Eosinophil-associated diseases: the Allergist's and Clinical Immunologist's perspective.

Summary: Eosinophil-associated diseases (EADs) refer to heterogeneous conditions in which eosinophils are believed to play critical pathological roles. They encompass common respiratory conditions, such as asthma, chronic rhinosinusitis with nasal polyps (CRSwNP), less common primary eosinophilic disorders of gastrointestinal tract, and rare conditions including eosinophilic granulomatosis with polyangiitis (EGPA) and hypereosinophilic syndrome (HES). A literature search was carried out in January 2024 in the MEDLINE and Scopus databases using the PubMed search engine (PubMed, National Library of Medicine, Bethesda, MD). We focused on blood eosinophilia and hypereosinophilia. A diagnostic workup is proposed. From allergist's point of view, we focused the review on 4 groups of eosinophilic disorders of specific interest. Our increased understanding of type 2 inflammation and biology has recently led to development of highly effective precision targeted therapies that are now approved for a growing number of eosinophilic disorders. Novel targeted biologics have a major impact on treatment strategies and have resulted in major advances in our understanding of the pathogenesis of these disorders. In the context of EADs, according to the heterogeneity of eosinophilic disorders a multidisciplinary approach should be adopted. Allergists and Clinical Immunologists play an important role as they have a clear understanding of the eosinophilic inflammation and the role of cytokines and are trained to recognize and characterize type 2 (T2) inflammation and its associated pathologies.

A nationwide survey of non-IgE-mediated gastrointestinal food allergies in neonates and infants.

BACKGROUND: Non-IgE-mediated gastrointestinal food allergies (non-IgE-GIFAs) seem to be increasing rapidly worldwide. However, nationwide studies have been limited to food-protein-induced enterocolitis (FPIES) and food-protein-induced allergic proctocolitis (FPIAP), with little attention to other non-IgE-GIFA subgroups. The aim of this study was to elucidate the clinical features of all patients with non-IgE-GIFAs, not just certain subgroups. METHODS: We conducted a nationwide cross-sectional survey of non-IgE-GIFAs in Japan from April 2015 through March 2016. A questionnaire was sent to hospitals and clinics throughout Japan. The questionnaire asked about the number of physician-diagnosed non-IgE-GIFA patients, the status of fulfillment of the diagnostic criteria, tentative classification into 4 clusters based on the initial symptoms, the day of onset after birth, complications, and the suspected offending food(s). RESULTS: The response rate to that questionnaire was 67.6% from hospitals and 47.4% from clinics. Analyses were conducted about "diagnosis-probable" patient cohort (n = 402) and the "diagnosis-confirmed" patients (n = 80). In half of the reported non-IgE-GIFA patients, onset occurred in the neonatal period. The patients were evenly distributed among 4 non-IgE-GIFA clusters. In Cluster 1, with symptoms of vomiting and bloody stool, the onset showed a median of 7 days after birth, which was the earliest among the clusters. Cow's milk was the most common causative food. CONCLUSIONS: In half of the patients, the onset of non-IgE-GIFAs was in the neonatal period. This highlights the importance of studying the pathogenesis in the fetal and neonatal periods.

Tolerability and safety of a new elimination diet for pediatric eosinophilic gastritis and duodenitis.

