1103–1134 © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
13989995, 2016, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/all.12886 by Albania Hinari NPL, Wiley Online Library on [29/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
De Weck
et al. (164)
(PMID:
19862935)
Korosec
et al. (169)
(PMID:
21293144)
Abuaf
et al. (176)
(PMID:
3236474)
Wismol
et al. (177)
(PMID:
21492991)
34
No. of pats
Median
age
(y.o.)
Paper
Table 5 (continued)
In vitro tests for drug hypersensitivity
46 Pats
45
Contrs
Ariza
et al. (178)
(PMID:
24443418)
Sensitivity, Specificity, NPV and PPV values are calculated based on all drugs tested. Data for individual drugs are not always available.
NSAID, Nonsteroidal anti-inflammatory drugs; NIUAA, single-NSAID-induced urticaria/angioedema or anaphylaxis; AERD, aspirin-exacerbated respiratory disease; ATA, aspirin-tolerant asthmatic; NECD, NSAID-exacerbated cutaneous disease; NIUA, NSAID-induced urticaria/angioedema; NERD, NSAID-exacerbated respiratory disease; F, female; M, male; NPT, nasal provocation test; RS, respiratory symptoms; URT, urticaria; N.D., no data; Sens, sensitivity, Spec, specificity, NPV, negative predictive value and PPV, positive predictive value; ACETM,
acetaminophen; ASA, acetyl salicylic acid; BL, beta-lactam; CELEC, celecoxib; DCL, diclofenac; IBU, ibuprofen; INDO, indomethacin; KETO, ketoprofen; METAM, metamizole; NAPRO,
naproxen; PARA, paracetamol.
NIUA
N.D.
N.D.
No
<2
5CH
41 DPT
No. of pats
Paper
39
26F
20M
NSAIDs
803.5
100
31.1
Comments
PPV (%)
NPV (%)
Spec (%)
Sens (%)
Commercialized
in vitro test
(Yes/No)
Time
study
(days)
Time
reaction
(hours)
Drugs
analysed
Methods
(CH/ST/
DPT/NPT)
Sex
(F/M)
Median
age
(y.o.)
Table 5 (continued)
•
•
The determination of granzyme B and granulysin is recommended for evaluating the cytotoxic mechanisms of
NIR (57, 146, 154) (LE 3) (GR C).
To improve the accuracy of the test, two or more cytokines determination can be used (146, 149) (LE 3) (GR C).
Cell markers and cytokine release. After in vitro drug
stimulation, T cells express or up-regulate a number of
surface molecules and produce different inflammatory
mediators that can be detected by flow cytometry and
ELISA.
Clinical studies.
CD69 is up-regulated early, potentially after 48–72 h, and
its determination by flow cytometry correlates with LTT
results for BLs, sulphamethoxazole and carbamazepine
DHR (166).
IFN-c, IL-10 and IL-5 measurements using ELISA in the
LTT supernatant are potentially useful for diagnosis (141,
146, 159, 167–169).
Combination of IL-5/IL-10/IFN-c measurements by flow
cytometry in NIR showed a sensitivity of 75% (167).
•
•
•
Technical recommendations.
The timing of sample collection is critical because the
mediators can be secreted in transitory peaks with
variations in the maintenance of detectable levels
(48).
Due to immunological control process, chemokines and
cytokines can be degraded by proteases (170).
•
•
Clinical recommendations.
CD69 can be used in the evaluation of NIR (166) (LE 3)
(GR C).
Combination of IL-5/IL-10/IFN-c measurements can
improve the evaluation of NIR (141, 146, 159, 167–169)
(LE 3) (GR C).
•
•
Combinations of tests.
Clinical studies.
The combination of granzyme B ELISpot, granulysin
expression and IFN-c production can increase the sensitivity in SJS/TEN to 80% (146).
Single cytokine analysis is often unhelpful – panels of
cytokines using ELISpot and flow cytometry have shown
a higher sensitivity (149, 167).
IL-5/IL-10/IFN-c measurement by flow cytometry combined with ELISA in NIR has shown a sensitivity of
100% (167).
•
•
•
Technical recommendations.
The same described above (for details, see sections ‘Lymphocyte transformation test’, ‘Enzyme-linked immunosorbent spot (ELISpot) assay’ and ‘Cell markers and
cytokine release’).
•
Allergy 71 (2016) 1103–1134 © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
1125
13989995, 2016, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/all.12886 by Albania Hinari NPL, Wiley Online Library on [29/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
In vitro tests for drug hypersensitivity
Mayorga et al.
Mayorga et al.
Figure 1 In vitro tests to determine the culprit drug based on the suspected immunological mechanism.
Clinical recommendations.
Because no in vitro test has high enough sensitivity, the
combination of results from different assays (LTT,
ELISpot, cell markers and cytokine release) can be used
in evaluating NIR (146, 149, 167) (LE 3 ) (GR D).
•
Nonallergic hypersensitivity
Most studies have been conducted with NSAID hypersensitivity, although with a lack of standardization (Table 5).
Arachidonic acid metabolites determination. Cysteinyl leukotrienes and 15-HETE can be specifically released in the supernatant of NSAID-stimulated isolated human leucocytes and
measured by ELISA.
Clinical studies.
The majority of these studies included cases with NECD
and NERD, with a sensitivity ranging from 24% to
100% and with a specificity from 88% to 96.7% (164–
167).
15-HETE generation by leucocytes has been measured in
NERD, showing a sensitivity from 63% to 83%, a specificity from 50% to 82%, a PPV value of 0.79 and a NPV
of 0.86 (175, 176).
15-HETE generation has also been determined for other
NSAIDs (naproxen, indomethacin, celecoxib) (175, 176).
•
•
•
Technical recommendations.
NSAID concentrations used in the tests vary among studies: aspirin: 0.1 lg/ml and 2.5 mg/ml; diclofenac: 20 lg/
•
1126
•
ml, 0.31 mg/ml, 0.08 mg/ml; ibuprofen: 20 lg/ml; indomethacin: 20 lg/ml; naproxen: 1.25 and 0.31 mg/ml;
metamizol: 5 and 0.625 mg/ml; and paracetamol: 1.25
and 0.31 mg/ml (174, 177).
Toxic concentrations of the drugs that cause a nonspecific
response should not be used in these tests (LE 2 ) (GR
C).
Clinical recommendations.
CysLTs or 15-HETE determinations have a limited value
for diagnosing nonallergic hypersensitivity to NSAID
(171–176) (LE 2 ) (GR C).
•
Basophil activation test. Basophil activation test has been
used for evaluating NSAID hypersensitivity, mostly by analysing CD63 up-regulation and CD203c expression, although
there is uncertainty regarding the underlying mechanism in
basophil activation caused by NSAIDs.
Clinical studies.
Results using aspirin stimulation show a great variability
in sensitivity and specificity, being 30–78% and 40–100%
when determining CD63 expression (171, 177–185) and
16.7–70% and 45–100%, respectively, when determining
CD203c (179, 180).
BAT sensitivity can vary from 30% to 78% in NERD
and between 37–100% for cutaneous symptoms (NECD
and NIUA). Specificity varies from 40% to 83% for
NERD and between 31–90% for NECD and NIUA
(179–183, 185).
