The Journal of Allergy and Clinical Immunology: In Practice
Original ArticleThe Basophil Activation Test Can Be of Value for Diagnosing Immediate Allergic Reactions to Omeprazole
Introduction
Proton pump inhibitors (PPIs) are drugs commonly used in clinical practice for the treatment of gastrointestinal diseases such as gastroesophageal reflux disease, gastrointestinal ulcers, or Helicobacter pylori infections. They are generally well tolerated, with a low incidence of adverse effects (between 1% and 3%),1 although in the last decade there has been an increase in hypersensitivity reactions, probably related to their increasing consumption.2 Most hypersensitivity reactions appear to be immediate, accounting for 86% of all immunological reactions to PPI,3, 4 with the most common clinical manifestations being urticaria (54%-65%), pruritus (33%-52%), angioedema (38%-42%), hypotension (22%-23%), and dyspnea (20%-22%), with half of the reactions considered to be anaphylactic.3, 4
Immediate hypersensitivity reactions to PPI are difficult to diagnose. Skin testing (ST) has a sensitivity ranging from 22.6% to 62.5%.5, 6, 7 However, few studies6, 7 have compared the results of standardized skin prick testing (SPT) and intradermal testing (IDT) with those of drug provocation testing (DPT) for patients with PPI-induced immediate hypersensitivity and for healthy controls. Although these studies gave different values for sensitivity (22.6%-58.8%) and negative predictive value (NPV; 70.8%-91.9%), they obtained the same specificity and positive predictive value (PPV; 100%). Therefore, DPT is still necessary to diagnose immediate allergic reactions to PPI, although it is not risk-free, especially for severe reactions and older patients.
Regarding in vitro tests, to our knowledge, only 2 case reports have studied the role of the basophil activation test (BAT) in the diagnosis of immediate reactions to PPIs,8, 9 obtaining positive results for the patients analyzed and negative results in healthy controls. Given these promising initial results, further studies are needed to assess the usefulness of BAT for diagnosing immediate reactions to PPIs. It is of note that to perform BAT, 2 basophil activation markers related to degranulation and histamine release can be used—CD6310, 11 and CD203c.12, 13 CD203c is constitutively expressed in basophils and increases in expression after activation, whereas CD63 is expressed only after activation and usually shows a bimodal expression, although it is also expressed in other cell types such as platelets.14 Moreover, the upregulation of one or the other may depend on the drug and the clinical entity,13, 15 making it important to determine which is the best activation marker for PPIs.
The PPIs most frequently involved in immediate hypersensitivity reactions are omeprazole and lansoprazole, although reactions with pantoprazole, esomeprazole, and ransoprazole have also been reported.3, 4, 16 Incidence varies by country and is probably related to consumption patterns. In Spain, the intake of PPIs has increased in recent years, with almost 10% of the Spanish population consuming this type of drug daily,17 and omeprazole being the most highly consumed compared with other antiulcer drugs,18, 19 which is likely why it is the most frequent inducer of immediate reactions to PPI in Spain.20, 21
PPIs consist of a benzimidazole and a pyridine ring, but vary in the specific side-ring substitution.22 Omeprazole, esomeprazole, and pantoprazole are substituted on the benzimidazole ring, whereas rabeprazole and lansoprazole are not.23 Different patterns of immunological recognition have been described, possibly because of their chemical structures.6, 24 It has been shown that patients with positive ST results to pantoprazole also give positive results to omeprazole.6, 7, 20, 21, 24, 25, 26, 27 However, patients reacting to lansoprazole or rabeprazole, which have a different side chain, can give negative ST results with omeprazole, pantoprazole, and esomeprazole.6, 7, 24, 26, 28 Nevertheless, cross-reactivity among the whole group of PPIs has also been reported, probably because of the recognition of the shared pyridine ring.24, 25
In our opinion, the underlying mechanisms and immunological responses have not been sufficiently investigated in patients with immediate reactions to PPIs. In this study, we have evaluated the use of BAT to diagnose omeprazole hypersensitivity in a group of well-characterized patients.
