Deubiquitination of NLRP6 inflammasome by Cyld critically regulates intestinal inflammation.

The inflammasome NLRP6 plays a crucial role in regulating inflammation and host defense against microorganisms in the intestine. However, the molecular mechanisms by which NLRP6 function is inhibited to prevent excessive inflammation remain unclear. Here, we demonstrate that the deubiquitinase Cyld prevents excessive interleukin 18 (IL-18) production in the colonic mucosa by deubiquitinating NLRP6. We show that deubiquitination inhibited the NLRP6-ASC inflammasome complex and regulated the maturation of IL-18. Cyld deficiency in mice resulted in elevated levels of active IL-18 and severe colonic inflammation following Citrobacter rodentium infection. Further, in patients with ulcerative colitis, the concentration of active IL-18 was inversely correlated with CYLD expression. Thus, we have identified a novel regulatory mechanism that inhibits the NLRP6-IL-18 pathway in intestinal inflammation.

Epizootic of enterocolitis and clostridial overgrowth in NSG and NSG-related mouse strains.

While the immunodeficient status of NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) and NSG-related mice provides utility for numerous research models, it also results in increased susceptibility to opportunistic pathogens. Over a 9-week period, a high rate of mortality was reported in a housing room of NSG and NSG-related mice. Diagnostics were performed to determine the underlying etiopathogenesis. Mice submitted for evaluation included those found deceased (n = 2), cage mates of deceased mice with or without diarrhea (n = 17), and moribund mice (n = 8). Grossly, mice exhibited small intestinal and cecal dilation with abundant gas and/or digesta (n = 18), serosal hemorrhage and congestion (n = 6), or were grossly normal (n = 3). Histologically, there was erosive to ulcerative enterocolitis (n = 7) of the distal small and large intestine or widespread individual epithelial cell death with luminal sloughing (n = 13) and varying degrees of submucosal edema and mucosal hyperplasia. Cecal dysbiosis, a reduction in typical filamentous bacteria coupled with overgrowth of bacterial rods, was identified in 18 of 24 (75%) mice. Clostridium spp. and Paeniclostridium sordellii were identified in 13 of 23 (57%) and 7 of 23 (30%) mice, respectively. Clostridium perfringens (7 of 23, 30%) was isolated most frequently. Toxinotyping of C. perfringens positive mice (n = 2) identified C. perfringens type A. Luminal immunoreactivity to several clostridial species was identified within lesioned small intestine by immunohistochemistry. Clinicopathologic findings were thus associated with overgrowth of various clostridial species, though direct causality could not be ascribed. A diet shift preceding the mortality event may have contributed to loss of intestinal homeostasis.

The Effect of the Ganglionic Segment Inflammatory Response to Postoperative Enterocolitis in Hirschsprung Disease.

INTRODUCTION: We examined the relationship between proinflammatory cytokines that occur in the inflammatory reaction in the intestine in Hirschsprung disease (HD) and Hirschsprung-associated enterocolitis (HAEC). METHODS: Thirty cases (M:27, F:3) operated on due to HD. The cases were divided into three groups: group 1 with pre and post operative EC, group 2 with post-operative, and group 3 with pre-operative EC. The intestinal segments were evaluated by immunohistochemistry for interleukin 1 beta (IL-1ß), tumor necrosis factor-alpha (TNF-α), and interleukin 6 (IL-6). RESULTS: IL-1ß staining was significantly higher in the ganglionic zone of groups with enterocolitis compared to the control group (p = 0.012). TNF-α staining in the transitional zone of Group 3 and IL-1ß staining in the ganglionic zone of Group 1 was significantly higher than the control group (p = 0.030, p = 0.020). CONCLUSION: In our study, older age at diagnosis and more than 20% IL-1ß staining in the ganglionic segment were found to be risk factors for HAEC. It is noteworthy that the increase in IL-1ß can be associated with HAEC.

