Received: 13 April 2023 | Revised: 29 September 2023 | Accepted: 17 October 2023

DOI: 10.1111/all.15933

REVIEW ARTICLE

Biomarkers of immediate drug hypersensitivity

Cristobalina Mayorga1,2 | Adriana Ariza1 | Rosa Muñoz-Cano3 | Vito Sabato4 |

Inmaculada Doña2 | Maria J. Torres1,2,5

1
Allergy Research Group, Instituto de
Investigación Biomédica de Málaga y Abstract
Plataforma en Nanomedicina - IBIMA
Immediate drug hypersensitivity reactions (IDHRs) are a burden for patients and the
Plataforma BIONAND, Málaga, Spain
2
Allergy Unit, Hospital Regional
health systems. This problem increases when taking into account that only a small
Universitario de Málaga-HRUM, Málaga, proportion of patients initially labelled as allergic are finally confirmed after an al-
Spain
3
lergological workup. The diverse nature of drugs involved will imply different interac-
Allergy Department, Hospital Clinic,
Institut d'Investigacions Biomediques tions with the immunological system. Therefore, IDHRs can be produced by a wide
August Pi i Sunyer – IDIBAPS, University array of mechanisms mediated by the drug interaction with specific antibodies or di-
of Barcelona, Barcelona, Spain
4 rectly on effector target cells. These heterogeneous mechanisms imply an enhanced
Department of Immunology, Allergology,
Rheumatology, Infla-Med Centre of complexity for an accurate diagnosis and the identification of the phenotype and en-
Excellence, Faculty of Medicine and
dotype at early stages of the reaction is of vital importance. Currently, several endo-
Health Sciences, University of Antwerp,
Antwerp, Belgium phenotypic categories (type I IgE/non-IgE, cytokine release, Mast-related G-protein
5
Medicine Department, Universidad de coupled receptor X2 (MRGPRX2) or Cyclooxygenase-1 (COX-1) inhibition and their
Málaga-UMA, Málaga, Spain
associated biomarkers have been proposed. A precise knowledge of endotypes will
Correspondence permit to discriminate patients within the same phenotype, which is crucial in order
Cristobalina Mayorga and Adriana Ariza,
Allergy Unit, Research Laboratory, to personalise diagnosis, future treatment and prevention to improve the patient's
Hospital Regional Universitario de quality of life.
Málaga-IBIMA, 29009 Málaga, Spain.
Email: [email protected] and adriana.
KEYWORDS
[email protected]
biomarker, drug, hypersensitivity, immediate
Funding information
Institute of Health ‘Carlos III’ (ISCIII) of the
Ministry of Economy and Competitiveness
(MINECO) (co-funded by European
Regional Development Fund), Grant/
Award Number: PI20/01734, PI22/01119
and REI-RICORSRD21/0002/0008 and
RD21/0002/0058; Andalusian Regional
Ministry of Health, Grant/Award Number:
PI-0076-2019, PI-0127-2020, PI-0129-
2021, PI21/00329, RH-0099-2020(co-
fundedbyEuropeanSocialFund) and
RC-0004-2021; ISCIII thorough AES 2019
within the ERANET-EuroNanoMed-III
framework (DrNanoDall project), Grant/
Award Number: AC19/00082; Flemish
Research Council, Grant/Award Number:
1804523N

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© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.

Allergy. 2024;79:601–612.  wileyonlinelibrary.com/journal/all | 601

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602 MAYORGA et al.

1 | I NTRO D U C TI O N (PAF) and interleukin 6 (IL-6) some of the most clinically relevant
markers in diagnosis.8 (Figure 2).
Drug hypersensitivity reactions (DHRs) are a burden for patients It is important to highlight that specific endotypes can be asso-
and the health systems, not only due to the increasing prevalence ciated with (i) high reoccurrence rate as it happens in urticaria an-
(10%–20% of hospitalised patients and up to 25% of outpatients) but gioedema after low doses of rocuronium in IgE-mediated reactions;
1
also to the complexity and severity of the reactions. (ii) dose effect, since lower in IgE-mediated reactions compared to
Labelling a patient as allergic represents not only a health prob- other mechanisms. Also, MRGPRX2-mediated reactions can be pre-
lem but also a significant financial burden for affected individuals vented by lowering the dose/infusion rate and (iii) role of cofactors
and health systems, with high medical costs mainly on inpatient like infectious diseases that are especially important in hypersensi-
care. This problem increases taking into account that only a small tivity to betalactams, …9–11
proportion of patients initially labelled as allergic are finally con- Therefore, clarification of these aspects will definitely help in
firmed as such after an allergological workup. 2 DHR diagnosis has the correct management of these patients. Consequently, the iden-
as main consequence the interruption of treatment and the switch tification of specific biomarkers would be the first milestone in this
to second-line therapeutic alternatives, which may be less effective, process (Box 1).
and more toxic and costly, usually causing a negative impact on life
quality and expectancy of these patients, in addition to increasing
the costs to the health system.3 2 | M EC H A N I S M S O N D RU G - I N D U C E D
From DHRs, immediate DHRs (IDHRs) are those occurring H Y PE R ​S E N ​S IT​I V IT Y
within 1–6 h after drug administration and the clinical symptoms
range from mild/moderate as urticaria or angioedema to more The mechanism involved in IDHRS has been classically referred to
severe ones like anaphylaxis, which can be life threatening.4 as an immune response mediated by drug-specific IgE (sIgE) anti-
The symptoms in IDHRs appear after drug-induced activation of bodies. However, the fact that sIgE levels are not detectable may
effector cells, mast cells and basophils or activation of inflam- indicate that another mechanism may be involved; in this sense, IgG-
matory pathways and the mediators release. Classical drugs trig- mediated mechanisms have been also reported by the low-affinity
gering these reactions are non-steroidal anti-inflammatory drugs IgG receptors (FcγRIII) on the surface of basophils, macrophages or
(NSAIDs), antibiotics, radiocontrast media (RCM), neuromuscular neutrophils that specifically need high amount of drug typically used
blocking agents (NMBAs) and anaesthetic agents drugs.1,5 But in in biological agents treatment.12
the last decades, other new drugs for the treatment of oncologic Another mechanism involved in chemotherapy or biological
or autoimmune diseases such as chemotherapy agents, monoclo- agent hypersensitivity is the cytokine release reaction (CRR) that
nal antibodies and biological agents have also demonstrated to can be produced by a direct activation or lysis of target cells by these
trigger these reactions, increasing their complexity. Therefore, drugs resulting in a massive secretion of cytokines in serum.12,13
all this highlights the need for identifying the specific biomarkers
for accurately labelling patients and performing the right future 1. IgE-mediated IDHRs
5
recommendations. 2. IgG-mediated IDHRs
Drug
The diverse nature of these drugs will imply different interac- Protein
tions with the immunological system having mast cells as main effec- IgE 3. Off target interaction
tor cells (Figure 1); therefore, although IDHRs have been classically FcεRI to MRGPRX2

