Breakthroughs in understanding and treating eosinophilic gastrointestinal diseases presented at the CEGIR/TIGERs Symposium at the 2022 American Academy of Allergy, Asthma & Immunology Meeting.

The Consortium of Eosinophilic Gastrointestinal Diseases and The International Gastrointestinal Eosinophil Researchers organized a day-long symposium at the 2022 Annual Meeting of the American Academy of Allergy, Asthma & Immunology. The symposium featured a review of recent discoveries in the basic biology and pathogenesis of eosinophilic gastrointestinal diseases (EGIDs) in addition to advances in our understanding of the clinical features of EGIDs. Diagnostic and management approaches were reviewed and debated, and clinical trials of emerging therapies were highlighted. Herein, we briefly summarize the breakthrough discoveries in EGIDs.

Efficacy of ultrasonographic caudal vena cava to aorta ratios for quantifying canine parvoviral enteritis rehydration.

Quantifying changes in intravascular fluid volume is important for treatment planning and follow-up assessment in dogs with dehydration. Recently, it has been reported that current standard methods used to estimate intravascular fluid volume in dogs are inadequate, invasive, or have complications such as thrombosis. The ultrasonographic ratio of dimensions for the caudal vena cava relative to the aorta (CVC/Ao) has been previously described as a promising, noninvasive method for quantifying changes in blood volume in dogs. This prospective observational study aimed to describe ultrasonographic CVC/Ao values before and after fluid replacement in a sample of dogs with varying degrees of dehydration due to naturally-occurring canine parvoviral enteritis (CPE), test correlations between this measure and clinical dehydration scores and determine the clinical efficacy of this measure for fluid therapy follow-up. The clinical dehydration score of 30 dogs naturally infected with canine parvovirus was determined at the first admission using standard clinical scoring methods, and then CVC/Ao was measured ultrasonographically. Following initial fluid therapy, the clinical dehydration scores and ultrasonographic CVC/Ao values were remeasured. On the basis of receiver operating characteristic analyses, ultrasonographic CVC/Ao was found to be a more sensitive and specific indicator than physical examination-based methods for estimating intravascular fluid alterations in dogs with dehydration due to parvovirus and rehydration following fluid therapy. Findings supported the use of this measure for treatment planning and follow-up in future dogs presenting with dehydration.

Elemental diet therapy for eosinophilic gastroenteritis and dietary habits.

BACKGROUND: Eosinophilic gastrointestinal disorders (EGID) are a group of conditions with increased eosinophilic infiltration in any part of the gastrointestinal tract. Although an allergic reaction to certain foods is considered the main cause of EGID, their detailed pathomechanism has not yet been elucidated, nor have proper management strategies been fully established. Moreover, some patients with intractable EGID are resistant to such therapies as an empirical elimination diet and corticosteroids. METHODS: We analyzed retrospectively the medical records of four children with intractable eosinophilic gastroenteritis (EGE) managed with elemental diet therapy (EDT) using an amino acid-based formula. RESULTS: All patients displayed resolution of their symptoms after 2 weeks of EDT. Three patients successfully completed food reintroduction and could return to their normal life. No adverse events related to EDT were recorded. CONCLUSIONS: Elemental diet therapy appears effective and safe for treating pediatric intractable EGE symptoms. Afterwards, the patient's dietary habits should be considered during carefully monitored food reintroduction. With the relatively small number of published case reports and no randomized trials, more study is needed on EDT for EGE.

Clinical features of pediatric eosinophilic gastroenteritis.

