Systematic review: disease activity indices for immune checkpoint inhibitor-associated enterocolitis.

BACKGROUND: Although there is interest in developing pharmacotherapies for the treatment of immune checkpoint inhibitor-associated enterocolitis (ICIC), there is currently no consensus on how to optimally measure disease activity in this condition. AIMS: To identify all scoring indices used for the measurement of disease activity in ICIC, assess their operating properties, and explore their potential utility as outcome measures. METHODS: We searched MEDLINE, EMBASE and the Cochrane Library from inception to November 2020 to identify studies that evaluated disease activity and severity in patients with ICI-associated enterocolitis. These scoring tools could be designed specifically for ICIC or adapted from other diseases, and assessed clinical, endoscopic, or histologic disease activity. RESULTS: Sixty-four studies were included. The Common Terminology Criteria for Adverse Events is commonly used to describe symptoms, although has only been partially validated and was not designed as a disease activity index. Endoscopic and histologic indices used in inflammatory bowel disease have been adopted for ICIC including the Mayo Endoscopic Subscore, Ulcerative Colitis Endoscopic Index of Severity, Simple Endoscopic Score for Crohn's Disease, Nancy Histological Index, Robarts Histopathological Index, and Geboes Score, among others. None of these indices has been validated for use in ICIC, and all lacked content validity and responsiveness. CONCLUSIONS: There are no validated clinical, endoscopic, or histologic outcomes to assess disease activity in ICIC. Development and validation of reliable and responsive outcome measures that can be used to measure disease activity will be paramount for both clinical practice and for the development of treatments.

'Diagnosing food protein-induced enterocolitis syndrome'.

Food protein-induced enterocolitis syndrome is still a mysterious disease, pathogenically poorly characterized, although the first FPIES case has been described in 1967. Mainly, food protein-induced enterocolitis syndrome diagnosis is based on clinical history. The oral food challenge remains the gold standard to confirm the diagnosis, especially in particular situations. Although there are no diagnostic laboratory or imaging tests which are specific for diagnosis, they could, however, sometimes be helpful to rule out clinical conditions which are similar to food protein-induced enterocolitis syndrome reactions. The purpose of this review is to define the clinical features of FPIES and to summarize the current available tools for the diagnosis of FPIES. This review is intended to be a practical guide for the clinician facing a patient with food protein-induced enterocolitis syndrome avoiding delayed diagnosis with unnecessary laboratory tests and detrimental treatments. Moreover, it highlights the unmet needs in diagnosis that require urgent attention from the scientific community to improve the management of patients with FPIES.

Disease Course and Treatment Response of Eosinophilic Gastrointestinal Diseases in Children With Liver Transplantation: Long-Term Follow-Up.

INTRODUCTION: To describe the clinical and laboratory profile, natural course, treatment outcome, and risk factors of posttransplant esophageal and nonesophageal eosinophilic gastrointestinal disorders (EGIDs). METHODS: All children (aged <18 years) who underwent liver transplantation, between 2011 and 2019, in a single transplant center with a follow-up period of 1 year or more posttransplant and with a history of posttransplant endoscopic evaluation were included in this study. RESULTS: During the study period, 89 children met the inclusion criteria. Patients were followed for a median of 8.0 years. A total of 39 (44%) patients were diagnosed with EGID after transplantation. Of these, 29 (33%) had eosinophilic esophagitis (EoE), and 10 (11%) had eosinophilic gastritis, gastroenteritis or enterocolitis. In comparison with the non-EGID group, patients with EGID were younger at transplant (P ≤ 0.0001), transplanted more frequently due to biliary atresia (P ≤ 0.0001), and had higher rates of pretransplant allergy (P = 0.019). In the posttransplant period, they had higher rates of mammalian Target of Rapamycin inhibitor use (P = 0.006), Epstein-Barr virus viremia (P = 0.03), post-transplant lymphoproliferative disease (P = 0.005), and allergen sensitization (P ≤ 0.0001). In regression analysis, young age at transplant, age at diagnosis, pretransplant atopic dermatitis, and post-transplant lymphoproliferative disease were associated with an increased risk of EGID or EoE. Laboratory abnormalities such as anemia (P = 0.007), thrombocytosis (P = 0.012), and hypoalbuminemia (P = 0.031) were more commonly observed in the eosinophilic gastritis, gastroenteritis or enterocolitis group than in the EoE group. Following treatment, most patients had symptomatic resolution at 3 months and histologic resolution at 6 months postdiagnosis. Among the patients who had 5 years of follow-up, none recurred. DISCUSSION: EGID is a common posttransplant diagnosis, which seems to affect patients who are transplanted earlier and who have pretransplant atopy. Posttransplant EGID is responsive to treatment, but as histologic remission occurs after symptomatic resolution, the decision to perform control endoscopy should be delayed.

