Animal models of eosinophilic esophagitis,review and perspectives

Eosinophilic oesophagitis(EoE)is an allergen/immune-mediated chronic esophageal disease characterized by esophageal mucosal eosinophilic infiltration and esophageal dysfunction.Although the disease was originally attributed to a delayed allergic reaction to allergens and a Th2-type immune response,the exact pathogenesis is complex,and the efficacy of existing treatments is unsatisfactory.Therefore,the study of the pathophysiological process of EOE has received increasing attention.Animal models have been used extensively to study the molecular mechanism of EOE pathogenesis and also provide a preclinical platform for human clinical intervention studies of novel therapeutic agents.To maximize the use of existing animal models of EOE,it is important to understand the advantages or limitations of each modeling approach.This paper systematically describes the selection of experimental animals,types of allergens,and methods of sensitization and excitation during the preparation of animal models of EoE.It also discusses the utility and shortcomings of each model with the aim of providing the latest perspectives on EoE models and leading to better choices of animal models.

Evolving strategies: Enhancements in managing eosinophilic esophagitis in pediatric patients

Eosinophilic esophagitis is a newly recognized disease first described about 50 years ago.The definition,diagnosis,and management have evolved with new published consensus guidelines and newly approved treatment available to pediatricians,enabling a better understanding of this disease and more targeted treatment for patients.We describe the definition,presentation,and diagnosis of eosinophilic esophagitis including management,challenges,and future directions in children.The definition,diagnosis,and management of eosinophilic esophagitis have evolved over the last 50 years.Consensus guidelines and newly approved biologic treatment have enabled pediatricians to better understand this disease and allow for more targeted treatment for patients.We describe the definition,presentation,diagnosis,management,and treatment in addition to the challenges and future directions of eosinophilic esophagitis management in children.

Diagnostic role of fractional exhaled nitric oxide in pediatric eosinophilic esophagitis, relationship with gastric and duodenal eosinophils

BACKGROUND Eosinophilic esophagitis(EoE)is an eosinophilic-predominant inflammation of the esophagus diagnosed by upper endoscopy and biopsies.A non-invasive and cost-effective alternative for management of EoE is being researched.Previous studies assessing utility of fractional exhaled nitric oxide(FeNO)in EoE were low powered.None investigated the contribution of eosinophilic inflammation of the stomach and duodenum to FeNO.AIM To assess the utility of FeNO as a non-invasive biomarker of esophageal eosinophilic inflammation for monitoring disease activity.METHODS Patients aged 6-21 years undergoing scheduled upper endoscopy with biopsy for suspected EoE were recruited in our observational study.Patients on steroids and with persistent asthma requiring daily controller medication were excluded.FeNO measurements were obtained in duplicate using a chemiluminescence nitric oxide analyzer(NIOX MINO,Aerocrine,Inc.;Stockholm,Sweden)prior to endoscopy.Based on the esophageal peak eosinophil count(PEC)/high power field on biopsy,patients were classified as EoE(PEC≥15)or control(PEC≤14).Mean FeNO levels were correlated with presence or absence of EoE,eosinophil counts on esophageal biopsy,and abnormal downstream eosinophilia in the stomach(PEC≥10)and duodenum(PEC≥20).Wilcoxon rank-sum test,Spearman correlation,and logistic regression were used for analysis.P value<0.05 was considered significant.RESULTS We recruited a total of 134 patients,of which 45 were diagnosed with EoE by histopathology.The median interquartile range FeNO level was 17 parts per billion(11-37,range:7-81)in the EoE group and 12 parts per billion(8-19,range:5-71)in the control group.After adjusting for atopic diseases,EoE patients had significantly higher FeNO levels as compared to patients without EoE(Z=3.33,P<0.001).A weak yet statistically significant positive association was found between the number of esophageal eosinophils and FeNO levels(r=0.30,P<0.005).On subgroup analysis within the EoE cohort,higher FeNO levels were noted in patients with abnormal gastric(n=23,18 vs 15)and duodenal eosinophilia(n=28,21 vs 14);however,the difference was not statistically significant.CONCLUSION After ruling out atopy as possible confounder,we found significantly higher FeNO levels in the EoE cohort than in the control group.

