2023+EAACI意见书：质子泵抑制剂的过敏反应.pdf

Allergy.2023;00:113.| October 2023|Accepted:8 November 2023DOI:10.1111/all.15961 E A AC I P O S I T I O N PA P E RHypersensitivity reactions to proton pump inhibitors.An EAACI position paperSevim Bavbek1|Seil Kepil zdemir2|Patrizia Bonadonna3|Marina Atanaskovic-Markovic4|Annick Barbaud5|Knut Brockow6|Jose Laguna Martinez7|Alla Nakonechna8|Mauro Pagani9|AlessandraArcolac10|Carla Lombardo11|Maria J.Torres121Division of Immunology and Allergy,Department of Chest Diseases,School of Medicine,Ankara University,Ankara,Turkey2Department of Chest Diseases,Allergy and Immunology Unit,İzmir Faculty of Medicine,Dr.Suat Seren Chest Diseases and Surgery Training and Research Hospital,University of Health Sciences,İzmir,Turkey3Allergy Unit,Borgo Roma University Hospital,Verona,Italy4Department of Allergology and Pulmonology,Faculty of Medicine,University of Belgrade,University Childrens Hospital,Belgrade,Serbia5Dpartement de dermatologie et allergologie,Sorbonne Universit,INSERM,Institut Pierre Louis dEpidmiologie et de Sant Publique,AP-HP,Sorbonne Universit,Hpital Tenon,Paris,France6Department of Dermatology and Allergy Biederstein,Faculty of Medicine,Technical University of Munich,Munich,Germany7Allergy Unit,Allergo-Anaesthesia Unit,Faculty of Medicine,Hospital Central de la Cruz Roja,Alfonso X El Sabio University,Madrid,Spain8Allergy and Clinical Immunology Department,University of Liverpool,Royal Preston Hospital,Lancashire Teaching Hospitals,NHS Foundation Trust,Liverpool,UK9Medicine Department,Medicine Ward Mantova Hospital,ASST di Mantova,Mantova,Italy10Immunology Unit,Borgo Roma University Hospital,Verona,Italy11Division of Dermatology and Allergy,APSS Trento Hospital,Trento,Italy12Allergy Unit,Regional University Hospital of Malaga,IBIMA-UMA-ARADyAL,Malaga,SpainThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License,which permits use and distribution in any medium,provided the original work is properly cited,the use is non-commercial and no modifications or adaptations are made.2023 The Authors.Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley&Sons Ltd.CorrespondenceSevim Bavbek,Division of Immunology and Allergy,Department of Chest Diseases,Ankara University,School of Medicine,Ankara,Trkiye.Email:bavbekmedicine.ankara.edu.trAbstractProton pump inhibitors(PPIs)are invaluable therapeutic options in a variety of dys-peptic diseases.In addition to their well-known risk profile,PPI consumption is related to food and environmental allergies,dysbiosis,osteoporosis,as well as immediate and delayed hypersensitivity reactions(HSRs).The latter,although a rare event,around 13%,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.K E Y W O R D Sallergy,anaphylaxis,drug hypersensitivity,hypersensitivity reaction,proton pump inhibitors2|BAVBEK et al.1|INTRODUCTIONProton pump inhibitors(PPIs)belong to a group of chemically re-lated compounds whose primary function is the inhibition of acid production by blocking the hydrogen potassium adenosine triphos-phatase enzyme system(H+/K+-ATPase).1,2 In adults and pediatric population,these drugs are widely used for the treatment of peptic conditions,such as gastric ulcers,gastroesophageal reflux disease,Helicobacter pylori infections,eosinophilic esophagitis,as well as used to prevent gastric damages due to prolonged use of cortico-steroids and nonsteroidal anti-inflammatory drugs(NSAIDs).3,4 They are usually well-tolerated leading to overprescription and consumption,with a risk of side effects of approximately 1%3%.5 Given the population-based PPI consumption ranging from 8%or 11%in the 2024 aged males or females,to 34%41%in the 6569 aged males or females,6 the risk for allergic side effects is substan-tial.Observational studies have suggested an association between PPI intake and risk of pneumonia,osteoporosis,enteric infection,Clostridium difficileassociated diarrhea,cerebrovascular events,chronic renal failure,dementia,and all-cause mortality,especially in long-term usage.7,8 Their long-term intake has been facilitated by over-the-counter sales in most countries and connects them with de novo induction of Th2 responses to food and environmental aller-gens,in experimental,clinical and population-based epidemiologic studies.Their mechanisms of promoting Th2 immunity and dysbiosis have been revealed in detail.6 Still,in addition to their well-known risk profile,PPIs can induce immediate and delayed hypersensitivity reactions(HSRs).9 The optimal management of patients with HSRs to PPIs is still a matter of discussion.This Position Paper aims to provide clinicians with practical evidence-based