considered type I IgE-mediated reactions according to Gells and IgG M

MRGPRX2
FcγR
Coombs classification, other mechanisms, such as immunological
non-IgE-mediated or non-immunological mechanisms due to off-tar- C3a
COX-1 4. Off target
C5a inhibition of COX-1
get interactions with effector cells receptor or enzymes have been
demonstrated.5–7
The identification of the phenotype and endotype at early stages
of the reaction is of vital importance. Phenotypes are characterized
by clinical features, the time elapsed between drug exposure and the
onset of symptoms and appearance after the first administration or Degranulation
Tryptase, histamine
repeated doses. The endotypes that accompany these phenotypes Prostaglandin, leukotriens, PAF

are defined by the mechanisms involved and by the molecular me-

diators released by the effector cells used as biomarkers. Currently, F I G U R E 1 Mast cells as central effector cells on immediate
drug hypersensitivity reactions (IDHRs). 1 and 2 are immunological
several endophenotypic categories (type I IgE/non-IgE, cytokine re-
mechanisms that need the drug binding to carrier molecules
lease, Mast-related G-protein coupled receptor X2 (MRGPRX2) or forming adducts; 3 and 4 are non-immunological mechanisms
Cyclooxygenase-1 (COX-1) inhibition and their associated biomark- produced by the direct interaction of the drug to either receptors
ers have been proposed, being tryptase, platelet activating factor or enzymes.
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MAYORGA et al. 603

Phenotyping Endotyping Effect of the

Effector cells
biomarkers biomarkers dose

IgE Tryptase,
histamine,
histamine
FcεRI • From second
IgE-mediated Mast cells, metabolites,
dose
reactions basophils sIgE, basophil
• Low dose
activation
markers; skin
tests

• From second
Mast cells,
dose
basophils, PAF, PAF-AH,
IgG-mediated • Higher dose
IgG neutrophils, Anaphylotoxin
reactions than IgE-
FcγR PFA macrophages, C3a, C5a
Pruritus, erythema, mediated
monocytes
urticaria, angioedema, reactions
rhinitis broncospasm,
abdominal pain, vomiting,
diarrhea, cardiovascular
colapse
MRGPRX2
Tryptase, • From first dose
MRGPRX2 Mast cells, histamine, • Higher dose
mediated (conditioned) MRGPRX2 than IgE-
reactions basophils polymorphisms mediated
Skin tests reactions

LTC4, LTD4,
LTE4,
• From first dose
9a,11b-PGF2
• Higher dose
NSAIDs cross- NERD
Mast cells than IgE-
hypersensitivity biomarkers: IL-5,
mediated
ECP, IFN-γ,
reactions
TGF-β1, DDP10,
SPD, foliculin

Fever, chills, rigor,

↑↑ IL-6
nausea, pain, headache, IL-6, IL-8, IL-10,
hypotension, oxygen IL-1, TNF-α,
Monocytes,
Cytokine desaturation (in mixed IFN-γ
macrophages,
release reactions with mast cells (in mixed From first dose
T cells, B cells
syndrome and basophils involving, reactions:
and NK cells
also flushing, urticaria tryptase,
and cardiovascular histamine)
collapse)

Serum BK,
plasma activity
of DPP-IV
Bradykinin protein and APP, Higher dose than
mediated Damaged tissues Angioedema serum IgE-mediated
angioedema endothelial- reactions
selectin,
angiopoietin-2,
6-keto-PG F1α

F I G U R E 2 Different mechanisms involved in IDHRs indicating the effector cells, phenotyping and endotyping biomarkers and the effect
of the drug dose and the sensitization need.

