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Objectives:To determine tolerance rates to cow’s milk and soy and to suggest guidelines for follow-up oral food challenges (FU-OFCs) in infantile food protein-induced enterocolitis syndrome (FPIES).Methods:The authors analysed the data of 23 patients with infantile FPIES who underwent two or more FU-OFCs and were followed up until over 2 years of age. The first FU-OFCs were performed at 6 months of age, and patients were randomly allocated to cow’s milk (n = 11) or soy (n = 12) challenge starting groups. Second and third FU-OFCs were performed at 2-month intervals in a crossed and switched-over manner.Results:Tolerance rates to cow’s milk and soy were 27.3% and 75.0% at 6 months of age, 41.7% and 90.9% at 8 months and 63.6% and 91.7% at 10 months, respectively. Patients outgrew cow’s milk and soy intolerance at age 20 and 14 months.Conclusions:In infantile FPIES, the first FU-OFC should be performed with soy at 6–8 months of age and cow’s milk FU-OFC should be conducted at over 12 months of age. Infants with FPIES were observed to outgrow food sensitivities during the first 2 years of life.

Background. Although newer studies have evaluated risk factors for recurrent Clostridium difficile infection (CDI), the vast majority did not measure important biomarkers such as endogenous anti–toxin A and anti–toxin B antibody levels. Methods. Data from the placebo group of a phase 2 trial testing monoclonal antibodies to C. difficile toxins A and B for preventing CDI recurrence (rCDI) were analyzed to assess risk factors associated with rCDI. Patients with symptomatic CDI taking metronidazole or vancomycin were enrolled. The primary outcome was rCDI within 84 days of treatment start. Univariate and multivariate logistic regression was used to examine associations between potential risk factors and rCDI. At baseline, demographic and clinical characteristics were recorded; endogenous antibody levels were assessed using 2 enzyme-linked immunosorbent assays. Results. A predictor of recurrence was age ≥65 years, and an antibody-mediated immune response to toxin B appears to be protective against rCDI. Conclusions. Our findings demonstrate the importance of clinical as well as immunological risk factors in rCDI and provide more robust evidence for the protective effects of antibody to toxin B in the prevention of rCDI. Clinical Trials Registration. NCT00350298.

Previous studies have demonstrated a correlation between Clostridium difficile anti-toxin A serum antibodies and protection against symptomatic disease and recurrence. A neutralizing monoclonal antibody to C. difficile toxin A (CDA1) developed by MBL and Medarex, Inc. was studied in a phase II, randomized, double-blind, placebo-controlled trial in patients receiving standard of care treatment for C. difficile infection (CDI). Twenty-nine subjects received a single intravenous infusion of 10mg/kg CDA1 and 17 subjects received placebo and were evaluated for recurrence of CDI during the 56-day study period. Serum antibodies against C. difficile toxin A and B were measured by ELISA and cytotoxicity assay at various time points before and after infusion. CDI recurrence occurred in 5 of 29 (17%) in the CDA1 group and 3 of 17 (18%) (p=NS) in the placebo group with a trend toward delay in time to recurrence in the group treated with CDA1. The geometric mean concentration of antibody to an epitope of the receptor-binding domain of toxin B (0.300 and 1.20μg/ml, respectively; p=0.02) and geometric mean titer of neutralizing B antibody (8.00 and 100, respectively; p=0.02) at study day 28 were lower for those subjects with recurrence compared to those who did not recur. In addition, a significantly greater proportion of subjects who recurred were infected with the epidemic BI/NAP1/027 strain compared with those that did not recur (88% vs. 22%; p=0.002). Finally, in a multiple logistic regression analysis neutralizing anti-toxin B at day 14 (p<0.001), anti-toxin A at day 28 (p<0.001) and infection with the BI/NAP1/027 strain at enrollment (p=0.002) were all predictive of CDI recurrence. In this prospective study, lower concentrations of neutralizing anti-toxin B and anti-toxin A antibody and infection with the BI/NAP1/027 strain of C. difficile were significantly associated with recurrence of CDI.