Phenotypes and natural history of food protein-induced enterocolitis syndrome in the east Mediterranean region.

Background: Food protein-induced enterocolitis syndrome (FPIES) is a rare non-IgE mediated food allergy. Objective: To delineate the differences in the spectrum of culprit foods, remission patterns, and predictors among varying cultures. Methods: We reviewed demographics, culprit foods, outcomes, and predictors in 81 children with a diagnosis of FPIES who were followed up between 2015 and 2020. Results: Eighty-one patients (55.6% boys) were enrolled, including 72 with acute FPIES and 9 with chronic FPIES. Hen's egg was the most common culprit food (36.6%), followed by fish (26.9%), and cow's milk (21.5%). Interestingly, cow's milk was significantly prevalent in chronic FPIES cases (p = 0.006). The most common clinical symptoms were vomiting (100%), pallor (63.4%), and lethargy (55.9%). Emergency department visits were noted in 39 patients (41.9%), of whom 37 (39.8%) were treated with intravenous (IV) fluid. The subjects were followed up for a median (interquartile range) of 19.4 months (12.3-41.2 months), and 26 subjects (32.1%) achieved tolerance. The median (interquartile range) age at tolerance was 2.5 years (2.1-3.2 years). With regard to the culprit foods, hen's egg was observed more frequently in the subjects with resolved FPIES cases (p = 0.008), whereas fish FPIES cases were high in the persistent group (p = 0.001). IgE sensitization of the culprit food was found to be an independent risk factor for the persistence of FPIES (odds ratio 4.855 [95% confidence interval, 1.131-20.844]; p = 0.034). Conclusion: In our cohort, unlike other published series, hen's egg and fish were the two most common culprit foods. Fish differed from other culprit foods, with significantly delayed onset and persistence, and may create a model that allows for the understanding of the disease.

A Rare Case of Fetal Onset, Food Protein-Induced Enterocolitis Syndrome.

BACKGROUND: Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy. The pathological mechanism of FPIES is intestinal inflammation, and cell-mediated hypersensitivity is presumed to play an important role in its development. CASE REPORT: The first case in which significant fetal intestinal distension suggested fetal onset of FPIES is reported. A 2,334-g male was born at 34 weeks by vaginal delivery. RESULTS: In utero, he had significant intestinal distension on ultrasonography and MRI. A few hours after the first feeding, he produced bloody stool and showed abdominal distension. In this case, FPIES was not only caused by cow's milk protein diagnosed clinically and by an allergen-specific lymphocyte stimulation test, but also by breast milk diagnosed by oral food challenge. The clinical course and laboratory results strongly suggested not only fetal sensitization but also fetal onset. CONCLUSION: This report might be helpful for prompt diagnosis and treatment and, furthermore, lead to elucidation of the pathogenesis and pathophysiology of FPIES.

Botulinum toxin injections after surgery for Hirschsprung disease: Systematic review and meta-analysis.

