Serum Interleukin 5 as an Indicator of Eosinophilic Esophagitis in Patients with ‎Chronic Upper GIT Symptoms‎ ‎ ‎

• Eosinophilic esophagitis represents unusual cause of chronic ‎esophageal dysfunction symptoms. ‎
• Serum biomarker for its diagnosis is required to be as an indicator ‎and complement of histological diagnosis. ‎
• The current study aimed to assess serum interleukin 5 as an ‎indicator of eosinophilic esophagitis (EoE) in patients with chronic ‎upper GIT symptoms. ‎
• The positive relationship between the ‎increased‎ level of serum ‎interleukin 5 and possibility of eosinophilic esophagitis diagnosis ‎was reported in this study. ‎
• However, histological diagnosis remains to be necessary and ‎further ‎studies are required to investigate the usage of serum ‎interleukin 5 in follow up of and monitoring disease therapy. 

Endoscopic examination is required for diagnosis of EoE in which typical endoscopic findings include esophageal rings, narrowing or strictures, linear furrows, white plaques/exudates and mucosal fragility also termed crêpe-paper mucosa. However, in a small proportion of cases, esophageal mucosa may appear normal and the diagnosis would be missed if biopsies are not taken [6].  At least two to four biopsies should be taken from the proximal, mid and distal esophagus to maximize the sensitivity of EoE diagnosis [7]. The presence of more than 15 eosinophils/HPF with history of non-intake of PPI for 30 days before were used as prerequisite diagnostic criteria for eosinophilic esophagitis [8]. Central role for interleukin 5 (IL-5) in inducing eosinophil trafficking to the esophagus which, is necessary for the induction of eosinophilic esophagitis [9]. Usage of humanized monoclonal blocking anti-IL-5 antibody, that brought about significant decrease in symptoms of esophageal eosinophilia [10]. Serum indicators fordiagnosisof EoEare required to be complement with histopathological assessment. This study aimed to determine the value of serum IL-5 as an indicator for EoE diagnosis.

Table (2): Clinical symptomatology in the studied patients.

Table (3):  CBC in the studied subjects.

Table (4): Endoscopic findings in the studied patients.

Table (5): Histopathological finding in the studied patients.

Table (6):  Interleukin-5 (IL-5) in the studied groups.

