Received: 24 October 2023? ?Accepted: 8 November 2023
|
DOI: 10.1111/all.15961
EAACI POSITION PAPER
Hypersensitivity reactions to proton pump inhibitors. An
EAACI position paper
1 2 3
Sevim Bavbek ?| Se?il Kepil ?zdemir ?| Patrizia Bonadonna ?|
4 5 6
Marina Atanaskovic-Markovic ?| Annick Barbaud ?| Knut Brockow ?|
7 8 9
Jose Laguna Martinez ?| Alla Nakonechna ?| Mauro Pagani ?|
10 11 12
Alessandra?Arcolac? ?| Carla Lombardo ?| Maria J. Torres
1
Division of Immunology and Allergy, Department of Chest Diseases, School of Medicine, Ankara University, Ankara, Turkey
2
Department of Chest Diseases, Allergy and Immunology Unit, ?zmir Faculty of Medicine, Dr. Suat Seren Chest Diseases and Surgery Training and Research
Hospital, University of Health Sciences, ?zmir, Turkey
3
Allergy Unit, Borgo Roma University Hospital, Verona, Italy
4
Department of Allergology and Pulmonology, Faculty of Medicine, University of Belgrade, University Children''s Hospital, Belgrade, Serbia
5
Département de dermatologie et allergologie, Sorbonne Université, INSERM, Institut Pierre Louis d''Epidémiologie et de Santé Publique, AP-HP, Sorbonne
Université, H?pital Tenon, Paris, France
6
Department of Dermatology and Allergy Biederstein, Faculty of Medicine, Technical University of Munich, Munich, Germany
7
Allergy Unit, Allergo-Anaesthesia Unit, Faculty of Medicine, Hospital Central de la Cruz Roja, Alfonso X El Sabio University, Madrid, Spain
8
Allergy and Clinical Immunology Department, University of Liverpool, Royal Preston Hospital, Lancashire Teaching Hospitals, NHS Foundation Trust,
Liverpool, UK
9
Medicine Department, Medicine Ward Mantova Hospital, ASST di Mantova, Mantova, Italy
10
Immunology Unit, Borgo Roma University Hospital, Verona, Italy
11
Division of Dermatology and Allergy, APSS – Trento Hospital, Trento, Italy
12
Allergy Unit, Regional University Hospital of Malaga, IBIMA-UMA-ARADyAL, Malaga, Spain
Correspondence
Sevim Bavbek, Division of Immunology Abstract
and Allergy, Department of Chest
Proton pump inhibitors (PPIs) are invaluable therapeutic options in a variety of dys-
Diseases, Ankara University, School of
Medicine, Ankara, Türkiye. peptic diseases. In addition to their well-known risk profile, PPI consumption is related
Email: bavbek@medicine.ankara.edu.tr
to food and environmental allergies, dysbiosis, osteoporosis, as well as immediate and
delayed hypersensitivity reactions (HSRs). The latter, although a rare event, around
1%–3%, due to the extraordinarily high rate of prescription and consumption of PPIs
are related to a substantial risk. In this Position Paper, we provide clinicians with prac-
tical evidence-based recommendations for the diagnosis and management of HSRs to
PPIs. Furthermore, the unmet needs proposed in the document aim to stimulate more
in-depth investigations in the topic.
KEYWORDS
allergy, anaphylaxis, drug hypersensitivity, hypersensitivity reaction, proton pump inhibitors
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? 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.
Allergy. 2023;00:1–13. wileyonlinelibrary.com/journal/all ?|?1atle
2? ??? BAVBEK .
|
1?|?INTRODUCTION 3?|?EPIDEMIOLOGY?AND?PPI?USE?AS?A?
RISK?FACTOR?FOR?ALLERGIC?DISEASES
Proton pump inhibitors (PPIs) belong to a group of chemically re-
lated compounds whose primary function is the inhibition of acid It has been reported that gastric acid suppression promotes allergy in
12,13
production by blocking the hydrogen potassium adenosine triphos- animal and observational human studies. In line with these trials, a
1,2
phatase enzyme system (H+/K?+?-ATPase). In adults and pediatric current population-based study provided evidence for an epidemiolog-
population, these drugs are widely used for the treatment of peptic ical association between gastric acid suppression and the development
conditions, such as gastric ulcers, gastroesophageal reflux disease, of allergic symptoms. In the study, ratios of using anti-allergic medica-
Helicobacter pylori infections, eosinophilic esophagitis, as well as tions, increased from 1.47 (95% CI: 1.45–1.49) in subjects <20?years, to
used to prevent gastric damages due to prolonged use of cortico- 5.20 (95% CI: 5.15–5.25) in >60?years old after gastric acid-inhibiting
3,4
steroids and nonsteroidal anti-inflammatory drugs (NSAIDs). drug prescriptions were found. This finding was specific to all gastric
6
They are usually well-tolerated leading to overprescription and acid-inhibiting drugs and was more prominent in females.
5
consumption, with a risk of side effects of approximately 1%–3%. There is also evidence that PPI use may be associated with de
Given the population-based PPI consumption ranging from 8% or novo type I allergic sensitizations to dietary compounds and to oral
6,13
11% in the 20–24 aged males or females, to 34%–41% in the 65–69 drugs. The risk for food allergy associated with PPI treatment
6
aged males or females, the risk for allergic side effects is substan - showed a dose-dependent effect related to days of treatment.
tial. Observational studies have suggested an association between Children who had been prescribed for more than 60?days of PPIs
PPI intake and risk of pneumonia, osteoporosis, enteric infection, had a 52% greater risk of being diagnosed with food allergy during
14
Clostridium difficile–associated diarrhea, cerebrovascular events, childhood than those prescribed for 1 to 60?days of PPIs. A low gas-
chronic renal failure, dementia, and all-cause mortality, especially tric pH (1–3.5) is necessary to activate gastric pepsin and only acidic
7,8
in long-term usage. Their long-term intake has been facilitated by chymus stimulates duodenal secretions and the release of pancreatic
over-the-counter sales in most countries and connects them with de enzymes at the next level of digestion hierarchy. When antacid drugs
novo induction of Th2 responses to food and environmental aller- inhibit acid gastric secretion, therefore, food-related allergens may
2
gens, in experimental, clinical and population-based epidemiologic remain intact and absorbed, facilitating an allergic sensitization.