Furthermore, drugs-induced reactions after the first exposure, that is, fluoroquinolones (FQs), NMBA and some other drugs interact
suggesting that non-immunologically mediated mechanism might be with MRGPRX2 on mast cells inducing their activation and inflam-
involved by off-target interaction with receptors on effector cells, matory mediators release.14 Another possible mechanism is through
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604 MAYORGA et al.

IgE-mediated reactions. 21,22 However, it seems that cross-linking of

BOX 1 Relevance of endophenotyping immediate IgE is not a condition sine qua non for degranulation of mast cell
drug hypersensitivity reactions and basophils because monovalent complexes can also induce de-

• Precise diagnostic: Avoid false-labelled patients and also granulation. 23 Future studies are needed to evaluate the role of this

causing harm in patients with reaction phenomenon in IgE-mediated drug allergy.

• Desensitization procedure application Identification of IgE-mediated IDHRs is mainly based on skin tests

• Future management of patients and the quantification of drug-sIgE in serum as a main biomarker.

• Accuracy of drug avoidance recommendations Skin tests normally include skin prick tests and intradermal tests

• Future alternative drug recommendations and under- at immediate readings and have been used for a large range of drugs

standing the role of comorbidities like BLs, perioperative drugs, heparins, platinum salts and RCM. 24 A
positive skin test suggests an IgE-mediated reaction to the incrimi-
nated drug. 24 Their sensitivity depends on the drug but is generally
more sensitive compared to sIgE determination. 24,25
the inhibition of enzymes in immunological cells, that is, COX-1 inhi- sIgE determination by in vitro methods is classically done by im-
bition by NSAIDs modifying the arachidonic acid metabolism.15 munoassays (commercial or in-house)1 as reported to BLs, 26 FQs, 27
Finally, there is a group of drugs like angiotensin-converting en- NSAIDs28 and NMBAs. 29 The most used commercial method for
zyme inhibitors (ACEI) drugs, dipeptidyl peptidase IV (DPPIV) inhib- detecting drug-sIgE is the fluoroimmunoassay ImmunoCAP®, how-
16
itors (gliptin drugs), neutral endopeptidase P/neprilysin inhibitors, ever, the availability is limited to only a few drugs and sensitivity and
fibrinolytic agents and oestrogen that produce angioedema mainly usefulness depend on analysed drug. For penicillins, sensitivity has
because they are involved in the decreased degradation of bradyki- been reported to be low and variable (0%–50%) depending on the
nin (BK) and other vasoactive substances17 (Figure 2). clinical symptoms26 and showing false-positive results to penicillin
These arrays of mechanisms can be associated with similar symp- G in an important percentage.30 Higher sensitivity values have been
toms and therefore the diagnosis of patients with IDHRs with correct reported for NMBAs31: rocuronium (83%–92%), morphine (78%–
endophenotyping is currently a major challenge during diagnosis. A 84%) and suxamethonium (44%). Moreover, high-sensitivity values
proper knowledge of endotypes based on specific biomarkers will (84%–97%) for sIgE to chlorhexidine, an increasingly relevant ele-
permit discriminating patients within the same phenotype. This will ment in perioperative hypersensitivity, should be noted.32 Despite
be important to personalise diagnosis, which will be crucial for fu- the increasing prevalence of hypersensitivity to biologicals, there
ture treatment as well as possible alternatives, and prevention to are no commercial kits available. Interestingly, it has been shown
improve the patient's quality of life. Moreover, endotyping patients that cetuximab can induce IDHRs even at first administration due
could also be relevant during the clinical decision of performing drug to cross-reactivity with galactose-α-1,3-galactose (α-gal) by natural
desensitizations since, as reported, these procedures are effective exposure indicating that α-gal-sIgE detection can predict cetux-
in IgE- or IgG-mediated reactions and some cases of CRR but not imab-induced anaphylaxis prior to first administration.33
18,19
in those produced after off-target interaction with MRGPRX2. Moreover, in-house methods, mostly using radiolabeled anti-IgE,
are indispensable to overcome sensitivity limitations of the fluoro-
immunoassays and analyse the immunological recognition of new
3 | B I O M A R K E R S I N I G E- M E D I ATE D chemical structures. In this sense, recent studies have shown the
R E AC TI O N S relevance of the inclusion of different determinant antigens for the
detection of drug sIgE to cephalosporins, carbapenems and mono-
IgE-mediated mechanism has been classically accepted as the un- bactams34,35 as well as the beta-lactamase inhibitors clavulanic acid
1
derlying mechanism in IDHRs. In this case, drugs, frequently low (CLV)36,37 and tazobactam.38 All these findings suggest the need to
molecular weight compounds, act as haptens needing to bind to include different antigenic structures in the same assay for diagnos-
macromolecules and form adducts that interact to IgE bound to ing the maximal number of patients, ensuring the detection of dif-
high-affinity receptor (FcεRI) on the surface of effector cells, mast ferent patterns of recognition. On the other hand, great efforts are
cells and basophils (Figure 1). Then, after subsequent contact, ad- being made in the implementation of more sensitive detection meth-
ducts cross-link with two or more adjacent sIgE molecules, trigger- ods by using ultra-sensitive chemiluminescence immunoassay,39 and
ing the activation and degranulation of mast cells and basophils, with a multiplex microimmunoassay,40 both of them reported being used
the release of preformed inflammatory mediators, and the synthesis for the detection of sIgE to penicillin. Additionally, the use of syn-
and secretion of lipid mediators and cytokines. 20 Drugs typically thetic structures that mimic carrier molecules, instead of classically
involved are antibiotics, beta-lactams (BLs) or FQs, RCM, NMBAs, used poly-L-lysine, and new solid phases can provide interesting al-
5,20
carbamazepine, sulphanilamides or pyrazolones. Furthermore, ternatives to improve the in vitro clinical diagnostic practice. Indeed,
in the last decades, other drugs like platins used in chemotherapy the use of nanoparticles decorated with BL-dendrimers shows
treatments and monoclonal antibodies used for the treatment of promising results for detecting sIgE to BLs, with a preliminary study
different immunological diseases have been reported as producing (N = 21) showing higher sensitivity values for the detection of sIgE
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MAYORGA et al. 605