BACKGROUND: Non-esophageal eosinophilic gastrointestinal disorders (non-EoE EGIDs) are chronic inflammatory disorders with massive infiltration of eosinophils into the gastrointestinal tract. Food elimination diets are potentially effective treatments. But the existing dietary therapies have various weak points. We developed a new regimen to compensate for the shortcomings of the elemental diet and 6-food elimination diet. The new regimen consists of an amino-acid-based formula, potatoes, vegetables, fruits and restricted seasonings. We named it the "Rainbow Elimination Diet (ED)." The aims of this study were to evaluate the tolerability and safety of this diet. METHODS: A retrospective medical record examination was conducted at the National Center for Child Health and Development covering the period from January 2010 through December 2018. The medical records of patients (age 2-17 y) with histologically diagnosed non-EoE EGIDs were reviewed. The tolerability, nutritional intake, symptoms, and blood test findings were evaluated. RESULTS: Nineteen patients were offered several kinds of food-elimination diets. Seven patients (eosinophilic gastritis: 5; gastroenteritis: 1; duodenitis: 1) were treated with Rainbow ED. Six patients were compliant with this diet. The median duration of the diet induction phase was 15 days (range 14-30). All 5 patients who had had symptoms just before the induction phase became symptom-free. The body weight decreased in 5 patients (median -0.6 kg), probably because the serum protein increased, resulting in reduced edema. All 5 patients with hypoproteinemia had elevated serum albumin (median 2.9-3.5 g/dL). The ingested nutritional elements were calculated, and most of them were sufficient, except for fat and selenium. CONCLUSIONS: The Rainbow ED was well-tolerated and safe for pediatric non-EoE EGIDs.

Determination of Biopsy Yield That Optimally Detects Eosinophilic Gastritis and/or Duodenitis in a Randomized Trial of Lirentelimab.

BACKGROUND & AIMS: Eosinophilic gastritis (EG) and eosinophilic duodenitis (EoD), characterized by chronic gastrointestinal (GI) symptoms and increased numbers or activation of eosinophils and mast cells in the GI tract, are likely underdiagnosed. We aimed to determine rates of EG and EoD and number of biopsies required to optimize detection using screening data from a randomized trial of lirentelimab (AK002), an antibody against siglec-8 that depletes eosinophils and inhibits mast cells. We also characterized endoscopic features and symptoms of EG and EoD. METHODS: Subjects with moderate-to-severe GI symptoms, assessed daily through a validated patient-reported outcome questionnaire, underwent endoscopy with a systematic gastric and duodenal biopsy protocol and histopathologic evaluation. EG diagnosis required presence of ≥30 eosinophils/high-power field (eos/hpf) in ≥5 hpfs and EoD required ≥30 eos/hpf in ≥3 hpfs. We analyzed diagnostic yields for EG and EoD and histologic, endoscopic, and clinical findings. RESULTS: Of 88 subjects meeting symptom criteria, 72 were found to have EG and/or EoD (EG/EoD), including patients with no prior diagnosis of EG/EoD. We found that GI eosinophilia was patchy and that examination of multiple biopsies was required for diagnosis-an average of only 2.6 per 8 gastric biopsies and 2.2 per 4 duodenal biopsies per subject met thresholds for EG/EoD. Evaluation of multiple nonoverlapping hpfs in each of 8 gastric and 4 duodenal biopsies was required to capture 100% of EG/EoD cases. Neither endoscopic findings nor symptom severity correlated with eosinophil counts. CONCLUSIONS: In an analysis of patients with moderate-to-severe GI symptoms participating in a clinical trial of lirentelimab for EG/EoD, we found eosinophilia to be patchy in gastric and duodenal biopsies. Counting eosinophils in at least 8 gastric and 4 duodenal biopsies is required to identify patients with EG/EoD, so they can receive appropriate treatment. (ClinicalTrials.gov, Number: NCT03496571).

Strategy for Food Reintroduction Following Empiric Elimination and Elemental Dietary Therapy in the Treatment of Eosinophilic Gastrointestinal Disorders.

PURPOSE OF REVIEW: This review presents the available data regarding efficacy of nutritional therapy, highlighting clinical decision points and a strategy for reintroduction of foods following an elemental diet for treatment of eosinophilic gastrointestinal disorders. RECENT FINDINGS: Elemental and empiric elimination diets are highly effective treatments for eosinophilic gastrointestinal diseases. Standardization in the reintroduction phase, after utilizing the diet for disease remission, is lacking. Clinicians are confronted with multiple challenges regarding the best practice for food reintroduction and identification of potential dietary triggers including order of foods being challenged and duration between endoscopic procedures. Individualization is required for preference and adherence to optimize quality of life and treatment success for this burdensome and life altering immune driven gastrointestinal disorder. Age specific concerns for children, teenagers, and adults should be assessed using a patient centric approach.

