Originalarbeit
379
Endoscopic findings in patients with eosinophilic esophagitis
Authors
O. Waidmann, F. Finkelmeier, M. W. Welker, K. Sprinzl, S. Zeuzem, J. G. Albert
Affiliation
Medizinische Klinik 1, Universitätsklinikum Frankfurt, Goethe-Universität, Frankfurt
Schlüsselwörter
Zusammenfassung
Abstract
"
!
!
Hintergrund: Die Endoskopie kann eine entscheidende Rolle bei der Diagnosestellung der Eosinophilen Ösophagitis (EoE) spielen. Hierzu müssen die typischen endoskopischen Befunde der EoE bekannt sein. Methoden: Mittels einer systematischen retrospektiven Abfrage im Klinikdatenbanksystem wurden alle Patienten, bei denen im Jahr 2008 bis zum Jahr 2013 eine EoE aufgrund der klinischen Verdachtsdiagnose und der histopathologischen Befunde diagnostiziert worden war, identifiziert. Die bei der Ösophagogastroduodenoskopie (ÖGD) erhobenen Befunde wurden von zwei erfahrenen Ärzten auf das Vorliegen typischer Befunde der EoE hin retrospektiv analysiert. Patienten bei denen kein Biopsiematerial asserviert worden war oder das Material nicht ausreichend für die Diagnose einer EoE war, wurden von der Auswertung ausgeschlossen. Ergebnisse: Es wurden 23 Patienten (17 Männer und 6 Frauen) in die Auswertung eingeschlossen. Das mediane Alter betrug 38 Jahre bei einer Altersspanne von 19 bis 71 Jahre. Zwölf (52 %) Patienten hatten Bolusereignisse erlitten und 18 (78 %) Patienten hatten über Dysphagie und/oder retrosternale Schmerzen berichtet. Bei der ÖGD fand sich bei 22 der 23 (96 %) Patienten zumindest ein typischer Befund der EoE, wobei das Schleimhautödem (52 %), Längs- (57 %) und Querfurchungen (48 %) sowie die Krepppapiermukosa mit Ablederungen (52 %) die häufigsten Befunde darstellten. Schlussfolgerung: Bei der überwiegenden Zahl der Patienten, bei denen eine EoE diagnostiziert worden war, fanden sich makroskopische Befunde der Erkrankung. Die Endoskopie nimmt daher eine Schlüsselstellung bei der Diagnosestellung der EoE.
Background: Endoscopy has a key role in establishing the diagnosis of eosinophilic esophagitis (EoE), but endoscopic features of EoE might not be well known. Methods: All patients aged 18 or older who were diagnosed with EoE from 2008 to 2013 were systematically identified retrospectively and findings at esophago-gastro-duodenoscopy (EGD) were reviewed by two experienced endoscopists through a query of the university hospital database. Patients in whom biopsies from the esophagus were lacking or inadequate for histopathological examination were excluded. Results: 23 patients (17 male, 6 female) were included into the study (median age: 38 years, range: 19 to 71 years). Patients presented with the following symptoms: 12 (52 %) had bolus obstruction and 18 (78 %) dysphagia and/or chest pain. At EGD, 22 of 23 (96 %) patients were observed with at least one endoscopic feature of EoE, i. e., mucosal edema (52 %), longitudinal furrows (57 %), vertical furrows (48 %), or crêpe paper esophagus (52 %). Conclusions: Typical endoscopic features were present in most patients in whom EoE was diagnosed. Recognizing typical characteristics of EoE is substantial for establishing the diagnosis and for taking biopsies.
● Endoskopie ● Ösophagus ● Refluxösophagitis ● Motilitätsstörung " " "
Key words
● endoscopy ● esophagus ● reflux esophagitis ● motility disorders " " " "
received accepted
6.8.2014 23.11.2014
Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1385767 Z Gastroenterol 2015; 53: 379–384 © Georg Thieme Verlag KG Stuttgart · New York · ISSN 0044-2771 Correspondence Dr. Oliver Waidmann Medizinische Klinik 1, Universitätsklinikum Frankfurt, Goethe-Universität Theodor-Stern-Kai 7 60594 Frankfurt Germany waidmann@biochem2. uni-frankfurt.de
Waidmann O et al. Endoscopic findings in … Z Gastroenterol 2015; 53: 379–384
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Endoskopische Befunde bei Eosinophiler Ösophagitis
Originalarbeit
Introduction !
Endoscopy has a main role in establishing the diagnosis of eosinophilic esophagitis (EoE), but while upper intestinal endoscopy is the key modality to evaluate symptoms from esophageal disease, endoscopic features of EoE might still be less well known. Only investigators with profound experience in EoE report a sensitivity of > 90 % for esophagogastroduodenoscopy (EGD) in identifying affected patients, whereas in physicians less familiar with EoE the sensitivity of EGD examinations for EOE diagnosis ranges from 50 % to 90 % [1, 2]. EoE was first described in 1977 and has an increasing awareness among gastroenterologists and general practitioners [3, 4]. Characteristic symptoms in adults include dysphagia, food impaction, stricture formation and chest pain [3, 4]. Prevalence of EoE is high (> 15 %) in patients who are evaluated for dysphagia, and is still significant (6.5 %) in unselected patients who undergo EGD. In a recent study, esophageal eosinophilia was detected in 4.8 % and EoE was diagnosed in 1.1 % of the population [5]. The diagnosis of EoE is established in patients with typical symptoms who provide ≥ 15 eosinophils per high-power field at histopathological examination of esophageal biopsies, and eosinophilia typically persists after proton pump inhibitor (PPI) treatment [4]. EoE is treated by adherence to an elimination diet and/or by ingestion of topical corticosteroids [4, 6, 7]. Topical steroids are effective in maintaining remission and may reestablish normal function of the esophagus [8]. Undiagnosed and untreated EoE leads to fibrotic remodeling of the esophagus and increases the risk of strictures [9]. Recognition of the disease should be straightforward to minimize the risk of severe and permanent complications. EGD is crucial to diagnose EoE as typical symptoms of the patient should lead the endoscopist to take biopsies for confirmation of the suspicion of EoE. Therefore, the typical endoscopic appearance of EoE must be known to physicians performing endoscopy of the upper gastrointestinal tract and it is of high interest to know the frequency of typical endoscopic findings. We therefore retrospectively analyzed those of our patients in whom the diagnosis of EoE was confirmed to evaluate the role of endoscopy in diagnosing EoE.