recommendations for the diagnosis and management of HSRs to PPIs along with unmet needs in this area.2|METHODSSEARCHSTRATEGYThe European Academy of Allergy and Clinical Immunology(EAACI)commissioned this position paper(PP).The appointed task force group(TF)performed a literature search in MEDLINE,PubMed,Web of Science,and Google Scholar databases of sci-entific societies,by using the keywords and combinations of key-words with the word and,including PPI,Proton pump inhibitors,hypersensitivity reactions,allergy,skin testing and provocation test.Through this search,the publications in the English language that reported the complete protocol followed were selected.Additionally,each TF member used extra keywords as appropri-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 Rimini/Italy.The TF members carefully reviewed the statements,recommendations,and unmet needs,including grading of the quality of evidence using the SIGN criteria as Grade A,B,C,D(Table S1).10,113|EPIDEMIOLOGYANDPPIUSEASARISKFACTORFORALLERGICDISEASESIt has been reported that gastric acid suppression promotes allergy in animal and observational human studies.12,13 In line with these trials,a current population-based study provided evidence for an epidemiolog-ical association between gastric acid suppression and the development of allergic symptoms.In the study,ratios of using anti-allergic medica-tions,increased from 1.47(95%CI:1.451.49)in subjects 60years old after gastric acid-inhibiting drug prescriptions were found.This finding was specific to all gastric acid-inhibiting drugs and was more prominent in females.6There is also evidence that PPI use may be associated with de novo type I allergic sensitizations to dietary compounds and to oral drugs.6,13 The risk for food allergy associated with PPI treatment showed a dose-dependent effect related to days of treatment.Children who had been prescribed for more than 60days of PPIs had a 52%greater risk of being diagnosed with food allergy during childhood than those prescribed for 1 to 60days of PPIs.14 A low gas-tric pH(13.5)is necessary to activate gastric pepsin and only acidic chymus stimulates duodenal secretions and the release of pancreatic enzymes at the next level of digestion hierarchy.When antacid drugs inhibit acid gastric secretion,therefore,food-related allergens may remain intact and absorbed,facilitating an allergic sensitization.2In a nested casecontrol retrospective cohort study on hospi-talized patients,the use of PPIs was associated with a significant increased risk of drug HSRs(OR:4.35;95%CI:29.45)along with a personal history of drug allergies and a long hospitalization time.15 PPI therapy is also considered a possible cofactor,along with exer-cise,anti-inflammatory medications,and alcohol,in decreasing the allergens eliciting threshold dose for anaphylaxis.2Additionally,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,long-term adverse events arising from PPI treatment and other pos-sible triggers are still uncertain and needs long-term follow-up.16The PPIs involved in the HSRs vary among countries:lansopra-zole in studies from Turkey,17,18 esomeprazole and lansoprazole in Italy3 and omeprazole in Spain,1924 probably reflecting the con-sumption/prescription rate.To date,there are no reported cases of HSRs to dexlansoprazole or tenatoprazole.The incidence of anaphylaxis due to PPIs is expected to grow in the next few years due to the increasing consumption,the over-the-counter availability,and greater awareness of clinicians.19,20,25,26 Nevertheless,epidemiological studies reporting true incidence and prevalence are still lacking.4|CLASSIFICATIONHSRs to PPIs may be immediate or nonimmediate/delayed and vary from mild symptoms to life-threatening disorders,including urti-caria,angioedema and anaphylaxis,maculopapular eruption,contact|3BAVBEK et al.dermatitis(occupational),photoallergic dermatitis,erythroderma,drug reaction with eosinophilia and systemic symptoms(DRESS)syndrome,Stevens-Johnson syndrome/Toxic epidermal necrolysis(SJS/TEN).27 Most reported reactions to PPIs are immediate HSRs3 and among them more than half are anaphylaxis.2,1719,23,28 Most HSRs to PPIs occur in female(61%),and almost all cases are described in adults with a mean age of 4613years.29 One case report described anaphylaxis second-ary to omeprazole in a 14-year-old boy30 and another anaphylaxis to omeprazole and pantoprazole in a 16-year-old girl is also described.315|PATHOGENESISPPIs include omeprazole,pantoprazole,esomeprazole,lansoprazole,rabeprazole,and the newer dexlansoprazole and tenatoprazole.