Adult eosinophilic esophagitis and advances in its treatment

Eosinophilic esophagitis(EoE)is a chronic eosinophil inflammation that seems to be T helper type 2 antigen-driven.The disease is one of several eosinophilic gastrointestinal disorders in which there appears to be inflammation of the gastrointestinal tract without any apparent underlying causes.Differential diagnosis needs to be made with gastroesophageal reflux,which is characterized by chronic inflammation due to gastric refluxate from disorders related to motility.EoE,however,is considered a chronic allergic inflammatory disorder related to destructive tissue remodeling.There seems to be a higher prevalence of EoE in Western countries.It is typically found in atopic male individuals.Physiopathological risk factors include atopy,environmental factors,esophageal epithelial barrier dysfunctions,etc.EoE can cause several symptoms that include retrosternal burning sensation,dysphagia,food impaction,chronic reflux symptoms,nausea,and vomiting.Early diagnosis,which requires a biopsy to assess for esophageal inflammation,is essential for proper treatment.The aim of our brief overview is to summarize the current literature regarding the characteristics,diagnosis,complications,mechanisms of pathology,clinical features,influence of comorbidities,and treatment in patients with EoE.

Eosinophilic esophagitis

Eosinophilic esophagitis is increasingly recognized in adults. The diagnosis is based on the presence of both typical symptoms and pathologic findings on esophageal biopsy. Patients usually present with dysphagia, food impaction and/or reflux-like symptoms, and biopsy of the esophagus shows more than 15 eosinophils per high-power fi eld. In addition, it is essential to exclude the presence of known causes of tissue eosinophilia such as gastroesophageal reflux disease, infections, malignancy, collagen vascular diseases, hypersensitivity, and inflammatory bowel disease. There are no standardized protocols for the therapy of eosinophilic esophagitis. A variety of therapeutic approaches including acid suppression, dietary modifications, topical corticosteroids and endoscopic dilation can be used alone or in combination.

Circumferential mucosal dissection and esophageal perforation in a patient with eosinophilic esophagitis

A young man with a previous history of episodes of mild solid food dysphagia was admitted with a total dysphagia. The esophagogastroduodenoscopy (EGDS) showed an extensive disruption of mucosal layer with a cul-de-sac in the lower part of the esophagus. Soon after the procedure, the patient suffered from an acute chest pain and subsequent CT scan demonstrated an intramural circumferential dissection of thoracic esophagus, and a mediastinal emphysema. An emergency right thoracotomy was performed, followed by a total esophagectomy with esophagogastroplasty and jejunostomy. The histopathology confirmed that mucosal and submucosal layers were circumferentially detached from muscular wall and showed an eosinophilic infiltration of the whole organ with necrosis and erosions of mucosal, submucosal and muscular layers. The diagnosis was esophageal perforation in eosinophilic esophagitis.

Overlap of reflux and eosinophilic esophagitis in two patients requiring different therapies:A review of the literature

Eosinophilic esophagitis (EE) and gastroesophageal reflux disease (GERD) have overlapping clinical, manometric, endoscopic and histopathologic features. The diagnosis of EE is nowadays based upon the presence of 15 or more eosinophils per high power field (eo/HPF) in esophageal biopsies. We report the cases of two young males suffering from dysphagia and recurrent food impaction with reflux esophagitis and more than 20 eo/HPF in upper-mid esophagus biopsies, both of which became asymptomatic on proton pump inhibitor (PPI) therapy. The first patient also achieved a histologic response, while EE remained in the other patient after effective PPI treatment, as shown by 24-h esophageal pH monitoring. Topical steroid therapy combined with PPI led to complete remission in this latter patient. GERD and EE may be undistinguishable, even by histology, so diagnosis of EE should only be established after a careful correlation of clinical, endoscopic and pathologic data obtained under vigorous acid suppression. These diagnostic difficulties are maximal when both diseases overlap. Limited data are available about this topic, and the interaction between EE and GERD is a matter of debate. In this setting, upper-mid esophagus step biopsies and esophageal pH monitoring of patients on PPI therapy are pivotal to evaluate the role of each disease. A PPI trial is mandatory in patients with a histopathologic diagnosis of EE; in those unresponsive to PPI treatment, EE should be suggested. However, a clinical response to PPI may not rule out quiescent EE, as shown in this report.