Aminopeptidase N Expression, Not Interferon Responses, Determines the Intestinal Segmental Tropism of Porcine Deltacoronavirus.

Porcine deltacoronavirus (PDCoV) is an economically important enteropathogen of swine with worldwide distribution. PDCoV primarily infects the small intestine instead of the large intestine in vivo However, the underlying mechanism of PDCoV tropism to different intestinal segments remains poorly understood as a result of the lack of a suitable in vitro intestinal model that recapitulates the cellular diversity and complex functions of the gastrointestinal tract. Here, we established the PDCoV infection model of crypt-derived enteroids from different intestinal segments. Enteroids were susceptible to PDCoV, and multiple types of different functional intestinal epithelia were infected by PDCoV in vitro and in vivo We further found that PDCoV favorably infected the jejunum and ileum and restrictedly replicated in the duodenum and colon. Mechanistically, enteroids from different intestinal regions displayed a distinct gene expression profile, and the differential expression of primary viral receptor host aminopeptidase N (APN) instead of the interferon (IFN) responses determined the susceptibility of different intestinal segments to PDCoV, although PDCoV substantially elicited antiviral genes production in enteroids after infection. Additional studies showed that PDCoV infection significantly induced the expression of type I and III IFNs at the late stage of infection, and exogenous IFN inhibited PDCoV replication in enteroids. Hence, our results provide critical inputs to further dissect the molecular mechanisms of PDCoV-host interactions and pathogenesis.IMPORTANCE The zoonotic potential of the PDCoV, a coronavirus efficiently infecting cells from a broad range species, including porcine, chicken, and human, emphasizes the urgent need to further study the cell and tissue tropism of PDCoV in its natural host. Herein, we generated crypt stem cell-derived enteroids from porcine different intestinal regions, which well recapitulated the events in vivo of PDCoV infection that PDCoV targeted multiple types of intestinal epithelia and preferably infected the jejunum and ileum over the duodenum and colon. Mechanistically, we demonstrated that the expression of APN receptor rather than the IFN responses determined the susceptibility of different regions of the intestines to PDCoV infection, though PDCoV infection markedly elicited the IFN responses. Our findings provide important insights into how the distinct gene expression profiles of the intestinal segments determine the cell and tissue tropism of PDCoV.

Clinicopathological findings in patients with COVID-19-associated ischaemic enterocolitis.

AIMS: Coronavirus disease 2019 (COVID-19) has been recognised as a predominantly respiratory tract infection, but some patients manifest severe systemic symptoms/coagulation abnormalities. The aim of this study was to evaluate the impact of severe COVID-19 infection on the gastrointestinal tract. METHODS AND RESULTS: We examined clinicopathological findings in 28 resected ischaemic bowels from 22 patients with severe COVID-19. Most patients required intubation preoperatively and presented with acute decompensation shortly before surgery. D-dimer levels were markedly elevated in all measured cases (mean, 5394 ng/ml). Histologically, 25 cases (19 patients) showed evidence of acute ischaemia with necrosis. In this group, the most characteristic finding was the presence of small vessel fibrin thrombi (24 of 25 cases, 96%), which were numerous in 64% of cases. Patients with COVID-19 were significantly more likely than a control cohort of 35 non-COVID-19-associated acute ischaemic bowels to show isolated small intestine involvement (32% versus 6%, P < 0.001), small vessel fibrin thrombi (100% versus 43%, P < 0.001), submucosal vessels with fibrinous degeneration and perivascular neutrophils (90% versus 54%, P < 0.001), fibrin strands within submucosal vessels (58% versus 20%, P = 0.007), and histological evidence of pneumatosis (74% versus 34%, P = 0.010). Three cases in this cohort had histopathological findings normally seen in the setting of chronic ischaemia, notably prominent fibroblastic proliferation affecting the outer layer of the muscularis propria. CONCLUSIONS: Herein, we describe the histopathological findings in COVID-19-associated ischaemic bowels and postulate a relationship with the hypercoagulable state seen in patients with severe COVID-19 infection. Additional experience with these cases may further elucidate specific features or mechanisms of COVID-19-associated ischaemic enterocolitis.