to BP and/or AX with nanoparticles as solid phase (100%) compared perioperative hypersensitivity showing that high tryptase values
with traditional cellulose discs (83% for AX, 78% for BP), and inter- determined as >11.4 ng/mL57 or >(1.2 × baseline-tryptase) + 2 μg/L58
estingly, the detection of false-positive results of BP sIgE for con- were more frequent in life-threatening reactions. On the other hand,
firmed AX-selective patients decreased from 41% for cellulose discs histamine is the most abundant inflammatory mediator for acute
to 0% for nanoparticles.41 This method provides high reproducibility anaphylaxis; however, limitations for the detection exist due to its
due to the homogeneous composition of nanoparticles and facili- short half-life in serum (20 min), therefore, detection of the metabo-
tates the effective exposure of drugs to sIgE improving sensitivity. lites N-methylhistamine and N-methylimidazole acetic acid in urine
Basophil activation test (BAT) is a useful additional tool for di- samples (24 h) is an alternative indirect method for the determina-
agnosing IgE-mediated reactions1,42 and has been recommended tion of histamine. It should be highlighted that the use of histamine
1
for diagnosing BLs, NMBAs, FQs, RCM and pyrazolone allergies. metabolites as a biomarker requires the avoidance of microbially
However, due to sensitivity limitations, different studies are fo- processed foodstuffs, which can contain large amounts of hista-
cused on improving it through the use of new chemical structures mine,59 as the oral administration of histamine has been reported to
derived from the parent drug or new methodological approaches. increase the 24 h excretion of N-methilimidazole acetic acid.60
In this sense, comparisons of basophil activation biomarkers, CD63
and CD203c, in a prospective evaluation of amoxicillin (AX) and CLV
allergic patients showed that the best sensitivity and specificity was 4 | B I O M A R K E R S I N I G G - M E D I ATE D
obtained for CD203c (46.6% and 94.6%), with good positive predic- R E AC TI O N S
tive value and like-hood ratio.43 These results are in line with those
obtained by Abuaf et al.44 However, another recent study in IDHRs Although the IgE-mediated pathway is classically considered the
to AX obtained lower sensitivity (23%) when selecting a high spec- main underlying mechanism of human IDHRs,61 the evidence sup-
45
ificity (95%). All this suggests that methodological or analytical porting the existence of alternative mechanisms has grown in the
variations in the classical procedure could be useful to improve the last years. In this sense, new data regarding IgG-mediated mecha-
diagnostic value of BAT. nism, complement and coagulation-dependent activation, and
Basophils can be also activated through non-IgE-mediated mech- MRGPRX2-induced reactions has arisen.14,62
46
anisms, limiting the capacity of BAT to differentiate between the IgG-mediated reactions are well studied and documented in
endotypic mechanism underlying the IDHR. So in order to consider mice, and the evidence in humans is frequently limited and extrap-
basophil activation as a biomarker for IgE-mediated reactions, the olated from these animal models.48,63,64 IgG immunocomplexes (IC)
involvement of the FcɛRI-mediated pathway should be confirmed. that engage low-affinity IgG receptors (FcγR) in different myeloid
Studies have performed BAT inhibition by using phosphatidylinositol cells such as macrophages/monocytes and neutrophils, but also ba-
47
3-kinase (PI3K) inhibitors to determine if basophil activation was sophils and mast cells, with the release of PAF as a major mediator,
mediated by sIgE instead of other mechanisms such as MRGPRX2- are considered the main actors in these reactions.48,64 Interestingly,
mechanisms. However, since IgG-mediated basophil activation has a higher amount of antigen/drug is required to induce IgG-mediated
been also proposed as an alternative pathway,48 which would be also anaphylaxis, reflecting the much higher affinity of IgE binding by
inhibited by PI3K inhibitors, other approaches should be applied to high-affinity IgE receptor (FcεRI) than IgG binding by FcγR.9 For this
confirm in vitro basophil activation mediated by IgE. This is the case reason, IgG-mediated IDHRs are mainly related to parenteral admin-
of designed ankyrin repeat proteins (DARPin), disruptive IgE inhib- istration and a high amount of drug, whereas food, absorbed in a
itors that are able to desensitise in vitro allergic effector cells by smaller amount, is more likely an IgE-dependent pathway.9 However,
actively removing IgE from cell surfaces.49,50 In the same line, hu- recent evidence shows that the most severe food anaphylaxis may
manised monoclonal anti-IgE antibodies, such as omalizumab51 or be also related to the simultaneous activation of both IgE and IgG
ligelizumab,52 with high potency to block IgE/FcεRI signalling have mechanisms.65
been applied in both in vitro and in vivo studies and eventually, bru- Understanding the physiopathology of IDHRs may help to iden-
53
ton tyrosin kinase inhibitors could also be used. tify potential biomarkers that could differentiate between IgE and
Another approach to indirectly confirm IgE-mediated reactions is IgG reactions. Considering that a high rate of patients suffering an
the negativisation in long-term studies due to the clearance of sIgE acute IDHR may not show any biomarker of an IgE-mediated reac-
if patients are not exposed to the culprit drug.54,55 These changes tion, the identification of the underlying mechanism is of the utmost
in the in vitro results do not happen when the activation is due to interest to stratify the risk before attempting a drug challenge and/
non-immunological mechanisms like the off-target interaction to or give avoidance recommendations.48
MRGPRX2 or enzyme inhibition, COX-1 for NSAIDs. In a recent study, Jönsson et al.48 have shown the utility of
Finally, IgE-mediated reactions are also characterised by the neutrophils, FcγR and PAF acetylhidrolase (PAF-AH) as potential
release of inflammatory mediators that can be measured as bio- biomarkers of IgG-mediated reactions using a cohort of patients
markers, although they are not limited to IgE-mediated mecha- with IHRs to NMBA. They observed that no IgE-related biomarkers
nisms. Serum tryptase is the most commonly analysed mediator in could be found in about 26% of cases that were classified as po-
the acute phase to confirm anaphylaxis,1,56 with recent studies in tential IgG-mediated reactions. These individuals showed higher
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606 MAYORGA et al.