•
•
Allergy 71 (2016) 1103–1134 © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
13989995, 2016, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/all.12886 by Albania Hinari NPL, Wiley Online Library on [29/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
In vitro tests for drug hypersensitivity
Table 6 Overview on in vitro tests with level of evidence (LE) and grade of recommendation (GR)
Tests to characterize the active phase of DHR
Tryptase determination
Histamine and its metabolites
LE
GR
2+
B
3
B
Cellular phenotypical analysis in skin biopsies
2
B
Cellular phenotypical analysis in peripheral blood
3
C
Tests to identify the culprit drug
IgE-mediated drug allergy
sIgE by Immunoassay
2+
B
sIgE to biological agents
2
B
Histamine and CysLT release
2
C
Basophil activation test
2
B
T-cell-mediated drug allergy
HLA allele determination
2+
B
Lymphocyte transformation test
2
C
Enzyme-linked immunosorbent spot assay
3
C
Cell markers and cytokine release
3
C
Combination of tests
3
D
Nonallergic drug hypersensitivity
CysLT release and 15-HETE
2
C
Basophil activation test
2
C
•
•
Basophil activation by NSAIDs especially at higher concentrations (i.e. 5 mg/ml) occurs to a variable extent in
healthy individuals who tolerate NSAIDs (171, 179, 182,
185).
The addition of CAST to BAT has a limited contribution in
the diagnosis of NSAID hypersensitivity (171, 177, 179).
Comments
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Determinations should be performed from 30–120 min
Basal levels are required for comparisons
Histamine metabolites measurement in urine
within 24 h after reaction
Comparison with basal levels required
Useful to assess the immunopathological response
Useful to assess the immunological response
ImmunoCAP is validated for BL and NMBA
Time interval from reaction to study is critical
for sensitivity
ImmunoCAP is validated for INFLIX and CETUX
Pre-existing CETUX-sIgE to a-gal
The in vitro stability of released mediators could
affect the results
It is validated for BLs and NMBA
Time interval from reaction to study is critical for sensitivity
HLA associations have a low PPV
Additional factors may be involved
Sensitivity depends on the types of reaction and drug
Sensitivity decreases in severe skin reactions
Analyse a few number of effector cells
Sensitivity could be increased with the combination
of several parameters
Sensitivity could be increased with the combination
of different methods and parameters
Interference with patients treatments
No knowledge of the cell source
Interference with patients treatments
No knowledge of the mechanism justifying the test
Technical recommendations.
Neither the use of CD203c or CD63 as activation
marker, nor the addition of other NSAIDs and/or
combination with CAST improved its overall sensitivity and specificity (171, 177, 179, 180, 183) (LE 2 )
(GR C).
•
Allergy 71 (2016) 1103–1134 © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
1127
13989995, 2016, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/all.12886 by Albania Hinari NPL, Wiley Online Library on [29/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
In vitro tests for drug hypersensitivity
Mayorga et al.
•
•
Mayorga et al.
Basophil selection with the combination of CCR3 and
CD203c in living cells can improve BAT sensitivity (185)
(LE 3) (GR C).
Toxic concentrations of the drugs that cause nonspecific
response should not be used in these tests (LE 2 ) (GR C).
Clinical recommendations.
BAT has a limited value for diagnosing nonallergic
hypersensitivity to NSAID mainly because of its low
specificity (175, 176) (LE 2 ) (GR C).
•
Conclusions and unmet needs
The diagnosis of DHR is complex, time-consuming, expensive and not risk-free. There are many in vitro tests that can
help in the diagnosis and identification of the culprit drug
(Fig. 1), but only a few of them show enough evidence for at
least a grade B recommendation. These recommendations
reflect current knowledge in the field, and the levels of evidence have been evaluated (Table 6). However, it should also
be acknowledged that there is a lack of well-controlled studies, and in many cases, information comes from small studies
with few subjects. Moreover, in many studies, patients
are included based on clinical history only, which can introduce bias. Finally, but not less important, only few tests are
licensed (Tables 2–5). Thus, the grades of recommendations
given here are generally rather low.
We have identified several unmet needs, which should be
addressed in future:
To validate the different protocols including sample processing, drug concentrations, drug and sample stability
and standardization between laboratories.
To perform studies in a large series of well-characterized
patients diagnosed by ST and/or DPT when possible.
To confirm the sensitivity, specificity, NPV and PPV for
the in vitro tests.
•
•
•
•
•
•
•
•
•
To analyse the results of the in vitro tests for specific
drugs and clinical symptoms.
To establish how treatments affect the results of the different in vitro tests and for how long.
To develop automatized systems that can be used as standard tests.
To identify the immunological mechanisms involved in
different types of DHR and to increase our knowledge of
the drug metabolic pathways involved.
To identify biological markers in serum, because this
sample type allows long-term storage and transportation
to reference laboratories.
To develop an algorithm for understanding which is the
best in vitro test approach for each patient according to
the implicated drug, patient history and time elapsed
since the reaction onset.
Author contributions
CM and MJT drafted the introduction and compiled the
entire manuscript; PB, JRC, AN, JJL and MJT, the sections
on DHR classification and diagnosis; KB, PR and JLG, the
sections on tryptase and histamine determination; PW, CM
and AR, the sections on skin biopsies and peripheral blood;
PR, MIM, AR, MJT, CM, HOE and JF, the section on
specific IgE determination; AV, the section on IgE to biological agents; PR and SV, the section on mediator release assays
and BATs; PW, CM, JCC and MIM, the section on T-cellmediated drug allergy; GC, JM and CM, the section on
nonallergic hypersensitivity to NSAID; KB, PD, AR, CM
and MJT, the section on conclusions and unmet needs; all
authors reviewed the entire final manuscript.
Conflicts of interest
The authors declare that they have no conflicts of interest.
References
1. Demoly P, Kropf R, Bircher A, Pichler
WJ. Drug hypersensitivity: questionnaire.
EAACI interest group on drug hypersensitivity. Allergy 1999;54:999–1003.
2. Brockow K, Romano A, Blanca M, Ring J,
Pichler W, Demoly P. General considerations for skin test procedures in the diagnosis of drug hypersensitivity. Allergy
2002;57:45–51.
3. Brockow K, Garvey LH, Aberer W, Atanaskovic-Markovic M, Barbaud A, Bilo
MB et al. Skin test concentrations for systemically administered drugs – an ENDA/
EAACI Drug Allergy Interest Group position paper. Allergy 2013;68:702–712.
4. Aberer W, Bircher A, Romano A, Blanca
M, Campi P, Fernandez J et al. Drug
provocation testing in the diagnosis of drug
hypersensitivity reactions: general considerations. Allergy 2003;58:854–863.
1128
5. Romano A, Torres MJ, Castells M, Sanz
ML, Blanca M. Diagnosis and management
of drug hypersensitivity reactions. J Allergy
Clin Immunol 2011;127(3 Suppl):S67–S73.
6. Torres MJ, Blanca M, Fernandez J,
Romano A, Weck A, Aberer W et al. Diagnosis of immediate allergic reactions to
beta-lactam antibiotics. Allergy
2003;58:961–972.
7. Blanca M, Romano A, Torres MJ,
Fernandez J, Mayorga C, Rodriguez J
et al. Update on the evaluation of hypersensitivity reactions to betalactams. Allergy
2009;64:183–193.
8. Brockow K, Romano A, Aberer W, Bircher
AJ, Barbaud A, Bonadonna P et al. Skin
testing in patients with hypersensitivity
reactions to iodinated contrast media - a
European multicenter study. Allergy
2009;64:234–241.
9. Kowalski ML, Asero R, Bavbek S, Blanca
M, Blanca-Lopez N, Bochenek G et al.
Classification and practical approach to the
diagnosis and management of hypersensitivity to nonsteroidal anti-inflammatory
drugs. Allergy 2013;68:1219–1232.
10. Demoly P, Adkinson NF, Brockow K,
Castells M, Chiriac AM, Greenberger PA
et al. International Consensus on drug
allergy. Allergy 2014;69:420–437.
11. Harbour R, Miller J. A new system for
grading recommendations in evidence based
guidelines. BMJ 2001;323:334–336.
12. Johansson SG, Bieber T, Dahl R, Friedmann PS, Lanier BQ, Lockey RF et al.
Revised nomenclature for allergy for global
use: report of the Nomenclature Review
Committee of the World Allergy Organization, October 2003. J Allergy Clin Immunol
2004;113:832–836.