Gastrointestinal immunopathology of food protein-induced enterocolitis syndrome and other non-immunoglobulin E-mediated food allergic diseases.

OBJECTIVE: To provide a concise summary of the current literature regarding gastrointestinal immunopathology of food protein-induced enterocolitis syndrome (FPIES) and other non-immunoglobulin E (IgE)-mediated food allergic diseases. DATA SOURCES: Data were extracted from PubMed, MEDLINE, and ScienceDirect databases. STUDY SELECTIONS: Original articles, review articles, and guidelines published in the past 5 years in peer-reviewed journals were first summarized. The original articles cited were then reviewed and relevant results were extracted. RESULTS: Patients with FPIES and non-IgE-mediated food allergic diseases developed vomiting, diarrhea, and food aversion expelled food allergen from their bodies. Aside from T helper type 2 (TH2) immunity, TH1, TH17, innate immunity, and epithelial mucosal barrier defect were also found to be important in the pathogenesis. Eosinophils, widely identified in the biopsy samples, were key players or were late-recruited cells for tissue repairs in those diseases. Intestinal dysbiosis and their metabolites stimulated enterochromaffin cells or enteroendocrine cells to produce serotonin, interfering with intestinal motility and subsequently affecting brain function. FPIES and non-IgE-mediated food allergic diseases were likely part of the atopic march. Allergic inflammation in intestinal mucosa might result in subsequent inflammation in the airway mucosa, suggesting the theory of "one mucosa, one disease." CONCLUSION: The immune responses of FPIES and non-IgE-mediated food allergic diseases were not limited to the gastrointestinal tract, but also trigger wider inflammatory responses beyond it. Further research will be required to determine the systemic effect and intestinal microbiome of those diseases.

Food protein-induced enterocolitis syndrome: Dynamic relationship among gastrointestinal symptoms, immune response, and the autonomic nervous system.

OBJECTIVE: To explore the relationship among gastrointestinal (GI) symptoms, immune response, and autonomic nervous system (ANS) in food protein-induced enterocolitis syndrome (FPIES) in relation to the current understanding of disease phenotype and pathogenesis. DATA SOURCES: Relevant studies related to FPIES, GI symptomatology, and ANS were reviewed. Literature search was performed using PubMed, with keyword combinations including but not limited to FPIES, allergic GI disorders, ANS, autonomic dysfunction, dysautonomia, GI, diarrhea, vomiting, neuroimmune, and clinical phenotyping tools. STUDY SELECTIONS: Peer-reviewed case-control studies, observational studies, reviews and guidelines, and systematic reviews related to FPIES and ANS were selected for review. RESULTS: There is limited research directly relating GI symptoms and FPIES to the ANS and immunologic response. To support the proposed mechanisms of action related to patient symptoms, studies relevant to coexisting GI-autonomic processes and FPIES immunologic triggers were examined. These related disease processes were extrapolated to FPIES based on the current knowledge of FPIES phenotype and pathogenesis. CONCLUSION: The etiology of FPIES and the underlying mechanisms triggering symptoms are not well understood. On the basis of the exaggerated GI symptoms and hemodynamic response observed, the ANS likely plays an important role in FPIES, possibly as a compensatory response. The trigger for this cascade of symptoms may be related to the disruption of immunologic homeostasis that typically contributes to immune tolerance. To more accurately evaluate FPIES pathophysiology necessitates understanding the diverse spectrum of presenting symptoms. A consistent and comprehensive symptom assessment tool may improve our understanding of this dynamic relationship.

Food protein-induced enterocolitis syndrome epidemiology.