values of neutrophil activation markers and lower FcγR expres- Although also FcεRI engagement can have a role in CRR amplify-
sion on neutrophils surface, which is related to IgG-mediated ac- ing the classical IgE-mediated anaphylaxis. The pro-inflammatory
tivation. 64 Interestingly, even those with suspected IgE-mediated mediators, like TNF-α, IFN-γ, IL-8 IL-10 and IL-1 and especially IL-6,
reactions showed signs of neutrophil activation through an IgG are considered as biomarkers for these CRR.13,74 However, measure-
mechanism, and lower values of PAF-AH, which correlates with ment of these cytokines is not routinely performed.
higher serum PAF values, although these biomarkers had lower
values when compared to those patients with suspected IgG-
mediated reactions. Indeed, they observed a correlation between 6 | BIOMARKERS IN
severity and the presence of both IgE and IgG biomarkers, sug- M RG PR X 2- M E D I ATE D R E AC TI O N S
gesting a double mechanism in most severe reactions, as previ-
ously suggested in a model of food allergy. 65 In this same line, PAF Different observations like the lack of detection of drug sIgE or the
directly correlated, whereas PAF-AH inversely correlated with appearance of IDHRs after the first drug administration suggest
anaphylaxis severity in a cohort of patients with anaphylaxis of the involvement of a non-immunological mechanism, with the in-
66
different aetiologies, including drugs. Considering that neutro- volvement of MRGPRX2 in the mast cell activation reinforcing it.75
phils are one of the main sources of PAF, and express FcγRI but Indeed, cationic peptidergic drugs such as NMBAs, FQs and icatibant
not FcεRI, 67 we may understand that these reactions may be also can have an off-target interaction with the MRGPRX2.75 Moreover,
IgG-related. resting basophils barely express MRGPRX2 on their surface, but
64
In a study, it has been concluded that a decreased expression this expression can be quickly upregulated after stimulation, making
of FcγRIII in neutrophils, without an increase of the expression of IL- ‘conditioned’ cells responsive to MRGPRX2 occupation.76
4Rɑ in T cells, IL-4 or IL-4ɑ soluble receptor levels in serum (markers The MRGPRX2 mechanism seems to display its own peculiarities
of IgE reactions) would likely indicate an IgG-dependent mechanism. and its diagnostic and therapeutic approach most likely differs from
This hypothesis, based on mice experiments, is supported by some the IgE-mediated process.14,53,77 However, there is no irrefutable ev-
observations in human models; IgE but not IgG receptors engage- idence for its clinical relevance. The most relevant limiting aspects
ment in human basophils induces the activation of IL-4 pathway.68 relate to (i) the oversimplified dichotomy IgE vs MRGPRX2, (ii) the
Moreover, human neutrophils incubated for 4 h with serum-contain- possible additive effect of IgE- and MRGPRX2-pathway78 and (iii)
ing drug-specific IgG-IC show a decrease of 60% in the expression the possibility of some drugs (e.g. FQs, NMBAs) possibly triggering
of FcγRIII compared with the same conditions but without drug-spe- both pathways. Therefore, the identification of specific clinical, diag-
cific IgG-IC.64 nostic and susceptibility biomarkers is pivotal for the comprehensive
Finally, the complement system, through the generation of ana- elucidation of the role of the MRGPRX2 endotype. Potential clinical
phylatoxins such as C3a, can also activate mast cells and basophils biomarkers include drug naivety, the requirement of higher doses
upon engagement with its receptor. Interestingly, C3a has demon- than for IgE-mediated reactions, and the impact of comorbidities. A
strated a synergistic effect with IgG activation, increasing up two- cardinal point is whether the different spatio-temporal dynamics of
fold the intensity of the reaction.69 In the same line, complement IgE and MRGPRX2 engagement79 are clinically discernible. IgE and
can be activated by IgG IC. Regarding its relationship with DHRs, it MRGPRX2 endotypes can cause the entire spectrum of clinical man-
has been demonstrated that drugs solubilized in therapeutic lipo- ifestations, including anaphylaxis. Onset and duration cannot practi-
somes or lipid-based excipients, as well as intravenous iron prepa- cally be used to discriminate IgE and putative MRGPRX2 anaphylaxis
rations, are able to induce complement activation.70 Serum C5b-9, mainly because both require prompt therapy. On the other hand, it is
final product of the complement activation cascade, may be used as tempting to speculate that in case of MRGPRX2 occupation: (a) ana-
a biomarker of complement-related DHRs. Actually, some authors phylaxis would invariantly present with cutaneous manifestations
have observed the correlation between complement levels increase and (b) resolution of isolated cutaneous symptoms should be faster.
and symptom duration, although the supporting evidence is based Diagnostic biomarkers comprise assessment of mast cell ac-
71,72
on in vitro and ex vivo studies, and animal models. tivation and mechanistic studies. Paired analyses of acute and
baseline serum tryptase are prerequisites for an appropriate as-
sessment of mast cell activation. 80 Recent in vitro data pointed out
5 | B I O M A R K E R S I N C Y TO K I N E R E LE A S E that tryptase levels cannot be used for differentiating between
R E AC TI O N S (C R R ) the IgE and MRGPRX2 endotype, for that, PBMCs were activated
via sIgE-mediated mechanism and via MRGPRX2-mediated path-
A mechanism of IDHRs recently associated with new treatments way and then, tryptase levels in the collected supernatants were
such as chemotherapy and biological agents is the massive cytokine determined by ImmunoCAP, and no significant difference in the
release by different cells, including monocytes or macrophages, T variation of the tryptase concentration (before and after stimula-
cells, B cells and natural killer cells. This CRR is a type of IDHR that tion) was observed. 81 In the same line, as shown by a retrospective
can occur at the first dose of the drug. These mechanisms can be in- analysis of rocuronium hypersensitivity, although the significant
duced after the direct interaction or through FcγRIII on target cells.73 rise in tryptase is observed more frequently in IgE endotype,
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MAYORGA et al. 607

