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CASE SERIES 245

Eosinophilic that develops during therapy with proton pump inhibitors : case series and possible mechanisms

Rok Orel1, Simon Murch2, Jorge Amil Dias3, Yvan Vandenplas4, Matjaž Homan1

(1) Department of , and Nutrition, University Children’s Hospital Ljubljana ; Faculty of Medicine, University of Ljubljana, Slovenia ; (2) University Hospital Coventry & Warwickshire, UK ; (3) Centro Hospitalar S. João, Porto, Portugal ; (4) Vrije Universiteit Brussel, Brussels, Belgium.

Abstract GERD. During peptic , presumably as a consequence of acid and pepsin induced damage to the Therapy with proton-pump inhibitors (PPIs) results in remis- sion in at least one third of patients with esophageal , esophageal , the epithelium becomes hyper- presumably because of both their acid-related and anti-inflamma- plastic and accumulates . In the 1980’s and tory mechanisms of action. However, eosinophilic esophagitis early 1990’s the presence of intraepithelial esophageal (EoE) may also develop during therapy with PPIs. We present a case series of four children who were initially diagnosed with infec- eosinophils was regarded as pathognomonic for tious esophagitis, gastroesophageal reflux disease or gastric ulcer, GERD (4,5), and early guidelines for diagnosis and treat- who had no eosinophilic infiltration of the , but subse- quently developed symptoms, endoscopic features and histological ment of EoE from 2007 recommended either 24-hour picture of typical EoE. We discuss mechanisms of action of PPIs of esophageal pH-metry or therapeutic trial with PPIs to likely relevance to an increased risk of development of EoE in some discriminate the two diseases (6). However, as EoE and patients , such as their influence on mucosal barrier function, inter- ference with pH-related protein digestion by pepsin, and antigen GERD may coexist or even increase the risk of each oth- processing by immune cells. (Acta gastro­enterol. belg., 2016, 79, 245- er (7), only unresponsiveness to PPIs has been regarded 250). necessary for confirming the diagnosis of EoE in more Key words : esophageal eosinophilia, eosinophilic esophagitis, proton recent guidelines (1,8). pump inhibitors, gastroesophageal reflux disease, digestion. Moreover, treatment with PPIs leads to a resolution of symptoms and esophageal eosinophilia in a substantial proportion of patients without GERD who do not having Introduction abnormal esophageal acid exposure. Although PPI re- sponsiveness is significantly higher in patients with Esophageal eosinophilia, the finding of eosinophilic ­documented GERD compared to those without it (9), it granulocytes in the squamous epithelium of the esopha- cannot be predicted by the degree of pathological acid gus, is abnormal, as in health the esophageal epithelium exposure measured by pH-metry (3). The phenotype of does not contain eosinophils. The current definition of non-GERD PPI-REE is (with the exception of respon- esophageal eosinophilia relies on the presence of high siveness to PPIs) practically indistinguishable to that of number of eosinophils in the esophageal epithelium (1). EoE unresponsive to PPIs, as both diseases were found to Esophageal eosinophilia can be found in many different share similar symptoms, macroscopic changes observed conditions, but three of them, eosinophilic esophagitis during , histology picture, gene expression (EoE), gastroesophageal reflux disease (GERD) and pro- and profile (3,10-14). ton-pump inhibitor-responsive esophageal eosinophilia A number of mechanisms have been recognized in re- (PPI-REE) are by far the most common. cent years that try to explain how PPIs may affect esoph- EoE is a chronic, immune/antigen-mediated disease ageal eosinophilia. As GERD itself can contribute to the characterized by symptoms related to esophageal dys- development of esophageal eosinophilia, both through function and histologically by -predominant damaging the esophageal epithelial barrier possibly al- inflammation, consisting of a peak value of ≥ 15 eosino- lowing penetration of allergens through the mucosa, and phils per high-power field (1,2). Tissue eosinophilic infil- through cytokine mediated inflammation, at least a part tration should be limited to the esophagus and secondary of the effect of PPIs can be attributed to the inhibition of causes of esophageal eosinophilia should be excluded. In gastric acid secretion (15). Besides this, PPIs may addition, the diagnosis of EoE is confirmed only when ­possess direct anti-inflammatory effects. In vitro studies esophageal eosinophilia does not resolve with treatment with high doses of PPIs lasting at least 8 weeks (1,2). Ac- cording to published data, between 35% to 75% of pa- tients who initially present with esophageal eosinophilia may achieve clinicopathologic remission on therapy with Correspondence to : Rok Orel, M.D., Ph.D., University Children’s Hospital Ljubljana, Faculty of Medicine, University of Ljubljana, Bohoričeva 20, PPIs (3). 