BACKGROUND: No study has analyzed more than100 cases of eosinophilic gastroenteritis (EGE) in children in a single center. We aimed to describe the clinical features of pediatric EGE. METHODS: This retrospective study was conducted at a single center. Between April 2007 and December 2017, 860 children between the ages of 1 year and 15 years underwent endoscopy for gastrointestinal symptoms of unknown cause. Among them, 109 (12.7%) were diagnosed with EGE according to the diagnostic criteria for EGE developed by the research group of the Ministry of Health, Labour and Welfare of Japan for eosinophilic gastrointestinal disorder in 2015. We investigated their symptoms, comorbidities, endoscopic findings, pathological findings, treatments, and outcomes. RESULTS: Seventy-one boys (65.1%) and 38 girls (34.9%) were diagnosed with EGE. The median age at diagnosis was 11 years (range, 1-15 years). The chief complaints were abdominal pain in 83 (76.1%) and diarrhea in 26 (23.9%). Upper and lower gastrointestinal endoscopies showed normal findings in 32 patients (29.4%). The most common treatment was a combination of elimination of foods suspected of causing EGE and anti-allergic agents in 50 cases (45.9%). The outcomes were symptom disappearance in 43 patients (39.4%) and symptom improvement in 53 patients (48.6%). CONCLUSIONS: For gastrointestinal symptoms of unknown cause in children, EGE should be considered as a differential diagnosis. Although the symptoms and endoscopic findings are nonspecific, cracked mucosa may be a specific endoscopic finding for pediatric EGE. An elimination diet and/or anti-allergic drugs were effective in most patients with pediatric EGE.

Lactobacillus johnsonii L531 ameliorates enteritis via elimination of damaged mitochondria and suppression of SQSTM1-dependent mitophagy in a Salmonella infantis model of piglet diarrhea.

Newly weaned piglets challenged with Salmonella infantis were particularly susceptible, whereas oral preadministration of Lactobacillus johnsonii L531 alleviated enteritis and promoted intestinal secretory IgA production. Salmonella infantis-induced activation of NLRC4 and NLRP3 inflammasomes and (nuclear factor kappa B) NF-κB signaling in the small intestine was also inhibited by L. johnsonii L531 pretreatment, thus limiting inflammation. An IPEC-J2 cell model of S. infantis infection yielded similar results. Salmonella infantis infection also resulted in mitochondrial damage and impaired mitophagy in the ileum and IPEC-J2 cells, as demonstrated by immunofluorescence colocalization of mitochondria with microtubule-binding protein light chain 3 (LC3) and high expression of autophagy-related proteins PTEN-induced putative kinase 1 (PINK1), sequestosome 1 (SQSTM1/p62), optineurin (OPTN), and LC3 by Western blotting analysis. However, L. johnsonii L531 pretreatment reduced both the extent of mitochondrial damage and autophagy-related protein expression. Our findings suggest that the amelioration of S. infantis-associated enteritis by L. johnsonii L531 is associated with regulation of NLRC4 and NLRP3 inflammasomes and NF-κB signaling pathway activation and suppression of mitochondrial damage. Amelioration of impaired mitophagy by L. johnsonii L531 could involve eliminating damaged mitochondria and regulating S. infantis-induced activation of the NF-κB-SQSTM1mitophagy signaling pathway in host cells to prevent the further mitochondrial damage and S. infantis dissemination.

Primary Eosinophilic Gastrointestinal Diseases Beyond Eosinophilic Esophagitis in Children.