there is no difference in acute titres between presumed IgE and vary according to external agents such as corticosteroid treatment,
82
alleged MRGPRPX2 phenotypes. It is appropriate to conclude tobacco smoke or alcohol.93,94
that no acute biomarker is available to ascertain of MRGRPX2- The total IgE in serum ≥100 IU/mL confirms the adaptive immune
induced mast cell degranulation. Identification of potential new system involvement in T2 asthma, although this biomarker has lit-
acute biomarkers can benefit from transcriptomics, metabolo- tle diagnostic or prognostic value.94 However, IgE level in NP tissue
mics and proteomics. Thus far, no mechanistic diagnostic tool is from NERD patients has been associated with faster recurrence of
available to document with certainty an MRGPRX2 endotype. NP compared to aspirin tolerants.95
Skin test positivity is expected for potent MRGPRX2 agonists and Recently, serum periostin has been proposed as an NERD bio-
cannot be used to differentiate an IgE from an MRGPRX2 mech- marker because it contributes to airway remodelling connected to
anism. Theoretically, bruton tyrosin kinase inhibitors53 could be T2 inflammation, although the clinical utility and cut-off points re-
used during skin testing to document IgE-mediated endotypes. main to be established.90,96 Moreover, plasma eosinophil-derived
Although sIgE detection can be considered the most valuable dis- neurotoxin, L-plastin, serum sphingosine-1-phosphate and urine
criminator, as mentioned above, sIgE assays are available only for a sphingosine have been also proposed as an NERD biomarker 97 al-
limited number of drugs, and their accuracy is suboptimal. For the though clinical validation is required.
time being there is no specific test able to demonstrate unambig- Increased expression of type 2 cytokines, including IL5, and eo-
uously an MRGPRX2-mediated mechanism. Identification of a pu- sinophil cationic protein (ECP) levels has been found to be higher
tative MRGPRX2-mediated IDHR remains a diagnosis by exclusion in the NP tissue and in nasal secretions of patients with NERD
when in vitro or in vivo mast cell activation is not associated with compared with aspirin tolerant asthmatics (ATA).98,99 Additionally,
a specific immune response (IgE or specific T cells). ‘MRGPRX2 as- type 1 inflammatory cytokines such as interferon (IFN)-γ has
says’ should include functional studies on cultured non-sensitised been found to be elevated in the nasal tissue of NERD compared
mast cells (direct mast cell activation test—dMAT) with measure- to chronic hyperplastic eosinophilic sinusitis.100 Serum levels of
ment of membrane markers, 83 mediator release, G-protein depen- TGF-β1 were significantly higher in NERD patients than in ATA and
dent (Ca++ endpoint) and independent (beta-arrestin endpoint) positively correlated with urinary LTE4 levels.101 Moreover, serum
84
pathways read-outs. In vitro analysis of ‘conditioned’ basophils levels of dipeptidyl peptidase 10 (DDP10) may be also a poten-
can serve as an additional model for exploring MRPGPRX2 ago- tial biomarker to distinguish NERD from ATA and predict disease
nism. However, none of these assays alone is diagnostic. Assays to severity as a positive correlation has been found with TGF-β1 in
document IgE endotype include passive mast cell activation tests patients with NERD.102
(based on sensitised, MRGPRX2-silenced mast cells) 85 BAT and Surfactant protein D (SPD) interacts with phagocytic cells at-
T-lymphocyte activation test. A theoretical algorithm to discrimi- tenuating airway inflammation and remodelling. Therefore, serum
nate MRGPRX2 and IgE endotype has been recently published.77 SPD levels were lower and negatively correlated with FEV1% de-
Finally, polymorphisms of MRGPRX2 can significantly impact crease after aspirin challenges in patients with NERD than with
the responsiveness of the receptor to agonistic drugs.86 This might ATA.103
explain why MRGPRX2-mediated reactions occur only in a minority Folliculin, an intracellular protein that regulates cell–cell adhe-
of the population and why an individual patient reacts only to some sion, is increased in the sera of NERD patients compared to ATA.104
agonists and tolerates others. Therefore, it is anticipated that analy- The provocation with aspirin is the most accurate biomarker to
sis of MRGPRX2 polymorphisms can provide significant advances in diagnose NSAID hypersensitivity, being typically performed orally
the identification of susceptibility biomarkers. but in NERD, it can also be done intranasally or inhaled. However,
this is a costly non-free-risk test that requires trained personnel and
resources.15,105
7 | B I O M A R K E R S I N N SA I DS NERD patients experience respiratory reactions after NSAID
C ROS S - H Y PE R ​S E N ​S IT​I V IT Y intake due to dysregulation of arachidonic acid (AA) metabolism
with an overproduction of LTs.15,106 Therefore, LTE4 serum levels
Another type of non-immunologically mediated IDHRS is those and the ratio LTE4/9a,11b-PGF2,107 as well as urinary and salival
induced by drugs which inhibit enzymes such as COX-1 in mast LTE4 have been found to be increased in NERD and could po-
cells, deviating the synthesis of prostaglandins (PGs) and throm- tentially be used to identify the risk of aspirin hypersensitivity in
boxanes towards overproduction of cysteinyl-leukotrienes (CysLTs; asthmatics.108,109 Recently, in sputum inflammatory cell distribu-
15
LTC4, LTD4 and LTE4). Most studies have focused on NSAIDs- tion, the concentrations of LTE4 and the LTE4/logPGE2 ratio have
exacerbated respiratory disease (NERD). NERD is a sub-endotype been used for subphenotyping NERD patients.110 Additionally, an
of T2 asthma, and therefore, inflammatory biomarkers eosinophils, increased concentration of LTE4 in urine, and nasal and broncho-
fractional exhaled nitric oxide (FENO) and serum IgE are typically alveolar lavage fluids have been found after oral aspirin challenge,
elevated and directly related to exacerbation risk.87–92 However, lev- being associated to the severity of the respiratory reaction during
els of these biomarkers and cut-off values are not clinically fixed and challenge.111
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608 MAYORGA et al.