Intestinal overexpression of IL-18 promotes eosinophils-mediated allergic disorders.

Baseline eosinophils reside in the gastrointestinal tract; however, in several allergic disorders, excessive eosinophils accumulate in the blood as well in the tissues. Recently, we showed in vitro that interleukin (IL)-18 matures and transforms IL-5-generated eosinophils into the pathogenic eosinophils that are detected in human allergic diseases. To examine the role of local induction of IL-18 in promoting eosinophil-associated intestinal disorders, we generated enterocyte IL-18-overexpressing mice using the rat intestinal fatty acid-binding promoter (Fabpi) and analysed tissue IL-18 overexpression and eosinophilia by performing real-time polymerase chain reaction, Enzyme-Linked Immunosorbent Assay and anti-major basic protein immunostaining. Herein we show that Fabpi-IL-18 mice display highly induced IL-18 mRNA and protein in the jejunum. IL-18 overexpression in enterocytes promotes marked increases of eosinophils in the blood and jejunum. Our analysis shows IL-18 overexpression in the jejunum induces a specific population of CD101+  CD274+ tissue eosinophils. Additionally, we observed comparable tissue eosinophilia in IL-13-deficient-Fabpi-IL-18 mice, and reduced numbers of tissue eosinophils in eotaxin-deficient-Fabpi-IL-18 and IL-5-deficient-Fabpi-IL-18 mice compared with Fabpi-IL-18 transgenic mice. Notably, jejunum eosinophilia in IL-5-deficient-Fabpi-IL-18 mice is significantly induced compared with wild-type mice, which indicates the direct role of induced IL-18 in the tissue accumulation of eosinophils and mast cells. Furthermore, we also found that overexpression of IL-18 in the intestine promotes eosinophil-associated peanut-induced allergic responses in mice. Taken together, we provide direct in vivo evidence that induced expression of IL-18 in the enterocytes promotes eotaxin-1, IL-5 and IL-13 independent intestinal eosinophilia, which signifies the clinical relevance of induced IL-18 in eosinophil-associated gastrointestinal disorders (EGIDs) to food allergens.

Elevated Tryptase in EoE Is an Independent Phenomenon Associated with Extra-Esophageal Symptoms.

BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic disease characterized histologically by > 15 eosinophils per high-power field (eos/hpf). Esophageal mucosal mast cells have been implicated in EoE pathogenesis. The association of atopy with EoE has been established but has not been correlated with levels of serum tryptase. The lack of concurrent atopy in some patients suggests the possibility that atopy may either be the related subtype of EoE or may be a sign of comorbidities. No study has looked at whether patients present with different phenotypes/comorbid disease when they have evidence of elevated serum tryptase. We hypothesized that these patients differ with respect to presentation and comorbidities with more refractory GI disease. AIMS: To examine whether elevations of serum tryptase associate with different, more severe clinical presentations in EoE patients which may be explained via mast cell activation. MATERIALS AND METHODS: Retrospective chart review identified 72 patients with EoE with results for serum tryptase between 2015 and 2016. Patients were classified as TryptaseHI (tryptase > 10.9 µg/l) and TryptaseLO (< 10.9 µg/l). Clinical characteristics and treatment response were compared using univariate analysis and multivariate regression between the groups. RESULTS: Out of 72 patients, 12 were tested as TryptaseHI (16.7%, 95% CI 8.1-25.3%). TryptaseHI was associated frequently with asthma (P = 0.0003), urticaria (P = 0.002), arthralgia (P = 0.005), sinusitis (P = 0.03), nausea/vomiting (P = 0.046), and eosinophilic gastrointestinal disease (P = 0.001). Asthma and arthralgia were found to be significantly associated with TryptaseHI (P = 0.0013, P = 0.0098, respectively). Mucosal eosinophil counts and tryptase levels were not correlated (R2 0.095, P = 0.77). Tryptase did not resolve with resolution of esophageal eosinophilia. CONCLUSIONS: We found that EoE patients with elevated tryptase levels more commonly presented with asthma, urticaria, arthralgia, nausea/vomiting, sinusitis, and more distal eosinophilia. This indicates that atopy in EoE patients warrants further exploration. The lack of correlation between histologic remission and reduction of serum tryptase levels post-treatment suggests that mast cell activation may be an independent, yet associated disease. More study into this unique association is warranted.