BACKGROUND: A large proportion of patients with Hirschsprung disease experience persistent obstructive symptoms after corrective surgery. Persistent obstructive symptoms may result in faecal stasis that can develop into Hirschsprung-associated enterocolitis, a potential life-threatening condition. Important treatment to improve faecal passage is internal anal sphincter relaxation using botulinum toxin injections. AIM: To give an overview of all empirical evidence on the effectiveness of botulinum toxin injections in patients with Hirschsprung disease. METHODS: A systematic review and meta-analysis was done by searching PubMed, EMBASE and the Cochrane Library, using entry terms related to: (1) Hirschsprung disease; and (2) Botulinum toxin injections. 14 studies representing 278 patients met eligibility criteria. Data that were extracted were proportion of patients with improvement of obstructive symptoms or less enterocolitis after injection, proportion of patients with adverse effects and data on type botulinum toxin, mean dose, average age at first injection and patients with associated syndromes. Random-effects meta-analysis was used to aggregate effects and random-effects meta-regression was used to test for possible confounding factors. RESULTS: Botulinum toxin injections are effective in treating obstructive symptoms in on average 66% of patients [event rate (ER) = 0.66, P = 0.004, I 2 = 49.5, n = 278 patients]. Type of botulinum toxin, average dose, average age at first injections and proportion of patients with associated syndromes were not predictive for this effect. Mean 7 duration of improvement after one botulinum toxin injections was 6.4 mo and patients needed on average 2.6 procedures. There was a significant higher response rate within one month after botulinum toxin injections compared to more than one month after Botulinum toxin injections (ER = 0.79, vs ER = 0.46, Q = 19.37, P < 0.001). Botulinum toxin injections were not effective in treating enterocolitis (ER 0.58, P = 0.65, I 2 = 71.0, n = 52 patients). There were adverse effects in on average 17% of patients (ER = 0.17, P < 0.001, I 2 = 52.1, n = 187 patients), varying from temporary incontinence to mild anal pain. CONCLUSION: Findings from this systematic review and meta-analysis indicate that botulinum toxin injections are effective in treating obstructive symptoms and that adverse effects were present, but mild and temporary.

A study of enterocyte membranes during activation of apoptotic processes in chronic carrageenan-induced gastroenterocolitis.

Aim To investigate the lipid membranes of rat enterocytes in chronic carrageenan-induced gastroenterocolitis accompanied by the activation of apoptotic processes. Methods Steady-state fluorescence spectroscopy: a study by fluorescent probes - by ortho-hydroxy derivatives of 2,5-diaryl-1,3- oxazole. Activity of apoptosis signal-regulating kinase 1 and poly (ADP-ribose) polymerase in small intestinal homogenates, blood serum levels of matrix metalloproteinase-2 and caspase-3 and the level of DNA fragmentation in small intestinal homogenates were determined. Results Biochemical analysis revealed that an activation of apoptotic processes occurred in the intestinal epithelium of rats during chronic carrageenan-induced gastroenterocolitis. The fluorescence probes showed that activation of apoptotic processes in carrageenan-induced gastroenterocolitis was accompanied by changes in polar regions of rat enterocyte membranes, while no changes were revealed in more hydrophobic regions of the membranes. Conclusion The increase in hydration of membranes was attributed to the activation of the apoptosis of enterocytes. It has been shown that a fluorescent probe (2-(2'-hydroxyphenyl)-5-phenyl-1,3-oxazole) can be used for the detection of apoptosis of enterocytes.

Characteristics of cytomegalovirus enterocolitis in patients with or without inflammatory bowel diseases.

OBJECTIVES: Cytomegalovirus (CMV) disease is more common in immunocompromised patients but may occur in people with normal immune function. In addition, CMV enterocolitis can aggravate inflammatory bowel diseases (IBD), but there was little knowledge of differences in clinical and endoscopic features of CMV enterocolitis between patients with IBD and without IBD. The aim of this study was to determine the difference in clinical implication in CMV enterocolitis between the IBD patients and non-IBD patients. METHODS: This was a retrospective study of 82 patients with CMV enterocolitis based on the pathologic findings at two tertiary referral hospitals from 2003 to 2013. Clinical and endoscopic characteristics and clinical course were analyzed according to the presence of IBD. RESULTS: Of the 82 patients, 25 (30.5%) had IBD and 57 (69.5%) did not have IBD. Hematochezia was more common in IBD patients (84.0% vs. 35.1%; p = .001), but fever and positive CMV antigenemia were more common in non-IBD patients (50.9% vs. 12.0%; p = .001; 54.4% vs. 28.0; p = .027). Endoscopic findings showed more ulcer with inflammation in IBD patients (68.0% vs. 35.2%; p = .005). Sixty-four patients were treated with antiviral agents and 12 patients who did not receive antiviral agents recovered spontaneously. All naturally healed patients were in normal immune status. CONCLUSIONS: Hematochezia is more common in IBD patients and fever/CMV antigenemia is more common in patients without IBD. In patients without IBD, the natural resolution of CMV enterocolitis is expected at least in normal immune function.