1000 Ljubljana, Slovenia. E-mail : [email protected] In some of these patients, classified as PPI-REE, the Submission date : 17/09/2015 initial eosinophilia can be attributed to the underlying Acceptance date : 15/12/2015

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revealed that PPIs block Th2 cytokine-stimulated expres- ­regurgitation, and cough that had been present sion of eotaxin-3, the main chemo-attractant for for a few months. Upper endoscopy demonstrated ero- eosinophils, in culture of esophageal epithelial cells tak- sive esophagitis (grade C of Los Angeles classification). en from both GERD and EoE patients, presumably No endoscopic features of EoE were present. Several through blocking the signal transducer and activator of ­biopsies from different parts of the esophagus revealed transcription (STAT) 6 signaling pathway (16,17). The typical signs of reflux esophagitis but with only few eo- transcriptome analysis in PPI-REE patients showed that sinophils. He was given PPI (40 mg/day) and his gastro- PPIs down-regulate gene expression of Th2 intestinal symptoms greatly diminished. After 13 months and chemokines in these patients in similar manner to of constant therapy with PPI follow-up endoscopy was steroids in EoE patients (13,14). performed. The boy had little gastrointestinal symptoms While the aforementioned data suggest that PPI-REE considering his neurologic condition, but endoscopy may probably constitute a subphenotype of EoE rather showed longitudinal esophageal furrows. Histological than a separate disease entity (3), the reasons why some changes demonstrated chronic esophagitis with dense eo- patients respond to PPI therapy and the others do not re- sinophilic infiltration of more than 50 eos/HPF. As there main unclear. Moreover the published literature has prac- were no signs of reflux esophagitis the PPI dose was re- tically overlooked the fact that some patients may even duced (20 mg/day) and skin prick tests, patch tests and develop de novo EoE during a long-term treatment with specific IgE determination for food were per- PPIs for the indications other than esophageal eosino- formed. All the results were negative, even though the philia. The aim of this paper is to report four such cases patient had positive personal and family history of respi- as well as to discuss the putative underlying mechanisms. ratory allergies and . The 6-food elimination diet (avoiding milk, egg, wheat, soy, nuts and see food) was Case # 1 proposed. However, elimination diet was not accepted by his parents, due to his neurological disorder which caused A 7-year old girl was admitted to the hospital with a feeding difficulties as well as his paucity of symptoms. five day history of severe chest pain, high fever, vomit- During several-years of follow-up his clinical condition ing, and food refusal. Her family history was positive for has remained stable and the patient’s parents have not asthma. Upper endoscopy showed profuse white exudates­ agreed to control endoscopy. and massive erosions in the esophagus. Histological find- ings of multiple esophageal biopsies were consistent with Case # 3 infective esophagitis, with numerous neutrophils in the epithelium. No fungal elements were found. Focally, A 9-year old boy was admitted to the hospital due to there were suspicious herpetic inclusions, but immuno- abdominal pain, and vomiting. He was allergic to histochemical reactions to HSV-1, HSV-2 and CMV dust-mite and also had positive family history for were negative. A maximum 3 eos/HPF were detected in ­allergies. Upper endoscopy showed low-grade erosive the epithelium. She received a 6-week course of PPI esophagitis and nodular antral . Histological find- (20 mg/day) and had symptom remission in a few days. ings confirmed Helicobacter pylori infection and reflux Four months later she presented with chest and upper ab- esophagitis without any eosinophil infiltration. He re- dominal pain. Treatment with PPIs was prescribed again. ceived triple therapy for Helicobacter pylori eradication Because there was no improvement of