OBJECTIVE: Food protein-induced enterocolitis syndrome (FPIES) is a condition with heterogeneous features (ie, age at presentation, severity, food triggers, comorbidities) and is not as rare as initially believed. In the last few years, the first population-based epidemiologic study, few prospective birth cohort evaluating FPIES prevalence, and several larger (>100 patients) studies have been published, making epidemiologic estimation more reliable. In this review, we report on the available data on the epidemiology of FPIES. DATA SOURCES: PubMed review using the following words: FPIES, epidemiology, and prevalence. STUDY SELECTIONS: The review focused on the population-based epidemiologic study, few prospective birth cohort evaluating FPIES prevalence, and several larger (>100 patients) studies. RESULTS: We identified 8 population or cohort studies. CONCLUSION: FPIES is not rare in both children and adults and may affect as many as 900,000 people in the United States alone. Most children and adult with FPIES seem to react to 1 to 2 foods; however, they may need further diet restriction owing to high level of comorbidity with immunoglobulin E-mediated food allergies and eosinophilic esophagitis. Globally, cow's milk, rice/oat, and seafood seem to be the most common triggers.

The evolution of food protein-induced enterocolitis syndrome: From a diagnosis that did not exist to a condition in need of answers.

OBJECTIVE: Although food protein-induced enterocolitis syndrome (FPIES) was first described approximately 50 years ago and research is increasing, there are still considerable unmet needs in FPIES. This article catalogs the areas of progress and areas for further research. DATA SOURCES: Through our personal experiences in caring for patients with FPIES, our personal research, and a review of the existing FPIES literature as indexed in PubMed, we explored what is known and what is needed in FPIES. STUDY SELECTIONS: The studies that have improved the knowledge of FPIES, defined phenotypes, allowed for better-informed management of FPIES, and laid the groundwork for further research. RESULTS: Further research is needed in the areas of prevalence, natural history, trigger foods, threshold doses, how and when to perform oral food challenges, and immunopathogenesis of this disorder. Development of a biomarker and determination of the best method to treat reactions is also needed. Furthermore, FPIES has a substantial psychosocial and economic impact on families, and more research is needed in developing and implementing ameliorating strategies. CONCLUSION: By partnering together, health care providers, advocacy organizations, and families can continue to advance our understanding and improve the care of patients and families living with FPIES.

Management of acute food protein-induced enterocolitis syndrome emergencies at home and in a medical facility.

OBJECTIVE: Acute food protein-induced enterocolitis syndrome (FPIES) is characterized by delayed repetitive vomiting after ingestion of a trigger food, and severe reactions may lead to dehydration, hypotension, and shock. We provide recommendations on management of FPIES emergencies in a medical facility and at home. DATA SOURCES: This review summarizes the literature on clinical context, pathophysiology, presentation, and treatment of FPIES emergencies. STUDY SELECTIONS: We referred to the 2017 International Consensus Guidelines for the Diagnosis and Management of FPIES and performed a literature search identifying relevant recent primary articles and review articles on clinical management. RESULTS: Management of FPIES emergencies in a medical facility is based on severity of symptoms and involves rehydration, ondansetron, and corticosteroids. A proactive approach for reactions occurring at home involves prescribing oral ondansetron and providing an individualized treatment plan based on the evolution of symptoms and severity of past reactions. A better understanding of the pathophysiology of FPIES and randomized trials on ondansedron and cocorticosteroid use could lead to more targeted treatments. CONCLUSION: Children with FPIES are at risk for severe symptoms constituting a medical emergency. Management of FPIES emergencies is largely supportive, with treatment tailored to the symptoms, severity of the patient's condition, location of reaction, and reaction history.

Food protein-induced enterocolitis syndrome oral food challenge: Time for a change?