Endoscopic findings in patients with Schatzki rings:Evidence for an association with eosinophilic esophagitis

AIM:To investigate endoscopic findings in patients with Schatzki rings(SRs) with a focus on evidence for eosinophilic esophagitis(EoE).METHODS:We consecutively approached all adult patients scheduled for elective outpatient upper endoscopy for a variety of indications at the German Diagnostic Clinic,Wiesbaden,Germany between July 2007 and July 2010.All patients with endoscopically diagnosed SRs,defined as thin,symmetrical,mucosal structures located at the esophagogastric junction,were prospectively registered.Additional endoscopic findings,clinical information and histopathological findings with a focus on esophageal eosinophilia(≥ 20 eosinophils/high power field) were recorded.The criteria for active EoE were defined as:(1) eosinophilic tissue infiltration ≥ 20 eosinophils/hpf;(2) symptoms of esophageal dysfunction;and(3) exclusion of other causes of esophageal eosinophilia.Gastroesophageal reflux disease was excluded by proton pump inhibitor treatment prior to endoscopy.The presence of ≥ 20 eosinophils/hpf in esophageal biopsies in patients that did not fulfil the criteria of EoE was defined as esophageal hypereosinophilia.RESULTS:A SR was diagnosed in 171(3.3%;128 males,43 females,mean age 66 ± 12.9 years) of the 5163 patients that underwent upper gastrointestinalendoscopy.Twenty of the 116 patients(17%) from whom esophageal biopsies were obtained showed histological hypereosinophilia(≥ 20 eosinophils/hpf).Nine of these patients(8 males,1 female,mean age 49 ± 10 years) did not fulfill all diagnostic criteria of EoE,whereas in 11(9%) patients with ≥ 20 eosinophils/hpf,a definite diagnosis of EoE was made.Three of the 11 patients(27%) with definite EoE had no suspicious endoscopic features of EoE.In contrast,in the 25 patients in whom EoE was suspected by endoscopic features,EoE was only confirmed in 7(28%) patients.Patients with EoE were younger(mean age 41.5 ± 6.5 vs 50.5 ± 11.5 years,P = 0.012),were more likely to have a history of allergies(73% vs 29%,P = 0.007) and complained more often of dysphagia(91% vs 34%,P = 0.004) and food impaction(36% vs 6%,P = 0.007) than patients without EoE.Endoscopically,additional webs were found significantly more often in patients with EoE than in patients without EoE(36% vs 11%,P = 0.04).Furthermore,the SR had a tendency to be narrower in patients with EoE than in those without EoE(36% vs 18%,P = 0.22).The percentage of males(73% vs 72%,P = 1.0) and frequency of heartburn(27% vs 27%,P = 1.0) were not significantly different in both groups.The 9 patients with esophageal hypereosinophilia that did not fulfil the diagnostic criteria of EoE were younger(mean age 49 ± 10 years vs 58 ± 6 years,P = 0.0008) and were more likely to have a history of allergies(78% vs 24%,P = 0.003) than patients with < 20 eosinophils/hpf.Predictors of EoE were younger age,presence of dysphagia or food impaction and a history of allergies.CONCLUSION:A significant proportion of patients with SRs also have EoE,which may not always be suspected according to other endoscopic features.

Confounding factors affect the pathophysiology of eosinophilic esophagitis

Eosinophilic esophagitis is a newly diagnosed esophageal disease in adult and children. The clinical and pathological characteristics of this disease have been established and were recently summarized in the expert clinical guideline published in 2011. In spite of the wide knowledge accumulated on this disease, there are many areas where scientific data are missing, especially in regard to the disease's pathophysiology. Recent publications have suggested that other confounding factors modify the disease and may affect its clinicalphenotypic presentation. Those factors may include place of living, air pollution, race, genetic factors and other. In the present report we discussed and review those confounding factors, the new developments, and what direction we should go to further advance our knowledge of this disease.