symptoms in two and had rapid remission of symptoms. However, due to months, a second endoscopy was performed, revealing his recurrent reflux symptoms and former diagnosis of longitudinal furrows in the esophagus. Histological ex- GERD he was treated with PPIs for several times in the amination demonstrated intense esophageal eosinophilic following four-year period and eventually continuously infiltration with up to 40 eos/HPF. The patient was tested for more than 6 months. Because of persistent symptoms for alimentary allergies with skin prick tests, patch tests upper endoscopy was performed and demonstrated and specific IgE determination, and the results revealed ­longitudinal esophageal furrows, while biopsy results cow’s milk protein . An elimination diet devoid of showed up to 10 eosinophils infiltrating the esophageal cow’s milk and dairy products was prescribed. After one mucosa. Twenty-four-hour esophageal pH-monitoring month on a cow’s milk-free diet, the intensity of her confirmed pathologic acid reflux. Therefore, he was symptoms decreased. The number of eosinophils in the put on a long-term PPI therapy (40 mg/day). While on esophageal mucosa at the control endoscopy 2 months therapy with PPI for two months, he developed food after introduction of diet was reduced, although not nor- ­impaction. Endoscopy showed longitudinal esophageal mal (9-12 eos/HPF). She continued to be on cow’s milk furrows with histologically proven dense eosinophilic elimination diet and was symptom free at follow-up. ­infiltrate(over 60 eos/HPF). Complete allergology evalu- ation confirmed dust-mite allergy, but no sensitization to Case # 2 food allergens was found. The patient received 6-food elimination diet without symptomatic or histologic An 11-year-old boy with spastic cerebral palsy was ­response. Therefore, swallowed 2 mg daily admitted to the hospital due to abdominal pain, food was prescribed. During several-years of follow-up the

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boy was having continuing symptoms including several Discussion episodes of food impaction (but not esophageal stenosis) as well as profound esophageal eosinophilia at control Awareness that therapy with PPIs results in both in spite of combined dietary/steroid treat- symptomatic and histological remission in at least one ment and PPI therapy for concomitant GERD. third of patients with esophageal eosinophilia, together with growing knowledge about the dual acid-related and Case # 4 anti-inflammatory mechanisms of their action, has led to an assumption that PPIs may to a greater extent also pre- vent the development of EoE, especially in patients with A 7-month old boy was urgently admitted to the re- underlying diseases that may increase the risk of this dis- gional hospital because of and that order. In contrast with that, Merwat and Spechler have appeared during mild febrile upper respiratory tract in- suggested plausible mechanisms by which acid-suppres- fection. With the exception of mild anemia (Hb 90 g/l), sive medications may actually predispose to the develop- all laboratory results were normal. He was immediately ment of EoE (18). We report four cases of patients who put on intravenous PPI 1mg/kg/12hours and transported developed EoE while or soon after taking therapy with to the university hospital, where upper endoscopy was PPIs. Protective and putative harmful mechanisms of performed within 24 hours from the beginning of symp- PPIs related to EoE development may be proposed. toms of bleeding. A large prepyloric ulcer with diameter From the mechanistically point of view, conditions about 2 cm covered with fibrin clot was identified, while that cause disruption of the esophageal epithelial barrier the mucosa of esophagus, stomach and and increase its permeability to antigens may be regarded ­appeared normal. The treatment with intravenous PPI as potential factors that enhance the risk for EoE. Both 1 mg/kg/day continued for another three days and was infectious esophagitis (19,20), and caustic ingestion (21) thereafter switched to oral route. A control endoscopy have been proposed as potential causes of increased 2 weeks later revealed partial but not complete healing of ­epithelial permeability that resulted in EoE. More impor- the ulcer and normal appearance of all other parts of up- tantly, one of the consequences of GERD is dilation of per . Several biopsies were taken intercellular spaces (DIS) between esophageal epithelial from the duodenum, stomach and lower third of the cells, also termed “spongiosis”, that