Assessment of Eosinophilic Esophagitis: Comparison
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Please note this is a comparison between Version 2 by Sirius Huang and Version 1 by Ksenia Maslenkina.

Eosinophilic esophagitis (EoE) is an immune-mediated disease that manifests with dysphagia and is characterized by the predominantly eosinophilic infiltration of the esophageal mucosa. Several instruments have been developed to assess the symptoms of EoE.

  • eosinophilic esophagitis
  • activity
  • severity
  • remission
  • EREFS
  • EoEHSS
  • I-SEE

1. Introduction

Eosinophilic esophagitis (EoE) is an immune-mediated disease of the esophagus that manifests with dysphagia and is characterized by the predominantly eosinophilic infiltration of the esophageal mucosa (>15 eosinophils in high power field, eos/hpf) [1,2,3,4,5][1][2][3][4][5]. EoE is a chronic disease arising in predisposed individuals that often harbor one or several atopic conditions: bronchial asthma, atopic rhinitis, atopic dermatitis, eczema, etc. [6,7,8][6][7][8]. EoE may present with seasonal exacerbations due to aeroallergen exposure [9,10][9][10].
The treatment of EoE is focused on the induction of the sustained remission that implies not only the absence of symptoms, but the absence of histological features of the disease [16][11]. The management of EoE is based on diet and drug therapy that includes proton pump inhibitors (PPIs), topical steroids, and biological therapy (with antibodies to IL-4, IL-5, IL-13, etc.) [17,18,19,20,21][12][13][14][15][16]. Esophageal strictures can be successfully treated with dilation.