Factores de riesgo asociados al desarrollo de enterocolitis en la enfermedad de Hirschsprung / Risk factors associated with the development of enterocolitis in Hirschsprung's disease

Objetivo. La enterocolitis (EC) asociada a la enfermedad de Hirschsprung (EdH) es una entidad de etiopatogenia desconocida y potencialmente mortal. Nuestro objetivo es identificar los factores implicados en el desarrollo de EC en una cohorte de pacientes con EdH tratados en el nuestro centro. Métodos. Se revisaron los pacientes tratados por EdH en el periodo 2000-2016. Se incluyeron 94 pacientes, recogiendo de las historias clínicas variables demográficas y todas las relacionadas con la enfermedad. Se realizó un estudio de riesgo uni y multivariado usando como variable dependiente la existencia de un cuadro de enterocolitis. Los resultados se presentan con riesgo relativo (RR) con su intervalo de confianza al 95%. Resultados. De los 94 pacientes estudiados, 27 (28,7%) sufrieron algún episodio de EC. Ninguno falleció por esta causa. La afectación intestinal extensa, la necesidad de una ostomía de descarga en el proceso diagnóstico, la cirugía abierta y el diagnóstico anterior a los 7,2 meses de vida se asociaron en el análisis univariante a un mayor riesgo de desarrollar EC. En el multivariante, tan solo el diagnostico precoz y la cirugía abierta quedaron como variables asociadas al riesgo de EC. Conclusiones. La EC sigue siendo una complicación habitual en la EdH, especialmente en las formas más largas y complejas. La identificación de los factores que la favorecen permitiría un mayor control, una mejor prevención secundaria ante el comienzo de los síntomas y un tratamiento más precoz, lo que lograría disminuir su morbilidad (AU)

Objectives. Hirschsprung's-associated enterocolitis (HAEC) is a live-threatening complication that remains badly understood. Our objective is to identify the risk factors related to the development of HAEC in the cohort of patients with Hirschsprung's disease (HD) treated in our center. Methods. We reviewed the patients treated for HD between 2000 and 2016. Ninety four patients were included, and the clinical details related to the disease were evaluated. Our primary outcome measure was the development of HAEC. Relative risks are presented with 95% confidence intervals. Results. Twenty seven patients out of the ninety four (28.7%) suffered HAEC. None of them died from this complication. The extended aganglionosis, the need of a preoperative stoma, a transabdominal surgery and the diagnosis before the age of 7.2 months were related to a higher risk of suffering HAEC. Conclusions. HAEC remains a common complication in patients suffering from HD, especially those with complex forms. The identification of the risk factors could result in a better control of the HAEC, which lead to a faster diagnosis and treatment, reducing the morbimortality related to HAEC (AU)

[THE STATUS OF VITAMIN В UNDER DISEASES OF SMALL INTESTINE IN CHILDREN IN THE ZONE OF INCREASED SUN INSOLATION].

The study was carried out to trace clinical laboratory parallels between levels of vitamin D under diseases of small intestine in children. The examined sampling included 160 children aged from 6 months to 18 years with diseases of small intestine. The patients were separated to three groups: 60 children with celiac disease aged from 3-16 years; 60 children with chronic post-infectious enterocolitis aged from 2 to 12 years; 40 children with allergic enterocolitis aged from 6 months to 4 years. The control group consisted of 31 children, including 15 children aged from 6 months to 4 years and 16 children aged from 5 to 18 years. The standard clinical, para-clinical and instrumental techniques of investigation were applied to every nosology. To analyze status of vitamin В the levels of calcidiol and parathormone were determined. In the process of tracing clinical laboratory parallels between levels of vitamin D under diseases of small intestine in children high percentage of decreasing of vitamin D (96.9%) was detected, and at that in 100% under celiac disease and chronic post-infectious enterocolitis. The feedback was established between levels of vitamin D and levels of calcidiol and parathormone and also activity of alkaline phosphatase in all groups of patients though more evident in patients with celiac disease and chronic post-infectious enterocolitis. The low values of level of vitamin D were detected in all children with celiac disease and chronic post-infectious enterocolitis whereas only in 87% under allergic enterocolitis. The decreasing of level of vitamin D was accompanied by increasing of content of calcidiol and parathormone and activity of alkaline phosphatase at that the most high numbers are observed in patients with celiac disease and then chronic post-infectious enterocolitis and allergic enterocolitis.