Allergy 71 (2016) 1103–1134 © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
13989995, 2016, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/all.12886 by Albania Hinari NPL, Wiley Online Library on [29/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
In vitro tests for drug hypersensitivity
13. Coombs PRGP. Classification of allergic
reactions responsible for clinical hypersensitivity and disease. In: Gell RR, editor. Clinical Aspects of Immunology. Oxford: Oxford
Univ Pr; 1968: 575–596.
14. Pichler WJ. Delayed drug hypersensitivity
reactions. Ann Intern Med 2003;139:683–
693.
15. Romano A, Blanca M, Torres MJ, Bircher
A, Aberer W, Brockow K et al. Diagnosis
of nonimmediate reactions to beta-lactam
antibiotics. Allergy 2004;59:1153–1160.
16. Sanz ML, Gamboa PM, Garcia-Figueroa
BE, Ferrer M. In vitro diagnosis of anaphylaxis. Chem Immunol Allergy
2010;95:125–140.
17. Vitte J. Human mast cell tryptase in biology and medicine. Mol Immunol
2015;63:18–24.
18. Schwartz LB. Diagnostic value of tryptase
in anaphylaxis and mastocytosis. Immunol
Allergy Clin North Am 2006;26:451–463.
19. Berroa F, Lafuente A, Javaloyes G, Ferrer
M, Moncada R, Goikoetxea MJ et al. The
usefulness of plasma histamine and different tryptase cut-off points in the diagnosis
of peranaesthetic hypersensitivity reactions.
Clin Exp Allergy 2014;44:270–277.
20. Dybendal T, Guttormsen AB, Elsayed S,
Askeland B, Harboe T, Florvaag E. Screening for mast cell tryptase and serum IgE
antibodies in 18 patients with anaphylactic
shock during general anaesthesia. Acta
Anaesthesiol Scand 2003;47:1211–1218.
21. Schwartz LB, Min HK, Ren S, Xia HZ,
Hu J, Zhao W et al. Tryptase precursors
are preferentially and spontaneously
released, whereas mature tryptase is
retained by HMC-1 cells, Mono-Mac-6
cells, and human skin-derived mast cells.
J Immunol 2003;170:5667–5673.
22. Schwartz LB, Yunginger JW, Miller J,
Bokhari R, Dull D. Time course of appearance and disappearance of human mast cell
tryptase in the circulation after anaphylaxis.
J Clin Invest 1989;83:1551–1555.
23. Valent P, Akin C, Arock M, Brockow K,
Butterfield JH, Carter MC et al. Definitions, criteria and global classification of
mast cell disorders with special reference to
mast cell activation syndromes: a consensus
proposal. Int Arch Allergy Immunol
2012;157:215–225.
24. Enrique E, Garcia-Ortega P, Sotorra O,
Gaig P, Richart C. Usefulness of UniCAPTryptase fluoroimmunoassay in the diagnosis of anaphylaxis. Allergy 1999;54:602–606.
25. Lin RY, Schwartz LB, Curry A, Pesola
GR, Knight RJ, Lee HS et al. Histamine
and tryptase levels in patients with acute
allergic reactions: an emergency department-based study. J Allergy Clin Immunol
2000;106(1 Pt 1):65–71.
26. Stone SF, Cotterell C, Isbister GK,
Holdgate A, Brown SG. Emergency
Department Anaphylaxis I. Elevated serum
cytokines during human anaphylaxis: identification of potential mediators of acute
allergic reactions. J Allergy Clin Immunol
2009;124:786–792.
27. Sala-Cunill A, Cardona V, Labrador-Horrillo M, Luengo O, Esteso O, Garriga T
et al. Usefulness and limitations of sequential serum tryptase for the diagnosis of anaphylaxis in 102 patients. Int Arch Allergy
Immunol 2013;160:192–199.
28. Komericki P, Arbab E, Grims R, Kranke
B, Aberer W. Tryptase as severity marker
in drug provocation tests. Int Arch Allergy
Immunol 2006;140:164–169.
29. Keyzer JJ, de MJ, van Doormaal JJ, van
Voorst Vader PC. Improved diagnosis of
mastocytosis by measurement of urinary
histamine metabolites. N Engl J Med
1983;309:1603–1605.
30. Laroche D, Gomis P, Gallimidi E,
Malinovsky JM, Mertes PM. Diagnostic
value of histamine and tryptase concentrations in severe anaphylaxis with shock or
cardiac arrest during anesthesia. Anesthesiology 2014;121:272–279.
31. Gueant JL, Aimone-Gastin I, Namour F,
Laroche D, Bellou A, Laxenaire MC. Diagnosis and pathogenesis of the anaphylactic
and anaphylactoid reactions to anaesthetics. Clin Exp Allergy 1998;28(Suppl 4):65–
70.
32. Keyzer JJ, van Saene HK, van den Berg
GA, Wolthers BG. Influence of decontamination of the digestive tract on the urinary
excretion of histamine and some of its
metabolites. Agents Actions 1984;15:238–
241.
33. Keyzer JJ, Breukelman H, Wolthers BG,
van den Heuvel M, Kromme N, Berg WC.
Urinary excretion of histamine and some of
its metabolites in man: influence of the diet.
Agents Actions 1984;15:189–194.
34. Hon YY, Jusko WJ, Zhou HH, Chen GL,
Guo D, Zhou G et al. Endogenous histamine and cortisol levels in subjects with
different histamine N-methyltransferase
C314T genotypes: a pilot study. Mol Diagn
Ther 2006;10:109–114.
35. Laroche D, Aimone-Gastin I, Dubois F,
Huet H, Gerard P, Vergnaud MC et al.
Mechanisms of severe, immediate reactions
to iodinated contrast material. Radiology
1998;209:183–190.
36. Mertes PM, Laxenaire MC, Alla F. Groupe
d’Etudes des Reactions Anaphylactoides P.
Anaphylactic and anaphylactoid reactions
occurring during anesthesia in France in
1999-2000. Anesthesiology 2003;99:536–545.
37. Hammar E, Berglund A, Hedin A, Norrman A, Rustas K, Ytterstrom U et al. An
Allergy 71 (2016) 1103–1134 © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
immunoassay for histamine based on monoclonal antibodies. J Immunol Methods
1990;128:51–58.
Hari Y, Frutig-Schnyder K, Hurni M,
Yawalkar N, Zanni MP, Schnyder B et al.
T cell involvement in cutaneous drug eruptions. Clin Exp Allergy 2001;31:1398–1408.
Pichler WJ, Yawalkar N, Britschgi M,
Depta J, Strasser I, Schmid S et al. Cellular
and molecular pathophysiology of cutaneous drug reactions. Am J Clin Dermatol
2002;3:229–238.
Sidoroff A, Halevy S, Bavinck JN, Vaillant
L, Roujeau JC. Acute generalized exanthematous pustulosis (AGEP)–a clinical reaction pattern. J Cutan Pathol 2001;28:113–
119.
Halevy S. Acute generalized exanthematous
pustulosis. Curr Opin Allergy Clin Immunol
2009;9:322–328.
Paulmann M, Mockenhaupt M. Severe
drug-induced skin reactions: clinical features, diagnosis, etiology, and therapy.
J Dtsch Dermatol Ges 2015;13:625–645.
Wu Y, Farrell J, Pirmohamed M, Park BK,
Naisbitt DJ. Generation and characterization of antigen-specific CD4+, CD8+, and
CD4+CD8+ T-cell clones from patients
with carbamazepine hypersensitivity. J
Allergy Clin Immunol 2007;119:973–981.
Yawalkar N, Shrikhande M, Hari Y, Nievergelt H, Braathen LR, Pichler WJ. Evidence for a role for IL-5 and eotaxin in
activating and recruiting eosinophils in
drug-induced cutaneous eruptions. J
Allergy Clin Immunol 2000;106:1171–1176.