OBJECTIVES: There are many unknowns about primary eosinophilic gastrointestinal disease (EGID) in childhood. The aim of this study is to provide data about the frequency, management, control level, and prognosis of well documented primary EGID in childhood. METHODS: This study was conducted in children who underwent endoscopy and/or colonoscopy at a single center over 10-year period up to August 2018. Primary EGID was diagnosed after exclusion of secondary EGID and classified as eosinophilic gastritis (EG), eosinophilic enteritis (EE), eosinophilic gastroenteritis (EGE: eosinophilic gastritis with eosinophilic enteritis) and eosinophilic colitis (EC) according to histopathological evaluation. The pathological number of eosinophil counts were accepted as >30 hpf for gastric mucosa in 5 hpf area, ≥20/hpf for duodenal, jejunal, and ileal mucosa, >50/hpf for right colonic mucosa, >35/hpf for transverse colonic mucosa, and >25/hpf for left colonic mucosa. Presenting symptoms, signs, management, follow-up, disease control level, and remission were analyzed. Remission is defined if the patient is controlled with all clinical, endoscopic/colonoscopic, and histopathologic parameters without any treatments or diet for at least a year. RESULTS: During the study period, 7457 biopsies were taken in 8262 endoscopy and/or colonoscopy procedures. Primary and secondary EGID frequencies were found 0.23% (n = 17 patients) and 0.1% (n =8 patients) per procedure with biopsy in children, respectively. Endoscopy/colonoscopy procedures were not able to performed in 9 patients because of short follow-up period (n = 6) or patients leaving follow-up (n = 3). Nine of the primary EGID patients had esophageal eosinophilia (EsE) at the time of diagnosis, 5 of them were previously managed as EoE. The median follow-up period of primary EGID patients excluding the ones without a control endoscopy/colonoscopy procedure was 3.35 years (min-max: 1.1-9.0 years). Proton pump inhibitors (PPI) were the most frequently used treatment alone or in combination with diet, systemic and/or topical corticosteroids. Disease control was evaluated in 8 of 17 patients and it was uncontrolled in 4, partially controlled in 1, and controlled in 3 patients. Remission was achieved in 2 patients. CONCLUSIONS: The frequency of primary EGID beyond eosinophilic esophagitis (EoE) in children is low. It may be difficult to achieve control in children with primary EGID in the long-term follow-up.

Advancing patient care through the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR).

Recent advances in rare disease research are accelerated by the work of consortia that have been supported by the National Institutes of Health. Development of such consortia rely on multidisciplinary relationships and engagement with patient advocacy groups, as well as the National Institutes of Health and industry and academic partners. In this rostrum we present the development of such a process that focuses on eosinophilic gastrointestinal diseases. Principal investigators, patient advocacy groups, research assistants, and trainees work together to perform natural history studies that promote clinical trial readiness tools, conduct clinical trials, train a new generation of investigators, and perform innovative pilot studies.

Radiation enteritis: from diagnosis to management.

PURPOSE OF REVIEW: As cancer treatments improve more patients than ever are living for longer with the side effects of these treatments. Radiation enteritis is a heterogenous condition with significant morbidity. The present review aims to provide a broad overview of the condition with particular attention to the diagnosis and management of the condition. RECENT FINDINGS: Radiation enteritis appears to be more prevalent than originally thought because of patient underreporting and a lack of clinician awareness. Patient-related and treatment-related risk factors have now been identified and should be modified where possible. Medical and surgical factors have been explored, but manipulation of the gut microbiota offers one of the most exciting recent developments in disease prevention. Diagnosis and treatment are best approached in a systematic fashion with particular attention to the exclusion of recurrent malignancy and other gastrointestinal conditions. Surgery and endoscopy both offer opportunities for management of the complications of radiation enteritis. Experimental therapies offer hope for future management of radiation enteritis but large-scale human trials are needed. SUMMARY: Radiation enteritis is an important clinical problem, but awareness is lacking amongst patients and physicians. Clinical guidelines would allow standardised management which may improve the burden of the disease for patients.

Future therapies for eosinophilic gastrointestinal disorders.

OBJECTIVE: To review novel therapeutics in development for treatment of eosinophilic gastrointestinal disorders (EGIDs). DATA SOURCES: Clinical trial data (clinicaltrials.gov) and literature search on PubMed. STUDY SELECTIONS: Studies on treatment and clinical trials in EGIDs were included in this review. RESULTS: During the past decade, significant progress has been made in understanding disease mechanisms in EGIDs. As a result, a variety of novel therapeutics have been developed for treatment of these disorders. Several monoclonal antibodies against targets, including interleukin (IL) 4, IL-5, IL-13, integrins, and siglec-8, have shown promise in early trials. Novel formulations of corticosteroids are also in development. CONCLUSION: The field of EGID research has advanced rapidly, and disease-modifying therapeutics are closer to clinical application.