The Anti-Inflammatory Effect of Spray-Dried Plasma Is Mediated by a Reduction in Mucosal Lymphocyte Activation and Infiltration in a Mouse Model of Intestinal Inflammation.

Spray-dried preparations from porcine and bovine plasma can alleviate mucosal inflammation in experimental models and improve symptoms in patients with enteropathy. In rodents, dietary supplementation with porcine spray-dried plasma (SDP) attenuates intestinal inflammation and improves the epithelial barrier function during intestinal inflammation induced by Staphylococcus aureus enterotoxin B (SEB). The aim of this study was to discern the molecular mechanisms involved in the anti-inflammatory effects of SDP. Male C57BL/6 mice were fed with 8% SDP or control diet (based on milk proteins) for two weeks, from weaning until day 33. On day 32, the mice were given a SEB dose (i.p., 25 µg/mouse) or vehicle. SEB administration increased cell recruitment to mesenteric lymph nodes and the percentage of activated Th lymphocytes and SDP prevented these effects). SDP supplementation increased the expression of interleukin 10 (IL-10) or transforming growth factor- ß (TGF-ß) compared to the SEB group. The SEB challenge increased six-fold the expression of mucosal addressin cell adhesion molecule 1 (MAdCAM-1) and intercellular adhesion molecule 1 (ICAM-1); and these effects were attenuated by SDP supplementation. SEB also augmented NF-κB phosphorylation, an effect that was prevented by dietary SDP. Our results indicate that the anti-inflammatory effects of SDP involve the regulation of transcription factors and adhesion molecules that reduce intestinal cell infiltration and the degree of the inflammatory response.

Enterocolitis and bowel function in children with Hirschsprung disease and trisomy 21.

BACKGROUND/PURPOSE: The purpose of this study was to study the effect of trisomy 21 (T21) on enterocolitis rates and bowel function among children with Hirschsprung disease (HD). METHODS: A retrospective cohort study of patients with HD treated at our tertiary children's hospital (2000-2015) and a cohort of patients with HD treated in our pediatric colorectal center (CRC) (2011-2015) were performed. RESULTS: 26/207 (13%) patients with HD had T21. 70 (41%) with HD alone were diagnosed with enterocolitis episodes compared to 9 (38%) with HD+T21 (p=0.71). 55/207 patients were managed in the CRC. 11/55 patients (20%) had HD+T21. 25 (58%) with HD had one or more enterocolitis episodes compared to 4 (36%) with HD+T21 (p=0.20). Number of hospitalizations for enterocolitis was similar between all groups. Toilet training was assessed in 32 CRC patients (25 HD, 7 HD+T21). One child with HD+T21 was toilet trained by age 4years versus 12 with HD (p=0.20). Laxative or enema therapy was required for constipation management in 57% HD versus 64% HD+T21. CONCLUSION: Enterocolitis rates in children with HD+T21 did not differ from rates in children with HD alone. The majority of patients with CRC follow-up had constipation requiring laxative or enema therapy, which demonstrates the need for consistent postoperative follow-up. LEVEL OF EVIDENCE: Retrospective Study - Level II.

Altered tryptophan hydroxylase 2 expression in enteric serotonergic nerves in Hirschsprung's-associated enterocolitis.

AIM: To determine if expression of colonic tryptophan hydroxylase-2 (TPH2), a surrogate marker of neuronal 5-hydroxytryptamine, is altered in Hirschsprung's-associated enterocolitis. METHODS: Entire resected colonic specimens were collected at the time of pull-through operation in children with Hirschsprung's disease (HSCR, n = 12). Five of these patients had a history of pre-operative Hirschsprung's-associated enterocolitis (HAEC). Controls were collected at colostomy closure in children with anorectal malformation (n = 10). The distribution of expression of TPH2 was evaluated using immunofluorescence and confocal microscopy. Protein expression of TPH2 was quantified using western blot analysis in the deep smooth muscle layers. RESULTS: TPH2 was co-expressed in nitrergic and cholinergic ganglia in the myenteric and submucosal plexuses in ganglionic colon in HSCR and healthy controls. Co-expression was also seen in submucosal interstitial cells of Cajal and PDGFRα(+) cells. The density of TPH2 immuno-positive fibers decreased incrementally from ganglionic bowel to transition zone bowel to aganglionic bowel in the myenteric plexus. Expression of TPH2 was reduced in ganglionic bowel in those affected by pre-operative HAEC compared to those without HAEC and healthy controls. However, expression of TPH2 was similar or high compared to controls in the colons of children who had undergone diverting colostomy for medically refractory HAEC. CONCLUSION: Altered TPH2 expression in colonic serotonergic nerves of patients with HSCR complicated by HAEC may contribute to intestinal secretory and motor disturbances, including recurrent HAEC.