Molecular diagnosis of eosinophilic esophagitis by gene expression profiling.

BACKGROUND & AIMS: Gene expression profiling provides an opportunity for definitive diagnosis but has not yet been well applied to inflammatory diseases. Here we describe an approach for diagnosis of an emerging form of esophagitis, eosinophilic esophagitis (EoE), which is currently diagnosed by histology and clinical symptoms. METHODS: We developed an EoE diagnostic panel (EDP) comprising a 96-gene quantitative polymerase chain reaction array and an associated dual-algorithm that uses cluster analysis and dimensionality reduction using a cohort of randomly selected esophageal biopsy samples from pediatric patients with EoE (n = 15) or without EoE (non-EoE controls, n = 14) and subsequently vetted the EDP using a separate cohort of 194 pediatric and adult patient samples derived from both fresh or formalin-fixed, paraffin-embedded tissue: active EoE (n = 91), control (non-EoE and EoE remission, n = 57), histologically ambiguous (n = 34), and reflux (n = 12) samples. RESULTS: The EDP identified adult and pediatric patients with EoE with approximately 96% sensitivity and approximately 98% specificity, and distinguished patients with EoE in remission from controls, as well as identified patients exposed to swallowed glucorticoids. The EDP could be used with formalin-fixed, paraffin-embedded tissue RNA and distinguished patients with EoE from those with reflux esophagitis, identified by pH-impedance testing. Preliminary evidence showed that the EDP could identify patients likely to have disease relapse after treatment. CONCLUSIONS: We developed a molecular diagnostic test (referred to as the EDP) that identifies patients with esophagitis in a fast, objective, and mechanistic manner, offering an opportunity to improve diagnosis and treatment, and a platform approach for other inflammatory diseases.

High prevalence of eosinophilic esophagitis in patients with inherited connective tissue disorders.

BACKGROUND: Eosinophilic esophagitis (EoE) is an emerging chronic inflammatory disease mediated by immune hypersensitization to multiple foods and strongly associated with atopy and esophageal remodeling. OBJECTIVE: We provide clinical and molecular evidence indicating a high prevalence of EoE in patients with inherited connective tissue disorders (CTDs). METHODS: We examined the rate of EoE among patients with CTDs and subsequently analyzed esophageal mRNA transcript profiles in patients with EoE with or without CTD features. RESULTS: We report a cohort of 42 patients with EoE with a CTD-like syndrome, representing 0.8% of patients with CTDs and 1.3% of patients with EoE within our hospital-wide electronic medical record database and our EoE research registry, respectively. An 8-fold risk of EoE in patients with CTDs (relative risk, 8.1; 95% confidence limit, 5.1-12.9; χ(2)1 = 112.0; P < 10(-3)) was present compared with the general population. Esophageal transcript profiling identified a distinct subset of genes, including COL8A2, in patients with EoE and CTDs. CONCLUSION: There is a remarkable association of EoE with CTDs and evidence for a differential expression of genes involved in connective tissue repair in this cohort. Thus, we propose stratification of patients with EoE and CTDs into a subset referred to as EoE-CTD.

A case of non-esophageal eosinophilic gastrointestinal disease diagnosed by mucosal incision-assisted biopsy.