OBJECTIVE: Food protein-induced enterocolitis syndrome (FPIES) is typically diagnosed based on a characteristic clinical history; however, an oral food challenge (OFC) may be necessary to confirm the diagnosis or evaluate for the development of tolerance. FPIES OFC methods vary globally, and there is no universally agreed upon protocol. The objective of this review is to summarize reported FPIES OFC approaches and consider unmet needs in diagnosing and managing FPIES. DATA SOURCES: PubMed database was searched using the keywords food protein-induced enterocolitis syndrome, oral food challenge, cow milk allergy, food allergy, non-immunoglobulin E-mediated food allergy and FPIES. STUDY SELECTIONS: Primary and review articles were selected based on relevance to the diagnosis of FPIES and the FPIES OFC. RESULTS: We reviewed the history of FPIES and the evolution and variations in the FPIES OFC. A summary of current literature suggests that most patients with FPIES will react with 25% to 33% of a standard serving of the challenged food, there is little benefit to offering a divided dose challenge unless there is suspicion of specific immunoglobulin E to the food being challenged, reactions typically appear within 1 to 4 hours of ingestion, and reactions during OFC rarely result in emergency department or intensive care unit admission. CONCLUSION: International standardization in the FPIES OFC approach is necessary with particular attention to specific dose administration across challenged foods, timing between the patient's reaction and offered OFC to verify tolerance, patient safety considerations before the OFC, and identification of characteristics that would indicate home reintroduction is appropriate.

The OSMR Gene Is Involved in Hirschsprung Associated Enterocolitis Susceptibility through an Altered Downstream Signaling.

Hirschsprung (HSCR) Associated Enterocolitis (HAEC) is a common life-threatening complication in HSCR. HAEC is suggested to be due to a loss of gut homeostasis caused by impairment of immune system, barrier defense, and microbiome, likely related to genetic causes. No gene has been claimed to contribute to HAEC occurrence, yet. Genetic investigation of HAEC by Whole-Exome Sequencing (WES) on 24 HSCR patients affected (HAEC) or not affected (HSCR-only) by enterocolitis and replication of results on a larger panel of patients allowed the identification of the HAEC susceptibility variant p.H187Q in the Oncostatin-M receptor (OSMR) gene (14.6% in HAEC and 5.1% in HSCR-only, p = 0.0024). Proteomic analysis on the lymphoblastoid cell lines from one HAEC patient homozygote for this variant and one HAEC patient not carrying the variant revealed two well distinct clusters of proteins significantly up or downregulated upon OSM stimulation. A marked enrichment in immune response pathways (q < 0.0001) was shown in the HAEC H187 cell line, while proteins upregulated in the HAEC Q187 lymphoblasts sustained pathways likely involved in pathogen infection and inflammation. In conclusion, OSMR p.H187Q is an HAEC susceptibility variant and perturbates the downstream signaling cascade necessary for the gut immune response and homeostasis maintenance.

Radiography and ultrasonography of pneumatosis intestinalis in a cat.

An adult cat was presented for acute history of vomiting and collapse. Radiographs showed the presence of air within small intestinal walls and arborizing gas patterns within the liver, compatible with pneumatosis intestinalis and presumed portal venous gas, respectively. An abdominal ultrasound the following day was suggestive of gas within the intestinal wall, however, gas within the hepatic vasculature, parenchyma, or biliary tree was not evident. Due to progressive clinical deterioration of the patient, the owners elected humane euthanasia. Necropsy revealed severe necrotizing hemorrhagic enterotyphlocolitis secondary to Clostridium difficile toxin.

A T-bet gradient controls the fate and function of CCR6-RORγt+ innate lymphoid cells.