Whey protein concentrate enhances intestinal integrity and influences transforming growth factor-ß1 and mitogen-activated protein kinase signalling pathways in piglets after lipopolysaccharide challenge.

Whey protein concentrate (WPC) has been reported to have protective effects on the intestinal barrier. However, the molecular mechanisms involved are not fully elucidated. Transforming growth factor-ß1 (TGF-ß1) is an important component in the WPC, but whether TGF-ß1 plays a role in these processes is not clear. The aim of this study was to investigate the protective effects of WPC on the intestinal epithelial barrier as well as whether TGF-ß1 is involved in these protection processes in a piglet model after lipopolysaccharide (LPS) challenge. In total, eighteen weanling pigs were randomly allocated to one of the following three treatment groups: (1) non-challenged control and control diet; (2) LPS-challenged control and control diet; (3) LPS+5 %WPC diet. After 19 d of feeding with control or 5 %WPC diets, pigs were injected with LPS or saline. At 4 h after injection, pigs were killed to harvest jejunal samples. The results showed that WPC improved (P<0·05) intestinal morphology, as indicated by greater villus height and villus height:crypt depth ratio, and intestinal barrier function, which was reflected by increased transepithelial electrical resistance and decreased mucosal-to-serosal paracellular flux of dextran (4 kDa), compared with the LPS group. Moreover, WPC prevented the LPS-induced decrease (P<0·05) in claudin-1, occludin and zonula occludens-1 expressions in the jejunal mucosae. WPC also attenuated intestinal inflammation, indicated by decreased (P<0·05) mRNA expressions of TNF-α, IL-6, IL-8 and IL-1ß. Supplementation with WPC also increased (P<0·05) TGF-ß1 protein, phosphorylated-Smad2 expression and Smad4 and Smad7 mRNA expressions and decreased (P<0·05) the ratios of the phosphorylated to total c-jun N-terminal kinase (JNK) and p38 (phospho-JNK:JNK and p-p38:p38), whereas it increased (P<0·05) the ratio of extracellular signal-regulated kinase (ERK) (phospho-ERK:ERK). Collectively, these results suggest that dietary inclusion of WPC attenuates the LPS-induced intestinal injury by improving mucosal barrier function, alleviating intestinal inflammation and influencing TGF-ß1 canonical Smad and mitogen-activated protein kinase signalling pathways.

Hirschsprung's associated enterocolitis.

PURPOSE OF REVIEW: Hirschsprung's disease (HSCR) is characterized by an absence of ganglion cells in the distal hindgut, extending from the rectum to a variable distance proximally, and results from a failure of cranial-caudal neural crest cell migration. Hirschsprung's-associated enterocolitis (HAEC) is a condition with classic manifestations that include abdominal distention, fever and foul-smelling stools, and is a significant and life-threatening complication of HSCR. The purpose of this review was to critically evaluate recent findings regarding the pathophysiology of HAEC. RECENT FINDINGS: Several recent studies have investigated the cause of HAEC in humans and mouse models. These studies suggest that alterations in the intestinal barrier, including goblet cell number and function, and Paneth cell function, impaired gastrointestinal mucosal immunity, including B-lymphocyte trafficking or function and secretory immunoglobulin A production, and dysbiosis of the intestinal microbiota may contribute to the development of HAEC. SUMMARY: Recent studies add to the body of literature, suggesting that the intestinal defects observed in HSCR are not restricted to the aganglionic segment but extend to the mucosal immune system within and beyond the gastrointestinal tract. Future studies further dissecting the mechanisms of HAEC and validating these findings in humans will allow for the development of directed therapeutic interventions.