The pathogenic model proposed for NERD has been extended Recently, serum endothelial-selectin and angiopoietin-2 have
to NSAID hypersensitivity manifested with the exclusively cutane- shown to be increased in BK-induced angioedema compared to his-
ous symptom, and urinary LTE4 have been proposed as a biomarker tamine-mediated angioedema, showing the role of endothelial dys-
for NSAID-exacerbated cutaneous disease (NECD).112 Similarly to function and serine proteases in this angioedema subtype.129
NERD, LTE4 and 9α,11β-PGF2, the main metabolite of PGD2, are The determination of 6-keto-PG F1α has also been proposed as
113
increased after aspirin challenge in NECD, NSAID-induced urti- a biomarker for assessing the risk of developing ACE-induced an-
caria/angioedema (NIUA)113 and blended reactions patients.114 gioedema, as it is increased in patients experiencing angioedema
Genetic variants have been associated with NSAID hypersensi- under ACEI therapy.130
tivity, being distinct in patients experiencing respiratory or cutane-
ous symptoms although most of them have not been replicated. Most
studies have focused on evaluating AA pathway-related variants or 9 | CO N C LU S I O N S
immune cell activation.115,116 In NERD, variants in genes associated
with LT production (5-Lipoxygenase, 5-LOX) and LTC4 synthase and IDHRs can be produced by a wide array of mechanisms after the
115
PGs production (COX) pathways were reported. Available data drug interaction with specific antibodies bound on their receptors
show that NECD and NIUA share similar genetic backgrounds; nev- or directly on effector target cells on their receptor. There is a need
ertheless, different gene polymorphisms have been reported.117,118 to accurately endophenotyping the patients for a precise diagnosis.
This is crucial for further drug prescription and alternative drug rec-
ommendations since readministration and cross-reactivity should
8 | BIOMARKERS IN be managed in a different way when immunological or non-immu-
B R A DY K I N I N - M E D I ATE D A N G I O E D E M A nological mechanisms are involved. To discriminate these reactions,
we can use both clinical and laboratory biomarkers. From them,
Another non-immunologically mediated IDHR is BK-mediated an- clinical biomarkers are difficult to manage and regarding diagnostic
gioedema, which has been associated with angiotensin-converting biomarkers, besides drug-sIgE, recent studies are indicating many
enzyme inhibitor (ACEI) drugs,119 DPPIV inhibitors (gliptin drugs),16 others that can characterize the different endotypes of IDHRs, al-
neutral endopeptidase P/neprilysin inhibitors,120 fibrinolytic agents though further analyses are necessary to precisely indicate whether
121
and oestrogen, although most studies focused on ACEI-induced we are dealing with a specific endotype or several of them occur-
angioedema. In these reactions, angioedema is believed to be the ring simultaneously. The presence of simultaneous endotypes that
consequence of the decreased degradation of BK and other vaso- could increase the severity of the reaction could not be ruled out,
active substrates, such as substance P16 leading to a rapid local in- especially for those drugs that could induce a reaction by different
crease of vascular permeability and extravasation of fluid into the mechanisms; however, further studies addressing this issue in drug
interstitial space in the dermis and subcutis.17 hypersensitivity are required.
Serum BK levels have been proposed as a biomarker as it has
been found to be elevated during acute attacks of ACEI-induced an- AU T H O R C O N T R I B U T I O N S
17
gioedema compared with remission. However, its clinical utility is MJT, CM and AA designed the review and coordinated the work.
questioned because of BK short half-life and technically challenging Authors contributed to different sections: CM ‘Mechanisms
measurement, and additionally, the role of BK as the main mediator on drug-induced hypersensitivity’; AA ‘Biomarkers in IgE medi-
of this angioedema subtype has recently been questioned.122 In ad- ated reactions’; RMC ‘Biomarkers in IgG-mediated reactions’; VS
dition, laboratory parameters associated with coagulation and fibri- ‘Biomarkers in MRGPRX2 mediated reactions’; ID ‘Biomarkers in
nolysis including cleaved high molecular weight kininogen, plasma NSAIDs cross-hypersensitivity and Biomarkers in Bradykinin medi-
kallikrein and activated coagulation factor FXII are also tedious.123 ated angioedema’; MJT ‘Introduction and Conclusions’. All authors
The normal level of complement component 4 and C1-inhibitor reviewed and accepted the manuscript.
(C1-INH) allows differentiating from hereditary angioedema
(HAE).124 Recently, an increase in C1-INH activity during acute ACEI- AC K N O​W L E D
​ G E ​M E N T S
induced AE attacks has been reported.125 In cases of ACEI-induced We thank Claudia Corazza for her invaluable English language
angioedema, C-reactive protein serum level has been reported to support. This work has been supported by the Institute of Health
be significantly increased by 7.3-fold compared to normal values in ‘Carlos III’ (ISCIII) of the Ministry of Economy and Competitiveness
patients with angioedema of unknown cause,126 and leukocytosis, (MINECO) (grants cofunded by European Regional Development).
especially in those patients with abdominal symptoms,127 has been Fund: PI20/01734; PI22/01119; REI-RICORS RD21/0002/0008,
reported. RD21/0002/0058. Andalusian Regional Ministry of Health (grant
Plasma activity of DPP-IV protein and aminopeptidase P (APP), nos. PI-0076-2019, PI-0127-2020, PI-0129-2021, PI21/00329).
which catabolises BK, has been shown to be decreased in patients DrNanoDall project by ISCIII thorough AES 2019 within the
with ACEI-associated angioedema compared to patients on ACEI ERANET-EuroNanoMed-III framework (AC19/00082). CM holds a
therapy and with no angioedema history.128 ‘Nicolas Monardes’ research contract with the Andalusian Regional
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MAYORGA et al. 609