studies. Their mechanisms of promoting Th2 immunity and dysbiosis In a nested case–control retrospective cohort study on hospi-
6
have been revealed in detail. Still, in addition to their well-known talized patients, the use of PPIs was associated with a significant
risk profile, PPIs can induce immediate and delayed hypersensitivity increased risk of drug HSRs (OR: 4.35; 95% CI: 2–9.45) along with a
9 15
reactions (HSRs). The optimal management of patients with HSRs personal history of drug allergies and a long hospitalization time.
to PPIs is still a matter of discussion. This Position Paper aims to PPI therapy is also considered a possible cofactor, along with exer-
provide clinicians with practical evidence-based recommendations cise, anti-inflammatory medications, and alcohol, in decreasing the
2
for the diagnosis and management of HSRs to PPIs along with unmet allergens eliciting threshold dose for anaphylaxis.
needs in this area. Additionally, PPIs may act as a cofactor in patients undergoing
oral immunotherapy (OIT), triggering adverse reactions, irrespective
of the PPI used or the dosage. Since OIT is a new form of treatment,
2?|?METHODS—SEARCH?STRATEGY long-term adverse events arising from PPI treatment and other pos-
16
sible triggers are still uncertain and needs long-term follow-up.
The European Academy of Allergy and Clinical Immunology The PPIs involved in the HSRs vary among countries: lansopra-
17,18
(EAACI) commissioned this position paper (PP). The appointed zole in studies from Turkey, esomeprazole and lansoprazole in
3 19–24
task force group (TF) performed a literature search in MEDLINE, Italy and omeprazole in Spain, probably reflecting the con-
PubMed, Web of Science, and Google Scholar databases of sci - sumption/prescription rate. To date, there are no reported cases of
entific societies, by using the keywords and combinations of key - HSRs to dexlansoprazole or tenatoprazole.
words with the word and, including PPI, Proton pump inhibitors, The incidence of anaphylaxis due to PPIs is expected to grow
hypersensitivity reactions, allergy, skin testing and provocation in the next few years due to the increasing consumption, the over-
19,20,25,26
test. Through this search, the publications in the English language the-counter availability, and greater awareness of clinicians.
that reported the complete protocol followed were selected. Nevertheless, epidemiological studies reporting true incidence and
Additionally, each TF member used extra keywords as appropri - prevalence are still lacking.
ate for each specific section. During the development of the PP,
the TF group consulted and discussed the process in meetings
organized in June 2019 Lisbon/Portugal, and in October 2019 in 4?|?CLASSIFICATION
Rimini/Italy. The TF members carefully reviewed the statements,
recommendations, and unmet needs, including grading of the HSRs to PPIs may be immediate or nonimmediate/delayed and vary
quality of evidence using the SIGN criteria as Grade A, B, C, D from mild symptoms to life-threatening disorders, including urti-
10,11
(Table S1). caria, angioedema and anaphylaxis, maculopapular eruption, contact ?tl?e?a??
BAVBEK . ??? ?3
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dermatitis (occupational), photoallergic dermatitis, erythroderma, drug ranging from maculopapular exanthemas to severe cutaneous adverse
reaction with eosinophilia and systemic symptoms (DRESS) syndrome, reactions (SCARs); positive patch tests support the confirmatory di-
27 27
Stevens-Johnson syndrome/Toxic epidermal necrolysis (SJS/TEN). agnosis. Type II and T-cell-mediated HSRs have also been reported.
3
Most reported reactions to PPIs are immediate HSRs and among them Statements and Recommendations
2,17–19,23,28
more than half are anaphylaxis. Most HSRs to PPIs occur in
female (61%), and almost all cases are described in adults with a mean ? Gastric acid suppression promotes allergy in animal and observa-
29
age of 46?±?13?years. One case report described anaphylaxis second- tional human studies (Grade D).
30
ary to omeprazole in a 14-year-old boy and another anaphylaxis to ? PPIs involved in the HSRs vary among countries related to their
31
omeprazole and pantoprazole in a 16-year-old girl is also described. consumption rate (Grade D).
? The majority of HSRs to PPIs are immediate, possibly IgE-mediated
(Grade D).
5?|?PATHOGENESIS ? T-cell-mediated delayed reactions to PPIs are less frequently ob-
served (Grade D).
PPIs include omeprazole, pantoprazole, esomeprazole, lansoprazole, ? Most HSRs to PPIs occurred in adult female and anaphylaxis is the
rabeprazole, and the newer dexlansoprazole and tenatoprazole. most common clinical presentation (Grade D).
They have a common chemical structure, represented by a ben-
zimidazole ring plus a pyridine ring, varying only in the side chain
substituted on both moieties. Omeprazole and pantoprazole have, 6?| ? I M M E D I A T E H Y P E R S E N S I T I V I T Y
respectively, a methoxy and a difluoromethoxy chain in their ben- REACTIONS
zimidazole rings, whereas lansoprazole and rabeprazole modify the
pyridine ring where the trifluoroethoxy and methoxypropoxy chains 6.1? |? Clinical?presentation
are located, respectively. Tenatoprazole is the only one with an imi-
dazopyridine, instead of a benzimidazole, ring structure, responsi- There are multiple case reports and studies of immediate type HSRs
2,32,33
ble for a longer half-life of the drug compared to other PPIs. to PPIs, ranging from mild to severe reactions, that generally occur
21,37–44
Chemical structures of PPIs are listed in Table 1. within a few hours after the last drug dose. Approximately,
The underlying mechanisms of HSRs to PPIs are not yet fully ex- half of the immediate HSRs to PPI were anaphylaxis, with a prev-
plained. Most of the PPI HSRs are IgE-mediated and confirmed by skin alence varying between 9.1% and 69.0%, while urticaria and/
prick tests (SPT) or intradermal tests (IDT) or basophil activation test or angioedema have been reported with a percentage of 26.2%–
14,15,19,23,28,45–47
(BAT) positivity. An IgE-mediated mechanism has also been reported 90.9%. Dyspnea, pruritus, nausea, vomiting, diar-
3,18,22,30,34 17,28
in reactions occurring after 3–24?h from PPI intake. This rhea, and rhinitis have also been reported.
may be due to the delayed-release formulation of some PPIs (enter-
ic-coated tablets) or polymorphisms in the cytochrome P450 CYP2C19
gene leading to slow drug metabolism. In addition, PPI as a prodrug 6.2? |? Diagnosis
is activated by acid and then binds covalently not only to the gastric
35 36
H+, K?+?-ATPase enzyme, but to a wide range of proteins. Thereby, 6.2.1? |? Skin tests
the PPI as a hapten may acquire the characteristics of a complete an-
tigen and lead to IgE formation, as previously demonstrated for other In the earliest reports the diagnosis of PPI allergy was based on
13 3,48–52
drugs. T-cell-mediated delayed reactions to PPIs are less frequent, clinical data or drug provocation test (DPT) test results, but,
TABLE 1?Chemical structures of PPIs.