At mucosal surfaces, the immune system should not initiate inflammatory immune responses to the plethora of antigens constantly present in the environment, but should remain poised to unleash a potent assault on intestinal pathogens. The transcriptional programs and regulatory factors required for immune cells to switch from homeostatic (often tissue-protective) function to potent antimicrobial immunity are poorly defined. Mucosal retinoic-acid-receptor-related orphan receptor-γt-positive (RORγt(+)) innate lymphoid cells (ILCs) are emerging as an important innate lymphocyte population required for immunity to intestinal infections. Various subsets of RORγt(+) ILCs have been described but the transcriptional programs controlling their specification and fate remain largely unknown. Here we provide evidence that the transcription factor T-bet determines the fate of a distinct lineage of CCR6(-)RORγt(+) ILCs. Postnatally emerging CCR6(-)RORγt(+) ILCs upregulated T-bet and this was controlled by cues from the commensal microbiota and interleukin-23 (IL-23). In contrast, CCR6(+)RORγt(+) ILCs, which arise earlier during ontogeny, did not express T-bet. T-bet instructed the expression of T-bet target genes such as interferon-γ (IFN-γ) and of the natural cytotoxicity receptor NKp46. Mice genetically lacking T-bet showed normal development of CCR6(-)RORγt(+) ILCs, but they could not differentiate into NKp46-expressing RORγt(+) ILCs (that is, IL-22-producing natural killer (NK-22) cells) and failed to produce IFN-γ. The production of IFN-γ by T-bet-expressing CCR6(-)RORγt(+) ILCs was essential for the release of mucus-forming glycoproteins required to protect the epithelial barrier during Salmonella enterica infection. Salmonella infection also causes severe enterocolitis that is at least partly driven by IFN-γ. Mice deficient for T-bet or depleted of ILCs developed only mild enterocolitis. Thus, graded expression of T-bet in CCR6(-)RORγt(+) ILCs facilitates the differentiation of IFN-γ-producing CCR6(-)RORγt(+) ILCs required to protect the epithelial barrier against Salmonella infections. Co-expression of T-bet and RORγt, which is also found in subsets of IL-17-producing T-helper (T(H)17) cells, may be an evolutionarily conserved transcriptional program that originally developed as part of the innate defence against infections but that also confers an increased risk of immune-mediated pathology.

Langerhans Cell Histiocytosis Presenting as Enterocolitis and Shock in Neonate.

INTRODUCTION: Enterocolitis is a relatively common disease in neonatal period that can be a result of many underlying pathologies. One of them, which is an unusual disorder especially in neonatal age and with gastrointestinal involvement, is Langerhans cell histiocytosis (LCH). This case shows a severe neonatal LCH with digestive involvement which required intensive care and had an abnormal presentation, being hard to diagnose attributable to the diversity of symptoms. CASE REPORT: Eleven-day-old newborn presented for excessive weight loss followed by deterioration to shock, abdominal distension, digestive bleeding, and purpuric exanthema. Exploratory laparotomy identified aggressive enterocolitis. After stabilization, a significant hepatosplenomegaly persists as well as bicytopenia, pyrexia, and cutaneous lesions evolving tangible purple. LCH was diagnosed through histology of cutaneous biopsy. CONCLUSIONS: Gastrointestinal involvement in neonatal LCH is infrequent and its symptoms can be really unspecific. It is important to know that the first clinical manifestation is usually dermatologic with very diverse morphologies. Having a high suspect rate will lead us to an early diagnosis with its correspondent impact upon the outcome.

Shigella flexneri targets the HP1γ subcode through the phosphothreonine lyase OspF.

HP1 proteins are transcriptional regulators that, like histones, are targets for post-translational modifications defining an HP1-mediated subcode. HP1γ has multiple phosphorylation sites, including serine 83 (S83) that marks it to sites of active transcription. In a guinea pig model for Shigella enterocolitis, we observed that the defective type III secretion mxiD Shigella flexneri strain caused more HP1γ phosphorylation in the colon than the wild-type strain. Shigella interferes with HP1 phosphorylation by injecting the phospholyase OspF. This effector interacts with HP1γ and alters its phosphorylation at S83 by inactivating ERK and consequently MSK1, a downstream kinase. MSK1 that here arises as a novel HP1γ kinase, phosphorylates HP1γ at S83 in the context of an MSK1-HP1γ complex, and thereby favors its accumulation on its target genes. Genome-wide transcriptome analysis reveals that this mechanism is linked to up-regulation of proliferative gene and fine-tuning of immune gene expression. Thus, in addition to histones, bacteria control host transcription by modulating the activity of HP1 proteins, with potential implications in transcriptional reprogramming at the mucosal barrier.