Viral enteritis in intestinal transplant recipients.

Intestinal transplant recipients (ITR) are at high risk for infections due to the high level of immunosuppression required to prevent rejection. There are limited data regarding viral enteritis post-intestinal transplantation. We retrospectively reviewed ITR transplanted between January 2008 and December 2016. Descriptive statistics, including mean (standard deviation) and median (range), were performed. Sixty-one (43.9%) of the 139 transplanted patients had viral enteritis: 26% norovirus, 25% adenovirus, and 9% each rotavirus and sapovirus. The median age of pediatric patients was 1.6 years (0.4-16.9) and for adults 36.3 years (27.1-48.2). Fifty-seven (58%) of 99 pediatric ITR had viral enteritis compared to 4 (10%) of 40 adult ITR. Median time-to-clinical resolution of enteritis for all patients was 5 days (1-92). Standard of care therapies administered: anti-motility agents (10%), anti-emetics agents (14%), and intravenous fluids (42%). There was a higher incidence of viral enteritis in pediatric compared to adults ITR. The majority of viral enteritis episodes resolved within 1 week and were treated with supportive therapy.

[Clinicopathologic features and postoperative outcome of the radiation-induced enteritis: a retrospective study of 41 patients]. / Caractéristiques clinicopathologiques et résultats postopératoires de l'entérite radio-induite : une étude rétrospective de 41 patients.

INTRODUCTION: Surgery is required in patients with symptoms of chronic radiation-induced enteritis (CRE) resistant to medical therapy. The study aimed to correlate histopathologic features of CRE to the clinical presentation and the postoperative recurrence. MATERIAL AND METHOD: All patients with small bowel resection performed for CRE between 2006 and 2017 were studied. Histological data were retrospectively correlated to initial clinical data and to postoperative recurrence of CRE (occlusion, need for parenteral nutrition) observed during a median follow-up of 32 months. RESULTS: Forty-one patients were studied (39 women and 2 men, median age 62 yo at time of radiation for pelvic cancer, 80% gynecologic). Median time to surgery after radiation was 3 years. Ileocaecal resections (80% of patients) removed 60cm (median length). Histologically, a diffuse obliterative arteriopathy was present in 24 (59%) patients, highly associated to amyotrophy, villous atrophy and ulceration observed in 66, 63 and 34% of patients respectively (P<.05). Diffuse arteriopathy was uncorrelated with patient's age and vascular risk factor (tobacco, diabetes, hypertension, dyslipidemia). Median time to surgery after radiation was longer in patients presenting with obliterative arteriopathy (13 years vs. 2.6 years, P=0.0002). During follow-up, half of the patients had a recurrence of CRE, uncorrelated to the arteriopathy. CONCLUSION: Radiation-induced enteritis requiring late surgery after radiation presented histologically with a diffuse obliterative arteriopathy and ischemic features. In our center, half of the patients were cured by surgery. The arterial injury was not a risk factor for postoperative recurrence.

Environmental enteric dysfunction: a review of potential mechanisms, consequences and management strategies.

BACKGROUND: Environmental enteric dysfunction (EED) is an acquired enteropathy of the small intestine, characterized by enteric inflammation, villus blunting and decreased crypt-to-villus ratio. EED has been associated with poor outcomes, including chronic malnutrition (stunting), wasting and reduced vaccine efficacy among children living in low-resource settings. As a result, EED may be a valuable interventional target for programs aiming to reduce childhood morbidity in low and middle-income countries. MAIN TEXT: Several highly plausible mechanisms link the proposed pathophysiology underlying EED to adverse outcomes, but causal attribution of these pathways has proved challenging. We provide an overview of recent studies evaluating the causes and consequences of EED. These include studies of the role of subclinical enteric infection as a primary cause of EED, and efforts to understand how EED-associated systemic inflammation and malabsorption may result in long-term morbidity. Finally, we outline recently completed and upcoming clinical trials that test novel interventions to prevent or treat this highly prevalent condition. CONCLUSIONS: Significant strides have been made in linking environmental exposure to enteric pathogens and toxins with EED, and in understanding the multifactorial mechanisms underlying this complex condition. Further insights may come from several ongoing and upcoming interventional studies trialing a variety of novel management strategies.