Benzimidazole group
R1 R2 R3 R4
Omeprazole –OCH –CH –OCH –CH
3 3 3 3
Lansoprazole – –CH –OCH CF –
3 2 3
Pantoprazole –OCF H –OCH –OCH –
2 3 3 3
Rabeprazole – –CH –O(CH ) -OCH –
3 2 3 3
Esomeprazole –OCH –OCH –OCH –CH
3 3 3 3
Dexlansoprazole – –CH –OCH CF –
3 2 3
Imidazopyridine group R1 R2 R3 R4
Tenatoprazole – –CH –OCH -CH
3 3 3teal
4? ??? BAVBEK .
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several large studies showed that skin tests are useful for the di- also provoked with the skin test-positive culprit PPI to confirm
3,22,56
agnosis of immediate HSRs due to PPIs and nonirritating skin test specificity.
3,17,18 3,17
concentrations have been defined. Two main studies have Furthermore, DPTs have been performed to identify tolerance
3
analyzed the accuracy of skin tests vs DPTs. Bonadonna et al. eval- to alternative PPIs for any future hiring needs and to study PPI
3,17–19,22,23,37,42,45,46,53,57,58,60,61
uated the diagnostic performance of skin tests versus DPT with the cross-reactivity. A placebo-controlled
suspected PPI in 53 patients with grade 1 and 2 immediate HSRs. approach has been performed in many studies, often with placebo
The authors report a high specificity and a positive predictive value capsules or tablets on the first day and the verum on the second day.
(PPV) both of 100%, whereas sensitivity was lower (61.3%) and In addition, Laguna et al. performed a two-day course at maximum
the negative predictive value (NPV) was 91.9%. In the study, 4/12 dosage if patients tolerated the suspected PPI administered during
19
patients who exhibited positive skin tests with the suspected PPI the DPT.
underwent a DPT, and the positivity was confirmed in all cases. During the DPT the titrated doses were administered at 30 or
Additionally, there are several case reports showing confirmation 60-min intervals as shown in Table 3.
34,53
of skin test positivity by DPT. These results are in agreement Positivity criteria were defined by the occurrence of clinical obje-c
17
with data from another multicenter study by Kepil ?zdemir et al. tive signs, such as urticaria, angioedema, rash, bronchospasm, hypo-
on 38 patients who had experienced immediate HSRs to PPIs. The tension, oxygen saturation below 90% or 20% fall in FEV1, one study
3,17
authors confirm the high specificity and PPV, 100% both, with lower also mentioned a 20% change in heart rate. Immediate HSRs with
18
values of sensitivity (58.8%) and NPV (70.8%). Based on the previous delayed onset may occur with PPIs. Most PPIs are slow-release and
data from the literature, they did not perform a confirmatory DPT in dose titration is challenging due to the formulation and potential loss
patients with skin test positivity to the culprit. The same group fur- of drug function. Consequently, the TF suggests prolonged observa-
18
ther confirmed their data in a following retrospective study where tion of ≥3?h after the last step of an oral DPT with PPI.
they managed a definitive diagnosis throughout skin testing and/or
DPTs with the suspected and/or alternative PPIs in 27 patients. Skin
testing was positive in 13/14 patients with confirmed PPI hypersen- 6.2.3? |? Value of in vitro tests
sitivity, while all 5 patients who had a negative DPT result with the
suspected PPI, also had a negative skin test result. Performing di- To date, there are no studies on the determination of specific IgE
agnostic tests within 6?months from a reaction has been shown to antibodies to PPI and, therefore, they are not available in the most
45
increase the likelihood of positivity of skin tests. widely used commercial platform for specific IgE determination to
29
The recommended nonirritating concentrations of SPTs are drugs, the ImmunoCAP system (Thermo Fisher, Uppsala, Sweden).
29
shown in Table 2. If the SPT is negative, IDT should be pursued. A promising tool for the diagnosis of immediate allergic reactions
19,21,38
IDT can be performed with 1:1000, 1:100, and 1:10 concentrations to PPI is the basophil activation test (BAT), which determine
of the medication (Table 2). It is not recommended to perform IDTs the basophil activation upon stimulation with the culprit drug or its
with solutions obtained from oral preparations due to the risk of metabolites by flow cytometry. Different strategies to identify ba-
2
false positive results. Skin tests are overall safe; no adverse reac - sophils (anti-IgE, CCR3, CRTH2, and CD203c) and to measure their
2 62
tions performing skin tests with PPIs have been reported so far. activation (CD63 and CD203c) have been proposed. Gamboa et al.
Based on an extensive literature review, we highlight skin testing were the first to report a positive BAT result to omeprazole in a pa -
as first step in the evaluation of patients who experienced mild to tient who developed immediate urticaria and angioedema after the
21
moderate HSRs to PPIs. Due to the high specificity, in case of a pos- i drug intake, result concordant with the positive skin test result.
tive skin test plus a corresponding clinical history, the patient should Later, a second case report of a patient with anaphylaxis after ome -
be advised to avoid the implicated PPI and the related ones. On the prazole administration confirmed the usefulness of BAT by detecting
other hand, due to the low sensitivity, a negative skin test alone is
not reliable in ruling out a drug allergy suspicion and the physician
TABLE 2?Recommended nonirritant skin test concentrations in
should consider proceeding with DPT after carefully evaluating the
immediate HSRs to PPIs.