Rack1 maintains intestinal homeostasis by protecting the integrity of the epithelial barrier.

Previously, we generated mouse models of Rack1 deficiency to identify key functions for Rack1 in regulating growth of intestinal epithelia: suppressing crypt cell proliferation and regeneration, promoting differentiation and apoptosis, and repressing development of neoplasia. However, other than low body weight, we did not detect an overt phenotype in mice constitutively deleted of Rack1 in intestinal epithelia ( vil-Cre: Rack1fl/fl mice), presumably because Rack1 was deleted in <10% of the total surface area of the epithelia. To assess the effect of Rack1 loss throughout the entire intestinal epithelia, we generated another mouse model of Rack1 deficiency, vil-Cre-ERT2: Rack1fl/fl. Within 5-10 days of the initial tamoxifen treatment, the mice lost over 20% of their body weight, developed severe diarrhea that for some was bloody, became critically ill, and died, if not euthanized. Necropsies revealed mildly distended, fluid-, gas-, and sometimes blood-filled loops of small and large bowel, inguinal lymphadenopathy, and thrombocytosis. Rack1 was deleted in nearly 100% of the epithelia in both the small intestine and colon when assessed by immunofluorescent or immunoblot analyses. Rack1 expression in other tissues and organs was not different than in control mice, indicating tissue specificity of the recombination. Histopathology revealed a patchy, erosive, hemorrhagic, inflammatory enterocolitis with denuded, sloughed off surface epithelium, and crypt hyperplasia. These results suggest a protective function for Rack1 in maintaining the integrity of intestinal epithelia and for survival. NEW & NOTEWORTHY Our findings reveal a novel function for Rack1 in maintaining intestinal homeostasis by protecting the epithelial barrier. Rack1 loss results in a patchy, erosive, hemorrhagic, inflammatory enterocolitis, which resembles that of inflammatory bowel diseases (IBD) in humans. Understanding mechanisms that protect barrier function in normal intestine and how loss of that protection contributes to the pathogenesis of IBD could lead to improved therapies for these and other erosive diseases of the gastrointestinal tract.

Vedolizumab treatment for immune checkpoint inhibitor-induced enterocolitis.

Immune checkpoint inhibitors (ICPI), such as ipilimumab [anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody] and nivolumab or pembrolizumab [anti-programmed cell death protein-1 (PD-1) antibodies], improve survival in several cancer types. Since inhibition of CTLA-4 or PD-1 leads to non-selective activation of the immune system, immune-related adverse events (irAEs) are frequent. Enterocolitis is a common irAE, currently managed with corticosteroids and, if necessary, anti-tumor necrosis factor-α therapy. Such a regimen carries a risk of serious side-effects including infections, and may potentially imply impaired antitumor effects. Vedolizumab is an anti-integrin α4ß7 antibody with gut-specific immunosuppressive effects, approved for Crohn's disease and ulcerative colitis. We report a case series of seven patients with metastatic melanoma or lung cancer, treated with vedolizumab off-label for ipilimumab- or nivolumab-induced enterocolitis, from June 2014 through October 2016. Clinical, laboratory, endoscopic, and histologic data were analyzed. Patients initially received corticosteroids but were steroid-dependent and/or partially refractory. One patient was administered infliximab but was refractory. The median time from onset of enterocolitis to start of vedolizumab therapy was 79 days. Following vedolizumab therapy, all patients but one experienced steroid-free enterocolitis remission, with normalized fecal calprotectin. This was achieved after a median of 56 days from vedolizumab start, without any vedolizumab-related side-effects noted. The patient in whom vedolizumab was not successful, due to active ulcerative colitis, received vedolizumab prophylactically. This is the first case series to suggest that vedolizumab is an effective and well-tolerated therapeutic for steroid-dependent or partially refractory ICPI-induced enterocolitis. A larger prospective study to evaluate vedolizumab in this indication is warranted.