Nassif A, Bensussan A, Boumsell L, Deniaud A, Moslehi H, Wolkenstein P et al.
Toxic epidermal necrolysis: effector cells
are drug-specific cytotoxic T cells. J Allergy
Clin Immunol 2004;114:1209–1215.
Rzany B, Hering O, Mockenhaupt M,
Schroder W, Goerttler E, Ring J et al.
Histopathological and epidemiological
characteristics of patients with erythema
exudativum multiforme major, StevensJohnson syndrome and toxic epidermal
necrolysis. Br J Dermatol 1996;135:6–11.
Fernandez TD, Canto G, Blanca M.
Molecular mechanisms of maculopapular
exanthema. Curr Opin Infect Dis
2009;22:272–278.
Mayorga C, Pena RR, Blanca-Lopez N,
Lopez S, Martin E, Torres MJ. Monitoring
the acute phase response in non-immediate
allergic drug reactions. Curr Opin Allergy
Clin Immunol 2006;6:249–257.
Torres MJ, Mayorga C, Fernandez TD,
Cornejo-Garcia JA, Antunez C, Valenzuela
M et al. T cell assessment in allergic drug
reactions during the acute phase according
to the time of occurrence. Int J Immunopathol Pharmacol 2006;19:119–130.
1129
13989995, 2016, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/all.12886 by Albania Hinari NPL, Wiley Online Library on [29/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
In vitro tests for drug hypersensitivity
Mayorga et al.
50. Blanca M, Posadas S, Torres MJ, Leyva L,
Mayorga C, Gonzalez L et al. Expression
of the skin-homing receptor in peripheral
blood lymphocytes from subjects with nonimmediate cutaneous allergic drug reactions. Allergy 2000;55:998–1004.
51. Fernandez TD, Mayorga C, Torres MJ,
Cornejo-Garcia JA, Lopez S, Chaves P
et al. Cytokine and chemokine expression
in the skin from patients with maculopapular exanthema to drugs. Allergy
2008;63:712–719.
52. Homey B, Alenius H, Muller A, Soto H,
Bowman EP, Yuan W et al. CCL27CCR10 interactions regulate T cellmediated skin inflammation. Nat Med
2002;8:157–165.
53. Posadas SJ, Leyva L, Torres MJ, Rodriguez JL, Bravo I, Rosal M et al. Subjects
with allergic reactions to drugs show
in vivo polarized patterns of cytokine
expression depending on the chronology of
the clinical reaction. J Allergy Clin Immunol
2000;106:769–776.
54. Cornejo-Garcia JA, Fernandez TD, Torres
MJ, Carballo M, Hernan I, Antunez C
et al. Differential cytokine and transcription factor expression in patients with allergic reactions to drugs. Allergy
2007;62:1429–1438.
55. Cho YT, Lin JW, Chen YC, Chang CY,
Hsiao CH, Chung WH et al. Generalized
bullous fixed drug eruption is distinct from
Stevens-Johnson syndrome/toxic epidermal
necrolysis by immunohistopathological features. J Am Acad Dermatol 2014;70:539–
548.
56. Tapia B, Padial A, Sanchez-Sabate E,
Alvarez-Ferreira J, Morel E, Blanca M
et al. Involvement of CCL27-CCR10 interactions in drug-induced cutaneous reactions. J Allergy Clin Immunol
2004;114:335–340.
57. Ebo DG, Leysen J, Mayorga C, Rozieres
A, Knol EF, Terreehorst I. The in vitro
diagnosis of drug allergy: status and perspectives. Allergy 2011;66:1275–1286.
58. Garcia JJ, Blanca M, Moreno F, Vega JM,
Mayorga C, Fernandez J et al. Determination of IgE antibodies to the benzylpenicilloyl determinant: a comparison of the
sensitivity and specificity of three radio
allergo sorbent test methods. J Clin Lab
Anal 1997;11:251–257.
59. Montanez MI, Perez-Inestrosa E, Suau R,
Mayorga C, Torres MJ, Blanca M. Dendrimerized cellulose as a scaffold for artificial antigens with applications in drug
allergy diagnosis. Biomacromolecules
2008;9:1461–1466.
60. Romano A, Gueant-Rodriguez RM, Viola
M, Amoghly F, Gaeta F, Nicolas JP et al.
Diagnosing immediate reactions to cepha-
1130
Mayorga et al.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
losporins. Clin Exp Allergy 2005;35:1234–
1242.
Manfredi M, Severino M, Testi S, Macchia
D, Ermini G, Pichler WJ et al. Detection
of specific IgE to quinolones. J Allergy Clin
Immunol 2004;113:155–160.
Aranda A, Mayorga C, Ariza A, Dona I,
Rosado A, Blanca-Lopez N et al. In vitro
evaluation of IgE-mediated hypersensitivity
reactions to quinolones. Allergy
2011;66:247–254.
Ruiz-Sanchez AJ, Montanez MI, Mayorga
C, Torres MJ, Kehr NS, Vida Y et al.
Dendrimer-modified solid supports: nanostructured materials with potential drug
allergy diagnostic applications. Curr Med
Chem 2012;19:4942–4954.
Fontaine C, Mayorga C, Bousquet PJ,
Arnoux B, Torres MJ, Blanca M et al. Relevance of the determination of serum-specific IgE antibodies in the diagnosis of
immediate beta-lactam allergy. Allergy
2007;62:47–52.
Blanca M, Mayorga C, Torres MJ, Reche
M, Moya MC, Rodriguez JL et al. Clinical
evaluation of Pharmacia CAP System
RAST FEIA amoxicilloyl and benzylpenicilloyl in patients with penicillin allergy.
Allergy 2001;56:862–870.
Torres MJ, Romano A, Mayorga C, Moya
MC, Guzman AE, Reche M et al. Diagnostic evaluation of a large group of patients
with immediate allergy to penicillins: the role
of skin testing. Allergy 2001;56:850–856.
Sanz ML, Gamboa PM, Antepara I, Uasuf
C, Vila L, Garcia-Aviles C et al. Flow cytometric basophil activation test by detection
of CD63 expression in patients with immediate-type reactions to betalactam antibiotics. Clin Exp Allergy 2002;32:277–286.
Rouzaire P, Proton G, Bienvenu F,
Guilloux L, Benoit Y, Piriou V et al. IgE
antibody detection in the diagnosis of
hypersensitivity to neuromuscular blocking
agents. Acta Anaesthesiol Scand
2012;56:263–264.
Laroche D, Chollet-Martin S, Leturgie P,
Malzac L, Vergnaud MC, Neukirch C et al.
Evaluation of a new routine diagnostic test
for immunoglobulin e sensitization to neuromuscular blocking agents. Anesthesiology
2011;114:91–97.
Ebo DG, Bridts CH, Hagendorens MM,
Mertens CH, De Clerck LS, Stevens WJ.
Flow-assisted diagnostic management of
anaphylaxis from rocuronium bromide.
Allergy 2006;61:935–939.
Garvey LH, Kroigaard M, Poulsen LK,
Skov PS, Mosbech H, Venemalm L et al.
IgE-mediated allergy to chlorhexidine. J
Allergy Clin Immunol 2007;120:409–415.
Johansson SG, Adedoyin J, van Hage M,
Gronneberg R, Nopp A. False-positive
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
penicillin immunoassay: an unnoticed common problem. J Allergy Clin Immunol
2013;132:235–237.
Romano A, Mayorga C, Torres MJ, Artesani MC, Suau R, Sanchez F et al. Immediate allergic reactions to cephalosporins:
cross-reactivity and selective responses. J
Allergy Clin Immunol 2000;106:1177–1183.