54
risk/benefit ratio in each patient.
a
PPIs SPT (mg/mL) IDT (mg/mL) References
3,23,24,53
Esomeprazole 40 4
3,17,23,24,42,53,55
6.2.2? |? Provocation tests Lansoprazole 30 1.5
3,17,23,24,38,41,43
Omeprazole 40 4
3,17,24,41,42,53,55
Because of high specificity and limited sensitivity of skin tests,
Pantoprazole 40 4
17,23,38,41,42,56
DPT should be performed in case of a negative result, despite a
Rabeprazole 20 2
compatible medical history. Several prospective studies and ret-
Abbreviations: IDT, Intradermal test; PPI, proton pump inhibitor; SPT,
rospective case series, but also a high number of single case re-
Skin prick test.
a
ports, have performed single-blind placebo-controlled DPTs with
It is recommended to perform IDTs only with injectable preparations
3,17–19,22,23,37,42,45,53–60
PPIs. Only exceptionally, patients were of PPIs.tael
BAVBEK . ??? ?5
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TABLE 3?Provocation doses for DPT with PPIs for the diagnosis of immediate HSRs.
Kepil Ozdemir S, Sanchez-Morillas, Kepil Ozdemir
22 3 17 23 18
Reference Lobera, 2009 Bonadonna P, 2012 2013 2014 S, 2016
Drug
Omeprazole 5, 10, 20?mg 5, 5, 10, 20?mg 5, 10, 20?mg 5, 10, 20?mg 5, 10, 20?mg
Pantoprazole 5, 10, 20?mg 5, 5, 10, 20?mg 5, 10, 20?mg 10, 20, 40?mg 5, 10, 20?mg
Rabeprazole nd 5, 5, 10, 20?mg 5, 10, 20?mg 5, 10, 20?mg 5, 10, 20?mg
Esomeprazole nd 5, 5, 10, 20?mg 5, 10, 20?mg nd 5, 10, 20?mg
Lansoprazole 3.25, 7.5, 15?mg 5, 10, 15?mg 7.5, 15, 30?mg 3.25, 7.5, 15?mg 7.5, 15, 30?mg
a positive result for the culprit PPI and negative results in healthy undergo acid-catalyzed cleavage of a chiral sulfoxide bond (ex-
38
controls. Laguna et al. analyzed in detail the role of BAT, using cept esomeprazole and dexlansoprazole which are nonchiral) into
9
CD63, for the diagnosis of 42 patients with immediate omeprazole active sulfenic acid and or sulfonamide. Cross-reactivity within
allergy confirmed by ST or DPT and 22 age- and sex-matched healthy the PPI family is likely related to their similar chemical struc -
19 29
controls. They detected a BAT sensitivity of 73.8%, a specificity of ture. Reports on cross-reactivity and/or tolerance in immediate
100%, a PPV of 100%, and a NPV of 66.7%. Moreover, BAT was HSRs to PPIs confirmed by skin tests and/or DPT are summa-
positive in 57.1% of patients with negative ST and by combining ST rized in Table 4. Among patients with an immediate PPI HSR that
and BAT it was possible to reach a confident diagnosis of PPI HSRs in has been confirmed with skin tests and/or DPTs, available stud-
3,17–20,22–24,37–45,53–58,60,61,63–69
85.7% of patients. There are no studies with other PPIs. ies, s u g g e s t t h a t 6 1 . 6 % w i l l s h o w
Statements and Recommendations cross-reactivity to another PPI and 8.9% will show cross-reactivity
to all available PPIs. However, these results may be underesti-
? Skin tests are useful in the diagnosis of immediate HSRs to PPIs mated, as most studies have investigated cross-reactivity only to-
and nonirritating concentrations for SPTs/IDTs are defined (Grade wards some preparations and not towards all available PPIs. The
C). highest rates of cross-reactivity are shown in patients who are al-
? Skin testing is the recommended first step in the evaluation of lergic to omeprazole, esomeprazole, or pantoprazole. This is prob -
patients with immediate HRSs to PPIs (Grade C). ably related to the fact that such drugs are structurally similar, in
? The sensitivity and NPV of skin testing with PPIs are not sufficient fact, their benzimidazole rings have a methoxy and a difluorometh-
59
to reliably exclude HSRs to PPIs (Grade C). oxy chain in common. Consistent with this, cross-reactivity rates
? In patients with negative skin tests and compatible history, a DPT are lower in patients allergic to lansoprazole or rabeprazole, see
is indicated to confirm a HSR to PPI (Grade C). Table 5. Therefore, patients monosensitized to lansoprazole or ra -
3
? In patients with confirmed HSR to a PPI and negative skin tests to beprazole would more likely tolerate other PPIs.
other PPIs, a DPT is indicated to find safe alternative PPIs (Grade Cross-reactivity rates between PPIs in immediate HSRs, accord-
D). ing to the available studies, are shown in Table 6. Many different
? There is an extensive cross-reactivity between PPIs, which can be patterns of cross-reactivity were detected among PPIs. Additionally,
assessed first by skin testing and subsequently confirmed by DPT not all these patterns (e.g., lansoprazole and pantoprazole cross-re-
(Grade C). activity; omeprazole and lansoprazole cross-reactivity) can be ex-
? Titrated doses of PPIs during DPT have been recommended based plained simply with the abovementioned structural similarity. The
on several studies. In case of severe anaphylaxis in the history, different patterns of cross-reactivity may be associated with the
lower starting doses and/or slower increments must be consid- chemical characteristics (e.g., substitutions, metabolites) and metab-
ered (Grade D). olism of the drugs, and, probably, the influence of some potential
? Prolonged observation of ≥3?h after the last step of an oral DPT cofactors.
with PPI is recommended (Grade D).
? BAT may be helpful in immediate type HSRs to PPI (Grade D).
6.3.2? |? Tolerance
6.3? |? Management?of?immediate?hypersensitivity? Current data highlight the importance of a thorough allergy work-
reactions to PPIs up to find safe alternative PPIs. Because of the high cross-reactivity
rates among PPIs (Table 5), a safe alternative PPI should only be rec-
6.3.1? |? Cross-reactivity ommended after a complete drug allergy work-up (Skin testing fol-
lowed by DPT in case of negative results). The PPI to be tested as a
33
All current PPIs consist of a benzimidazole and a pyridine ring. safe alternative may be selected according to the cross-reactivity
PPIs are pro-drugs, they are highly bound to proteins and they rates reported in the literature and listed in Table 6.ealt
6? ??? BAVBEK .
|
TABLE 4?Reports of cross-reactivity and/or tolerance in immediate HSRs to PPIs.