PD-1 inhibitor gastroenterocolitis: case series and appraisal of 'immunomodulatory gastroenterocolitis'.

AIMS: PD-1 inhibitors facilitate immune response against certain tumour types, including melanoma. These drugs have led to prolonged survival but can also result in autoimmune-type side effects, including gastrointestinal inflammation. The histopathological effects of this medication class have not been well studied. METHODS AND RESULTS: We identified 37 gastrointestinal tract biopsies from 20 patients taking a PD-1 or PD-L1 inhibitor and evaluated clinicopathological findings. Diarrhoea was the most common symptom, and endoscopic findings ranged from mild erythema to erosion/ulceration. Common histological findings included lamina propria expansion, villous blunting (if applicable), intra-epithelial neutrophils and increased crypt/gland apoptosis, although intra-epithelial lymphocytes were rarely prominent. A few cases showed crypt rupture with resultant histiocytic/granulomatous response. Most patients responded to drug cessation and/or steroids, but follow-up endoscopies were not performed. CONCLUSIONS: PD-1/PD-L1 inhibitors can cause gastritis, enteritis and colitis, similar to other immunomodulatory antibodies (such as CTLA-4 inhibitors and PI3Kδ inhibitors), but the histological findings vary somewhat among drug classes. Clinical history, lack of prominent intra-epithelial lymphocytes and crypt rupture may help to distinguish PD-1 inhibitor gastroenterocolitis from mimics, which include other medication effect, inflammatory bowel disease, graft-versus-host disease, cytomegalovirus infection and autoimmune enteropathy.

The role of intravenous access during oral food challenges in food protein-induced enterocolitis syndrome.

BACKGROUND: Food protein-induced enterocolitis syndrome (FPIES) is a non-immunoglobulin E mediated food hypersensitivity syndrome characterized by profuse vomiting and diarrhea, which leads to lethargy, dehydration, and hypotension. Given the potential severity of reactions, resolution of FPIES is confirmed via oral food challenge (OFC) during which intravenous (IV) access is recommended to facilitate IV fluids (IVF) and steroid therapy. Risk factors for IV treatment are not well characterized. OBJECTIVES: The objectives of this study were to analyze predictors for IV treatment during OFC in patients with FPIES. METHODS: A retrospective chart review was conducted of patients with The International Classification of Diseases, Ninth Revision codes 558.3 and 558.9, and with OFC who were seen in an allergy and immunology clinic from January 2000 to October 2015. OFC reaction severity was scored (1, mild; 2, moderate; 3, severe), and demographics, IV treatment frequency, and OFC outcomes were evaluated. The Fisher exact test and Wilcoxon rank sum test statistical analyses were performed. RESULTS: Of 184 patients, 28 met inclusion criteria, with 39 OFCs performed. The median age of onset of FPIES was 6 months. The median age at OFC was 2.6 years. This was 2.2 years (range, 0.3-8.5 years) from symptom onset. Of 39 OFCs, IV treatment, including IVF and/or steroids, was required in only 7.7%. Thirty-eight OFCs (97.4%) were of equal or lesser severity than historical reactions. The median severity of presenting reaction (3[IV+]:1[IV-]; p = 0.05) was greater in those who required IV treatment. OFCs with IV treatment were in younger patients (15 months [IV+]:32 months [IV-]; p = 0.039) who underwent OFCs earlier relative to the time of diagnosis (8 months [IV+]:28 months [IV-]); p = 0.018). CONCLUSION: Although FPIES can potentially elicit severe symptomatology, the patients most commonly experienced only vomiting and diarrhea, which often resolved with minimal treatment. Reactions generally did not worsen over time. Fewer than 10% of the patients challenged required IV treatment, all were young and with severe FPIES. It is reasonable to consider age and length of time from historical reactions when evaluating the necessity of IV placement in patients undergoing FPIES OFC.