A 46-year-old woman presented at our hospital with anorexia, vomiting, and diarrhea. Blood tests indicated markedly increased eosinophil counts, and esophagogastroduodenoscopy revealed slight erythema in the gastric body. Computed tomography showed edematous thickening of the stomach and small intestinal walls and peritonitis. Thus, eosinophilic gastrointestinal disease was suspected. Endoscopic biopsies from the esophagus, stomach, and duodenum were collected, but no significant increases in eosinophil counts were observed. Little ascites effusion was detected and puncture cytology was difficult to perform. Thus, a sample of the muscularis propria layer was obtained by mucosal incision-assisted biopsy. Histopathological examination of the biopsy revealed significant eosinophilic infiltration within the muscularis propria layer of the stomach, confirming the diagnosis of non-eosinophilic esophagitis eosinophilic gastrointestinal disease. The patient was treated with a leukotriene receptor antagonist and prednisolone, and her clinical symptoms and gastrointestinal wall thickening rapidly improved. The Japanese diagnostic guideline for non-eosinophilic esophagitis eosinophilic gastrointestinal disease requires endoscopic biopsy or eosinophilic infiltration of ascites fluid. When diagnosis is difficult using conventional methods, as in this case, mucosal incision-assisted biopsy is useful as a next step.

Impact of Atopic Status on Clinical Presentation and Treatment Response in Pediatric Patients With Eosinophilic Esophagitis.

BACKGROUND: Nearly 80% of patients with eosinophilic esophagitis (EoE) have coexisting atopic disease, yet a subset do not. It is unclear if this lack of atopy impacts presentation or response to therapy. OBJECTIVES: To characterize the presentation and response to therapy in atopic versus nonatopic pediatric patients with EoE. METHODS: A case-control study of patients with EoE aged 6 months to 18 years (between 2018 and 2021) was performed. Patients were eligible if they had allergy testing, assessment of atopic history, and at least 1 endoscopy after initiation of treatment. Patients were considered nonatopic if they had negative allergy testing and no history of significant atopy. Response to therapy was classified as complete (peak eosinophils [eos] <15/high power field [hpf]), partial (≥15 eos/hpf but at least a 50% reduction in peak eos), or nonresponse. RESULTS: A total of 168 participants were enrolled. The majority were White (n = 141, 84%), male (n = 124, 74%), and non-Hispanic (n = 158, 95%). The mean age at diagnosis was 9.4 years (standard deviation: ±4.8 years). A total of 123 participants (73.2%) were atopic, and 45 (26.8%) were nonatopic. There was no significant difference between atopic and nonatopic for most demographics or presenting symptoms. Nonatopic participants were younger than atopic participants (8.14 vs 9.8 years, P = .046). Swallowed topical corticosteroids (STC) and food elimination diets (FED) were used at a similar rate. There were no differences in treatment response between atopic/nonatopic participants in regard to STC, FED, or STC+FED. CONCLUSIONS: Atopic status does not significantly impact presentation or response to treatment in pediatric EoE, but a lack of atopy may be a risk for earlier onset of disease.

Pathophysiology of Non-Esophageal Eosinophilic Gastrointestinal Disorders.

Eosinophilic gastrointestinal disorder (EGID) is an umbrella term encompassing a group of chronic, immune-mediated disorders characterized by eosinophil-rich inflammation affecting one or more segments of the gastrointestinal tract. A recent consensus in nomenclature and emerging data made possible through multi-center consortia are beginning to unravel the molecular and cellular underpinnings of EGIDs below the esophagus. These emerging findings are revealing both overarching commonalities related to a food allergen-driven, chronic, Th2-mediated immune response as well as location-specific nuances in the pathophysiology of the collective EGIDs. Altogether, these advances offer promise for improved diagnoses and more efficacious interventional strategies.

Dupilumab Leads to Clinical Improvements including the Acquisition of Tolerance to Causative Foods in Non-Eosinophilic Esophagitis Eosinophilic Gastrointestinal Disorders.