Culprit Diagnostic
Author, year, reference Patients (n) drugs evaluation Cross-reactivity Tolerance
45 a
Kepil ?zdemir S, et al, 2019 88 All ST, DPT L-E; L-P; O-P-E; L-R L-P CR patient tolerated R; L-R CR patient tolerated P; L-E CR
patient tolerated R; L-E CR patient tolerated P
17 a
Kepil ?zdemir S, et al, 2013 65 All ST, DPT L-P; L-E; O-L; L-R; All; O-P; O-L-E; O-L-P-R 4?L-P CR patients tolerated O,R,E; 1?L-P CR patient tolerated O,R;
2?L-E CR patients tolerated O,P,R; 1?L-E CR patient tolerated
O,R; 2 O-L CR patients tolerated P,R,E; L-R CR patient
tolerated O,P,E; O-P CR patient tolerated R,E; L-O-E CR
patient tolerated P,R; 1 O-L-P-R CR patient tolerated E
18 a
Kepil ?zdemir S, et al, 2016 60 All ST, DPT L-P; P-E; O-L; L-E; L-R-E; L-P-E; O-P-R-E 1?L-P CR patient tolerated O, E; 1?L-P CR patient tolerated E; 1 P-E
CR patient tolerated O,L,R; 1 P-E CR patient tolerated L; O-L
CR patient tolerated P,E; L-E CR patient tolerated P; L-R-E CR
patient tolerated P; L-P-E CR patient tolerated O,R; O-P-R-E
CR patient tolerated L
3
Bonadonna P, et al, 2012 53 All ST, DPT P-O; P-E
19
Laguna JJ, et al, 2018 42 O ST, DPT, BAT O-P; O-P-L
57
Tourillon C, et al, 2019 38 All ST, DPT O-P; O-E; O-P-E; P-E; O-L; O-L-P; E-R; 1 O-E CR patient tolerated L
P-R-E; O-P-R; L-P-R; O-R-E; O-P-R-E;
All
23
Sánchez-Morillas L, et al, 2014 11 O ST, DPT All
22
Lobera T, et al, 2009 9 O ST, DPT O-P; O-L 6 O-P CR patients tolerated L
20
Abdul Razzak E, et al, 2012 8 O ST, DPT O-P
24
Sobrevia Elfau MT, et al, 2010 5 O ST All
63
Mota I, et al, 2016 5 O, P, E ST P-O; O-P-E
65
Pita JS, et al, 2019 4 O, P, E ST, DPT All; O-P; P-E O-P CR patient tolerated E; P-E CR patient tolerated O
66
Kara M, et al, 2014 3 L ST, DPT — 3?L allergic patients tolerated E
44
Natsch S, et al, 2000 2 O, P DPT O-L
39
Vovolis V, et al, 2008 2 O ST, DPT O-P O-P CR patient tolerated E; 1 O allergic patient tolerated L, P
43
Galindo PA, et al, 1999 1 O ST O-L
67
Fardet L, et al, 2002 1 P DPT - Tolerated L
37
Gonzalez P, et al, 2002 1 O ST, DPT O-L-P
42
Porcel S, et al, 2005 1 L ST, DPT L-R L-R CR patient tolerated O, P, E
64
Demirkan K, et al, 2006 1 L ST, DPT — L allergic patient tolerated O
56
Perez Pimiento AJ, et al, 2006 1 L ST, DPT L-R L-R CR patient tolerated O, P
40
Confino-Cohen R, et al, 2006 1 O ST O-P
41
Garrido S, et al, 2008 1 O ST Alllaet
BAVBEK . ??? ?7
|
6.3.3? |? Desensitization
A successful oral desensitization protocol has been reported in
a patient with omeprazole-induced anaphylaxis and positive skin
40
test results with both omeprazole and pantoprazole. Oral de-
sensitization was performed with increasing doses, at 20-min in -
tervals, with a starting dose of 0.001?mg. A final dose of 16?mg was
reached in 5.6?h. The patient tolerated the drug without reactions
and completed 14?days of treatment without any evidence of hy -
40
persensitivity. Another successful oral desensitization protocol
with rabeprazole, in a patient with pantoprazole-induced ana -
phylaxis and cross-reactivity to all available PPIs, has also been
70
reported. In cases where a PPI is essential for treatment and a
safe alternative cannot be found, or a complete allergy work-up
cannot be performed, for example, due to the severity of the re -
ported reaction or patient refusal, desensitization may be a useful
approach.
6.4? |? Algorithm?for?management?of?immediate?
HSRs to PPIs
A great portion of the patients with immediate HSR to PPIs refer
more than one episode with the same drug, probably related to
the fact that these drugs are usually not suspected as triggers
19
of HSRs by physicians. Therefore, the first step in the manage -
ment of immediate HSRs to PPIs is to consider a possible cause-
effect relationship between PPIs and HSRs. Given the specificity
of skin tests in immediate PPI HSRs, these should precede the
DPTs with the culprit or an alternative PPI. In case of negative
skin test results a DPT is required to exclude PPI hypersensitivity.
The choice of the alternative PPI should be based on the results
of in vivo and in vitro (when available) tests, and DPTs should be
performed with PPIs tested negative. An algorithm that outlines
the management of PPI HSRs is provided in Figure 1.Statements
and Recommendations
? There is a high rate of cross-reactivity among PPIs (Grade C).
? Different patterns of cross-reactivity were detected among PPIs
(Grade C).
? The highest rates of cross-reactivity are shown in patients
who are allergic to omeprazole, esomeprazole or pantoprazole
(Grade D).
? Approximately 9% of PPI hypersensitive subjects will show
cross-reactivity to all PPIs (Grade D).
? A safe alternative PPI should only be recommended after a drug
allergy work-up (Grade D).
? In immediate HSRs skin testing should precede DPTs with
the culprit or the alternative PPIs. In case of negative skin
test results, DPT is required to exclude PPI hypersensitivity
(Grade D).
? In case of lack of safe alternative and a PPI is essential, desensiti -
zation can be performed (Grade D).