Antunez C, Blanca-Lopez N, Torres MJ,
Mayorga C, Perez-Inestrosa E, Montanez
MI et al. Immediate allergic reactions to
cephalosporins: evaluation of cross-reactivity with a panel of penicillins and cephalosporins. J Allergy Clin Immunol
2006;117:404–410.
Guilloux L, Ricard-Blum S, Ville G, Motin
J. A new radioimmunoassay using a commercially available solid support for the
detection of IgE antibodies against muscle
relaxants. J Allergy Clin Immunol
1992;90:153–159.
Gueant JL, Mata E, Monin B, MoneretVautrin DA, Kamel L, Nicolas JP et al.
Evaluation of a new reactive solid phase
for radioimmunoassay of serum specific
IgE against muscle relaxant drugs. Allergy
1991;46:452–458.
Gueant JL, Mata E, Masson C, Gerard P,
Moneret-Vautrin DA, Mouton-Faivre C
et al. Non-specific cross-reactivity of
hydrophobic serum IgE to hydrophobic
drugs. Mol Immunol 1995;32:259–266.
Himly M, Jahn-Schmid B, Pittertschatscher
K, Bohle B, Grubmayr K, Ferreira F et al.
IgE-mediated immediate-type hypersensitivity to the pyrazolone drug propyphenazone.
J Allergy Clin Immunol 2003;111:882–
888.
Harrer A, Lang R, Grims R, Braitsch M,
Hawranek T, Aberer W et al. Diclofenac
hypersensitivity: antibody responses to the
parent drug and relevant metabolites. PLoS
One 2010;5:e13707.
Fernandez TD, Torres MJ, Blanca-Lopez
N, Rodriguez-Bada JL, Gomez E, Canto G
et al. Negativization rates of IgE radioimmunoassay and basophil activation test in
immediate reactions to penicillins. Allergy
2009;64:242–248.
Vultaggio A, Matucci A, Virgili G, Rossi
O, Fili L, Parronchi P et al. Influence of
total serum IgE levels on the in vitro detection of beta-lactams-specific IgE antibodies.
Clin Exp Allergy 2009;39:838–844.
Vultaggio A, Virgili G, Gaeta F, Romano
A, Maggi E, Matucci A. High Serum betaLactams Specific/Total IgE Ratio Is Associated with Immediate Reactions to beta-Lactams Antibiotics. PLoS One 2015;10:
e0121857.
Chung CH, Mirakhur B, Chan E, Le QT,
Berlin J, Morse M et al. Cetuximabinduced anaphylaxis and IgE specific for
Allergy 71 (2016) 1103–1134 © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
13989995, 2016, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/all.12886 by Albania Hinari NPL, Wiley Online Library on [29/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
In vitro tests for drug hypersensitivity
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
galactose-alpha-1,3-galactose. N Engl J
Med 2008;358:1109–1117.
Mariotte D, Dupont B, Gervais R, Galais
MP, Laroche D, Tranchant A et al. Anticetuximab IgE ELISA for identification of
patients at a high risk of cetuximab-induced
anaphylaxis. MAbs 2011;3:396–401.
Vultaggio A, Matucci A, Nencini F, Pratesi
S, Parronchi P, Rossi O et al. Anti-infliximab IgE and non-IgE antibodies and
induction of infusion-related severe anaphylactic reactions. Allergy 2010;65:657–661.
Matucci A, Pratesi S, Petroni G, Nencini
F, Virgili G, Milla M et al. Allergological
in vitro and in vivo evaluation of patients
with hypersensitivity reactions to infliximab. Clin Exp Allergy 2013;43:659–664.
Vultaggio A, Matucci A, Nencini F, Pratesi
S, Petroni G, Cammelli D et al. Drug-specific Th2 cells and IgE antibodies in a
patient with anaphylaxis to rituximab. Int
Arch Allergy Immunol 2012;159:321–326.
Stubenrauch K, Wessels U, Birnboeck H,
Ramirez F, Jahreis A, Schleypen J. Subset
analysis of patients experiencing clinical
events of a potentially immunogenic nature
in the pivotal clinical trials of tocilizumab
for rheumatoid arthritis: evaluation of an
antidrug antibody ELISA using clinical
adverse event-driven immunogenicity testing. Clin Ther 2010;32:1597–1609.
Munoz-Cano R, Carnes J, Sanchez-Lopez
J, Saiz A, Bartra J, Lopez-Matas MA et al.
Biological agents: new drugs, old problems.
J Allergy Clin Immunol 2010;126:394–395.
Georgitis JW, Browning MC, Steiner D,
Lorentz WB. Anaphylaxis and desensitization to the murine monoclonal antibody
used for renal graft rejection. Ann Allergy
1991;66:343–347.
Vultaggio A, Maggi E, Matucci A. Immediate adverse reactions to biologicals: from
pathogenic mechanisms to prophylactic
management. Curr Opin Allergy Clin Immunol 2011;11:262–268.
De Week AL, Sanz ML, Gamboa PM,
Aberer W, Sturm G, Bilo MB et al. Diagnosis of immediate-type beta-lactam allergy
in vitro by flow-cytometric basophil activation test and sulfidoleukotriene production:
a multicenter study. J Investig Allergol Clin
Immunol 2009;19:91–109.
Demoly P, Lebel B, Messaad D, Sahla H,
Rongier M, Daures JP et al. Predictive
capacity of histamine release for the diagnosis of drug allergy. Allergy 1999;54:500–506.
Mata E, Gueant JL, Moneret-Vautrin DA,
Bermejo N, Gerard P, Nicolas JP et al.
Clinical evaluation of in vitro leukocyte histamine release in allergy to muscle relaxant
drugs. Allergy 1992;47:471–476.
Garcia-Aviles C, Sanz ML, Gamboa PM,
Urrutia I, Antepara I, Jauregui I et al.
96.
97.
98.
99.
100.
101.
102.
103.
104.
105.
106.
Antigen specific quantification of sulfidoleukotrienes in patients allergic to Betalactam antibiotics. J Investig Allergol Clin
Immunol 2005;15:37–45.
Gamboa PM, Garcia-Aviles MC, Urrutia I,
Antepara I, Esparza R, Sanz ML. Basophil
activation and sulfidoleukotriene production in patients with immediate allergy to
betalactam antibiotics and negative skin
tests. J Investig Allergol Clin Immunol
2004;14:278–283.
Torres MJ, Padial A, Mayorga C, Fernandez T, Sanchez-Sabate E, Cornejo-Garcia
JA et al. The diagnostic interpretation of
basophil activation test in immediate allergic reactions to betalactams. Clin Exp
Allergy 2004;34:1768–1775.
Torres MJ, Ariza A, Mayorga C, Dona I,
Blanca-Lopez N, Rondon C et al. Clavulanic acid can be the component in amoxicillin-clavulanic acid responsible for
immediate hypersensitivity reactions. J
Allergy Clin Immunol 2010;125:502–505.
Longo N, Gamboa PM, Gastaminza G,
Audicana MT, Antepara I, Jauregui I et al.
Diagnosis of clavulanic acid allergy using
basophil activation and leukotriene release
by basophils. J Investig Allergol Clin Immunol 2008;18:473–475.
Abuaf N, Rajoely B, Ghazouani E, Levy
DA, Pecquet C, Chabane H et al. Validation of a flow cytometric assay detecting
in vitro basophil activation for the diagnosis of muscle relaxant allergy. J Allergy Clin
Immunol 1999;104(2 Pt 1):411–418.
Kvedariene V, Kamey S, Ryckwaert Y,
Rongier M, Bousquet J, Demoly P et al.
Diagnosis of neuromuscular blocking agent
hypersensitivity reactions using cytofluorimetric analysis of basophils. Allergy
2006;61:311–315.
Sudheer PS, Hall JE, Read GF, Rowbottom AW, Williams PE. Flow cytometric
investigation of peri-anaesthetic anaphylaxis using CD63 and CD203c. Anaesthesia
2005;60:251–256.