Patients and methods !
Patients who were diagnosed with EoE were identified retrospectively by a systematic information retrieval from the hospital database (ORBIS nice, Agfa HealthCare GmbH, Bonn, Germany). All patients who were treated on an outpatient or inpatient ward or who had been investigated by EGD at our endoscopy unit were screened for the diagnosis of EoE by ICD codes (K20) as well as for free text entries at the medical reports (“Eosinophile Ösophagitis”). All data that were thereby retrieved, were reviewed by two doctors to identify those patients who had a definite diagnosis of EoE based on histopathological findings. Also, the endoscopic findings at EGD were reviewed by two experienced investigators. Thereby, all still images or video data (if available) of the esophagus were re-evaluated together with the endoscopy report. A query of the university hospital database was performed for the years 2008 to 2013 in patients aged 18 or older. Inclusion criteria to this study were a histopathologically confirmed diagnosis of EoE in patients who had undergone EGD and had received at least four biopsies of the lower esophagus and at least four biopsies of the middle third and/or upper esoph-
Waidmann O et al. Endoscopic findings in … Z Gastroenterol 2015; 53: 379–384
agus. Exclusion criteria were lack of or inadequate biopsy material for histopathological examination. Clinical and demographic data including age and gender were obtained from medical history and medical reports.
Endoscopic technique and histopathological examination !
Patients with clinical suspicion of EoE undergo a diagnostic work-up including EGD with biopsies from the tubular esophagus at our unit. EGD examinations were performed with local anesthesia (topical xylocain) or intravenous sedation with propofol using diagnostic or therapeutic gastroscopes (e. g., GIF-H180, GIF-1TQ 160, all Olympus medical Europe, Hamburg, Germany) with a working channel of 2.8 or 3.7 mm. Endoscopic images and videos were stored at the clinical information system (ORBIS nice, Agfa HealthCare GmbH, Bonn, Germany). Endoscopy guided biopsies were taken with a standard biopsy forceps (Radial Jaw 4 Standard Capacity Forceps, Boston Scientific Medizintechnik GmbH, Ratingen, Germany). Biopsy specimen was immediately transferred to 10 % neutral buffered formalin. Tissue was embedded in paraffin and 10 µm tissue sections were transferred to slides. Hematoxylin and eosin (H&E) stained sections were evaluated by an experienced pathologist for presence of signs of inflammation and eosinophils. Diagnosis of EoE was established if ≥ 15 eosinophils per high-power field were found at histopathological examination of specimens obtained from the lower esophagus and the middle third and/or upper esophagus.
Definition and analysis of data !
Still image and video documentation and the medical reports were retrospectively analyzed by two experienced gastroenterologists for typical endoscopic signs of EoE including major and minor features according to Hirano et al. [2]. Major endoscopic features included fixed rings, exsudates, furrows, edema and strictures. Minor features were feline esophagus, narrow caliber esophagus and crepe paper esophagus. The patients’ history was reviewed and symptoms such as dysphagia and/or bolus obstruction were noted. Bougienage was performed using a Savary-Gilliard system together with a Eder-Puestow guidewire, and dilation effect was restricted to at most three millimeters per session, e. g., from 9 to 12 mm. The procedure was controlled by endoscopic placement of the guidewire and X-ray imaging in cases where the stricture could not be passed endoscopically. Written informed consent was obtained from all patients before performing EGD. The retrospective analysis was approved by the local institutional review board of the University Hospital Frankfurt (No. 460/13).
Results !
23 patients (17 male, 6 female) were included into this study. The median age of the patients was 38 years with a range from 19 to 71 years. 12 (52 %) patients reported at least one episode of bolus obstruction and 18 (78 %) individuals had complaints of dysphagia and/or chest pain, and 19 out of 23 (83 %) subjects were considered to present with symptoms highly suggestive of EoE. The remaining four patients underwent EGD examinations for unspe-
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Histopathological characteristics of individual patients.
availability of biopsies showing pathognomonic histopathological findings patient
Table 2
Patient characteristics.
age, median, (range)
♀: 6 (26 %), ♂: 17 (74 %)
bolus obstruction, n (%)
12, (52 %)
dysphagia, n (%)
18, (78 %)
PPI treatment
upper
middle
lower
endoscopic signs
at day of biopsy
third
third
third
fixed rings, n (%)
1
yes
+
+
+
2
no
+
+
+
3
no
*
*
*
4
yes
+
*
*
5
no
-
+
+
6
no
+
+
+
7
no
+
-
+
8
no
+
+
+
9
no
*
*
*
10
no
+
+
+
11
no
+
+
+
12
no
-
+
+
13
no
-
+
+
14
yes
+
+
+
15
no
+
+
+
16
no
+
+
+
17
no
+
+
-
18
no
+
+
+
19
yes
*
*
*
20
no
*
*
*
21
yes
+
-
-
22
no
+
+
+
23
no
+
+
+
PPI = proton pump inhibitor. * Locations (upper part, middle part or lower part) of biopsies which show pathognomonic histopathological findings were not further specified in the histopathological reports.