2. Clinical Symptom Assessment in EoE

The clinical symptoms of EoE vary in patients of different age groups [15,40,41,42][17][18][19][20]. In little children, they include feeding problems, food refusal, nausea, vomiting, and failure to thrive; older children complain of abdominal pain, vomiting/regurgitation, and heartburn and may present with weight loss. In children, pain may also lead to sleeping problems [43][21]. Dysphagia and food impaction prevail in teenagers and adults. Indeed, in adults, EoE is the most frequent reason for dysphagia and food impaction [44][22]. Food impaction requiring endoscopy is observed in 33–53% of adults with EoE [45][23]. It should be mentioned that EoE implies changes in eating behaviors that involves the use of coping mechanisms to avoid symptoms. Patients eat more slowly, chew excessively, take smaller pieces, imbibe fluids with meals, and avoid hard-textured foods [18][13]. The use of these coping mechanisms hampers the assessment of symptoms [39][24]. Several patient-reported outcomes were developed to evaluate the severity of symptoms of EoE and the response to the therapy [38][25]: Daily Symptom Questionnaire (DSQ) [32[26][27][28][29][30],46,47,48,49], EoE Activity Index (EEsAI) [50[31][32],51], Pediatric EoE Symptom Severity (PEESSv2) [52][33], etc. Dellon ES et al. [46][27] developed DSQ, which includes three questions for the identification of dysphagia: (1) did you eat solid food this day, (2) has food gone down slowly or been stuck, and (3) did you have to do anything to make the food go down or to get relief? The DSQ results showed a correlation with the number of dysphagia days (R = 0.96; p < 0.001) and the Straumann Dysphagia Instrument (SDI, R = 0.77; p < 0.001). The DSQ was successfully validated [47][28]. The treatment of the oral suspension of budesonide (BOS) resulted in a substantial decrease in DSQ (from 29.3 to 15.0 in the BOS group vs. from 29.0 to 21.5 in the placebo group, p = 0.0096) [48][29]. A decrease in DSQ ≥ 30% was a criterion of therapy efficacy [32,49][26][30]. The dysphagia symptom diary (DSD) [53][34] is a modification of the DSQ, which contains a fourth question about the presence and severity of pain during dysphagia. A decrease in the symptom score was more prominent in the group receiving 360 mg RPC4046 than in the placebo group. The EEsAI [50][31] includes an evaluation of the following parameters: duration, frequency, and severity of dysphagia, pain when swallowing, a visual dysphagia question concerning food consistency, and behavioral adaptations (avoidance, modification, and slow eating of various foods). The optimal time of symptom recall was 7 days. The values of the EEsAI were greater in active EoE in terms of endoscopic and histological features. EEsAI ≤ 20 allowed for the identification of patients with endoscopic remission with an accuracy of 65.1% and for the identification of patients with histological remission (<20 eos/mm2, which corresponds with <5 eos/hpf) with an accuracy of 62.1% [37][35]. The EEsAI was successfully validated and was used in different studies [29,51,54,55,56,57,58][32][36][37][38][39][40][41]. The Straumann Dysphagia Instrument (SDI) is a nonvalidated questionnaire that rates the frequency and intensity of dysphagia from 0 to 9 points [59][42]. The SDI was used to show the efficacy of budesonide in EoE (SDI decreased from 5.61 to 2.22, p < 0.0001). The SDI was used to evaluate clinical response in other studies [54,60,61][37][43][44]. A decrease in the SDI > 3 points was the criterion of symptomatic remission. The Dysphagia Symptom Score (DSS) is a nonvalidated questionnaire, reflecting the frequency, intensity, duration of symptoms, and presence of lifestyle changes [62,63][45][46]. The Mayo Dysphagia Questionnaire (MDQ) is a validated instrument for the assessment of dysphagia in esophageal diseases [64,65][47][48]. It was not developed for EoE, and in clinical studies [36[49][50],66], the assessment of symptoms using the MDQ did not show a correlation with the induction of histological remission. The results of dysphagia assessment using a visual analogous scale (VAS) demonstrated a correlation with the Likert scale (R = 0.77; p < 0.0001) and MDQ (R = 0.46, p = 0.001) [67][51]. PEESSv2 was developed for children and their parents [52][33], and it includes an assessment of the following parameters: chest pain, heartburn, abdominal pain, dysphagia/food impaction, vomiting, nausea, regurgitation, and poor appetite. The PEESSv2 dysphagia domain showed a correlation with biological signs of activity in EoE [68][52], with the expression of eosinophil peroxidase in both distal and proximal biopsies (ρ = 0.23–0.37, p = 0.019–0.17), and with the expression of the tryptase and chymase of mast cells (ρ = 0.34, p = 0.036 and ρ = 0.32, p = 0.041, respectively). Moreover, there was an association between dysphagia and the expression of CPA3 (ρ = 0.36, p = 0.02). A transcriptome analysis revealed that dysphagia was associated with the expression of genes related to eosinophilia, chemokines, mast cells, neurosensory, cytokines, and inflammation. Other patient-reported outcomes include the symptom scoring tool (SST) [69,70][53][54] and clinical symptom score (CSS) [71][55]. The SST [69][53] represents seven questions for the identification of heartburn/regurgitation, abdominal pain, nocturnal awakening, nausea/vomiting, anorexia/early satiety, dysphagia/odynophagia, and gastrointestinal hemorrhage. Dysphagia and anorexia/early satiety were associated with EoE (odds ratio 15 (95% CI, 6–68), p < 0.001). Symptoms of dysphagia and anorexia/early satiety are also correlated with the average epithelial score (r = 0.32, p < 0.05). Dysphagia is correlated with the maximum lamina propria score (r = 0.45, p < 0.05). In a randomized placebo-controlled study, the use of oral viscous budesonide was associated with a decrease in the severity of symptoms measured by SST (p = 0.0007) [70][54]. The CSS [71][55] evaluates the following symptoms in points from 0 to 3: (1) heartburn, (2) abdominal pain, (3) nocturnal awakening due to the symptoms, (4) nausea, regurgitation, or vomiting, (5) anorexia or early satiety, and (6) dysphagia, odynophagia, or food impaction. The clinical response was defined as a decrease in CSS ≥ 50%, and clinical remission was defined as 0 points of CSS. An assessment of compensatory mechanisms is an advantage of CSS, although the use of CSS did not allow for the differentiation between the oral budesonide suspension group and the placebo group. To sum up, there are different instruments to evaluate the symptoms of EoE (Table 1), but not all of them are responsive to treatment and correlate with histological remission. While the criteria of the response to treatment vary in different studies, an intuitive definition of remission should be the absence of symptoms. Nevertheless, the absence of symptoms does not designate the absence of biological activity of the disease [37][35]; therefore, there is a need for a complex evaluation of symptoms, endoscopic features, and histological findings.
Table 1.
Comparison of different instruments for symptom assessment in EoE.
Features DSQ DSD EEsAI SDI DSS MDQ PEESSv2 SST CSS
Age                  
For adults + + + + + +      
For children
 