Monneret G, Benoit Y, Debard AL,
Gutowski MC, Topenot I, Bienvenu J.
Monitoring of basophil activation using
CD63 and CCR3 in allergy to muscle relaxant drugs. Clin Immunol 2002;102:192–199.
Hagau N, Gherman-Ionica N, Sfichi M,
Petrisor C. Threshold for basophil activation test positivity in neuromuscular blocking agents hypersensitivity reactions.
Allergy Asthma Clin Immunol 2013;9:42.
Uyttebroek AP, Sabato V, Leysen J, Bridts
CH, De Clerck LS, Ebo DG. Flowcytometric diagnosis of atracurium-induced anaphylaxis. Allergy 2014;69:1324–1332.
Gamboa PM, Sanz ML, Caballero MR,
Antepara I, Urrutia I, Jauregui I et al. Use
of CD63 expression as a marker of in vitro
Allergy 71 (2016) 1103–1134 © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
107.
108.
109.
110.
111.
112.
113.
114.
115.
116.
117.
basophil activation and leukotriene determination in metamizol allergic patients.
Allergy 2003;58:312–317.
Gomez E, Blanca-Lopez N, Torres MJ,
Requena G, Rondon C, Canto G et al.
Immunoglobulin E-mediated immediate
allergic reactions to dipyrone: value of
basophil activation test in the identification
of patients. Clin Exp Allergy 2009;39:1217–
1224.
Ben Said B, Berard F, Bienvenu J, Nicolas
JF, Rozieres A. Usefulness of basophil activation tests for the diagnosis of IgEmediated allergy to quinolones. Allergy
2010;65:535–536.
Blanca-Lopez N, Ariza A, Dona I, Mayorga C, Montanez MI, Garcia-Campos J
et al. Hypersensitivity reactions to fluoroquinolones: analysis of the factors involved.
Clin Exp Allergy 2013;43:560–567.
Rouzaire P, Nosbaum A, Denis L, Bienvenu F, Berard F, Cozon G et al. Negativity of the basophil activation test in
quinolone hypersensitivity: a breakthrough
for provocation test decision-making. Int
Arch Allergy Immunol 2012;157:299–
302.
Pinnobphun P, Buranapraditkun S,
Kampitak T, Hirankarn N, Klaewsongkram
J. The diagnostic value of basophil activation test in patients with an immediate
hypersensitivity reaction to radiocontrast
media. Ann Allergy Asthma Immunol
2011;106:387–393.
Salas M, Gomez F, Fernandez TD, Dona
I, Aranda A, Ariza A et al. Diagnosis of
immediate hypersensitivity reactions to
radiocontrast media. Allergy 2013;68:1203–
1206.
Hoffmann HJ, Santos AF, Mayorga C,
Nopp A, Eberlein B, Ferrer M et al. The
clinical utility of basophil activation testing
in diagnosis and monitoring of allergic disease. Allergy 2015;70:1393–1405.
Mayorga C, Andreu I, Aranda A, Dona I,
Montanez MI, Blanca-Lopez N et al. Fluoroquinolone photodegradation influences
specific basophil activation. Int Arch
Allergy Immunol 2013;160:377–382.
Sousa-Pinto B, Pinto-Ramos J, Correia C,
Goncalves-Costa G, Gomes L, Gil-Mata S
et al. Pharmacogenetics of abacavir hypersensitivity: a systematic review and metaanalysis of the association with HLAB*57:01. J Allergy Clin Immunol
2015;136:1092–1094.
Mallal S, Phillips E, Carosi G, Molina JM,
Workman C, Tomazic J et al. HLA-B*5701
screening for hypersensitivity to abacavir.
N Engl J Med 2008;358:568–579.
Phillips EJ, Chung WH, Mockenhaupt M,
Roujeau JC, Mallal SA. Drug hypersensitivity: pharmacogenetics and clinical
1131
13989995, 2016, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/all.12886 by Albania Hinari NPL, Wiley Online Library on [29/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
In vitro tests for drug hypersensitivity
Mayorga et al.
118.
119.
120.
121.
122.
123.
124.
125.
126.
127.
syndromes. J Allergy Clin Immunol
2011;127(3 Suppl):S60–S66.
Colombo S, Rauch A, Rotger M, Fellay J,
Martinez R, Fux C et al. The HCP5 singlenucleotide polymorphism: a simple screening tool for prediction of hypersensitivity
reaction to abacavir. J Infect Dis
2008;198:864–867.
Chung WH, Hung SI, Hong HS, Hsih MS,
Yang LC, Ho HC et al. Medical genetics: a
marker for Stevens-Johnson syndrome.
Nature 2004;428:486.
Locharernkul C, Loplumlert J, Limotai C,
Korkij W, Desudchit T, Tongkobpetch S
et al. Carbamazepine and phenytoin
induced Stevens-Johnson syndrome is
associated with HLA-B*1502 allele in
Thai population. Epilepsia 2008;49:2087–
2091.
Mehta TY, Prajapati LM, Mittal B, Joshi
CG, Sheth JJ, Patel DB et al. Association
of HLA-B*1502 allele and carbamazepineinduced Stevens-Johnson syndrome among
Indians. Indian J Dermatol Venereol Leprol
2009;75:579–582.
Tangamornsuksan W, Chaiyakunapruk N,
Somkrua R, Lohitnavy M, Tassaneeyakul
W. Relationship between the HLA-B*1502
allele and carbamazepine-induced StevensJohnson syndrome and toxic epidermal
necrolysis: a systematic review and metaanalysis. JAMA Dermatol 2013;149:1025–
1032.
Niihara H, Kakamu T, Fujita Y, Kaneko
S, Morita E. HLA-A31 strongly associates
with carbamazepine-induced adverse drug
reactions but not with carbamazepineinduced lymphocyte proliferation in a Japanese population. J Dermatol 2012;39:594–
601.
Genin E, Chen DP, Hung SI, Sekula P,
Schumacher M, Chang PY et al. HLAA*31:01 and different types of carbamazepine-induced severe cutaneous adverse
reactions: an international study and metaanalysis. Pharmacogenomics J 2014;14:281–
288.
Hung SI, Chung WH, Liou LB, Chu CC,
Lin M, Huang HP et al. HLA-B*5801
allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc Natl Acad Sci USA
2005;102:4134–4139.
Lonjou C, Borot N, Sekula P, Ledger N,
Thomas L, Halevy S et al. A European
study of HLA-B in Stevens-Johnson syndrome and toxic epidermal necrolysis
related to five high-risk drugs. Pharmacogenet Genomics 2008;18:99–107.
Kaniwa N, Saito Y, Aihara M, Matsunaga
K, Tohkin M, Kurose K et al. HLA-B
locus in Japanese patients with anti-epileptics and allopurinol-related Stevens-Johnson
1132
Mayorga et al.
128.
129.
130.
131.
132.
133.
134.
135.
136.
137.
syndrome and toxic epidermal necrolysis.
Pharmacogenomics 2008;9:1617–1622.
Tassaneeyakul W, Jantararoungtong T,
Chen P, Lin PY, Tiamkao S, Khunarkornsiri U et al. Strong association between
HLA-B*5801 and allopurinol-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in a Thai population.
Pharmacogenet Genomics 2009;19:704–709.
Goncalo M, Coutinho I, Teixeira V,
Gameiro AR, Brites MM, Nunes R et al.
HLA-B*58:01 is a risk factor for allopurinol-induced DRESS and Stevens-Johnson
syndrome/toxic epidermal necrolysis in a
Portuguese population. Br J Dermatol
2013;169:660–665.
Kang HR, Jee YK, Kim YS, Lee CH, Jung
JW, Kim SH et al. Positive and negative
associations of HLA class I alleles with
allopurinol-induced SCARs in Koreans.