Eosinophilic esophagitis in patients with esophageal atresia and chronic dysphagia

Esophageal atresia(EA)is defined as a discontinuity of the lumen of the esophagus repaired soon after birth.Dysphagia is a common symptom in these patients,usually related to stricture,dysmotility or peptic esophagitis.We present 4 cases of patients with EA who complained of dysphagia and the diagnosis of Eosinophilic esophagitis(Eo E)was made,ages ranging from9 to 16 years.Although our patients were on acid suppression years after their EA repair,they presented with acute worsening of dysphagia.Esophogastroduodenoscopy and/or barium swallow did not show stricture and biopsies revealed elevated eosinophil counts consistent with Eo E.Two of 4 patients improved symptomatically with the topical steroids.It is important to note that all our patients have asthma and 3 out of 4 have tested positive for food allergies.One of our patients developed recurrent anastomotic strictures that improved with the treatment of the Eo E.A previous case report linked the recurrence of esophageal strictures in patients with EA repair with Eo E.Once the Eo E was treated the strictures resolved.On the other hand,based on our observation,Eo E could be present in patients without recurrent anastomotic strictures.There appears to be a spectrum in the disease process.We are suggesting that Eo E is a frequent concomitant problem in patients with history of congenital esophageal deformities,and for this reason any of these patients with refractory reflux symptoms or dysphagia(with or without anastomotic stricture)may benefit from an endoscopic evaluation with biopsies to rule out Eo E.

Eosinophilic esophagitis: A newly established cause of dysphagia

Eosinophilic esophagitis has rapidly become a recognized entity causing dysphagia in young adults. This review summarizes the current knowledge of eosinophilic esophagitis including the epidemiology, clinical presentation, diagnostic criteria, pathophysiology, treatment, and prognosis. An extensive search of PubMed/Medline （1966-December 2005） for available English literature in humans for eosinophilic esophagitis was completed. Appropriate articles listed in the bibliographies were also attained. The estimated incidence is 43/10s in children and 2.5/10s in adults. Clinically, patients have a long history of intermittent solid food dysphagia or food impaction. Some have a history of atopy. Subtle endoscopic features may be easily overlooked, including a ＂feline＂ or corrugated esophagus with fine rings, a diffusely narrowed esophagus that may have proximal strictures, the presence of linear furrows, adherent white plaques, or a friable （crepe paper） mucosa, prone to tearing with minimal contact. Although no pathologic consensus has been established, a histologic diagnosis is critical. The accepted criteria are a dense eosinophilic infiltrate （〉20/high power field） within the superficial esophageal mucosa. In contrast, the esophagitis associated with acid reflux disease can also possess eosinophils but they are fewer in number. Once the diagnosis is established, treatment options may include specific food avoidance, topical corticosteroids, systemic corticosteroids, leukotriene inhibitors, or biologic treatment. The long-term prognosis of EE is uncertain; however available data suggests a benign, albeit inconvenient, course. With increasing recognition, this entity is taking its place as an established cause of solid food dysphagia.

Eosinophilic esophagitis: New insights in pathogenesis and therapy

Eosinophilic esophagitis(Eo E) is a clinico-pathological entity with esophageal symptoms and dense esophageal eosinophilic infiltration throughout the esophagus that may persist despite treatment with proton pump inhibitors. This eosinophilic infiltration is usually absent in the stomach, small intestine and colon, although there are a number of reports of patients with a multiorgan involvement. EoE is associated with abnormalities involving TH2-dependent immunity, with multiple environmental factors strongly contributing to disease expression. The layer of the esophagus affected by the eosinophilic infiltration causes the specific symptoms. Esophageal involvement results mostly in dysphagia for solids that can be severe enough to cause recurrent esophageal obstruction with typical endoscopic features suggesting esophageal remodeling and pathological changes of eosinophilic infiltration of the mucosa, sub-epithelial fibrosis and muscle hypertrophy. This disease is frequently associated with other allergic conditions such as allergic asthma, allergic dermatitis and eosinophilia. The treatment of patients with Eo E depends on the severity of the symptoms and of the inflammatory process as well as to their response to a gradual step-up treatment. The first line of treatment consists of steroid containing local inhalers. If unresponsive they are then treated with oral steroids. Intravenous interleukin blockers seem to have a consistent positive therapeutic effect.