DISCUSSION

EoE is a chronic disorder characterized by symptoms of esophageal dysfunction and esophageal inflammation with intraepithelial eosinophils [14]. The common symptoms of EoE included dysphagia and food impaction but other symptoms such as heartburn, nausea, vomiting, chest or epigastric pain can also occur [15]. In this study, six cases of EoE (7.5%) out of 80 adult patients presenting with chronic upper GIT symptoms not responded to standard daily PPI therapy for 8 weeks, had been detected by histopathological examination of esophageal biopsies. This was in concordance with a study on 200 consecutive adult patients who underwent upper endoscopy and reported a 6.5% prevalence of EoE in the studied cases [16]. However, a national pathological data base to detect the prevalence of EoE had revealed 363 (~0.5%) cases from 74162 participants in the age ranged from 1 to 98 years [17]. In the current study EoE was revealed in females more than males with ratio 2 to 1 and mean age of EoE patients was 36.3±18.8years. This is in agreement with another study done by Foroutan et al, who stated that EoE patients were more to be in females younger than 52 years [18]. Unlike this study, another oneby Veerappan et al, reported that EoE positive patients were more likely to be males younger than 50 years [16]. In this study, heartburn was present in all six patients with EoE (100%), dysphagia was present in five EoE patients (83.3%) and food impaction was present in four patients with EoE (66.7%). In the same track, Brian et al concluded that, dysphagia and heartburn were the primary presenting symptom of EoE then food impaction [19].  Other study by Straumann et al reported that, the most characteristic symptoms of EoE in adults were intermittent dysphagia, heartburn and may accompanied by food impaction [20]. In the same track, earlier study done by Kapel et al who stated that, the most common indication for endoscopy in EoE patients was dysphagia (70%) and heartburn was in (27.1%)[17].  While, another by Rodrigues et al reported that, the percentage of heartburn in EoE was 52% and food impaction was 48% [21]. The difference may be attributed to relatively small sample size of this study.  In this study, the median of blood eosinophils was 5% with range 2.3-7% in EoE while, it was 3% with range 0.5-6% in non EoE patients and 1.5% with range 0-3% in controls (P value = 0.009). Blood eosinophils could significantly predict EoE at cutoff value of ≥3.5% with 83.3% sensitivity, 73% specificity, PPV%:20%, NPV%:98.2%, Accuracy:73.8%, AUC=0.814, 95%CI=0.64-0.98 and P value (0. 011). This was described in previous studies, which found EoE patients had higher numbers of eosinophils with 80% sensitivity also other one reported that the peripheral blood absolute eosinophil count (AEC) significantly correlated with esophageal eosinophil density (P < 0.05) [22-23]. Several lines of evidence support a role for allergic inflammation in the pathogenesis of EoE, and the most obvious evidence for such involvement is the central role of the eosinophil[24]. Despite the eosinophilia presence is common but not universal, that range from 30% to 100% in children and in an adult series mild eosinophilia occurred only in 50% of patients [25]. By upper endoscopic examination, three (50%) of the six positive cases of EoE showed esophageal furrows, fissures and/or wrinkles; five cases (83.3%) showed white exudate and/or granularity and five cases (83.3%) showed esophageal concentric rings (trachealization). Similar finding was reported by a prospective study done by Dellon (2014), in which endoscopic findings of EoE, such as esophageal fixed or transient concentric rings, furrows, fissures and/or wrinkles, and white exudate and/or granularity, are diagnostic but not specific [26]. However, Kim et al reported that, about 20% of EoE patients had normal endoscopic appearance of the esophagus [6]. Higher percentage had by Mackenzie et al. study who found that, about 42% of patients with EoE did not have the classic endoscopic picture of EoE [27]. In this study, 18 patients had hiatus hernia (22.5%) and 2 out of them had EoE. While, Dellon et al (2015), stated that younger age, male sex, presence of dysphagia, food allergies, presence of esophageal rings/furrows/plaques and lack a hiatal hernia had predicted EoE diagnosis with a very high degree of accuracy[28]. Also, Jeremy and colleagues, revealed that endoscopic esophageal ring was more in EoE and hiatus hernia was more in non-eosinophilic [29]. In this study, GERD in non- EoE patients was 78.8% mainly with Los Angeles grade B (50.9%) and GERD in cases of EoE was 100% which is in concordance with Kirsch et al., who diagnosed GERD in 86% of their EoE cases[30]. Role of acid reflux in the pathogenesis of EoE is a debate matter and the clinical crossover between the two diseases in some patients would be explained as the esophageal microenvironment becomes better recognized [31]. The difference of endoscopic finding may be attributed the small number of EoE cases in this study and lower prevalence rate of the disease. By histopathological examination of esophageal biopsies there was statistically significant difference between patients with EoE and non-eosinophilic regarding mucosal and sub mucosal edema with P value (0.013), basal hyperplasia with P value (0.013), elongation of the papillae with P value (0.03), thinning of the squamous cell layer with P value (0.038) and inflammatory cells lymphocytic or neutrophilic with P value (0.03). Gunasekaran et al., compared esophageal histology in detail, apart from the eosinophil count, between EoE and in non-eosinophilic biopsies, the results were eosinophilic micro-abscesses, mucosal and sub mucosal edema, elongation of the papillae and epithelial desquamation were twice as common and significant in EoE group than non-eosinophilic [32]. In contrast Sá et al., who reported that histopathological findings are nonspecific and cannot be used to distinguish between EoE and GERD[33]. In this study, serum IL-5 can significantly predict EoE at cutoff value of ≥103.2pg/ml with 100% sensitivity, 93.2% specificity, PPV% 54.5%, NPV% 100%, 93.8% Accuracy, AUC =0.989, 95%CI = 0.96-1.0 and P value (<0.001). In concordance with these reports, Ishihara and colleagues, reported IL-5 as possible biomarkers of eosinophilic esophagitis and adequately sensitive for clinical use[34]. Another prospective study considered IL-5 is a promising serum biomarker for diagnosing EoE with 89% sensitivity [35].  Unlike these results, another study in 2015 done by Dellon and colleagues who reported the difference in IL-5 between EoE cases and patients did not meet EoE criteria at baseline before and after therapy was non-significant [36]. Beside interleukin 5, other non-invasive biomarkers (eotaxin 3; interleukin 13; major basic protein and transforming growth factor beta 1) were assessed by Sarbinowska et al in EoE patients and concluded that, it is not possible to select one serum biomarker as efficient tool in prediction and prognosis of EoE. However, it is necessary to determine the markers several times and no parameter alone should be considered, but the whole group together, taken into consideration for the pathophysiological role and interdependencies [37].

CONCLUSION

This study concluded that serum interleukin 5 and peripheral blood eosinophils count ‎showed significant positive relation with eosinophilic esophagitis and could be helpful ‎as indicators of the disease in patients with chronic upper GIT symptoms. Still, ‎histopathological diagnosis of EoE continues to be necessary‎.‎

Limitations: Drawback of this study was the small number of EoE patients in studied subjects, which could be attributed to the disease is not common.

Recommendations: This study recommends studying of other biomarkers with emphasize on the serum concentration of individual marker in the diagnosis EoE and monitoring changes of these biomarkers from baseline after therapy. Also, EoE should be considered as an etiology in patients with long-standing upper GIT symptoms after standard PPI therapy with stress on of multiple, different level, esophageal biopsies taken during diagnostic upper GIT endoscopy.

Finding source: None.

Conflicts of interest: The authors declare that they have no conflict of interest.

Ethical approval: Approved.

Acknowledgement: The authors would thank all our colleagues who helped us.