cific abdominal discomfort. All patients underwent at least one EGD examination. Five (22 %) of the 23 patients were on PPI treatment at the day of the endoscopic examination. In all patients the endoscopically suspected EoE diagnosis was confirmed by histopathological examination of biopsies taken from the lower and " Table 1). In 22 (96 %) out of 23 pamiddle/upper esophagus (● tients one or more typical endoscopic features of EoE were found. The common findings were mucosal edema (52 %), longitudinal furrows (57 %), vertical furrows (48 %) and crêpe paper esophagus (52 %). Additional typical signs of EoE, namely fixed rings, exsudates, feline esophagus, narrow caliber esophagus or strictures were found in less than 50 % of patients. The relative distribution " Table 2. of endoscopic findings among patients is shown in ● " Fig. 1. Typical endoscopic features of EoE are shown in ● Strictures are typical complications of untreated EoE and the risk of stricture development increases within time. In nine of the 23 patients strictures were found in the endoscopic examinations and two patients had severe strictures and suffered from symptomatic stenosis of the esophagus. Both individuals were treated with topical steroids, one with fluticasone and the other person with budesonide. Additionally, in both patients wire-guided bougienage was used to treat symptomatic stenosis. In one patient three sessions of bougienage and in the other individual one session were necessary to ameliorate symptoms and to restore food passage. Bougienage of EoE stricture was strictly restricted to a dilation effect of at most three millimeters per session. The endoscopic findings of the patient undergoing three courses of bougienage and concomitant treatment with local steroids before
38, (19 – 71) years
gender, n (%)
exudates, n (%) longitudinal furrows, n (%)
8, (35 %) 6, (26 %) 13, (57 %)
vertical furrows, n (%)
11, (48 %)
mucosal edema, n (%)
12, (52 %)
feline esophagus, n (%) crêpe paper esophagus, n (%)
5, (22 %) 12, (52 %)
narrow caliber esophagus, n (%)
2, (9 %)
stricture, n (%)
9, (39 %)
" Fig. 2. This 38-year-old female and after therapy are shown in ● patient had presented with progressive dysphagia over a period of more than 12 months. At initial endoscopy, frail mucosa adjacent to a subtotal stenosis at the upper third of the esophagus was observed and the endoscope caused superficial laceration. Initiating topical treatment with fluticasone and careful dilation of the stenosis yielded complete resolution of the stenosis. Symptoms completely dissolved. Bougienage was not complicated by perforation and there were no side effects observed due to the treatment with topical steroids. Topical corticosteroids are the established treatment for patients with EoE. Twelve of the 23 patients received consecutive treatment with topical steroids after establishment of EoE diagnosis. In eight patients fluticasone was prescribed. Three individuals took budesonide. In one patient the type of steroid could not be identified retrospectively. Three patients did not receive any specific treatment due to minor symptoms at the time of first diagnosis and in eight patients no information on the kind of pharmacological treatment was accessible. In seven of the twelve individuals treated with topical steroids follow-up EGD examinations were performed in our institution. In six patients a substantial improvement of the endoscopic findings as well as clinical presentation of EoE were evident. In one individual an amelioration of clinical symptoms was found, however there were no relevant changes in endoscopic signs of EoE.
Discussion !
In this case series, 96 % of patients in whom the diagnosis of EoE was established at our clinic presented with typical endoscopic features of EoE. Therefore, it is crucial for the endoscopist to identify the endoscopic features of EoE in the patient who presents with typical symptoms, i. e., retro-sternal pain, dysphagia and/or bolus obstruction. Recognition of EoE as a formerly underestimated but common disease has been improved recently, but awareness amongst non-specialized centers and in community health care might be still inadequate [3, 4]. In symptomatic patients with dysphagia in whom esophageal malignancy can be excluded by EGD, typical endoscopic signs of EoE have to be intensively sought after, and biopsies for histopathology should be obtained from the upper, middle and lower thirds of the esophagus and from those areas where visible exudates suggest nests of eosinophils [4]. The lack of severe symptoms and the subtle endoscopic presentation may hamper a straightforward diagnosis of EoE in
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Table 1
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Fig. 1 Spectrum of typical endoscopic findings in patients with eosinophilic esophagitis. A fixed rings; B white exsudates; C edema and longitudinal and vertical furrows; D feline esophagus; E Crêpe paper esophagus; F stricture. ( " Fig. 1A, D, E are reproduced with kind permission of the Dustri-Verlag, Dr. Karl Feistle GmbH & Co. KG, D- 82 034 Deisenhofen, Germany).
●
some patients, but awareness of the disease in the endoscopist might improve detection rates and prevent progression and development of complications of EoE, namely strictures and stenoses by early treatment [9]. The gold standard for the diagnosis of EoE is the combination of typical symptoms together with characteristic histopatholgical findings, i. e., ≥ 15 eosinophils per high-power field in esophageal biopsies that had been taken from the lower and from the middle third and/or upper part of the esophagus [4]. Esophageal eosinophilia is not pathognomonic of EoE. Gastro-esophageal reflux disease (GERD) and proton-pump inhibitor-responsive esophageal eosinophilia (PPI-REE) are the most important differentials [10]. It is important to mention that patients suffering from PPI-REE may complain of similar clinical symptoms and present with eosinophilia in biopsies of the lower esophagus. However, symptoms are relieved in these patients after treatment with PPI, whereas PPI treatment does not improve symptoms in individuals affected by EoE. Importantly, other than empirical PPI treatment biopsies taken from the upper esophagus can distinguish EoE from reflux related tissue eosinophilia with high specificity [10]. There are several typical endoscopic features in individuals suffering from EoE [4]. Longitudinal and vertical furrows are major endoscopic findings in EoE. These indicators of EoE were frequently found in our patients as well in other cohorts of individuals suffering from EoE [11]. However, esophageal edema has been the most common endoscopic feature in our patients.
