lNTRODUCTlON

We report the case of a patient with eosinophilic esophagitis (EoE) with concomitant severe asthma who achieved complete histological resolution of the first after the initiation of therapy with benralizumab for asthma.

Until now, benralizumab has been approved only for severe eosinophilic asthma based on three studies[1-3].

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CASE PRESENTATlON

Chief complaints

Intermittent dysphagia and poorly controlled asthma.

History of present illness

Born in 1965, our patient developed the first symptoms of dyspepsia and food impaction at the age of 28. The diagnosis of EoE was made 19 years later in 2012 on the basis of symptoms, endoscopy, and histology. We only have part of the histology report at hand and it only mentions slightly active eosinophilic esophagitis, no signs of thrush or virus infection, and no dysplasia. We do not know the eosinophilic count at that time. Celiac disease and inflammatory bowel diseases as other disorders possibly presenting with esophageal eosinophilia were excluded at that time. The first treatment began in 2013 with oral topical glucocorticoids (fluticasone, off-label, and from 2016 onwards switched to budesonide mostly, but intermittent back to fluticasone). Difficulties with swallowing intensified, despite consistent therapy with oral glucocorticoids. The following gastroscopy in December 2014 sowed strictures in the esophagogastric area, which were treated with argon plasma coagulation and dilation with bougies, with reported clinical improvement. The same year, asthma was diagnosed, exhaled NO was 39 ppb and the medication for asthma was as follows: Inhaled combination of formoterol and budesonide, ciclesonide, and, as needed salbutamol. Gastroesophageal reflux disease (GERD) was diagnosed in 2015

24-h pH-metry.

There is an association of EoE with atopic disorders such as asthma, rhinitis, eczema, and food allergies[9,13].

The patient also had recurrent exacerbations of his asthma. The exact number cannot be assessed from the medical history available to us. At least three exacerbations in 2015 and one exacerbation due to an influenza A infection in March 2019 even needed a 4-d hospitalization. For these exacerbations, he received systemic pulse steroid therapy. In September 2019, the patient discontinued oral topical glucocorticoids (budesonide), reporting vertigo.

History of past illness

Delay between symptoms and diagnosis is not uncommon in EoE and correlates with the development of esophageal strictures[4]. Common symptoms of EoE in teenagers and adults are dysphagia, food impaction, abdominal pain, chronic reflux symptoms, heartburn, and spontaneous rupture of the esophagus. Younger children can present nausea, vomiting, feeding difficulties, and growth retardation[5].

Psychosomatic aspects

The usual delay to diagnosis and the chronic nature of EoE predispose patients to associated psychiatric conditions. A retrospective study between 2002 and 2018 showed that psychiatric comorbidities are common in EoE, with the most common comorbidities being anxiety and depression. Approximately one-third of adults had a diagnosis of a psychiatric condition, and just as many received a prescription medication for a psychiatric illness. The longer the duration of symptoms preceding diagnosis, the more likely that psychiatric comorbidities were found[6]. A recent review article stated the necessity for more research, as there is not even a single prospective study; therefore, the effect of these comorbidities on patients with EoE remains unclear. In addition, anxiety could be driven by limited treatment options[7].

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Personal and family history

Other comorbidities were moderate obstructive sleep apnea syndrome diagnosed in June 2016, postnasal drip syndrome, hiatal hernia diagnosed in December 2014, ectopic gastric mucosa diagnosed in April 2015, allergic rhinoconjunctivitis, status post prostatectomy for prostatic hyperplasia, status post cholecystectomy, status post multiple vertebral surgeries, and status post left shoulder surgery. Although there is no documented diagnosis for a psychiatric comorbidity, a medical report from December 2019 mentioned treatment with escitalopram and mirtazapin in the patient's medication list, suggesting that the patient might have suffered from depression.

Physical examination

EoE is a chronic condition affecting both adults and children[4] characterized by symptoms related to esophageal dysfunction and esophageal eosinophilia. Other causes of esophageal eosinophilia, such as GERD, parasitic infections, vasculitis, and Morbus Crohn’s disease, should be excluded[9]. EoE is a chronic antigen-mediated or immune-mediated disease. Most antigens seem to be food-based[9].

Laboratory examinations

Histologic examination of esophageal biopsies.

Imaging examinations

Gastroscopy in May 2019 (Figure 1).

FlNAL DlAGNOSlS

Eosinophilic esophagitis.