may facilitate anti- esophagus. Histology results were unremarkable includ- gen penetration and exposure to antigen-recognizing ing practically normal appearance of the esophageal mu- cells (22,23). Several studies reported, although not uni- cosa ­without any eosinophilic infiltration. To speed up formly, that a prevalence of GERD is considerably in- ulcer healing the dose of PPI was raised to 2 mg/kg/day. creased among EoE patients in comparison to general At ­discharge, the infant was completely symptom-free. population (24-27), and that the prevalence of EoE may Two months later, a control endoscopy was performed. be high in patients after repair of esophageal atresia, a While only a small scar was found at the place of former condition often associated with severe GERD (28,29). It ulceration, discrete furrowing and white plaques were has been shown that treatment with PPIs results in im- found in the esophagus. Multiple biopsies taken from dif- provement of structural changes of the esophageal epi- ferent parts of the esophagus revealed typical signs of thelium in both GERD (30) and PPI-REE (31). In this EoE with up to 40 eos/HPF in distal but normal histology regard it is interesting that three of our cases with dis- picture in proximal parts of the esophagus. Complete al- eases affecting esophageal permeability, especially the lergy work-up including skin prick and patch tests and two with erosive reflux esophagitis, did not develop EoE specific IgEs were negative. As the boy had nosymp- at the time of active disease but much later, when the toms, no food ­allergen sensitization was found and­ disease was well controlled with medication. family history for allergic disease was negative, parents One of the possible explanations is that the restoration refused any treatment for EoE but continued with PPI of the epithelial integrity during therapy with PPIs may 1 mg/kg/day. At endoscopy 3 months later, longitudinal be incomplete or may not even occur, as observed in furrows of esophagus were more pronounced and histol- many patients with non-erosive reflux disease (NERD) ogy confirmed progression of EoE with up to 88 eos/HPF who do not respond to PPIs (32). This would mean that, in distal and 37 eos/HPF in proximal esophagus. Because despite therapeutic efficacy of PPIs regarding symptom the boy was still symptom-free, the only treatment control and healing of the erosions, the epithelium might ­accepted by the family was a therapeutic trial with cow’s remain permeable for macromolecules in some patients. milk protein elimination diet. At control endoscopy Even more controversial are the results of the study from ­following 4 months of the diet, the esophagus looked Mullin et al. that compared mucosal permeability by su- macroscopically normal. Consistent with this, histologic crose permeability test before, during and after stopping examination showed no residual signs of EoE, demon- treatment with esomeprazole in patients with GERD and strating almost complete disappearance of eosinophils healthy controls (33). Surprisingly they found that, in a from both proximal and distal esophagus. The boy con- few days after beginning therapy with PPI, mucosal per- tinued on cow’s milk elimination diet and remained meability increased both in GERD patients and healthy symptom-free. volunteers, while it normalized in the latter only when

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the treatment was stopped. This suggests that PPIs in- treatment 26% of patients had positive specific IgEs. To duce a significant transmucosal leak and compromise up- exclude the influence of other environmental factors, per GI barrier function. such as a season of the year, they used a control group of There is as yet no evidence that direct passage of trig- 50 healthy subjects. The proportion of initially sensitized gering allergens through esophageal mucosal barrier and individuals with positive specific IgEs was similar to the their local presentation to immune cells underlies the de- experimental group but did not change until the end of velopment of EoE. EoE is not a mucosa-restricted but a the observation period. The calculated relative risk of de- transmural disease of the esophagus, as demonstrated by velopment food sensitization after 3-months of anti-acid endoscopic ultrasound and computed tomography stud- therapy was 10.5 (95% confidence interval : 1.44-76.48 ; ies as well as transmural sections in an EoE patient who p = 0,0203). In addition, before therapy total IgE levels underwent