Waidmann O et al. Endoscopic findings in … Z Gastroenterol 2015; 53: 379–384
Esophageal edema is found in several diseases of the esophagus including GERD, bacterial or viral infections but may also be a concomitant finding in esophageal cancer. Therefore, the retrieval of biopsies for histopathological examination is essential to establish the correct diagnosis. Especially white exudates should be biopsied which are characterized by eosinophilic infiltrates, in order to establish a suspected diagnosis of EoE. Such exudates were less common in our patients compared to the individuals presented in the series of Straumann [12]. However, we found exudates more often than Remedios et al. [11]. Fixed rings and strictures are complications of EoE and particularly strictures are considered to be results of long running inflammatiory disease [9]. We found in our patients a lower number of strictures compared to the data reported before [11, 12]. One might speculate that an increased awareness of the EoE disease might lead to an earlier diagnosis with less fibrotic complications present. However, the time from first symptoms to EoE diagnosis was not accessible in our patients and therefore this assumption might not be reviewed. The cause of furrowing and ring-like formations in EoE is unknown in detail, but they are thought to represent tissue edema, inflammation and possibly fibrosis. Crêpe paper esophagus, a result of increased vulnerability due to the inflammation of the mucosa, has also been a common finding among our patients. It is quite specific for EoE, however also viral infections, such as herpes simplex virus or cytomegalovirus may show similar endoscopic features and should in particular be consid-
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ered in patients with immunosuppressive therapy. The presence of white exudates is an additional typical finding in EoE patients and could potentially be misinterpreted as thrush. The white exudates are thought to be clusters of eosinophils and should therefore be the target of biopsies. Undetected EoE may cause progressive scarring, strictures, and potentially results in permanent narrowing of the esophagus. The risk of development of severe complications is increasing with the duration of symptoms until the diagnosis is confirmed [9]. However, even in cases of stricture development anti-inflammatory therapy with steroids and endoscopic bougienage was able to substantially reverse the symptoms of our two patients with severe strictures. A relevant limitation of our study is the retrospective design. We may therefore not exclude that every patient with clinical suspicion of EoE underwent the diagnostic protocol during EGD as established at our unit, Moreover, EoE patients who do not present with typical clinical features of EoE might have been missed. The proportion of EoE patients presenting without typical endoscopic findings is fairly unknown. In a recent prospective study, only about 10 % of patients with symptoms of dysphagia and normal endoscopic examinations were finally diagnosed with EoE [13]. In conclusion, given the high and still increasing prevalence of EoE, it is crucial for the endoscopist to be aware of EoE and to recognize the endoscopic characteristics of EoE in order to prevent severe complications of unrecognized disease. Typical endoscopic signs of EoE might be present in the predominant number of symptomatic EoE patients. The knowledge of endoscopic features can support detecting the disease in all symptomatic patients.
Abbreviations EoE EGD H&E GERD PPI PPI-REE
eosinophilic esophagitis esophagogastroduodenoscopy hematoxylin and eosin gastroesophageal reflux disease proton-pump inhibitor proton-pump inhibitor-responsive esophageal eosinophilia
References 01 Mackenzie SH, Go M, Chadwick B et al. Eosinophilic oesophagitis in patients presenting with dysphagia – a prospective analysis. Aliment Pharmacol Ther 2008; 28: 1140 – 1146 02 Hirano I, Moy N, Heckman MG et al. Endoscopic assessment of the oesophageal features of eosinophilic oesophagitis: validation of a novel classification and grading system. Gut 2013; 62: 489 – 495 03 Straumann A. Eosinophilic esophagitis: a bulk of mysteries. Dig Dis 2013; 31: 6 – 9 04 Dellon ES, Gonsalves N, Hirano I et al. ACG clinical guideline: Evidenced based approach to the diagnosis and management of esophageal eosinophilia and eosinophilic esophagitis (EoE). Am J Gastroenterol 2013; 108: 679 – 692 05 Ludvigsson JF, Aro P, Walker MM et al. Celiac disease, eosinophilic esophagitis and gastroesophageal reflux disease, an adult populationbased study. Scand J Gastroenterol 2013; 48: 808 – 814 06 Straumann A, Conus S, Degen L et al. Budesonide is effective in adolescent and adult patients with active eosinophilic esophagitis. Gastroenterology 2010; 139: 1526 – 1537 07 Peterson KA, Byrne KR, Vinson LA et al. Elemental diet induces histologic response in adult eosinophilic esophagitis. Am J Gastroenterol 2013; 108: 759 – 766 08 Straumann A, Conus S, Degen L et al. Long-term budesonide maintenance treatment is partially effective for patients with eosinophilic esophagitis. Clin Gastroenterol Hepatol 2011; 9: 400 – 409 09 Schoepfer AM, Safroneeva E, Bussmann C et al. Delay in diagnosis of eosinophilic esophagitis increases risk for stricture formation in a timedependent manner. Gastroenterology 2013; 145: 1230 – 1236
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Fig. 2 Treatment success of high grade esophageal stenosis and vulnerability after endoscopic and medical treatment. A 38-year-old female patient had presented with progressive dysphagia. At initial endoscopy, frail mucosa adjacent to a subtotal stenosis at the upper third of the esophagus was observed and the endoscope caused superficial laceration. After establishment of the diagnosis of EoE, topical treatment with fluticason and careful stepwise dilation of the stenosis led to complete resolution of the stenosis. Symptoms completely disappeared. Endoscopic features before (A, B) and after successful treatment (C, B).