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,respectively,a methoxy and a difluoromethoxy chain in their ben-zimidazole rings,whereas lansoprazole and rabeprazole modify the pyridine ring where the trifluoroethoxy and methoxypropoxy chains are located,respectively.Tenatoprazole is the only one with an imi-dazopyridine,instead of a benzimidazole,ring structure,responsi-ble for a longer half-life of the drug compared to other PPIs.2,32,33 Chemical structures of PPIs are listed in Table 1.The underlying mechanisms of HSRs to PPIs are not yet fully ex-plained.Most of the PPI HSRs are IgE-mediated and confirmed by skin prick tests(SPT)or intradermal tests(IDT)or basophil activation test(BAT)positivity.An IgE-mediated mechanism has also been reported in reactions occurring after 324h from PPI intake.3,18,22,30,34 This 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 is activated by acid and then binds covalently not only to the gastric H+,K+-ATPase enzyme,35 but to a wide range of proteins.36 Thereby,the PPI as a hapten may acquire the characteristics of a complete an-tigen and lead to IgE formation,as previously demonstrated for other drugs.13 T-cell-mediated delayed reactions to PPIs are less frequent,ranging from maculopapular exanthemas to severe cutaneous adverse reactions(SCARs);positive patch tests support the confirmatory di-agnosis.Type II and T-cell-mediated HSRs have also been reported.27Statements and Recommendations Gastric acid suppression promotes allergy in animal and observa-tional human studies(Grade D).PPIs involved in the HSRs vary among countries related to their consumption rate(Grade D).The majority of HSRs to PPIs are immediate,possibly IgE-mediated(Grade D).T-cell-mediated delayed reactions to PPIs are less frequently ob-served(Grade D).Most HSRs to PPIs occurred in adult female and anaphylaxis is the most common clinical presentation(Grade D).6|IMMEDIATEHYPER SEN SIT IVITYREACTIONS6.1|ClinicalpresentationThere are multiple case reports and studies of immediate type HSRs to PPIs,ranging from mild to severe reactions,that generally occur within a few hours after the last drug dose.21,3744 Approximately,half of the immediate HSRs to PPI were anaphylaxis,with a prev-alence varying between 9.1%and 69.0%,while urticaria and/or angioedema have been reported with a percentage of 26.2%90.9%.14,15,19,23,28,4547 Dyspnea,pruritus,nausea,vomiting,diar-rhea,and rhinitis have also been reported.17,286.2|Diagnosis6.2.1|Skin testsIn the earliest reports the diagnosis of PPI allergy was based on clinical data or drug provocation test(DPT)test results,3,4852 but,Benzimidazole groupR1R2R3R4OmeprazoleOCH3CH3OCH3CH3LansoprazoleCH3OCH2CF3PantoprazoleOCF2H3OCH3OCH3RabeprazoleCH3O(CH2)3-OCH3EsomeprazoleOCH3OCH3OCH3CH3DexlansoprazoleCH3OCH2CF3Imidazopyridine groupR1R2R3R4TenatoprazoleCH3OCH3-CH3TABLE 1Chemical structures of PPIs.4|BAVBEK et al.several large studies showed that skin tests are useful for the di-agnosis of immediate HSRs due to PPIs and nonirritating skin test concentrations have been defined.3,17,18 Two main studies3,17 have analyzed the accuracy of skin tests vs DPTs.Bonadonna et al.3 eval-uated the diagnostic performance of skin tests versus DPT with the suspected PPI in 53 patients with grade 1 and 2 immediate HSRs.The authors report a high specificity and a positive predictive value(PPV)both of 100%,whereas sensitivity was lower(61.3%)and the negative predictive value(NPV)was 91.9%.In the study,4/12 patients who exhibited positive skin tests with the suspected PPI underwent a DPT,and the positivity was confirmed in all cases.Additionally,there are several case reports showing confirmation of skin test positivity by DPT.34,53 These results are in agreement with data from another multicenter study by Kepil zdemir et al.17 on 38 patients who had experienced immediate HSRs to PPIs.The authors confirm the high specificity and PPV,100%both,with lower values of sensitivity(58.8%)and NPV(70.8%).Based on the previous data from the literature,they did not perform a confirmatory DPT in patients with skin test positivity to the culprit.The same group fur-ther confirmed their data in a following retrospective study18 where 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-sitivity,while all 5 patients who had a negative DPT result with the suspected PPI,also had a negative skin test result.Performing diagnostic tests within 6months from a reaction has been shown to increase the likelihood of positivity of skin tests.45The recommended nonirritating concentrations of SPTs29 are shown in Table 2.If the SPT is negative,IDT should be pursued.29 IDT can be performed with 1:1000,1:100,and 1:10 concentra