Frequency     + + + + +    
) [73][57]. The EREFS showed a moderate level of interobserver agreement (κ for different features varies from 0.50 to 0.58, the proportion of pairwise agreement for experts and non-experts was 81% and 74% for exudates, 90% and 77% for edema, and 98% and 90% for crepe paper esophagus. In another study [74][58], interobserver agreement was substantial for rings (κ 0.70), white exudates (κ 0.63), and crepe paper esophagus (κ 0.62), moderate for furrows (κ 0.49) and strictures (κ 0.54), and slight for edema (κ 0.12). The EREFS classification system identifies patients with EoE in an area under the receiver operator characteristic curve of 0.934 [75][59]. The threshold of a score of 2 allowed for EoE to be diagnosed with a sensitivity of 88%, specificity of 92%, positive predictive value of 84%, negative predictive value of 94%, and accuracy of 91%. The EREFS score decreased after treatment, and a more prominent reduction was observed in patients with histological response (<15 eos/hpf).
Table 2. EREFS score [73].
EREFS score [57].
Endoscopic Feature Description Grade
Major features    
Fixed rings None 0
            + + +
  Mild (subtle circumferential ridges) 1 Dysphagia                  
  Moderate (distinct rings that do not impair

passage of a standard diagnostic adult endoscope (outer diameter 8–9.5 mm))		 2 Presence + + + + + + + + +
  Severe (distinct rings that do not permit passage of a diagnostic endoscope) 3 Duration     +   + +
Exudates (white spots, plaques)  None  0
  Mild (lesions involving <10% of the esophageal surface area) 1 Severity + + + + + + +   +
  Severe (lesions involving >10% of the esophageal surface area) 2 Presence of pain   + +         +  
Furrows (vertical lines,

longitudinal furrows)		 Absent 0 Behavior adaptation + + +   + + +  
  
Present 1 Heartburn           + + +
Edema (vascular pattern, mucosal pallor)+
Absent (distinct vascularity present) 0 Regurgitation           + + + +
Odynophagia           +   + +
Presence of allergies or asthma           +      
  Loss of clarity or absence of vascular markings 1 Medication/treatment used
Stricture Absent 0          +      
Chest pain             +    
Abdominal pain             + + +
  Present Vomiting             + + +
Nausea  
63]. In most studies, the treatment results are described as a decrease in the EREFS score [32,48,49,53,54,57,58,60,75,79][26][29][30][34][37][40][41][43][59][64]. Safroneeva E. et al. [37][35] gave the following three definitions of endoscopic remission: endoscopic inflammatory remission, endoscopic fibrotic remission, and total endoscopic remission (inflammatory and fibrotic remission). Endoscopic inflammatory remission included the following: the absence of white exudates; furrows and edema may be present, but not in combination. Endoscopic fibrotic remission was defined as the absence of moderate and severe rings, and the absence of strictures. Total endoscopic remission included signs of both inflammatory and fibrotic remission. Greuter T. et al., 2019 [81][65] and Miehlke S. et al., 2022 [29][36] defined endoscopic remission as the absence of inflammatory features of EoE (exudates, furrows, and edema), while mild rings may be present. Thus, a uniform definition of endoscopic remission currently is not developed.

4. Histological Criteria of Tthe rRemission in EoE

The diagnosis of EoE requires the presence of >15 eos/hpf [1–3] [1][2][3].. Currently, there is no uniform definition of the histological response to the treatment of EoE, and the histological criteria of the remission vary in different studies.  In some studies, the histological criterion of the remission is PEC < 15 eos/hpf [32,49,63,77,81,85] [26][30][46][65][66][67]. Wolf W.A. et al. [85][67] showed that PEC < 15 was associated with endoscopic response in 90% of patients, with the decrease in symptoms in 88% of patients and with both clinical and endoscopic responses in 81% of patients. The logistic regression showed that a more prominent decrease in the eosinophil count is associated with a higher probability of the symptomatic response; for every 10% decrease in the eosinophil count, the symptom response increased by approximately 7% (p = 0.04), the endoscopic response increased by 6% (p < 0.001), and combined symptomatic and endoscopic responses increased by 10% (p = 0.01) [86][68]. PEC < 15 eos/hpf was a criterion for including studies in a meta-analysis [87][69]. This meta-analysis has shown that observational studies more often used the threshold of <15 eos/hpf, while interventional studies used more stringent criteria: <6 [32,49,54[26][30][37][54][55],70,71], <5 eos/hpf, and even <1 eos/hpf [53,88][34][70]. Gupta S.K., 2015 [71][55] defined  a histological response as <6 eos/hpf, and histological remission as <1 eos/hpf.