A Novel Therapy of Eosinophilic Esophagitis-Treatment of Eosinophilic Esophagitis Using a Single Dose of Intramuscular Corticosteroid and Proton Pump Inhibitor

Background： Ee （Eosinophilic esophagitis） is an inflammatory condition characterized by a dense eosinophilic infiltrate in the esophageal epithelium. Its pathophysiology mimics that of allergic esophagitis, and evolves clinically as a chronic disease with periods of exacerbation. Symptoms and endoscopic findings are usually non-specific and similar to those of other esophageal illnesses. The mainstay of treatment of Ee is with corticosteroids and/or specific diets, which have been shown to cause symptom remission and histological improvement. Aim： The objective of this study was to demonstrate the efficacy of a novel and promising treatment protocol for Ee. Materials and methods： We prospectively evaluated 24 patients with Ee over two years. Patients were treated with a single intramuscular injection of betamethasone sodium phosphate associated with betamethasone dipropionate and a PPI （proton pump inhibitor） （rabeprazole 20 mg PO）. After 4 weeks of treatment, patients underwent endoscopy and biopsy. We evaluated patients＇ clinical response as well as the results of endoscopic and histological examinations. Results： After 4 weeks of treatment, all patients （100%） are reported significant clinical improvement, which was corroborated by the findings on endoscopy and histology. There were no complications or adverse reactions. Conclusions： In this cohort of patients with eosinophilic esophagitis, treatment with a single intramuscular dose of corticosteroids led to complete remission of symptoms and improvement in endoscopic and histological findings.

Significance of feeding dysfunction in eosinophilic esophagitis

Feeding dysfunction is a frequent presenting symptom of eosinophilic esophagitis(EoE). Here we present 3 children of various ages whose manifestations of EoE associated feeding dysfunction led to significant and life altering impact on their growth and development. Early identification of presenting symptoms of EoE will allow for prompt diagnosis and initiation of appropriate treatments. Recognition of salient features of dysfunction and treatment by feeding therapists and nutritionists led to symptom resolution and growth.

Esophageal squamous papillomas with focal dermal hypoplasia and eosinophilic esophagitis

Focal dermal hypoplasia(FDH) is a rare disorder of the mesodermal and ectodermal tissues. Here we present an eight-year-old female known to have FDH who presents with poor weight gain and dysphagia. She was diagnosed with multiple esophageal papillomas and eosinophilic esophagitis. She was successfully treated with argon plasma coagulation and ingested fluticasone propionate, which has not been described previously in a child.

Histological remission of eosinophilic esophagitis under asthma therapy with IL-5 receptor monoclonal antibody:A case report

BACKGROUND Benralizumab is a monoclonal antibody targeting the IL-5 receptor used in the treatment of asthma.The use of benralizumab in other conditions is only emerging and could represent a therapeutic option for other eosinophil-associated diseases.Here,we report the case of a patient suffering from eosinophilic esophagitis and asthma who achieved histological remission of eosinophilic esophagitis(EoE)under benralizumab treatment for his asthma.CASE SUMMARY Our patient was a 56-year-old white male with a history of eosinophilic esophagitis and severe asthma.After years of usual treatments,including topical steroids,biological treatment with mepolizumab,and standard asthma treatment,only poor control of both conditions was obtained.A control gastroscopy after the initiation of benralizumab showed complete histological remission of his EoE.CONCLUSION Our case shows the effects of therapy with a novel agent not yet approved for this condition but for other diseases,with histological resolution of EoE after treatment.Complete clinical remission was not observed,which exemplifies the complex nature of EoE,its associated psychosomatic burden,and the chronification of the disease.Nevertheless,monoclonal antibodies targeting the Th2 response and,in our case,an IL5 receptor antagonist,achieved complete histological remission,which was not the case with an antibody against IL-5,which was also initiated to treat asthma.

Unusual presentations of eosinophilic gastroenteritis:Case series and review of literature

Eosinophilic gastroenteritis (EG) is an uncommon disease characterized by focal or diffuse eosinophilic infiltration of the gastrointestinal tract, and is usually associated with dyspepsia, diarrhea and peripheral eosinophilia. Diffuse gastrointestinal tract and colonic involvement are uncommon. The endoscopic appearance may vary from normal to mucosal nodularity and ulceration. Gastrointestinal obstruction is unusual and is associated with predominantly muscular disease. We present five unusual cases of EG associated with gastric outlet and duodenal obstruction. Two cases presented with acute pancreatitis and one had a history of pancreatitis. Four cases responded well to medical therapy and one had recurrent gastric outlet obstruction that required surgery. Four out of the five cases had endoscopic and histological evidence of esophagitis and two had colitis. Two patients had ascites. These cases reaffirm that EG is a disorder with protean manifestations and may involve the entire gastrointestinal tract. Gastric outlet and/or small bowel obstruction is an important though uncommon presentation of EG. It may also present as esophagitis, gastritis with polypoid lesions, ulcers or erosions, colitis and pancreatitis and may mimic malignancy.