esophagectomy because of adenocarcino- in experimental and control group were similar, while ma (34). The initial events contributing to eosinophil re- they were significantly increased after 3 months of thera- cruitment by stimulated T cells may well take place in the py in the first compared to the second. While the specific deeper layers of the esophagus (35). Therefore, the site of IgE levels normalized in majority of patients in the five primary sensitization of the immune cells responsible for months after the end of the therapy the percentage of pa- the development of Th2 driven immune response that re- tients with positive skin prick tests remained significantly sults in EoE may be at sites distant from the esophagus, higher than in control group. such as nasal-associated lymphoid tissue (NALT) in case The use of PPIs may induce increased intraepithelial of and gut-associated lymphoid tissue infiltration with lymphocytes and inflammation in the (GALT) in the case of food antigens (35). lamina propria of the colon (41). A study retrospectively Increase of gastric pH due to therapy with PPIs pre- reviewed the medical records and histological reports of vents activation of pepsinogens and the initiation of 78 patients receiving PPIs who had no symptoms of ­protein digestion in the stomach (36). That increases the ­, and their age- and gender- matched controls. possibility that, despite subsequent proteolysis by pan- The authors found a significantly higher intraepithelial creatic and intestinal proteases and peptidases, some pep- lymphocyte count (p < 0.001) as well as the extent of the tides remain big enough to serve as antigenic epitopes for inflammation (p < 0.001) in the PPI group than in intestinal immune cells and induce immune response. A ­controls. These findings are quite unexpected with group of scientists from Austria and Hungary published a ­respect to known anti-inflammatory actions of PPIs and series of papers demonstrating that highly digestible may represent a distal GI tract counterpart of EoE, ­proteins such as codfish proteins remain undigested when ­antigen/immune-mediated inflammation. pH was only marginally shifted from 2.5 to 2.75 (37). In addition, there is the possibility that the increase in Ingestion experiments in healthy volunteers revealed ab- esophageal luminal pH induced by PPI therapy may sorption of biologically active undigested fish allergens ­directly affect eosinophil recruitment, because of the only 10 minutes after ingestion, with maximal serum lev- ­notable pH dependency of signaling through the CCR3 els after 1 to 2 hours (38). In patients with known codfish chemokine receptor. Indeed, an increase in pH from 7 to allergy, skin prick testing with extract of experimental 7.6 causes a 10-fold increase in signaling, and would peptic digestion of fish proteins at pH 2 did not provoke thus facilitate eosinophil recruitment through enhanced skin reaction while extract digested at higher pH values ­eotaxin-CCR3 response. did. When food challenge was performed in five of the According to all aforementioned observations, use of patients with codfish allergy with predigested fish pro- PPIs, especially long-term, may significantly increase the teins, this revealed a 10- to 30-fold reduction of the toler- risk of sensitization to common food antigens. The baby ated cumulative antigen dose when the proteins had been boy presented as our fourth case, for example, did not digested under hypoacidic conditions. In vivo, the influ- have any other risk factor except long lasting treatment ence of acid-suppression on allergenicity of food proteins with high doses of PPI when he developed EoE and was tested in a BALB/c mice model (39,40). While feed- cow’s . It is speculative to claim that PPI ing with caviar or hazelnut extract did not result in sensi- played a crucial role in this case. However, the influence tization in untreated animals, mice taking acid-suppres- of acid inhibition on protein digestion and immunogenic- sive medications developed high titre food-specific IgE ity may have additional implications. During reflux epi- and IgG1 antibodies, T-cell reactivity and positive skin sodes the esophagus and in some instances the lymphatic tests towards test allergens. Most importantly, the same tissues of pharynx (Waldeyer ring) can be exposed not group proved the relevance of these findings in humans only to acid and enzymes but also to food in stomach by comparing markers of specific food sensitization, contents for much longer periods of time. Several studies ­specific IgE formation and cytokine patterns, before and using combined pH/impedance monitoring revealed that after 3 months of treatment with H2-blockers or PPIs in PPI therapy results only in significant reduction in esoph- the cohort of 152 adult patients with negative history for ageal acid exposure time but does not affect the total or allergy (36). Before treatment, 10% of patients number of reflux episodes, the duration of esophageal had preexisting food-specific IgE antibodies to at least 1 bolus exposure and proximal extent of the reflux (42-6). of 19 tested food allergens, when after three months of PPIs may also delay gastric emptying of solids that may