Pharmacogenet Genomics 2011;21:303–307.
Pirmohamed M, Ostrov DA, Park BK.
New genetic findings lead the way to a better understanding of fundamental mechanisms of drug hypersensitivity. J Allergy
Clin Immunol 2015;136:236–244.
Stamp LK, Day RO, Yun J. Allopurinol
hypersensitivity: investigating the cause and
minimizing the risk. Nat Rev Rheumatol
2016;12:235–242.
Rauch A, Nolan D, Martin A, McKinnon
E, Almeida C, Mallal S. Prospective genetic
screening decreases the incidence of abacavir hypersensitivity reactions in the Western Australian HIV cohort study. Clin
Infect Dis 2006;43:99–102.
Waters LJ, Mandalia S, Gazzard B, Nelson
M. Prospective HLA-B*5701 screening and
abacavir hypersensitivity: a single centre
experience. AIDS 2007;21:2533–2534.
Zucman D, Truchis P, Majerholc C,
Stegman S, Caillat-Zucman S. Prospective
screening for human leukocyte antigenB*5701 avoids abacavir hypersensitivity
reaction in the ethnically mixed French
HIV population. J Acquir Immune Defic
Syndr 2007;45:1–3.
Research C for DE. Postmarket Drug
Safety Information for Patients and Providers—Information for Healthcare Professionals: Dangerous or Even Fatal Skin
Reactions—Carbamazepine (marketed as
Carbatrol, Equetro, Tegretol, and generics)
(Internet). http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124718. htm.
Accessed 3 May 2015.
Khanna D, Fitzgerald JD, Khanna PP,
Bae S, Singh MK, Neogi T et al. American
College of Rheumatology guidelines for
management of gout. Part 1: systematic
nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia.
138.
139.
140.
141.
142.
143.
144.
145.
146.
147.
148.
149.
Arthritis Care Res (Hoboken)
2012;64:1431–1446.
Schnyder B, Pichler WJ. Skin and laboratory tests in amoxicillin- and penicillininduced morbilliform skin eruption. Clin
Exp Allergy 2000;30:590–595.
Luque I, Leyva L, Jose Torres M, Rosal
M, Mayorga C, Segura JM et al. In vitro
T-cell responses to beta-lactam drugs in
immediate and nonimmediate allergic reactions. Allergy 2001;56:611–618.
Rodriguez-Pena R, Lopez S, Mayorga C,
Antunez C, Fernandez TD, Torres MJ
et al. Potential involvement of dendritic
cells in delayed-type hypersensitivity reactions to beta-lactams. J Allergy Clin Immunol 2006;118:949–956.
Khalil G, El-Sabban M, Al-Ghadban S,
Azzi S, Shamra S, Khalife S et al. Cytokine
expression profile of sensitized human T
lymphocytes following in vitro stimulation
with amoxicillin. Eur Cytokine Netw
2008;19:131–141.
Rozieres A, Hennino A, Rodet K,
Gutowski MC, Gunera-Saad N, Berard F
et al. Detection and quantification of drugspecific T cells in penicillin allergy. Allergy
2009;64:534–542.
Pichler WJ, Tilch J. The lymphocyte transformation test in the diagnosis of drug
hypersensitivity. Allergy 2004;59:809–820.
Mayorga C, Sanz ML, Gamboa P, GarciaAviles MC, Fernandez J, Torres MJ et al.
In vitro methods for diagnosing nonimmediate hypersensitivity reactions to drugs. J
Investig Allergol Clin Immunol 2013;23:
213–225.
Thong BY, Mirakian R, Castells M, Pichler
W, Romano A, Bonadonna P et al. A
world allergy organization international
survey on diagnostic procedures and therapies in drug allergy/hypersensitivity. World
Allergy Organ J 2011;4:257–270.
Porebski G, Pecaric-Petkovic T, GrouxKeller M, Bosak M, Kawabata TT, Pichler
WJ. In vitro drug causality assessment in
Stevens-Johnson syndrome - alternatives
for lymphocyte transformation test. Clin
Exp Allergy 2013;43:1027–1037.
Nyfeler B, Pichler WJ. The lymphocyte
transformation test for the diagnosis of
drug allergy: sensitivity and specificity. Clin
Exp Allergy 1997;27:175–181.
Kano Y, Hirahara K, Mitsuyama Y,
Takahashi R, Shiohara T. Utility of the
lymphocyte transformation test in the diagnosis of drug sensitivity: dependence on its
timing and the type of drug eruption.
Allergy 2007;62:1439–1444.
Polak ME, Belgi G, McGuire C, Pickard
C, Healy E, Friedmann PS et al. In vitro
diagnostic assays are effective during the
acute phase of delayed-type drug hypersen-
Allergy 71 (2016) 1103–1134 © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
13989995, 2016, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/all.12886 by Albania Hinari NPL, Wiley Online Library on [29/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
In vitro tests for drug hypersensitivity
150.
151.
152.
153.
154.
155.
156.
157.
158.
159.
sitivity reactions. Br J Dermatol
2013;168:539–549.
Lopez S, Torres MJ, Rodriguez-Pena R,
Blanca-Lopez N, Fernandez TD, Antunez
C et al. Lymphocyte proliferation response
in patients with delayed hypersensitivity
reactions to heparins. Br J Dermatol
2009;160:259–265.
Antunez C, Barbaud A, Gomez E, Audonnet S, Lopez S, Gueant-Rodriguez RM
et al. Recognition of iodixanol by dendritic
cells increases the cellular response in
delayed allergic reactions to contrast media.
Clin Exp Allergy 2011;41:657–664.
Gomez ECJ, Torres MJ, Blanca M, Mayorga C. Effect of metabolising cell system
in lymphocyte transformation test to evaluate non immediate reactions to anticonvulsivants. In: EAACI Istanbul: EAACI; 2011.
Srinoulprasert Y, Pichler WJ. Enhancement
of Drug-Specific Lymphocyte Proliferation
Using CD25-Depleted CD3 Effector Cells.
Int Arch Allergy Immunol 2014;163:198–
205.
Zawodniak A, Lochmatter P, Yerly D,
Kawabata T, Lerch M, Yawalkar N et al.
In vitro detection of cytotoxic T and NK
cells in peripheral blood of patients with
various drug-induced skin diseases. Allergy
2010;65:376–384.
Jurado-Palomo J, Cabanas R, Prior N,
Bobolea ID, Fiandor-Roman AM, LopezSerrano MC et al. Use of the lymphocyte
transformation test in the diagnosis of
DRESS syndrome induced by ceftriaxone
and piperacillin-tazobactam: two case
reports. J Investig Allergol Clin Immunol
2010;20:433–436.
Roujeau JC, Albengres E, Moritz S,
Piacentino A, Cuny M, Revuz J et al.
Lymphocyte transformation test in druginduced toxic epidermal necrolysis. Int
Arch Allergy Appl Immunol 1985;78:22–
24.
Mauri-Hellweg D, Bettens F, Mauri D,
Brander C, Hunziker T, Pichler WJ. Activation of drug-specific CD4+ and CD8+ T
cells in individuals allergic to sulfonamides,
phenytoin, and carbamazepine. J Immunol
1995;155:462–472.
Orasch CE, Helbling A, Zanni MP,
Yawalkar N, Hari Y, Pichler WJ. T-cell
reaction to local anaesthetics: relationship
to angioedema and urticaria after subcutaneous application–patch testing and LTT in
patients with adverse reaction to local
anaesthetics. Clin Exp Allergy
1999;29:1549–1554.
Sachs B, Erdmann S. Malte Baron J, Neis
M, al Masaoudi T, Merk HF. Determination of interleukin-5 secretion from drugspecific activated ex vivo peripheral blood
mononuclear cells as a test system for the
160.