TABLE 4?(Continued)
Culprit Diagnostic
Author, year, reference Patients (n) drugs evaluation Cross-reactivity Tolerance
55
Stefenaki EC, et al, 2008 1 O ST, DPT - O allergic patient tolerated L and R
38
Pérez-Ezquerra PR, et al, 2010 1 O ST, BAT O-L-P-R
53
Vovolis V, et al, 2010 1 R ST, DPT - R allergic patient tolerated O and L
58
Aksu K, et al, 2011 1 L ST, DPT - L allergic patient tolerated O
68
Canpolat U, et al, 2011 1 P ST O-P
60
Karabacak E, et al, 2012 1 L ST, DPT - L allergic patient tolerated O, P, R, E
69
González-Rubio F, et al, 2017 1 O ST All
61
Turedi O, et al, 2017 1 P ST, DPT All
Abbreviations: BAT, basophil activation test; CR, cross reactive; DPT, drug provocation test; E, esomeprazole; L, lansoprazole; P, pantoprazole; O, omeprazole; R, rabeprazole; ST, skin testing (prick and
intradermal tests).
a
Mainly lansoprazole.atle
8? ??? BAVBEK .
|
7?|?DELAYED?HYPERS ? ENS ? ITIVI ? TY? reduced in powder at 30% in petrolatum, demonstrated that the
REACTIONS final active PPI concentrations in patch tests were esomeprazole
at 2.92% (diluting Inexium? 40?mg tablet), omeprazole at 2.59%
7.1 ? |? Clinical?features (Mopral? 10?mg capsule) and pantoprazole at 6.09% (Eupantol?
83
40?mg tablet).
27
All clinical features of delayed HSRs have been reported with PPI. According to recommendations for drug patch test prepara-
71,72 84
They can induce mild maculopapular eruption (MPE), fixed tions, we recommend to reduce granules/tablets to a fine powder,
71,73
drug eruption (FDE) but also severe generalized bullous FDE dilute this material at 30% in petrolatum, and note the final concen -
71
(GBFDE), photosensitization with rabeprazole and esomepra- tration of the active ingredient. In case of PPIs that exist in injectable
74 47
zole, symmetrical drug-induced flexural exanthema (SDRIFE), forms (esomeprazole and pantoprazole), it is recommended to dilute
71,75,76 71,77,78
DRESS, acute generalized exanthematous pustulosis them at 10% in petrolatum.
71,79–82
and TEN. Positive patch tests results have been mainly reported in
71,76
DRESS. The value of SPT and ?DT with delayed readings have
not been investigated in delayed reactions to PPI.
7. 2 ? |? Diagnosis Classification into 2 PPI subgroups, the omeprazole group (ome-
prazole/ esomeprazole/ pantoprazole) and the structurally similar
7.2.1? |? Value of skin tests lansoprazole group (lansoprazole/ dexlansoprazole/rabeprazole),
may explain the cross-reactivity in delayed HS. Among 16 reintro-
83
Brajon et al. have reported the nonirritating concentrations ductions in 15 patients with delayed HSRs, the cross-reactivity was
71
of PPI used in patch tests prepared with commercially available studied by Lin et al. In 13 cases (10 MPE, 2 SJS/TEN, 1 DRESS),
forms of PPIs. In literature, there are different suggested concen - there were no cross-reactions between structurally different PPIs.
47
trations to perform patch test with PPIs preparation, but these In 3 other cases (1 MPE, 1 SJS/TEN, 1 DRESS), the reintroduction of
data cannot be compared with each other as the active PPI con - PPIs belonging to the same group as the causative PPI induced a re-
centration in the final preparation is not known. We advise that lapse of the reaction. Data is too scarce to make recommendations,
capsules always contain gastro-resistant granules, which are dif - but, these preliminary results suggest that in cases of delayed HSRs
ficult to be crushed and that PPI concentration in the granules is switching to a structurally different PPI should be considered.
low. In regards, Brajon et al., after diluting the granules/tablets
Contact dermatitis due to PPI
TABLE 5?Cross-reactivity rates in immediate HSR to individual In an occupational airborne contact dermatitis (CD) due to PPI, the
3,17–20,22–24,3437–44,53–56,58–59,61–62,64–69
PPI.
erythematous lesions of the face predominating on eyelids led to
85
vitiligo lesions, patch tests were positive with the handled PPI
Cross-reactivity
85
a
(pantoprazole and rabeprazole). In the literature, 10 cases of oc -
Hypersensitivity rate, n (%)
cupational CD due to PPI have been reported in workers in pharma-
Any PPI 117/190, (61.6)
86
ceutical industry or in horse trainers. In all cases it was an airborne
Omeprazole 60/69, (87.0)
eczema predominating on the face, mainly on the eyelids, the neck,
Lansoprazole 28/79, (35.4)
arms, and hands. Patch tests have proven to be a useful diagnostic
Pantoprazole 18/26, (69.2)
tool frequently with strong positive results even with low concen-
Rabeprazole 1/4, (25.0)
trations. Therefore, as in these peculiar cases, it is possible to ob-
Esomeprazole 10/12, (83.3)
tain the PPI pure in powder and we recommend to begin with patch
a
Patients proven to be allergic to a PPI. tests at not more than 1% in petrolatum, then, if negative, at 10% in
3,17–20,22–24,37–45,53–58,60,61,64–69
TABLE 6?Cross-reactivity rates between individual PPIs in immediate HSR.
Omeprazole reaction Lansoprazole Pantoprazole Rabeprazole Esomeprazole
rate n (%) reaction rate n (%) reaction rate n (%) reaction rate n (%) reaction rate n (%)
a
Allergy to
Omeprazole — 21/34 (61.8) 50/53 (94.3) 16/17 (94.1) 20/23 (87.0)
Lansoprazole 8/43 (18.6) — 14/57 (24.6) 7/47 (14.9) 9/48 (18.8)
Pantoprazole 13/16 (81.3) 3/11 (27.3) — 5/9 (62.5) 9/12 (75.0)
Rabeprazole 1/3 (33.3) 0/2 (0) 0/2 (0) — 1/2 (50.0)
Esomeprazole 6/7 (85.7) 0/3 (0) 6/9 (66.7) 1/3 (33.3) —
a
Patients proven to be allergic to a PPI.laγte
BAVBEK . ??? ?9
|
FIGURE?1?Algorithm for management of patients with a history of immediate HSR to PPI. DPT, drug provocation test; PPI, Proton pump
inhibitor.
petrolatum. Multiple sensitizations to different subclasses are pos- with patch testing is generally considered sufficient to detect PPI-
28
sible and might be due to cross-reactivity or, more likely, to multiple delayed hypersensitivity. We do not know of any study evaluating
exposures to different PPI. the role of the DPT in PPI-delayed hypersensitivity. However, we
do recommend DPT in case of a doubtful history and negative skin
test results in nonsevere delayed reactions in order to exclude PPI
7.2.2? |? Value of in vitro tests hypersensitivity as a 100% sensitivity cannot be assumed.