Nevertheless, a low PEC is accompanied by the alleviation of symptoms only in a fraction of patients. In 85% of children with histological remission (PEC 0–5 eos/hpf), symptoms persisted [35][71]. Alexander J.A. et al. [36][49] revealed a histological response (>90% decrease in eosinophil count from baseline) in 61.9% of adults with EoE on fluticasone therapy and a symptomatic response in 42.9% of patients. Histological remission (<1 eos/hpf) was reached in 76.1% of patients in the group using high doses of oral budesonide suspension, but symptoms were absent only in 17.6% of patients [71][55]. Safroneeva E. et al. [37][35] showed that the area under the curve for symptoms measured by EEsAI and histological remission comprised 0.60 for PEC < 20/мм2 (which is equivalent to <5 eos/hpf) and 0.61 for PEC <60/мм2 (which is equivalent to <15 eos/hpf), and the accuracy rates were 62.1% and 61.7%, respectively. Therefore, PEC is not a sufficient histological criterion to define remission. Moreover, PEC reflects only inflammatory changes and does not reflect remodeling and stenofibrosis.

Collins M.H. et al. [93][72] developed an eosinophilic esophagitis histological scoring system (EoEHSS), which includes the following parameters: PEC, dilated intercellucar spaces (DIS), basal zone hyperplasia (BZH), eosinophilic abscesses (EA), eosinophil surface layering (SL), surface epithelial alteration (SEA), dyskeratotic epithelial cells (DEC), and lamina propria fibrosis (LPF). EoEHSS evaluates not only the severity of features (grade), but also the extension of histological changes (stage). It allows for EoE to be diagnosed and for the discrimination between active EoE and treatment status. Moreover, logistic regression shows better results of EoEHSS compared with PEC in identifying treatment status.

Distinct parameters of EoEHSS show a correlation with clinical symptoms given the low PEC. Whelan K.A. et al. [94][73] demonstrated that BZH persisted almost in 30% patients with PEC < 15 eos/hpf and was associated with ongoing symptoms of EoE (odds ratio 2.14; 95% CI, 1.03–4.42; p = 0.041) and endoscopic features of EoE (odds ratio 7.10; 95% CI, 3.12–16.18; p < 0.001). It can be explained by the elevated count of mast cells in patients with BZH and DIS that induce an IgE-mediated allergic response and are the component of Th2 inflammation in EoE [95][74]. Bolton S.M. et al. [95][74] identified BZH in 48.4% of distal biopsies and in 45.1% of biopsies from the mid-esophagus. In this study, BZH was associated both with an elevated count of mast cells and with their degranulation. Interestingly, in patients with EoE without symptoms, the count of mast cells was lower than in patients with active EoE.

Even though lamina propria may not present in biopsies, the following combination of parameters can be an indirect indicator of the presence (but not stage) of LPF: age, BZH, DEC, and SEA [96][75]. The accuracy of this model for the identification of LPF comprised 84%. In other study, the strongest correlation was identified between LPF and two parameters of EoEHSS—DEC (r = 0.75; p < 0.001) and CEA (r = 0.70; p < 0.001) [91][76]. In logistic regression, the presence of DEC and CEA predicted LPF with an area under the curve of 0.91 (0.85–0.98) for CEA and 0.90 (0.83–0.97) for DEC.

Based on EoEHSS, Collins M.H. et al. [97][77] proposed the EoE histology remission score (EoEHRS) that includes two criteria: (1) PEC <15 eos/hpf and (2) EoEHSS grade < 3 and EoEHSS stage < 3. The authors give the reason for their approach that PEC is not the only hallmark and component of inflammation in EoE and the evaluation of biopsies with EoEHSS may better define the remission. Moreover, the authors demonstrated a moderate correlation of EoEHRS with a decrease in symptoms of dysphagia (0.39–0.30, p ≤ 0.01), pain (0.48–0.34, p ≤ 0.01), and GERD symptoms (0.51–0.32, p ≤ 0.01) evaluated by PEESSv2.0. The correlation of PEC with symptom severity was weaker compared with EoEHRS. Moreover, biopsies that reached remission refined by EoEHRS showed a low expression of CPA3 (p = 0.0022) and thryptase (p = 0.0088), which confirms the low biological activity of EoE.

5. Multidisciplinary Approach to Estimate Severity of EoE

The data suggest that the evaluation of severity and the definition of the remission in EoE should be built on a combination of symptoms, endoscopic findings, and histology. Therefore, an instrument for the evaluation of EoE severity should be developed based on a multidisciplinary approach, using clinical, endoscopic, and histological features. A multidisciplinary international research group recently developed the Index of Severity of Eosinophilic Esophagitis (I-SEE) [98][78], grading the severity of EoE in points, where 0–6 correspond to mild EoE, 7–14 points correspond to moderate EoE, and ≥ 15 points correspond to severe EoE (Table 3). The I-SEE needs further validation and will be doubtlessly applied in clinical practice.

77].