A recent report showed that most pediatric cases of non-eosinophilic esophagitis (EoE) eosinophilic gastrointestinal disorders (EGIDs) (non-EoE EGIDs) are persistent and severe compared with those of EoE, thus requiring further effective therapeutic approaches. In this study, we present the first case based on a systematic search of non-EoE EGID for which tolerance to causative foods and histological and symptomatic improvements were achieved following dupilumab administration, after elimination diets and omalizumab and mepolizumab treatments. Driven by this case, we investigated the efficacies of biological treatments in non-EoE EGID cases based on the patient studied herein, and other patients identified in the conducted systematic review. Seven articles, including five different biologics, were reviewed. Both clinical efficacies and impact differences among the targeted molecules are demonstrated in this study. Our findings show that dupilumab may affect mechanisms that can suppress symptoms induced by offending foods that are different from those induced by other biologics as identified in the conducted systematic review. Additional studies are required to address the unmet needs of non-EoE EGID treatments.

The efficacy of dupilumab in induction and maintenance of remission in an adult patient with steroid-dependent eosinophilic enteritis (EoN).

Eosinophilic enteritis (EoN) is associated with an eosinophilic infiltrate confined to the small intestine, but treatment options other than diet and corticosteroid therapy are scarce. There is only one report of the use of dupilumab for eosinophilic gastrointestinal disease, involving three pediatric patients. We report a case of successful induction of remission with dupilumab in a 53 year-old female patient with steroid-dependent EoN. The patient presented to the emergency room with uncontrollable abdominal pain and CT revealed a thickened ileal wall and small amount of ascites. Despite no abnormalities on endoscopy, histological examination revealed numerous eosinophilic infiltrates (> 100/HPF) and degranulation in the ileal lamina propria, diagnosing the patient with EoN. The patient achieved clinical remission with prednisolone, but EoN relapsed during tapering. Long-term steroid therapy was inappropriate due to mandibular osteomyelitis and osteoporosis, and she was switched to 9 mg budesonide, an intestine-soluble topical steroid without effect. Dupilumab administration resulted in resolution of abdominal pain, and remission was maintained after discontinuation of budesonide. Histological remission was confirmed 2 months after dupilumab administration. This is the first report of remission induced and maintained with dupilumab in an adult patient with EoN.

Eosinophilic gastrointestinal disorders in patients with inborn errors of immunity: Data from the USIDNET registry.

Rationale: Eosinophilic gastrointestinal disorders (EGID), including eosinophilic esophagitis (EoE), are inflammatory disorders of the gastrointestinal mucosa mediated by complex immune mechanisms. Although there have been initial reports of EGID in patients with inborn errors of immunity (IEI), little is known about the presentation of EGID in immunodeficient individuals. Methods: We queried the U.S. Immunodeficiency Network (USIDNET) for patient records including the terms eosinophilic esophagitis, gastritis, enteritis, or colitis. We analyzed 74 patient records from the database, including diagnoses, demographics, infectious history, laboratory findings, genetic studies, therapeutic interventions, and clinical outcomes. Results: We examined 74 patient records. A total of 61 patients had isolated EoE, and 13 had distal gastrointestinal involvement consistent with EGID. The most common IEI were common variable immunodeficiency (43.2%), some form of combined immunodeficiency (21.6%), chronic granulomatous disease (8.1%), hyper-IgE syndrome (6.8%), and autoimmune lymphoproliferative syndrome (6.8%). The median age at presentation with IEI was 0.5 years (IQR 1.725, max 39 years) and 56.76% were male. Approximately 20% of the patients in the cohort received a hematopoietic stem cell transplantation for treatment of IEI, but the timing of the HSCT in relationship to the EGID diagnosis was unknown. Conclusions: Here, we report EGID in a diverse cohort of IEI patients, suggesting that both non-EoE EGID and EoE can be seen as comorbid conditions with a variety of IEI. Our data suggests that EGID may be more common in patients with IEI than would be expected based on estimates of EGID in the general population.

Eosinophilic Esophagitis Patients Are Not at Increased Risk of Severe COVID-19: A Report From a Global Registry.