Statements and Recommendations
The in vitro diagnostic method most frequently used for diagnos-
ing delayed HSRs is the lymphocyte transformation test (LTT). This ? As the content of PPI is low in capsules granules capsules should
test identifies the proliferation of drug-specific T cells from patients be reduced to fine powder, then diluted at 30% in petrolatum,
with HSR upon the stimulation with the suspected drug(s) by meas - (Grade D). Injectable PPIs (esomeprazole and pantoprazole),
62
uring the incorporation of [3H]. However, to our knowledge there should be diluted as the powder at 10% in petrolatum.
is only one study using this method with PPI. In this study, LTT was ? Switching to a structurally alternative PPI should be considered
performed in 28 subjects with occupational allergy to omeprazole (Grade D).
diagnosed by positive patch test results. From these patients, 23 ? Sensitivity and specificity of LTT and LAT are low (Grade D).
showed a positive LTT result, yielding a sensitivity of 82%. From the ? DPTs are commonly not needed to confirm delayed T cell-medi-
56 subjects with negative patch test results, 46 showed a negative ated reactions to PPI (Grade D).
87
LTT, yielding a specificity of 82%. Another study has analyzed the ? In nonsevere delayed HSRs, DPT is recommended in case of a
role of drug lymphocyte activation test (LAT) measuring granulysin doubtful history and negative skin tests in order to exclude PPI
and interferon- in 69 cases of PPI-delayed reactions including SJS/ hypersensitivity (Grade D).
71
TEN and DRESS. They found that LAT measuring granulysin had a
sensitivity of 59.3% and specificity of 96.4%.
7. 3 ? |? Management
7.2.3? |? Provocation tests in nonimmediate Data regarding PPI-induced delayed HSRs and the role of diagnostic
hypersensitivity to PPIs tests in these types of reactions are limited. Cross-reactivities have
been reported in nonimmediate HSRs to PPIs as seen in immediate
47,71
The value of DPT with PPIs for delayed T cell-mediated reactions reactions. DPT with the culprit drugs in patients with severe de-
is unknown. Delayed T cell-mediated reactions after PPI intake layed HSRs may cause fatal recurrence of the reactions and it is not
are rare. For delayed reactions to PPI, the clinical history together recommended. In patients who mandatory required PPI, the choice etla
10? ??? BAVBEK .
|
TABLE 7?Unmet needs and future research area for HSRs to PPIs.
Epidemiology Studies on the incidence and prevalence of HSRs to PPI reactions, especially in children
Randomized controlled studies for cause-and-effect statements between PPIs and allergic diseases
Additional investigations on the influence of different PPIs in OIT maintenance phase
Pathogenesis Pathogenesis of PPI-induced HSRs especially after 3–24?h, as well as cofactors'' impact on the type and severity of
reactions (fasting, food intake, infection, simultaneously intake of NSAID), route of administration, dose, type of
coating and metabolism
Role of IgE in PPI-induced immediate HSRs
Immediate type HSRs
Skin tests The factors related to skin test positivity
Larger scale multicenter studies to confirm optimal test concentrations
Unified algorithm for testing with culprit and alternative PPIs
DPT Larger scale multicenter studies to confirm optimal test doses and provide the risk stratification
The exact degree of cross-reactivity between different PPIs
In vitro tests Determination of specific IgE antibodies to PPIs
The role of BAT in the diagnosis of HSRs to PPIs
Management Drug antigenic determinants responsible for cross-reactivity
More data regarding desensitization to PPIs
The role of risk factors and cofactors in the type of reaction as in cross-reactivity determination
Delayed type HSRs
Skin tests Role of patch tests and delayed readings of IDTs in diagnosis
Optimal concentrations and vehicles for patch tests, method of skin testing protocol
To study cross-reactivity profiles
DPT The role of DPT in the diagnosis
In vitro tests The roles of LTT and LAT in the diagnosis
Management More data about PPI-induced delayed HSRs
Abbreviations: BAT, basophil activation test; DPT, drug provocation test; HSR, hypersensitivity reaction; IDT, Intradermal test, LAT, lymphocyte
activation test; LTT, lymphocyte transformation test; NSAID, nonsteroidal anti-inflammatory drugs, OIT, oral immunotherapy; PPI, proton pump
inhibitor.
of an alternative PPI may be based on LAT and/or patch test results ACKNO?WLED ? GE?MENTS
47,71
and tolerance should be tested by DPT. The authors would like to thank the European Academy of Allergy
and Clinical Immunology (EAACI) for support enabling the develop-
ment and publication of this position paper.
8?|?CONCLUSION
AUTHORS?CONTRIBUTION
Although, except in long-term use, PPIs are generally well tolerated, Sevim Bavbek and Patrizia Bonadonna as chair and secretary led the
their widespread use has been associated with immediate and de- task force, managing, the development and integration of the manu-
layed HSRs, some of which might be life-threatening. Correct iden- script, seeking approval by the EAACI regulatory bodies, and mak-
tification of PPI HSRs and of safe alternative drugs for future use is ing the final editorial decisions. Sevim Bavbek authored “Abstract,
crucial to prevent severe drug reactions and unnecessary avoidance Introduction, Material and Methods, Management of Immediate
of the whole PPI group. Skin tests are useful in diagnosing immedi- hypersensitivity reactions and its algorithm and Conclusion.” Jose
ate HSRs to PPIs; however, their sensitivity is low. There is a sub- Laguna Martinez and Marina Atanaskovic-Markovic co-authored
stantial cross-reactivity between PPIs, which can be assessed first “Epidemiology,” “Classification,” and “Pathogenesis.” Patrizia
by skin testing and subsequently by DPT in immediate HSRs. Cross- Bonadonna, Mauro Pagani, Alessandra Arcolac?, and Sevim Bavbek
reactivity rates between PPIs in immediate type HSRs are analyzed co-authored “Diagnosis” of immediate hypersensitivity reactions.
according to the available studies and are given in the current PP Patrizia Bonadonna, Mauro Pagani, and Alessandra Arcolac? co-au-
to guide the selection of possible alternative PPIs for diagnostic thored “Value of skin tests” of immediate hypersensitivity reactions.
tests. Although rarely reported we need to be aware of the potential Knut Brockow authored “Role of DPTs” of immediate hypersensi-
whole group cross-reactivity in the setting of both immediate and tivity reactions and of delayed hypersensitivity reactions. Maria J.