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additionally contribute to gastroesophageal reflux (47). It eosinophilia and eosinophilic esophagitis in patients undergoing upper endoscopy : a prospective cohort study. Am. J. Gastroenterol., 2013, 108 : still remains to be explored whether the reflux and pro- 1854-1860. longed exposure of upper GI and respiratory tract to 11. Moawad F.J., Schoepfer A.M., Safroneeva E., Ally M.R., ­undigested food proteins is more harmful regarding their Chen Y.-J., Maydonovitch C.L. et al. Eosinophilic oesophagitis and proton pump-responsive oesophageal eosinophilia have similar clinical, allergenic potential than to more digested ones. endoscopic and histological findings. Alliment. Pharmacol. Ther., 2014, 39 : Given that some patients show reduction in esopha- 603-608. geal eosinophilia upon PPI therapy, while others show 12. Dellon E.S., Speck O., Woodward K., Covey S., Rusin S., Gebhart J.H. et al. Markers of eosinophilic inflammation for diagnosis of increase, it is likely that different mechanisms may eosinophilic esophagitis and proton pump inhibitor-responsive esophageal ­modulate eosinophil recruitment in different patients. No eosinophilia : a prospective study. Clin. Gastroenterol. Hepatol., 2014, 12 : evidence has however yet emerged for differential muco- 2015-2022. 13. Molina-Infante J., Rivas MD., Hernandez-Alonso M., sal gene expression between these variants of EoE, and it Vinagre-Rodríguez G., Mateos-Rodríguez JM., Dueñas- thus remains possible that the effects of PPIs, for good or Sadornil C. et al. Proton pump inhibitor-responsive oesophageal bad, may be mediated outside the esophagus itself in the eosinophilia correlates with downregulation of eotaxin-3 and Th2 cytokines overexpression. Alliment. Pharmacol. Ther., 2014, 40 : 955-965. inductive lymphoid tissues where primary sensitization 14. Wen T., Dellon E.S., Moawad F.J., Furuta G.T., Aceves S.S., takes place. Rothenberg M.E. Transcriptome analysis of proton pump inhibitor- The principal limitation of our study is that we made responsive esophageal eosinophilia reveals proton pump inhibitor-reversible allergic inflammaton.J. Allergy Clin. Immunol., 2015, 135 : 187-197. conclusions on small study size- four children. More- 15. Cheng E. Proton pump inhibitors for eosinophilic esophagitis. Curr. Opin. over, it is also possible that we somehow missed the EoE Gastroenterol., 2013, 29 : 416-420. diagnosis in our group of patients at initial endoscopy, 16. Cheng E., Zhang X., Huo X., Yu C., Zhang Q., Wang D.H. et al. blocks eotaxin-3 expression by esophageal squamous cells from due to patchy distribution of the histological changes of patients with eosinophilic oesophagitis and GORD. Gut, 2013, 62 : 824-832. the esophageal mucosa or seasonal variations of the 17. Zhang X., Cheng E., Huo X., Yu C., Zhang Q., Pham T.H. et al. esophageal eosinophilic inflammation. Omeprazole blocks STAT6 binding to the eotaxin-3 promoter in eosinophilic esophagitis cells. PloS One, 2012, 7 : e50037. In conclusion, anti-secretory and anti-inflammatory 18. Merwat S.N., Spechler S.J. Might the use of acid-suppresive effects of PPIs may have relevant impact on EoE, and medication predispose to the development of eosinophilic esophagitis ? Am. consequences of treatment with them may be potentially J. Gastroenterol., 2009, 104 : 1897-1902. 19. Sehgal S., Darbari A., Bader A. Herpex simplex virus and harmful in some patients. The awareness of this risk eosinophilic esophagitis. J. Pediatr. Gastroenterol. Nutr., 2013, 56 : e1. needs to be considered in planning future research on the 20. Squires K.A., Cameron D.J., Oliver M., da Fonesca pathogenesis, possible prevention and treatment of EoE Jacnqueira J.C. 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Acta Gastro-Enterologica Belgica, Vol. LXXIX, April-June 2016

11-orel-.indd 250 23/05/16 12:09