Retrospective study recommends endoscopy when diagnosing lymphocytic colitis or eosinophilic gastrointestinal disorder in children with abdominal pain.

AIM: This study assessed the prevalence, clinical presentation and outcome of lymphocytic colitis (LC) and eosinophilic gastrointestinal disease (EGID) in children with severe, recurrent abdominal pain (RAP), by describing the predominant symptoms, diagnostic approaches and treatment options. METHODS: We performed a retrospective follow-up study at a Danish regional hospital by reviewing the histology reports of the children who had undergone gastrointestinal endoscopy for RAP. Data were retrieved from the medical records of those who met the diagnostic criteria for LC and, or, EGID from 2011 to 2016. The study population comprised 381 patients who underwent a diagnostic process to clarify RAP. RESULTS: A total of 74 patients (39 females) aged 2-17 years, with severe RAP as the most predominant symptom underwent gastrointestinal endoscopy. This identified 16/74 (21.6%) with LC (n = 6) and, or, EGID (n = 11), which equated to 4.2% with RAP. No biochemical patterns of abnormalities were found. Medical treatment and, or, diet generally induced and maintained clinical remission. CONCLUSION: We found 16 children with LC and, or, EGID. The predominant symptom was severe RAP. All patients had a macroscopically normal mucosa at endoscopy, a specific histopathological feature and no characteristic biochemical findings. Endoscopy should be considered in these cases.

Erosive Enteritis and Intestinal Obstructions Caused by Decomposed Granite in a Flock of Lesser Flamingos (Phoeniconaias minor).

Decomposed granite is a material commonly used in zoos as a base for flamingo exhibits. In 2012, the artificial turf over the decomposed granite in the Fort Worth Zoo flamingo exhibit was removed and pressure washed, the granite was replaced, and the turf was then restretched in place. Approximately 8 months later, 3 lesser flamingos (Phoeniconaias minor) showed signs of lethargy and hematochezia. Results of physical examination revealed poor body condition in all birds, with variable hematologic abnormalities, including anemia, hypoproteinemia, and electrolyte disturbances. Radiographs of birds showed large amounts of radiopaque material in the ventriculus and dilated intestinal loops. Two birds died either during treatment or surgery, and 1 bird was euthanatized. Postmortem examination of all 3 birds revealed large amounts of fine, granite-like material in the ventriculus and intestines, severe congestion of intestinal mucosa, and obstruction of intestinal lumen by caseous plugs surrounded by fecal material. Microscopic evaluation of the material removed from the ventriculus showed birefringent crystals that corresponded to microscopic silica grains, consistent with the decomposed granite from the exhibit. Histologic examination of tissues showed marked chronic erosive colitis, mild erosive proventriculitis, and lesions in the muscular layer of the ventriculus. Subsequently, 82 remaining flamingos in the flock were radiographed. Results showed the same material in the ventriculus of most birds, but no intestinal obstructions were identified. Different treatment techniques were attempted unsuccessfully to remove the material from the flamingos that had the largest amount of decomposed granite in their gastrointestinal tracts. Ultimately, all birds were treated with oral gastrointestinal protectants, adsorbents, laxatives, and lubricants, along with antibiotics administered in drinking water. No further mortalities occurred once medical treatments were implemented.

[Severe coagulation abnormality during treatment for ischemic enteritis in an older patient taking a direct oral anticoagulant].