Originalarbeit
10 Dellon ES et al. Clinical and endoscopic characteristics do not reliably differentiate PPI-responsive esophageal eosinophilia and eosinophilic esophagitis in patients undergoing upper endoscopy: a prospective cohort study. Am J Gastroenterol 2013; 108: 1854 – 1860 11 Remedios M, Campbell C, Jones DM et al. Eosinophilic esophagitis in adults: clinical, endoscopic, histologic findings, and response to treatment with fluticasone propionate. Gastrointest Endosc 2006; 63: 3 – 12
12 Straumann A, Spichtin HP, Bucher KA et al. Eosinophilic esophagitis: red on microscopy, white on endoscopy. Digestion 2004; 70: 109 – 116 13 Mackenzie SH, Go M, Chadwick B et al. Eosinophilic oesophagitis in patients presenting with dysphagia – a prospective analysis. Aliment Pharmacol Ther 2008; 28: 1140 – 1146
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384
Waidmann O et al. Endoscopic findings in … Z Gastroenterol 2015; 53: 379–384
379
Endoscopic findings in patients with eosinophilic esophagitis
Authors
O. Waidmann, F. Finkelmeier, M. W. Welker, K. Sprinzl, S. Zeuzem, J. G. Albert
Affiliation
Medizinische Klinik 1, Universitätsklinikum Frankfurt, Goethe-Universität, Frankfurt
Schlüsselwörter
Zusammenfassung
Abstract
"
!
!
Hintergrund: Die Endoskopie kann eine entscheidende Rolle bei der Diagnosestellung der Eosinophilen Ösophagitis (EoE) spielen. Hierzu müssen die typischen endoskopischen Befunde der EoE bekannt sein. Methoden: Mittels einer systematischen retrospektiven Abfrage im Klinikdatenbanksystem wurden alle Patienten, bei denen im Jahr 2008 bis zum Jahr 2013 eine EoE aufgrund der klinischen Verdachtsdiagnose und der histopathologischen Befunde diagnostiziert worden war, identifiziert. Die bei der Ösophagogastroduodenoskopie (ÖGD) erhobenen Befunde wurden von zwei erfahrenen Ärzten auf das Vorliegen typischer Befunde der EoE hin retrospektiv analysiert. Patienten bei denen kein Biopsiematerial asserviert worden war oder das Material nicht ausreichend für die Diagnose einer EoE war, wurden von der Auswertung ausgeschlossen. Ergebnisse: Es wurden 23 Patienten (17 Männer und 6 Frauen) in die Auswertung eingeschlossen. Das mediane Alter betrug 38 Jahre bei einer Altersspanne von 19 bis 71 Jahre. Zwölf (52 %) Patienten hatten Bolusereignisse erlitten und 18 (78 %) Patienten hatten über Dysphagie und/oder retrosternale Schmerzen berichtet. Bei der ÖGD fand sich bei 22 der 23 (96 %) Patienten zumindest ein typischer Befund der EoE, wobei das Schleimhautödem (52 %), Längs- (57 %) und Querfurchungen (48 %) sowie die Krepppapiermukosa mit Ablederungen (52 %) die häufigsten Befunde darstellten. Schlussfolgerung: Bei der überwiegenden Zahl der Patienten, bei denen eine EoE diagnostiziert worden war, fanden sich makroskopische Befunde der Erkrankung. Die Endoskopie nimmt daher eine Schlüsselstellung bei der Diagnosestellung der EoE.
Background: Endoscopy has a key role in establishing the diagnosis of eosinophilic esophagitis (EoE), but endoscopic features of EoE might not be well known. Methods: All patients aged 18 or older who were diagnosed with EoE from 2008 to 2013 were systematically identified retrospectively and findings at esophago-gastro-duodenoscopy (EGD) were reviewed by two experienced endoscopists through a query of the university hospital database. Patients in whom biopsies from the esophagus were lacking or inadequate for histopathological examination were excluded. Results: 23 patients (17 male, 6 female) were included into the study (median age: 38 years, range: 19 to 71 years). Patients presented with the following symptoms: 12 (52 %) had bolus obstruction and 18 (78 %) dysphagia and/or chest pain. At EGD, 22 of 23 (96 %) patients were observed with at least one endoscopic feature of EoE, i. e., mucosal edema (52 %), longitudinal furrows (57 %), vertical furrows (48 %), or crêpe paper esophagus (52 %). Conclusions: Typical endoscopic features were present in most patients in whom EoE was diagnosed. Recognizing typical characteristics of EoE is substantial for establishing the diagnosis and for taking biopsies.
● Endoskopie ● Ösophagus ● Refluxösophagitis ● Motilitätsstörung " " "
Key words
● endoscopy ● esophagus ● reflux esophagitis ● motility disorders " " " "
received accepted
6.8.2014 23.11.2014
Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1385767 Z Gastroenterol 2015; 53: 379–384 © Georg Thieme Verlag KG Stuttgart · New York · ISSN 0044-2771 Correspondence Dr. Oliver Waidmann Medizinische Klinik 1, Universitätsklinikum Frankfurt, Goethe-Universität Theodor-Stern-Kai 7 60594 Frankfurt Germany waidmann@biochem2. uni-frankfurt.de
Waidmann O et al. Endoscopic findings in … Z Gastroenterol 2015; 53: 379–384
Downloaded by: National University of Singapore. Copyrighted material.
Endoskopische Befunde bei Eosinophiler Ösophagitis
Originalarbeit
Introduction !