nonimmediate PPI HSRs. Data regarding delayed PPI HSRs are lim- Torres authored “Value of in vitro Tests” of immediate hypersen-
ited. There are several unmet needs, as listed in Table 7, that require sitivity reactions and of delayed hypersensitivity reactions. Sevim
further research in this topic and greater knowledge on the manage- Bavbek and Se?il Kepil ?zdemir co-authored “Management of re-
ment of PPI-induced HSRs. actions” and “Algorithm” of immediate hypersensitivity reactions. late
BAVBEK . ??? ? 11
|
4. Ward RM, Kearns GL. Proton pump inhibitors in pediatrics. Pediatr
Annick Barbaud managed the development of delayed hypersensi-
Drugs. 2013;15:119-131.
tivity reactions and authored “Value of Skin Tests” and “Management
5. Thomson ABR, Sauve MD, Kassam N, Kamitakahara H. Safety of
of reactions.” Each author was responsible for their own section and
the long-term use of proton pump inhibitors. World J Gastroenterol.
has presented many drafts, revisions, and agreed on final versions.
2010;16:2323-2330.
Sevim Bavbek, Se?il Kepil ?zdemir, Patrizia Bonadonna, Annick 6. Jordakieva G, Kundi M, Untersmayr E, Pali-Sch?ll I, Reichardt B,
Jensen-Jarolim E. Country-wide medical records infer increased
Barbaud, Alla Nakonechna, and Carla Lombardo contributed to the
allergy risk of gastric acid inhibition. Nat Commun. 2019;10:3298.
final editing.
7. Attwood SE, Ell C, Galmiche JP, et al. Long-term safety of proton
pump inhibitor therapy assessed under controlled, randomised clin-
FUNDING?INFORMATION ical trial conditions: data from the SOPRAN and LOTUS studies.
Aliment Pharmacol Ther. 2015;41:1162-1174.
This Position Paper was supported by the European Academy
8. Moayyedi P, Eikelboom JW, Bosch J, et al. Safety of proton
of Allergy and Clinical Immunology (EAACI) under the EAACI
pump inhibitors based on a large, multi-year, randomized trial
Management of PPI and antacid drug allergy Task Force and the
of patients receiving rivaroxaban or aspirin. Gastroenterology.
Drug Allergy Interest Group (19 December 2018).
2019;157:682-691.
9. Strand DS, Kim D, Peura DA. 25?years of proton pump inhibitors: a
comprehensive review. Gut Liver. 2017;11:27-37.
CONFLICT OF INTEREST STATEMENT
10. Baird AG, Lawrence JR. Guidelines: is bigger better? A review of
SB is on the GSK, AstraZeneca and Novartis advisory board and
SIGN guidelines. BMJ Open. 2014;4:e004278.
speaker bureau, all outside the present work. SK? has received hon-
11. Scottish Intercollegiate Guidelines Network. SIGN 50: A guideline
developer''s handbook. Accessed September 1, 2022. https://www .
oraria for presentations and support for attending meetings from
s g n a c u k / o u r - g u d e n e s / s g n - 5 0 - a - g u d e n e - d e v e o p e r s - h a n d b
Novartis and GSK, all outside the present work. MJT has received
ook / . Edinburgh, SIGN; 2019.
grants/research supports from the European Commission, ISCIII,
1 2. Diesner SC, Knittelfelder R, Krishnamurthy D, et al. Dose-
and SEAIC, honoraria or consultation fees from Leti Laboratories and
dependent food allergy induction against ovalbumin under
acid-suppression: a murine food allergy model. Immunol Lett.
Aimmune Therapeutics, and has participated in Diater Laboratories
2008;121:45-51.
and Leti Laboratories sponsored speaker''s bureau. MP, PB, AA, CL,
13. Riemer AB, Gruber S, Pali-Sch?ll I, Kinaciyan T, Untersmayr E,
JJL, KB, MAM, AN and AB have no conflict of interest.
Jensen-Jarolim E. Suppression of gastric acid increases the risk
of developing immunoglobulin E-mediated drug hypersensitivity:
DATA?AVAILABILITY?STATEMENT human diclofenac sensitization and a murine sensitization model.
Clin Exp Allergy. 2010;40:486-493.
The data that support the findings of this study come from a lit-
14. Mitre E, Susi A, Kropp LE, Schwartz DJ, Gotman GH, Nylund CM.
erature search in MEDLINE, PubMed, Web of Science, and Google
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15. Ramírez E, Caba?as R, Laserna LS, et al. Proton pump inhibitors are
ORCID
associated with hypersensitivity reactions to drugs in hospitalized
Sevim Bavbek https://orcid.org/0000-0002-7884-0830
patients: a nested case-control in a retrospective cohort study. Clin
Se?il Kepil ?zdemir https://orcid.org/0000-0003-2688-9867
Exp Allergy. 2013;43:344-352.
Patrizia Bonadonna https://orcid.org/0000-0003-0476-1934
16. Vega M, Alonso SB, Espa?a AP, et al. Treatment with proton pump
inhibitors as a cofactor in adverse reactions of patients undergoing
Marina Atanaskovic-Markovic https://orcid.
oral food immunotherapy: observational study. Allergol Imunopathol
org/0000-0003-1354-6072
(Madr). 2021;49:169-172.
Annick Barbaud https://orcid.org/0000-0001-8889-1589
17. Kepil ?zdemir S, Y?lmaz I, Ayd?n O, et al. Immediate-type hyper-
Knut Brockow https://orcid.org/0000-0002-2775-3681
sensitivity reactions to proton pump inhibitors: usefulness of skin
tests in the diagnosis and assessment of cross-reactivity. Allergy.
Jose Laguna Martinez https://orcid.org/0000-0001-5909-8979
2013;68:1008-1014.
Alla Nakonechna https://orcid.org/0000-0002-0141-6361
18. Kepil ?zdemir S, ?ner Erkekol F, ünal D, et al. Management of
Mauro Pagani https://orcid.org/0000-0002-0591-5416
Hypersensitivity Reactions to proton pump inhibitors: a retrospec-
Alessandra Arcolac? https://orcid.org/0000-0001-5567-4190
tive experience. Int Arch Allergy Immunol. 2016;171:54-60.
19. Laguna JJ, Bogas G, Salas M, et al. The basophil activation test can
Carla Lombardo https://orcid.org/0009-0005-5162-6091
Be of value for diagnosing immediate allergic reactions to omepra -
Maria J. Torres https://orcid.org/0000-0001-5228-471X
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