BACKGROUND: The impact of coronavirus disease 2019 (COVID-19) on eosinophilic esophagitis (EoE) and eosinophilic gastrointestinal diseases (EGIDs) is unknown. OBJECTIVE: We aimed to characterize patients with EoE and EGIDs who had COVID-19, assess severity of COVID-19 in the EoE/EGID population, and evaluate for COVID-19-induced EoE/EGID flares. METHODS: We established an online global registry collecting physician entered, deidentified data related to patient demographics, EoE/EGID disease features, comorbidities, and treatments, COVID-19 source of exposure, symptoms, illness severity, hospitalizations, and deaths. RESULTS: Ninety-four cases were reported between March 2020 and April 2021 (median age, 21 years; range, 1.5-53 years; 73% male). Most had atopy (73%), and 80% had isolated EoE. Before COVID-19, the EoE/EGID activity was reported as clinical remission in 51 (54%) and moderate in 20 (21%). EoE/EGID treatments at the time of COVID-19 included proton pump inhibitors 49 (52%), swallowed/topical steroids 48 (51%), and dietary elimination 34 (36%). COVID-19 symptoms included cough (56%), fever (49%), anosmia (21%), and ageusia (22%). Most patients with COVID-19 had a mild course (70%), with 15% asymptomatic, 12% moderate, and 2% severe. Three patients were hospitalized, and no intensive care unit admissions or deaths were reported. Mean time from first symptoms to resolution in symptomatic patients was 10 days (range, 1-90 days). A single EGID flare was reported during COVID-19. CONCLUSIONS: In a global EoE/EGID registry, relatively few COVID-19 cases have been reported. COVID-19 severity was comparable to the general population. Based on this registry, it does not appear that patients with EoE are at increased risk for severe COVID-19 infection or that COVID-19 leads to EGID flares.

Experimental Modeling of Eosinophil-Associated Diseases.

Eosinophils are an important subtype of leukocytes derived from bone marrow multipotent hematopoietic stem cells and represent about 1% of leukocytes in circulating blood. In homeostatic conditions, eosinophils reside in the intestine to maintain the balance of immune responses by communicating with gut microbes without causing inflammation. However, under the stressed or diseased condition, eosinophils degranulate, releasing their granule-derived cytotoxic proteins that are involved in inflammatory responses. Various eosinophil-associated inflammatory diseases are eosinophilic esophagitis (EoE), eosinophilic gastroenteritis (EG), and eosinophilic colitis (EC), together called EGID, asthma, hypereosinophilic syndrome, and eosinophilic pneumonia (EP). Eosinophil degranulation results in the release of their four toxic proteins [major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil peroxidase (EPO), and eosinophil-derived neurotoxin (EDN)] which promote disease pathogenesis. Pancreatitis is the inflammatory disease of the pancreas that arises due to blockage of the pancreatic duct, trypsinogen mutation, alcohol consumption, and repeated occurrence of pancreatitis leading to chronic pancreatitis (CP); subsequently some CP patients may also develop pancreatic cancer. The presence of eosinophils is now shown in various case reports with acute, recurrent acute, and chronic pancreatitis and pancreatic cancer indicating the role of eosinophils in the pathogenesis of various pancreatic inflammatory disorders. However, the details of eosinophil accumulation during pancreatic diseases are not well explored and need further attention. Overall, the chapter provides the current understanding of reported eosinophils associated with inflammatory diseases like EGID diseases, asthma, and pancreatic disorders, i.e., acute, chronic pancreatitis, and pancreatic cancer. This knowledge will be helpful for future studies to develop novel treatment options for the eosinophils associated diseases. Therefore, more efforts are needed to perform preclinical and clinical studies in this field for the successful development of eosinophil-targeting treatments for a variety of eosinophil-associated diseases.

Clinical and Psychological Impact of COVID-19 Infection in Adult Patients with Eosinophilic Gastrointestinal Disorders during the SARS-CoV-2 Outbreak.