Endoscopy has a main role in establishing the diagnosis of eosinophilic esophagitis (EoE), but while upper intestinal endoscopy is the key modality to evaluate symptoms from esophageal disease, endoscopic features of EoE might still be less well known. Only investigators with profound experience in EoE report a sensitivity of > 90 % for esophagogastroduodenoscopy (EGD) in identifying affected patients, whereas in physicians less familiar with EoE the sensitivity of EGD examinations for EOE diagnosis ranges from 50 % to 90 % [1, 2]. EoE was first described in 1977 and has an increasing awareness among gastroenterologists and general practitioners [3, 4]. Characteristic symptoms in adults include dysphagia, food impaction, stricture formation and chest pain [3, 4]. Prevalence of EoE is high (> 15 %) in patients who are evaluated for dysphagia, and is still significant (6.5 %) in unselected patients who undergo EGD. In a recent study, esophageal eosinophilia was detected in 4.8 % and EoE was diagnosed in 1.1 % of the population [5]. The diagnosis of EoE is established in patients with typical symptoms who provide ≥ 15 eosinophils per high-power field at histopathological examination of esophageal biopsies, and eosinophilia typically persists after proton pump inhibitor (PPI) treatment [4]. EoE is treated by adherence to an elimination diet and/or by ingestion of topical corticosteroids [4, 6, 7]. Topical steroids are effective in maintaining remission and may reestablish normal function of the esophagus [8]. Undiagnosed and untreated EoE leads to fibrotic remodeling of the esophagus and increases the risk of strictures [9]. Recognition of the disease should be straightforward to minimize the risk of severe and permanent complications. EGD is crucial to diagnose EoE as typical symptoms of the patient should lead the endoscopist to take biopsies for confirmation of the suspicion of EoE. Therefore, the typical endoscopic appearance of EoE must be known to physicians performing endoscopy of the upper gastrointestinal tract and it is of high interest to know the frequency of typical endoscopic findings. We therefore retrospectively analyzed those of our patients in whom the diagnosis of EoE was confirmed to evaluate the role of endoscopy in diagnosing EoE.
Patients and methods !
Patients who were diagnosed with EoE were identified retrospectively by a systematic information retrieval from the hospital database (ORBIS nice, Agfa HealthCare GmbH, Bonn, Germany). All patients who were treated on an outpatient or inpatient ward or who had been investigated by EGD at our endoscopy unit were screened for the diagnosis of EoE by ICD codes (K20) as well as for free text entries at the medical reports (“Eosinophile Ösophagitis”). All data that were thereby retrieved, were reviewed by two doctors to identify those patients who had a definite diagnosis of EoE based on histopathological findings. Also, the endoscopic findings at EGD were reviewed by two experienced investigators. Thereby, all still images or video data (if available) of the esophagus were re-evaluated together with the endoscopy report. A query of the university hospital database was performed for the years 2008 to 2013 in patients aged 18 or older. Inclusion criteria to this study were a histopathologically confirmed diagnosis of EoE in patients who had undergone EGD and had received at least four biopsies of the lower esophagus and at least four biopsies of the middle third and/or upper esoph-
Waidmann O et al. Endoscopic findings in … Z Gastroenterol 2015; 53: 379–384
agus. Exclusion criteria were lack of or inadequate biopsy material for histopathological examination. Clinical and demographic data including age and gender were obtained from medical history and medical reports.
Endoscopic technique and histopathological examination !
Patients with clinical suspicion of EoE undergo a diagnostic work-up including EGD with biopsies from the tubular esophagus at our unit. EGD examinations were performed with local anesthesia (topical xylocain) or intravenous sedation with propofol using diagnostic or therapeutic gastroscopes (e. g., GIF-H180, GIF-1TQ 160, all Olympus medical Europe, Hamburg, Germany) with a working channel of 2.8 or 3.7 mm. Endoscopic images and videos were stored at the clinical information system (ORBIS nice, Agfa HealthCare GmbH, Bonn, Germany). Endoscopy guided biopsies were taken with a standard biopsy forceps (Radial Jaw 4 Standard Capacity Forceps, Boston Scientific Medizintechnik GmbH, Ratingen, Germany). Biopsy specimen was immediately transferred to 10 % neutral buffered formalin. Tissue was embedded in paraffin and 10 µm tissue sections were transferred to slides. Hematoxylin and eosin (H&E) stained sections were evaluated by an experienced pathologist for presence of signs of inflammation and eosinophils. Diagnosis of EoE was established if ≥ 15 eosinophils per high-power field were found at histopathological examination of specimens obtained from the lower esophagus and the middle third and/or upper esophagus.
Definition and analysis of data !
Still image and video documentation and the medical reports were retrospectively analyzed by two experienced gastroenterologists for typical endoscopic signs of EoE including major and minor features according to Hirano et al. [2]. Major endoscopic features included fixed rings, exsudates, furrows, edema and strictures. Minor features were feline esophagus, narrow caliber esophagus and crepe paper esophagus. The patients’ history was reviewed and symptoms such as dysphagia and/or bolus obstruction were noted. Bougienage was performed using a Savary-Gilliard system together with a Eder-Puestow guidewire, and dilation effect was restricted to at most three millimeters per session, e. g., from 9 to 12 mm. The procedure was controlled by endoscopic placement of the guidewire and X-ray imaging in cases where the stricture could not be passed endoscopically. Written informed consent was obtained from all patients before performing EGD. The retrospective analysis was approved by the local institutional review board of the University Hospital Frankfurt (No. 460/13).
Results !
