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.
Features | DSQ | DSD | EEsAI | SDI | DSS | MDQ | PEESSv2 | SST | CSS |
---|---|---|---|---|---|---|---|---|---|
Age | |||||||||
For adults | + | + | + | + | + | + | |||
For children | + | + | + | ||||||
Dysphagia | |||||||||
Presence | + | + | + | + | + | + | + | + | + |
Duration | + | + | + | ||||||
Frequency | + | + | + | + | + | ||||
Severity | + | + | + | + | + | + | + | + | |
Presence of pain | + | + | + | ||||||
Behavior adaptation | + | + | + | + | + | + | |||
Heartburn | + | + | + | + | |||||
Regurgitation | + | + | + | + | |||||
Odynophagia | + | + | + | ||||||
Presence of allergies or asthma | + | ||||||||
Medication/treatment used | + | ||||||||
Chest pain | + | ||||||||
Abdominal pain | + | + | + | ||||||
Vomiting | + | + | + | ||||||
Nausea | + | + | + | ||||||
Poor appetite | + | ||||||||
Nocturnal awakening | + | + | |||||||
Gastrointestinal hemorrhage | + | ||||||||
Anorexia or early satiety | + | + |
Endoscopic Feature | Description | Grade |
---|---|---|
Major features | ||
Fixed rings | None | 0 |
Mild (subtle circumferential ridges) | 1 | |
Moderate (distinct rings that do not impair passage of a standard diagnostic adult endoscope (outer diameter 8–9.5 mm)) |
2 | |
Severe (distinct rings that do not permit passage of a diagnostic endoscope) | 3 | |
Exudates (white spots, plaques) | None | 0 |
Mild (lesions involving <10% of the esophageal surface area) | 1 | |
Severe (lesions involving >10% of the esophageal surface area) | 2 | |
Furrows (vertical lines, longitudinal furrows) |
Absent | 0 |
Present | 1 | |
Edema (vascular pattern, mucosal pallor) | Absent (distinct vascularity present) | 0 |
Loss of clarity or absence of vascular markings | 1 | |
Stricture | Absent | 0 |
Present | 1 | |
Minor features | ||
Crepe paper esophagus | Absent | 0 |
Present | 1 |
The diagnosis of EoE requires the presence of >15 eos/hpf [1–3]. 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]. Wolf W.A. et al. [85] 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]. PEC <15 eos/hpf was a criterion for including studies in a meta-analysis [87]. 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 [32,49,54,70,71], <5 eos/hpf, and even <1 eos/hpf [53,88]. Gupta SK 2015 [71] 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]. Alexander JA et al. [36] 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]. Safroneeva E. et al. [37] 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] 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] 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]. Bolton S.M. et al. [95] 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]. 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]. 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] 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.
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], 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.
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) |
- |
- |
This entry is adapted from the peer-reviewed paper 10.3390/biomedicines11123204