Section snippets
Patients and controls
All patients referred to the Allergy Service of the Regional University Hospital of Malaga and the Allergy Unit of Cruz Roja Hospital of Madrid, over a 3-year period (2013-2015) and with a clear clinical history of an immediate hypersensitivity reaction after administration of omeprazole, were prospectively eligible for inclusion in the study. Of these, those who were confirmed as allergic were finally included. Patients were confirmed as allergic on the basis of a compatible clinical history
Results
The study included 42 patients with confirmed immediate hypersensitivity reactions to omeprazole (Table I). Of these, 64.3% (n = 27) were female, the median age was 41.5 years (interquartile range [IQR], 36-48.75 years), the median time interval between the reaction and study was 180 days (IQR, 120-360 days), and the median time interval between drug administration and onset of the reaction was 30 minutes (IQR, 20-50 minutes). Regarding the clinical entities, 10 (23.8%) patients suffered
Discussion
PPIs are among the most highly prescribed drugs worldwide and although they are generally well tolerated, especially for short-term use, hypersensitivity reactions have been known. The PPIs involved in the reactions vary among countries: lansoprazole in studies from Turkey,7, 16 esomeprazole and lansoprazole for Italy,6 and omeprazole for Spain.5, 8, 20, 21, 24 This is probably related to PPI consumption, because in 2012 omeprazole represented 79.1% of all consumed PPIs in Spain.2 This
Conclusions
We have demonstrated for the first time that BAT represents a promising complementary tool for inclusion in the allergological workup for patients allergic to omeprazole. When combined with ST it can be of great value to the clinician in guiding the decision of whether to perform a DPT. This is particularly important for PPIs, because they frequently cause severe reactions.
Acknowledgment
We thank James R. Perkins for help with the English version of the article.
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Cited by (35)
Diagnostic Approach of Hypersensitivity Reactions to Cefazolin in a Large Prospective Cohort
2021, Journal of Allergy and Clinical Immunology: In PracticeBasophil and mast cell activation tests by flow cytometry in immediate drug hypersensitivity: Diagnosis and beyond
2021, Journal of Immunological MethodsCitation Excerpt :Interestingly, in contrast to skin testing, the BAT was suggestive of cross-reactivity between omeprazole and esomeprazole, a frequent phenomenon (Tourillon et al., 2019). The finding, which was obtained when the BAT was used as a complementary test to skin testing in the diagnosis of proton pump inhibitor hypersensitivity, is in line with the findings by Laguna et al. (Laguna et al., 2018), who reported that the BAT was positive in 57.1% of the patients with negative skin tests in 42 patients who had undergone skin testing or had been diagnosed with provocation proven omeprazole hypersensitivity. Although the BAT has proven to be a performant diagnostic test in IDHRs that adds to our understandings of the underlying mechanistic processes of IDHRs, there is still room for improvement.
Practical Guidance for the Evaluation and Management of Drug Hypersensitivity: Specific Drugs
2020, Journal of Allergy and Clinical Immunology: In PracticeAuthor's reply
2020, Nefrologia
The present study has been supported by the Institute of Health “Carlos III” of the Ministry of Economy and Competitiveness (grants cofunded by European Regional Development Fund: grant nos. PI12/02529, PI15/01206, CP15/00103, RETICS ARADyAL RD16/0006/0001, and RD16/0006/0033) and by the Andalusian Regional Ministry of Economy and Knowledge (grants cofunded by European Regional Development Fund: grant no. CTS-06603); Andalusian Regional Ministry Health (grant nos. PI-0699-2011, PI-0352-2012, PI-0179-2014, and PI-0241-2016); Merck-Serono Research Grant from Fundacion Salud 2000; and Allergology and Clinical Immunology Spanish Society Foundation and Alfonso X el Sabio University Foundation. M.S. holds a “Rio Hortega” research contract (grant no. CM13/00029) supported by the Institute of Health “Carlos III” of the Ministry of Economy and Competitiveness (grants cofounded by European Social Fund [ESF]); I.D. holds a “Juan Rodes” contract (grant no. JR15/00036) supported by the Institute of Health “Carlos III” of the Ministry of Economy and Competitiveness (grants cofounded by ESF; C.M. holds a “Nicolas Monardes” research contract by Andalusian Regional Ministry of Health (grant no. C-0044-2012); A.A. holds an Andalucía Talent Hub Fellowship (grant no. TAHUB/II-004) cofunded by the Junta de Andalucia and the UE, VII Framework Programme of the European Commission (grant agreement no. 291780); and T.D.F. holds a “Ramon y Cajal” research contract by the Ministry of Economy and Competitiveness cofunded by ESF (grant no. RYC-2013-01283).
Conflicts of interest: None of the authors have any conflict of interest and nor have they received any money for the present study. Research is part of their daily activities. All the authors had full access to all the data and take responsibility for the integrity of the data and the accuracy of the data analysis.
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These authors contributed equally to this work.
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These authors contributed equally to this work.