Proposed criteria to differentiate heterogeneous eosinophilic gastrointestinal disorders of the esophagus, including eosinophilic esophageal myositis

AIM To define clinical criteria to differentiate eosinophilic gastrointestinal disorder(Eo GD) in the esophagus. METHODS Our criteria were defined based on the analyses of the clinical presentation of eosinophilic esophagitis(Eo E), subepithelial eosinophilic esophagitis(s Eo E) and eosinophilic esophageal myositis(Eo EM), identified by endoscopy, manometry and serum immunoglobulin E levels(s-Ig E), in combination with histological and polymerase chain reaction analyses on esophageal tissue samples.RESULTS In five patients with Eo E, endoscopy revealed longitudinal furrows and white plaques in all, and fixed rings in two. In one patient with s Eo E and four with Eo EM, endoscopy showed luminal compression only. Using manometry, failed peristalsis was observed in patients with Eo E and s Eo E with some variation, while Eo EM was associated with hypercontractile or hypertensive peristalsis, with elevated s-Ig E. Histology revealed the following eosinophils per high-power field values. Eo E = 41.4 ± 7.9 in the epithelium and 2.3 ± 1.5 in the subepithelium; s Eo E = 3 in the epithelium and 35 in the subepithelium(conventional biopsy); Eo EM = none in the epithelium, 10.7 ± 11.7 in the subepithelium(conventional biopsy or endoscopic mucosal resection) and 46.8 ± 16.5 in the muscularis propria(peroral esophageal muscle biopsy). Presence of dilated epithelial intercellular space and downward papillae elongation were specific to Eo E. Eotaxin-3, IL-5 and IL-13 were overexpressed in Eo E.CONCLUSION Based on clinical and histological data, we identified criteria, which differentiated between Eo E, s Eo E and Eo EM, and reflected a different pathogenesis between these esophageal Eo GDs.

Esophagitis and its causes:Who is “guilty” when acid is found “not guilty”?

Esophagitis is mainly a consequence of gastroesophageal reflux disease, one of the most common diseases affecting the upper digestive tract. However the esophageal mucosa can also be targeted by some infectious, systemic or chemical conditions. Eosinophilic esophagitis(Eo E) is an immune-mediated inflammatory disease, characterized by eosinophilic infiltration in the mucosa. Esophageal localization of Crohn's disease is not very common, but it should always be considered in patients with inflammatory bowel disease complaining of upper digestive tract symptoms. There are also forms of infectious esophagitis(e.g., Herpes simplex virus or Candida albicans) occurring in patients with a compromised immune system, either because of specific diseases or immunosuppressive therapies. Another kind of damage to esophageal mucosa is due to drug use(including oncologic chemotherapeutic regimens and radiotherapy) or caustic ingestion, usually of alkaline liquids, with colliquative necrosis and destruction of mucosa within a few seconds. Dysphagia is a predominant symptom in Eo E, while infectious, drug-induced and caustic damages usually cause chest pain and odynophagia. Endoscopy can be useful for diagnosing esophagitis, although no specific pattern can be identified. In conclusion when a patient refers upper gastrointestinal tract symptoms and the diagnosis of gastro-esophageal reflux disease is not convincing we should always carefully investigate the patient's clinical history to consider possibilities other than the gastric refluxate.

Treatment of eosinophlic esophagitis with swallowed topical corticosteroids

Eosinophilic esophagitis(EoE)is an emerging chronic local immune-mediated disease of the esophagus.Beside proton pump inhibitors and food-restrictiondiets swallowed topical corticosteroids(STC)can be offered as a first line therapy according to current guidelines.This review describes the background and practical management of STCs in EoE.So far,mainly asthma inhalers containing either budesonide or fluticasone have been administered to the esophagus by swallowing these medications“off label”.Recently esophagus-targeted formulations of topical steroids have been developed showing clinicopathological response rates up to 85%-an orodispersible tablet of budesonide has been approved as the first“in label”medication for EoE in Europe in June 2018.Whereas it was shown that disease remission induction of EoE by STCs is highly effective,there is still a lack of data regarding long-term and maintenance therapy.However,current studies on STC maintenance therapy add some movement into the game.