161.
162.
163.
164.
165.
166.
167.
168.
169.
170.
171.
in vitro detection of drug sensitization. Clin
Exp Allergy 2002;32:736–744.
Beeler A, Engler O, Gerber BO, Pichler
WJ. Long-lasting reactivity and high frequency of drug-specific T cells after severe
systemic drug hypersensitivity reactions.
J Allergy Clin Immunol 2006;117:455–462.
Suzuki Y, Miwa S, Shirai M, Ohba H,
Murakami M, Fujita K et al. Drug lymphocyte stimulation test in the diagnosis of
adverse reactions to antituberculosis drugs.
Chest 2008;134:1027–1032.
Sullivan A, Gibson A, Park BK, Naisbitt
DJ. Are drug metabolites able to cause Tcell-mediated hypersensitivity reactions?
Expert Opin Drug Metab Toxicol
2015;11:357–368.
Esser S, Jablonka R, Heinemann FM, Reuter S, Jaeger H, von Krosigk A et al.
Detection of abacavir hypersensitivity by
ELISpot method. Inflamm Allergy Drug
Targets 2012;11:227–234.
Tanvarasethee B, Buranapraditkun S,
Klaewsongkram J. The potential of using
enzyme-linked immunospot to diagnose
cephalosporin-induced maculopapular exanthems. Acta Derm Venereol 2013;93:66–69.
Fu M, Gao Y, Pan Y, Li W, Liao W,
Wang G et al. Recovered patients with
Stevens-Johson syndrome and toxic epidermal necrolysis maintain long-lived IFNgamma and sFasL memory response. PLoS
One 2012;7:e45516.
Beeler A, Zaccaria L, Kawabata T, Gerber
BO, Pichler WJ. CD69 upregulation on T
cells as an in vitro marker for delayed-type
drug hypersensitivity. Allergy 2008;63:181–
188.
Martin M, Wurpts G, Ott H, Baron JM,
Erdmann S, Merk HF et al. In vitro detection and characterization of drug hypersensitivity using flow cytometry. Allergy
2010;65:32–39.
Lochmatter P, Beeler A, Kawabata TT,
Gerber BO, Pichler WJ. Drug-specific
in vitro release of IL-2, IL-5, IL-13 and
IFN-gamma in patients with delayed-type
drug hypersensitivity. Allergy 2009;64:1269–
1278.
Halevy S, Grossman N. Multiple drug
allergy in patients with cutaneous adverse
drug reactions diagnosed by in vitro druginduced interferon-gamma release. Isr Med
Assoc J 2008;10:865–868.
Niwa Y, Akamatsu H, Sumi H, Ozaki Y,
Abe A. Evidence for degradation of cytokines in the serum of patients with atopic
dermatitis by calcium-dependent protease.
Arch Dermatol Res 2000;292:391–396.
De Weck AL, Sanz ML, Gamboa PM,
Aberer W, Blanca M, Correia S et al. Nonsteroidal anti-inflammatory drug hypersensitivity syndrome. A multicenter study. I.
Allergy 71 (2016) 1103–1134 © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
172.
173.
174.
175.
176.
177.
178.
179.
180.
181.
Clinical findings and in vitro diagnosis.
J Investig Allergol Clin Immunol 2009;
19:355–369.
Bavbek S, Dursun AB, Birben E, Kalayci
O, Misirligil Z. Cellular allergen stimulation
test with acetylsalicylic acid-lysine is not a
useful test to discriminate between asthmatic patients with and without acetylsalicylic acid sensitivity. Int Arch Allergy
Immunol 2009;149:58–64.
Lebel B, Messaad D, Kvedariene V, Rongier M, Bousquet J, Demoly P. Cysteinylleukotriene release test (CAST) in the diagnosis of immediate drug reactions. Allergy
2001;56:688–692.
May A, Weber A, Gall H, Kaufmann R,
Zollner TM. Means of increasing sensitivity
of an in vitro diagnostic test for aspirin
intolerance. Clin Exp Allergy 1999;29:1402–
1411.
Kowalski ML, Ptasinska A, Jedrzejczak M,
Bienkiewicz B, Cieslak M, Grzegorczyk J
et al. Aspirin-triggered 15-HETE generation in peripheral blood leukocytes is a
specific and sensitive Aspirin-Sensitive
Patients Identification Test (ASPITest).
Allergy 2005;60:1139–1145.
Korosec P, Tisler U, Bajrovic N, Silar M,
Mrhar A, Kosnik M. Acetylsalicylic acidtriggered 15-HETE generation by peripheral leukocytes for identifying ASA sensitivity. Respir Med 2011;105(Suppl 1):S81–S83.
Sanz ML, Gamboa P, de Weck AL. A new
combined test with flowcytometric basophil
activation and determination of sulfidoleukotrienes is useful for in vitro diagnosis of hypersensitivity to aspirin and other
nonsteroidal anti-inflammatory drugs. Int
Arch Allergy Immunol 2005;136:58–72.
Gamboa P, Sanz ML, Caballero MR,
Urrutia I, Antepara I, Esparza R et al. The
flow-cytometric determination of basophil
activation induced by aspirin and other
non-steroidal anti-inflammatory drugs
(NSAIDs) is useful for in vitro diagnosis of
the NSAID hypersensitivity syndrome. Clin
Exp Allergy 2004;34:1448–1457.
Celik GE, Schroeder JT, Hamilton RG,
Saini SS, Adkinson NF. Effect of in vitro
aspirin stimulation on basophils in patients
with aspirin-exacerbated respiratory disease.
Clin Exp Allergy 2009;39:1522–1531.
Bavbek S, Ikinciogullari A, Dursun AB,
Guloglu D, Arikan M, Elhan AH et al.
Upregulation of CD63 or CD203c alone or
in combination is not sensitive in the diagnosis of nonsteroidal anti-inflammatory
drug intolerance. Int Arch Allergy Immunol
2009;150:261–270.
Rodriguez-Trabado A, Camara-Hijon C,
Ramos-Cantarino A, Porcel-Carreno SL,
Jimenez-Timon S, Pereira-Navarro G et al.
Basophil activation test for the in vitro
1133
13989995, 2016, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/all.12886 by Albania Hinari NPL, Wiley Online Library on [29/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
In vitro tests for drug hypersensitivity
Mayorga et al.
diagnosis of nonsteroidal anti-inflammatory
drug hypersensitivity. Allergy Asthma Proc
2008;29:241–249.
182. Korosec P, Mavsar N, Bajrovic N, Silar M,
Mrhar A, Kosnik M. Basophil responsiveness and clinical picture of acetylsalicylic
acid intolerance. Int Arch Allergy Immunol
2011;155:257–262.
183. Abuaf N, Rostane H, Barbara J, TolyNdour C, Gaouar H, Mathelier-Fusade P
1134
Mayorga et al.
et al. Comparison of CD63 Upregulation
Induced by NSAIDs on Basophils and
Monocytes in Patients with NSAID Hypersensitivity. J Allergy (Cairo)
2012;2012:580873.
184. Wismol P, Putivoranat P, Buranapraditkun
S, Pinnobphun P, Ruxrungtham K, Klaewsongkram J. The values of nasal provocation test and basophil activation test in the
different patterns of ASA/NSAID hyper-
sensitivity. Allergol Immunopathol (Madr)
2012;40:156–163.
185. Ariza A, Fernandez TD, Dona I, Aranda
A, Blanca-Lopez N, Melendez L et al.
Basophil activation after nonsteroidal antiinflammatory drugs stimulation in patients
with immediate hypersensitivity reactions
to these drugs. Cytometry A 2014;85:400–
407.
Allergy 71 (2016) 1103–1134 © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
13989995, 2016, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/all.12886 by Albania Hinari NPL, Wiley Online Library on [29/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
In vitro tests for drug hypersensitivity