23 patients (17 male, 6 female) were included into this study. The median age of the patients was 38 years with a range from 19 to 71 years. 12 (52 %) patients reported at least one episode of bolus obstruction and 18 (78 %) individuals had complaints of dysphagia and/or chest pain, and 19 out of 23 (83 %) subjects were considered to present with symptoms highly suggestive of EoE. The remaining four patients underwent EGD examinations for unspe-
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Histopathological characteristics of individual patients.
availability of biopsies showing pathognomonic histopathological findings patient
Table 2
Patient characteristics.
age, median, (range)
♀: 6 (26 %), ♂: 17 (74 %)
bolus obstruction, n (%)
12, (52 %)
dysphagia, n (%)
18, (78 %)
PPI treatment
upper
middle
lower
endoscopic signs
at day of biopsy
third
third
third
fixed rings, n (%)
1
yes
+
+
+
2
no
+
+
+
3
no
*
*
*
4
yes
+
*
*
5
no
-
+
+
6
no
+
+
+
7
no
+
-
+
8
no
+
+
+
9
no
*
*
*
10
no
+
+
+
11
no
+
+
+
12
no
-
+
+
13
no
-
+
+
14
yes
+
+
+
15
no
+
+
+
16
no
+
+
+
17
no
+
+
-
18
no
+
+
+
19
yes
*
*
*
20
no
*
*
*
21
yes
+
-
-
22
no
+
+
+
23
no
+
+
+
PPI = proton pump inhibitor. * Locations (upper part, middle part or lower part) of biopsies which show pathognomonic histopathological findings were not further specified in the histopathological reports.
cific abdominal discomfort. All patients underwent at least one EGD examination. Five (22 %) of the 23 patients were on PPI treatment at the day of the endoscopic examination. In all patients the endoscopically suspected EoE diagnosis was confirmed by histopathological examination of biopsies taken from the lower and " Table 1). In 22 (96 %) out of 23 pamiddle/upper esophagus (● tients one or more typical endoscopic features of EoE were found. The common findings were mucosal edema (52 %), longitudinal furrows (57 %), vertical furrows (48 %) and crêpe paper esophagus (52 %). Additional typical signs of EoE, namely fixed rings, exsudates, feline esophagus, narrow caliber esophagus or strictures were found in less than 50 % of patients. The relative distribution " Table 2. of endoscopic findings among patients is shown in ● " Fig. 1. Typical endoscopic features of EoE are shown in ● Strictures are typical complications of untreated EoE and the risk of stricture development increases within time. In nine of the 23 patients strictures were found in the endoscopic examinations and two patients had severe strictures and suffered from symptomatic stenosis of the esophagus. Both individuals were treated with topical steroids, one with fluticasone and the other person with budesonide. Additionally, in both patients wire-guided bougienage was used to treat symptomatic stenosis. In one patient three sessions of bougienage and in the other individual one session were necessary to ameliorate symptoms and to restore food passage. Bougienage of EoE stricture was strictly restricted to a dilation effect of at most three millimeters per session. The endoscopic findings of the patient undergoing three courses of bougienage and concomitant treatment with local steroids before
38, (19 – 71) years
gender, n (%)
exudates, n (%) longitudinal furrows, n (%)
8, (35 %) 6, (26 %) 13, (57 %)
vertical furrows, n (%)
11, (48 %)
mucosal edema, n (%)
12, (52 %)
feline esophagus, n (%) crêpe paper esophagus, n (%)
5, (22 %) 12, (52 %)
narrow caliber esophagus, n (%)
2, (9 %)
stricture, n (%)
9, (39 %)
" Fig. 2. This 38-year-old female and after therapy are shown in ● patient had presented with progressive dysphagia over a period of more than 12 months. At initial endoscopy, frail mucosa adjacent to a subtotal stenosis at the upper third of the esophagus was observed and the endoscope caused superficial laceration. Initiating topical treatment with fluticasone and careful dilation of the stenosis yielded complete resolution of the stenosis. Symptoms completely dissolved. Bougienage was not complicated by perforation and there were no side effects observed due to the treatment with topical steroids. Topical corticosteroids are the established treatment for patients with EoE. Twelve of the 23 patients received consecutive treatment with topical steroids after establishment of EoE diagnosis. In eight patients fluticasone was prescribed. Three individuals took budesonide. In one patient the type of steroid could not be identified retrospectively. Three patients did not receive any specific treatment due to minor symptoms at the time of first diagnosis and in eight patients no information on the kind of pharmacological treatment was accessible. In seven of the twelve individuals treated with topical steroids follow-up EGD examinations were performed in our institution. In six patients a substantial improvement of the endoscopic findings as well as clinical presentation of EoE were evident. In one individual an amelioration of clinical symptoms was found, however there were no relevant changes in endoscopic signs of EoE.
Discussion !
In this case series, 96 % of patients in whom the diagnosis of EoE was established at our clinic presented with typical endoscopic features of EoE. Therefore, it is crucial for the endoscopist to identify the endoscopic features of EoE in the patient who presents with typical symptoms, i. e., retro-sternal pain, dysphagia and/or bolus obstruction. Recognition of EoE as a formerly underestimated but common disease has been improved recently, but awareness amongst non-specialized centers and in community health care might be still inadequate [3, 4]. In symptomatic patients with dysphagia in whom esophageal malignancy can be excluded by EGD, typical endoscopic signs of EoE have to be intensively sought after, and biopsies for histopathology should be obtained from the upper, middle and lower thirds of the esophagus and from those areas where visible exudates suggest nests of eosinophils [4]. The lack of severe symptoms and the subtle endoscopic presentation may hamper a straightforward diagnosis of EoE in
Waidmann O et al. Endoscopic findings in … Z Gastroenterol 2015; 53: 379–384
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Table 1
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Fig. 1 Spectrum of typical endoscopic findings in patients with eosinophilic esophagitis. A fixed rings; B white exsudates; C edema and longitudinal and vertical furrows; D feline esophagus; E Crêpe paper esophagus; F stricture. ( " Fig. 1A, D, E are reproduced with kind permission of the Dustri-Verlag, Dr. Karl Feistle GmbH & Co. KG, D- 82 034 Deisenhofen, Germany).