TREATMENT

For many years, our patient received a proton pump inhibitor (PPI) and budesonide, a swallowed glucocorticoid, according to guidelines, but there was neither clinical nor histological improvement. The dilation of esophageal strictures provided a temporary relief of symptoms. It is difficult to assess the exact diet of our patient, and it is unknown if he practiced dietary restrictions. The patient was on anti-IL5 mepolizumab since October 2016, for approximately 2.5 years, but interestingly, only after treatment with the IL-5 receptor antagonist benralizumab were there no eosinophils found in the esophageal mucosa. This histological remission was observed on May 2019, only approximately 4 mo after treatment began with the IL-5 receptor antagonist. Perhaps a lower concentration of mepolizumab (100 mg), which was the dose that our patient received, was just not enough to reduce the number of eosinophils in tissues

As the patient was under PPIs and topical swallowed glucocorticoids for years and a gastroscopy (October 2018) under this medication showed increased eosinophils, we do not think it likely that this medication with PPI and glucocorticoids alone could have had an impact on the histologic remission. Although they might have contributed to that.

In retrospect, it is difficult to assess the exact medication and the small changes in the medication that the patient received. One problem is that he visited many different specialists in different locations for second opinions. Treatment with systemic glucocorticoids over a longer time than for the exacerbations was not reported. He was under a PPI (esomeprazole) at least since February 2015 and in changing dosages (from esomeprazole 20 mg twice daily to esomeprazole 40 mg twice daily). In March 2019, which was shortly before the gastroscopy in May 2019 (Figure 1) showed a full depletion of eosinophils in the esophagus, it is stated that the dosage was esomeprazole 40 mg twice daily. It is not known whether the patient tried an elimination diet.

This case harbors typical aspects of the complexity of treating EoE and includes a long interval between the initial symptoms and diagnosis, the interaction with other eosinophilic conditions, psychiatric comorbidities or associated symptoms and chronic illnesses and possible new therapeutic approaches.

OUTCOME AND FOLLOW-UP

Although our patient showed objective improvement of his disease under treatment with benralizumab in terms of total depletion of eosinophils in peripheral blood samples as well as in the histological examination, with zero eosinophilic granulocytes (0/high power field), there was limited clinical improvement.

The patient has only partially controlled asthma according to GINA guidelines. He is dependent on inhaled corticosteroids but not systemic corticosteroids. Dyspnea and coughing are troubling at night, but his comorbidity of obstructive sleep apnea syndrome and postnasal drip syndrome likely play a role, in addition to his asthma. He experiences limitations in daily life, cannot perform physical work, and can perform office work only 2 h/d. This goes along with findings that IL-5-receptor targeted therapy leads to fewer exacerbations and lesser steroid dependence but not to many improvements in lung function itself or bronchial hyperreactivity[8]. Indeed, the spirometry results in the case of our patient remained approximately the same.

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A multicenter randomized double blind, parallel group, placebo-controlled phase 3 study is recruiting at the moment to investigate the use of benralizumab for eosinophilic esophagitis (MESSINA; ClinicalTrials.gov Identifier: NCT04543409), measuring clinical and histological outcomes.

There also seems to be limited clinical improvement concerning the patient’s gastrointestinal symptoms. Intermittent dysphagia was present when he underwent the last gastroscopy, where the histological evaluation showed no signs of eosinophils under benralizumab treatment. The resolution of esophageal strictures under therapy is still debated, but it is generally assumed that esophageal strictures are not responsive to medical therapy. The subepithelial fibrosis associated with strictures, especially in adults with long-lasting disease, is less reversible by anti-IL-5 therapy.

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With the patient’s long history of nearly 30 years of EoE, pain chronification and underlying psychiatric condition are possible.

DlSCUSSlON

EoE

Not applicable.

The pathogenesis of EoE is multifactorial and not fully understood. Genetic predisposition, environmental factors (microbiome, breastfeeding, and population density), and food antigens play a role. These antigens stimulate Th2 cells, which produce different cytokines, one of which is IL-5, which activates eosinophils, leading to the inflammation of the esophagus[10].

Due to the probable allergic nature of EoE, the avoidance of triggers in food or aeroallergens could cure the disease. Treatment includes both pharmacological and dietary measures. Triggers cannot be identified in every case, and the pharmacological treatment includes PPIs and topical steroids.

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Huguenot M and Bruhm AC contributed equally to this article; Essig M revised the manuscript.

Some cases of EoE respond to a PPI alone, and these cases could represent this associated condition. Up to 40% of children with EoE experience remission under a PPI alone. This subset of patients are considered to have PPI-responsive eosinophilic esophagitis (PPI-REE)[11]. Why this group experiences symptom relief when others do not is unclear. However, GERD may be difficult to rule out because neither the response to PPIs nor the duration of exposure to esophageal acid, measured by means of ambulatory pH monitoring, definitively distinguishes GERD from eosinophilic esophagitis[12].