 

Points per Feature1 Point2 Points4 Points15 Points
Symptoms and

complications		    
SymptomsWeeklyDailyMultiple times per day or disrupting social functioning 
Complications-Food impaction with ER visit or endoscopy (patient ≥18 years)
  • Food impaction with ER visit or endoscopy (patient < 18 years)
  • Hospitalization due to EoE
  • Esophageal perforation
  • Malnutrition with body mass < 5th percentile or decreased growth trajectory
  • Persistent inflammation requiring elemental formula, or systemic corticosteroid, or immunomodulatory treatments
Inflammatory features    
Endoscopy (edema, furrows,

and/or exudates)

Histology		Localized





15–60 eos/hpf		Diffuse





>60 eos/hpf		-





-		-





-
Fibrostenotic features    
Endoscopy (rings, strictures)Present, but endoscope

passes easily		Present, but requires dilation or a snug fit when passing a standard endoscope

-

Cannot pass standard upper endoscope; repeated dilations (in an adult ≤ 18 years); or any dilation (in a child < 18 years)
 
 
Histology-BZH or LPF (or DEC/SEA if no LP)--       + + +
Poor appetite             +    
Nocturnal awakening               + +
Gastrointestinal hemorrhage               +  
Anorexia or early satiety               + +

3. Evaluation of Endoscopic Features in EoE

Endoscopic findings in EoE include linear furrows (in 48% of patients), esophageal rings (in 44% of patients), pallor/decreased vascularity (in 41% of patients), white plagues (in 27% of patients), strictures (in 21% of patients), and narrow-caliber esophagus (in 9% of patients) [72][56]. Rings and strictures are more often identified in adults (57% and 25%, respectively) than in children (11% and 8%, respectively, p < 0.05). Plagues and pallor/decreased vascularity are more often seen in children (36% and 58%, respectively) than in adults (19% and 18%, respectively, p < 0.05). The gold standard of endoscopic evaluation in EoE implies the use of the Endoscopic Reference Score (EREFS), which includes the assessment of the following features: edema, rings, exudates, furrows, and strictures (Table 2
1
Minor features
 
 
Crepe paper esophagus
Absent
0
  Present 1
Rings, strictures, and crepe paper esophagus correspond to fibrotic lesions and exudates, while edema and furrows stand for inflammatory lesions [13,76][60][61]. Rodríguez-Sánchez J. et al. [63][46] showed that exudates (p = 0.03), furrows (p = 0.03), and inflammatory score (p < 0.001) predicted the histological activity of EoE, although only exudates correlated with histological response after treatment, while furrows and edema persisted in 50% and 70% patients with histological remission, respectively. Crepe paper esophagus, diffuse exudates, and severe rings correlated with a higher EREFS score. Chen J.W., 2016 [78][62] demonstrated that higher ring scores were associated with a lower distensibility plateau (rs = −0.46; p < 0.0001) and a higher risk of food impaction. Food impaction in anamnesis was observed in 20% patients with a ring score of 0, in 25% of patients with a ring score of 1, in 39% patients with a ring score of 2, and in 100% patients with a ring score of 3 (p = 0.002). The severity of exudates (r = 0.27; p = 0.02) and furrows (r = 0.49; p < 0.0001) correlated with the density of intraepithelial eosinophils in biopsies. Moreover, the severity of endoscopic features is the main determinant of disease activity for gastroenterologists [80][

Points per Feature

1 Point

2 Points

4 Points

15 Points

Symptoms and

complications

 

 

 

 

Symptoms

Weekly

Daily

Multiple times per day or disrupting social functioning

 

Complications

-

Food impaction with ER visit or endoscopy (patient ≥ 18 years)

• Food impaction with ER visit or endoscopy (patient <18 years)

• Hospitalization due to EoE

• Esophageal perforation

• Malnutrition with body mass <5th percentile or decreased growth trajectory

• Persistent inflammation requiring elemental formula, or systemic corticosteroid, or immunomodulatory treatments

Inflammatory features

 

 

 

 

Endoscopy (edema, furrows,

and/or exudates)

Histology

 

 

 

15–60 eos/hpf

Diffuse

 

 

>60 eos/hpf

-

 

 

-

-

 

 

-

Fibrostenotic features

 

 

 

 

Endoscopy (rings, strictures)

Present, but endoscope

passes easily

Present, but requires dilation or a snug fit when passing a standard endoscope

 

-

 

Cannot pass standard upper endoscope; repeated dilations (in an adult ≤18 years); or any dilation (in a child <18 years)

Histology

-

BZH or LPF (or DEC/SEA if no LP)

-

-

Table 3. Eosinophilic Esophagitis Severity Index [

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