An 85-year-old woman hospitalized for rehabilitation after cerebral infarction developed persistent bloody diarrhea and was transferred to our hospital (day 1). Contrast-enhanced computed tomography of the abdomen showed edematous thickening extending from the left side of the transverse colon to the rectum, with decreased mucosal enhancement. She was diagnosed with ischemic enteritis. She fasted and was treated with fluids and antibiotics. The bloody diarrhea stopped, and she was restarted on the direct oral anticoagulant (DOAC) edoxaban on day 5. Endoscopy on day 11 showed linear ulceration and severe mucosal edema in the rectum. The diarrhea was persistent, so fasting and fluid therapy were continued. A blood test on day 18 showed significant prolongation of the prothrombin time (≥100 s), International Normalized Ratio (14.03), and activated partial thromboplastin time (87.5 s), as well as a significant increase in protein induced by vitamin K absence-II (12,469 mAU/mL). Her condition was diagnosed as a coagulation abnormality due to vitamin-K deficiency. A vitamin-K preparation was administered immediately, and her coagulation abnormality improved rapidly. In general, DOACs do not require routine monitoring with blood tests. However, frequent monitoring of the coagulation function is required in fasting patients on DOACs because acute coagulation abnormalities can be induced rapidly by vitamin-K deficiency. Given that non-valvular atrial fibrillation and ischemic enteritis are among the most prevalent diseases affecting older people, the likelihood of encountering these diseases in daily clinical practice will increase with the aging of the population. We herein report this instructive case suggesting that a severe coagulation abnormality may develop during treatment for ischemic enteritis in older people taking a DOAC.

Eosinophilic gastrointestinal diseases beyond eosinophilic esophagitis.

OBJECTIVE: Eosinophilic gastrointestinal diseases (EGIDs) are a rare group of disorders that can have varied clinical presentations dependent on the involved segment within the gastrointestinal tract. Eosinophilic gastritis presents with abdominal pain or vomiting, eosinophilic gastroenteritis presents with diarrhea and anemia or hypoalbuminemia, and eosinophilic colitis can present with diarrhea or bloody stools. These nonspecific symptoms remain poorly understood in their relation to the underlying pathogenesis, but a significant percentage of patients have atopy. In this review, we discuss the current literature on EGIDs to promote a practical approach to diagnosis and care. DATA SOURCES: Review of published literature. STUDY SELECTIONS: Clinically relevant literature from 1900 through 2018 was obtained from a PubMed search. Those that addressed prevalence, diagnosis, clinical manifestations, natural history, and treatment of EGIDs were reviewed and are summarized in this article. RESULTS: Of the 485 articles found in the search, most of which were case reports, 71 were selected for review. The natural history of EGIDs is based primarily on case series and small numbers of patients, making therapeutic decisions difficult. Treatment remains limited to dietary restriction that is not effective in many patients and topical or systemic corticosteroids whose long-term use is to be avoided if possible. CONCLUSION: With the seeming increase in all types of EGIDs, phenotypic descriptions are emerging that will likely promote better understanding of the pathogenesis and identification of novel therapeutic targets.

Nonesophageal Eosinophilic Gastrointestinal Disorders: Clinical Care and Future Directions.

Eosinophilic gastrointestinal disorders are a set of conditions with a wide range of clinical manifestations and treatment modalities. The disorders are suspected to result from an abnormal inflammatory response to allergen (s), and individuals may develop a relapsing or chronic disease, if the allergen is not eliminated. Mechanisms of disease pathogenesis, including the humoral immune response, need to be fully elucidated. A variety of therapies are used, although there is a lack of well-defined randomized, prospective studies. Other therapeutic options are needed as the current treatments have potential concerns; elimination diets may impair a child's quality of life, and corticosteroids have adverse risks with long-term use. We review what is known about nonesophageal eosinophilic gastrointestinal disorders, and discuss research investigations which need to be conducted to facilitate diagnosis and enhance treatment methods.