Because of therapy-resistant asthma, the first biological treatment with mepolizumab was initiated in addition to standard asthma therapy in 2016 at a dose of 100 mg s.c. monthly. Both as a follow-up and because of increasing dyphagia, the patient underwent another gastroscopy in October 2018. Histology showed 20 eosinophils per high-power field in the distal esophagus and 19 eosinophils per high-power field in the proximal esophagus. Because of suboptimal control of asthma (exhaled NO 34 ppb to that time), the standard asthma therapy was switched to benralizumab between January and March 2019 at a dose of 30 mg s.c. monthly for the first 3 mo and then once every 2 mo until today. In the patient's regular consultations with a pneumologist both before and after treatment with mepolizumab and benralizumab, only partly controlled asthma was described according to GINA guidelines (waking due to asthma, daytime symptoms more than twice a week, use of short acting beta agonist as reliever more than twice a week, and activity limitation due to asthma).

Anti-IL-5 drug mechanisms

IL-5 is one of the cytokines responsible for the activation of eosinophils by binding to their IL-5Rα receptors, resulting in subsequent activation of the NF-κB pathway. From a pathophysiological point of view, this activation of the NF-κB pathway causes tissue damage due to endothelial cell damage, changed repair mechanisms, and fibrosis. There are humanized monoclonal antibodies such as mepolizumab and reslizumab that target IL-5, blocking its binding to the receptor. Benralizumab targets the alpha subunit of the IL-5 receptor itself and inhibits the described pathway. Moreover, the antibody benralizumab, through its Fc region, is able to recruit NK cells, mast cells, and basophils and to induce antibody-dependent cellular cytotoxicity.

The result is an entire depletion of eosinophils in the bone marrow and blood and a significant decrease of eosinophils in sputum and tissue[14,15]

With their eosinophil-depleting effect, theoretically, there is a possible application of anti-IL-5 drugs in every disease associated with the pathological presence of eosinophils, namely, eosinophilic asthma, eosinophilic esophagitis, hypereosinophilic syndrome, and eosinophilic granulomatosis with polyangiitis[16].

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Existing data on IL-5 and EoE

A systematic review confirmed that anti-IL-5 monoclonal antibodies do not lead to histological depletion of eosinophils or to the improvement of clinical discomfort[17]. One can speculate on the reason for this; perhaps, unlike IL-5 antibodies, IL-5-receptor antibodies can induce cytotoxicity against eosinophils, as described earlier. Other biological drugs targeting the Th2 response, such as anti-IL-13 antibodies, are under evaluation[10].

Studies examining IL-5 or IL-5-receptor antagonists in EoE

Most studies had a very small study population size. Only two studies included adults, both with very small sample sizes and with a relatively short follow-up. The most recent study was from 2018, and the others were from 2012 or earlier. First, there was a clear lack of recent studies. Second, there was a lack of studies with a meaningful number of adult participants. Additionally, there have been no clinical studies that examine the effect of IL-5 receptor antagonists in patients with EoE (mepolizumab and reslizumab are IL-5 antagonists).

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Historically, the complex interplay between gastroesophageal reflux and eosinophilic esophagitis has been assumed to represent the same entity.

CONCLUSlON

In our case, it is unclear as well whether the patient's remaining discomforts have a purely somatic cause or are influenced by psychiatric comorbidity. There is a known discrepancy between symptom relief and histological disappearance of eosinophils, as well as a discussion about which of these should be considered to evaluate therapy success. Further studies, one already ongoing, should bring better answers to this question.

FOOTNOTES

In previous years, patients with pathological results in pH-metry were categorized as GERD patients, and GERD and EoE were seen as two distinct diseases. Since 2011, a patient who responded to PPI therapy, independent of the pH measurement, was considered to have PPI-responsive EoE (PPI-REE). Now, we know that GERD and PPI-REE are hardly distinguishable from each other (clinically or histologically). The term PPI-REE disappeared from the actual guidelines.

The patient gave informed consent to the publication of this article and general consent is applicable.

The authors declare that there are no conflicts of interest for this article.

The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).

This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BYNC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is noncommercial. See: https://creativecommons.org/Licenses/by-nc/4.0/

Switzerland

The flakes8 of snow covered her long fair hair, which fell in beautiful curls around her neck; but of that, of course, she never once now thought. From all the windows the candles were gleaming, and it smelt9 so deliciously of roast goose, for you know it was New Year s Eve; yes, of that she thought.

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Marc Huguenot 0000-0002-1618-1710; Anne-Catherine Bruhm 0000-0003-0590-4765; Manfred Essig 0000-0002-7940-2795.

With these words he continued his way, and very soon met the third knave13, who said to him, God bless you, sir; are you by any chance coming from the market? Yes, I am, replied Simon

Liu JH

Wang TQ

Liu JH

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