●
some patients, but awareness of the disease in the endoscopist might improve detection rates and prevent progression and development of complications of EoE, namely strictures and stenoses by early treatment [9]. The gold standard for the diagnosis of EoE is the combination of typical symptoms together with characteristic histopatholgical findings, i. e., ≥ 15 eosinophils per high-power field in esophageal biopsies that had been taken from the lower and from the middle third and/or upper part of the esophagus [4]. Esophageal eosinophilia is not pathognomonic of EoE. Gastro-esophageal reflux disease (GERD) and proton-pump inhibitor-responsive esophageal eosinophilia (PPI-REE) are the most important differentials [10]. It is important to mention that patients suffering from PPI-REE may complain of similar clinical symptoms and present with eosinophilia in biopsies of the lower esophagus. However, symptoms are relieved in these patients after treatment with PPI, whereas PPI treatment does not improve symptoms in individuals affected by EoE. Importantly, other than empirical PPI treatment biopsies taken from the upper esophagus can distinguish EoE from reflux related tissue eosinophilia with high specificity [10]. There are several typical endoscopic features in individuals suffering from EoE [4]. Longitudinal and vertical furrows are major endoscopic findings in EoE. These indicators of EoE were frequently found in our patients as well in other cohorts of individuals suffering from EoE [11]. However, esophageal edema has been the most common endoscopic feature in our patients.
Waidmann O et al. Endoscopic findings in … Z Gastroenterol 2015; 53: 379–384
Esophageal edema is found in several diseases of the esophagus including GERD, bacterial or viral infections but may also be a concomitant finding in esophageal cancer. Therefore, the retrieval of biopsies for histopathological examination is essential to establish the correct diagnosis. Especially white exudates should be biopsied which are characterized by eosinophilic infiltrates, in order to establish a suspected diagnosis of EoE. Such exudates were less common in our patients compared to the individuals presented in the series of Straumann [12]. However, we found exudates more often than Remedios et al. [11]. Fixed rings and strictures are complications of EoE and particularly strictures are considered to be results of long running inflammatiory disease [9]. We found in our patients a lower number of strictures compared to the data reported before [11, 12]. One might speculate that an increased awareness of the EoE disease might lead to an earlier diagnosis with less fibrotic complications present. However, the time from first symptoms to EoE diagnosis was not accessible in our patients and therefore this assumption might not be reviewed. The cause of furrowing and ring-like formations in EoE is unknown in detail, but they are thought to represent tissue edema, inflammation and possibly fibrosis. Crêpe paper esophagus, a result of increased vulnerability due to the inflammation of the mucosa, has also been a common finding among our patients. It is quite specific for EoE, however also viral infections, such as herpes simplex virus or cytomegalovirus may show similar endoscopic features and should in particular be consid-
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ered in patients with immunosuppressive therapy. The presence of white exudates is an additional typical finding in EoE patients and could potentially be misinterpreted as thrush. The white exudates are thought to be clusters of eosinophils and should therefore be the target of biopsies. Undetected EoE may cause progressive scarring, strictures, and potentially results in permanent narrowing of the esophagus. The risk of development of severe complications is increasing with the duration of symptoms until the diagnosis is confirmed [9]. However, even in cases of stricture development anti-inflammatory therapy with steroids and endoscopic bougienage was able to substantially reverse the symptoms of our two patients with severe strictures. A relevant limitation of our study is the retrospective design. We may therefore not exclude that every patient with clinical suspicion of EoE underwent the diagnostic protocol during EGD as established at our unit, Moreover, EoE patients who do not present with typical clinical features of EoE might have been missed. The proportion of EoE patients presenting without typical endoscopic findings is fairly unknown. In a recent prospective study, only about 10 % of patients with symptoms of dysphagia and normal endoscopic examinations were finally diagnosed with EoE [13]. In conclusion, given the high and still increasing prevalence of EoE, it is crucial for the endoscopist to be aware of EoE and to recognize the endoscopic characteristics of EoE in order to prevent severe complications of unrecognized disease. Typical endoscopic signs of EoE might be present in the predominant number of symptomatic EoE patients. The knowledge of endoscopic features can support detecting the disease in all symptomatic patients.
Abbreviations EoE EGD H&E GERD PPI PPI-REE
eosinophilic esophagitis esophagogastroduodenoscopy hematoxylin and eosin gastroesophageal reflux disease proton-pump inhibitor proton-pump inhibitor-responsive esophageal eosinophilia
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Fig. 2 Treatment success of high grade esophageal stenosis and vulnerability after endoscopic and medical treatment. A 38-year-old female patient had presented with progressive dysphagia. At initial endoscopy, frail mucosa adjacent to a subtotal stenosis at the upper third of the esophagus was observed and the endoscope caused superficial laceration. After establishment of the diagnosis of EoE, topical treatment with fluticason and careful stepwise dilation of the stenosis led to complete resolution of the stenosis. Symptoms completely disappeared. Endoscopic features before (A, B) and after successful treatment (C, B).
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10 Dellon ES et al. Clinical and endoscopic characteristics do not reliably differentiate PPI-responsive esophageal eosinophilia and eosinophilic esophagitis in patients undergoing upper endoscopy: a prospective cohort study. Am J Gastroenterol 2013; 108: 1854 – 1860 11 Remedios M, Campbell C, Jones DM et al. Eosinophilic esophagitis in adults: clinical, endoscopic, histologic findings, and response to treatment with fluticasone propionate. Gastrointest Endosc 2006; 63: 3 – 12
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