Eosinophilic gastrointestinal diseases (EGIDs) are chronic gastrointestinal conditions requiring corticosteroid and immunosuppressive therapy for disease control. Patients with EGIDs usually report impaired quality of life. We aimed to report the clinical and psychological impact of COVID-19 infection in EGID patients. In this prospective web-based study we invited all consecutive EGID patients attending the University Hospital of Salerno (Campania) and Padua (Veneto) to fill an ad hoc COVID-19 survey. Moreover, a telemedicine service for direct consultation was organized. Data regarding the occurrence and perception of COVID-19 infection as well as clinical information were recorded. The study population included 102 EGID patients (mean age 36.6 years, 34 females), of whom 89 had eosinophilic esophagitis, nine had gastroenteritis, and four had colitis. No patient was diagnosed with COVID-19 or had recurrence of his/her primary disease. All of them were adherent to therapy and preventive measures adoption. Most patients were worried because of COVID-19 and social preventing measures but did not consider themselves at major risk or susceptible to COVID-19 or other infections due to their chronic condition or therapy. Female gender and low education level were associated to a higher psychological perception of COVID-19 compared to lockdown status or other demographic and clinical factors (p < 0.05). Overall, COVID-19 had a limited clinical impact on patients with EGIDs. The degree of education and sex, but not the fact of living in a lockdown area, influenced the perception of SARS-CoV-2 infection.

Eosinophilic Disorders of the Gastrointestinal Tract.

Eosinophilic gastrointestinal disorders represent a spectrum of disorders demonstrating gastrointestinal eosinophilia without any known cause for eosinophilia. Pathogenesis is not clearly established, but immune responses to dietary antigens are implicated. These disorders affect children and adults and are seen in association with allergic disorders. Eosinophilic esophagitis is diagnosed in the setting of mucosal eosinophilia on endoscopic biopsy and symptoms of esophageal dysfunction. Eosinophilic gastroenteritis is also diagnosed with endoscopic biopsies. Eosinophilic colitis commonly presents with lower gastrointestinal symptoms and is a diagnosis of exclusion.

Elements Involved In Promoting Eosinophilic Gastrointestinal Disorders.

Eosinophilic gastrointestinal disorders (EGID) are food allergen-induced allergic gastrointestinal disorders, characterized by accumulation of highly induced eosinophils in different segments of gastrointestinal tract along with eosinophil microabssess and extracellular eosinophilic granules in the epithelial layer. EGID are both IgE- and cell-mediated group of diseases that include eosinophilic esophagitis (EoE), eosinophilic gastritis (EG), eosinophilic gastroenteritis (EGE) and eosinophilic colitis (EC). Despite the increased incidences and considerable progress made in understanding EGID pathogenesis. The mechanism is still not well understood. It has been shown that IL-4, IL-5, IL-13, IL-15, IL-18, eotaxin-1, eotaxin-2 and eotaxin-3 play a critical role in EGID pathogenesis. Currently, the only criterion for diagnosing EoE, EGE and EC are repetitive endoscopic and histopathological evaluation of biopsies along with other clinical characteristics/manifestations. Antigen elimination and corticosteroid therapies are the most effective therapies currently in practice for the treatment of EGID. The cytokines (anti-IL-5 and anti-IL-13) therapy trials were not very successful in case of EoE. Most recently, a clinical trial using anti-IL-13 reported only 60% reduced esophageal eosinophilia without achieving primary endpoint. This clinical finding is not surprising and is in accordance with our earlier report indicating that IL-13 is not critical in the initiation of EoE. Notably, EGID still has no reliable noninvasive diagnostic biomarkers. Hence, there is a great necessity to identify novel noninvasive diagnostic biomarkers that can easily diagnose EGID and provide an effective therapy. Now, the attention is required to target cell types like iNKT cells that produce eosinophil active cytokines and is found induced in the pathogenesis of both experimental and human EoE. iNKT cell neutralization is shown to protect allergen-induced EoE in experimental model. In this review, we have discussed the key elements that are critical in the disease initiation, progression, pathogenesis and important for future diagnostic and therapeutic interventions for EGID.