Ministry of Health (RC-0004-2021). AA holds a Senior Postdoctoral 14. McNeil BD. MRGPRX2 and adverse drug reactions. Front Immunol.
2021;12:676354.
Contract (RH-0099-2020) with the Andalusian Regional Ministry
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of Health (cofunded by European Social Fund (ESF): ‘Andalucía standing hypersensitivity reactions to nonsteroidal anti-inflamma-
se mueve con Europa’). VS is a Senior Clinical Investigator of the tory drugs. Allergy. 2020;75(3):561-575.
Flemish Research Council (FWO; grant 1804523N). 16. Lepelley M, Khouri C, Lacroix C, Bouillet L. Angiotensin-
converting enzyme and dipeptidyl peptidase-4 inhibitor–in-
duced angioedema: a disproportionality analysis of the WHO
C O N FL I C T O F I N T E R E S T S TAT E M E N T
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The authors declare that they have no conflicts of interest. 2020;8(7):2406-2408 e1.
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DATA AVA I L A B I L I T Y S TAT E M E N T gioedema. N Engl J Med. 2002;347(8):621-622.
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Data sharing is not applicable to this article as no new data were cre-
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ORCID tryptase. Curr Opin Allergy Clin Immunol. 2015;15(4):329-336.
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Cristobalina Mayorga https://orcid.org/0000-0001-8852-8077
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Adriana Ariza https://orcid.org/0000-0003-1524-9602 2022;77(4):1129-1138.
Rosa Muñoz-Cano https://orcid.org/0000-0001-8566-8285 21. Sloane D, Govindarajulu U, Harrow-Mortelliti J, et al. Safety,
Vito Sabato https://orcid.org/0000-0002-1321-314X costs, and efficacy of rapid drug desensitizations to chemo-
therapy and monoclonal antibodies. J Allergy Clin Immunol Pract.
Inmaculada Doña https://orcid.org/0000-0002-5309-4878
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Maria J. Torres https://orcid.org/0000-0001-5228-471X 22. Isabwe GAC, Garcia Neuer M, de Las Vecillas Sanchez L, Lynch
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