The graded expression of the transcription factor T-bet in CCR6 − RORγt + innate lymphoid cells is found to be involved in the control of interferon-γ expression, a cytokine that is required to protect the epithelial barrier against Salmonella infections. T-bet protein role in intestinal immunity The mechanisms by which immune cells switch from their routine tissue-protective mode to potent antimicrobial activity are poorly defined. This study shows that co-expression of the transcription factor T-bet and the nuclear receptor RORγt is required for the production of interferon gamma by the innate lymphoid cells in the lamina propria of the small intestine that provide epithelial protection against Salmonella infection in mice. 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 1 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 2 . Various subsets of RORγt + ILCs have been described 3 , 4 , 5 , 6 , 7 , 8 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) 3 , 9 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 10 , 11 . Salmonella infection also causes severe enterocolitis that is at least partly driven by IFN-γ 12 . 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 13 , 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.

Non-immunoglobulin E-mediated gastrointestinal food allergic disorders (non-IgE-GI-FA) include food protein-induced enterocolitis syndrome (FPIES), food protein-induced enteropathy (FPE) and food protein-induced allergic proctocolitis (FPIAP), which present with symptoms of variable severity, affecting the gastrointestinal tract in response to specific dietary antigens. The diagnosis of non-IgE-GI-FA is made clinically, and relies on a constellation of typical symptoms that improve upon removal of the culprit food. When possible, food reintroduction should be attempted, with the documentation of symptoms relapse to establish a conclusive diagnosis. Management includes dietary avoidance, nutritional counselling, and supportive measures in the case of accidental exposure. The prognosis is generally favorable, with the majority of cases resolved before school age. Serial follow-up to establish whether the acquisition of tolerance has occurred is therefore essential in order to avoid unnecessary food restriction and potential consequent nutritional deficiencies. The purpose of this review is to delineate the distinctive clinical features of non-IgE-mediated food allergies presenting with gastrointestinal symptomatology, to summarize our current understanding of the pathogenesis driving these diseases, to discuss recent findings, and to address currents gaps in the knowledge, to guide future management opportunities.

Immune checkpoint blockade has become standard treatment for many types of cancer. Such therapy is indicated most often in patients with advanced or metastatic disease but has been increasingly used as adjuvant therapy in those with early-stage disease. Adverse events include immune-related organ inflammation resembling autoimmune diseases. We describe a case of severe immune-related gastroenterocolitis in a 4-month-old infant who presented with intractable diarrhea and failure to thrive after in utero exposure to pembrolizumab. Known causes of the symptoms were ruled out, and the diagnosis of pembrolizumab-induced immune-related gastroenterocolitis was supported by the results of histopathological assays, immunophenotyping, and analysis of the level of antibodies against programmed cell death protein 1 (PD-1). The infant’s condition was successfully treated with prednisolone and infliximab. After a pregnant woman with melanoma received pembrolizumab therapy, severe autoimmune enteritis developed in her healthy newborn infant. The condition was treated with prednisolone and infliximab.

Mucosal immunity is influenced by commensal bacteria. Liu and colleagues show that commensals direct selective cargo sorting in Paneth cells through the cytosolic sensor NOD2 and the kinase LRRK2 to promote symbiosis. Mucosal immunity protects a host from intestinal inflammation and infection and is profoundly influenced by symbiotic bacteria. Here we report that in mice symbiotic bacteria directed selective cargo sorting in Paneth cells to promote symbiosis through Nod2, a cytosolic bacterial sensor, and the multifunctional protein kinase LRRK2, both encoded by inflammatory bowel disease (IBD)-associated genes. Commensals recruited Nod2 onto lysozyme-containing dense core vesicles (DCVs), which was required for DCV localization of LRRK2 and a small GTPase, Rab2a. Deficiency of Nod2, LRRK2 or Rab2a or depletion of commensals resulted in lysosomal degradation of lysozyme. Thus, commensal bacteria and host factors orchestrate the lysozyme-sorting process to protect the host from enteric infection, implicating Paneth cell dysfunction in IBD pathogenesis.

Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy that has been well-characterized clinically, yet it is still poorly understood. Acute FPIES is characterized by vomiting 1–4 h and/or diarrhea within 24 h after ingestion of a culprit food. Chronic FPIES is the result of chronic exposure to an offending food that can result in chronic watery diarrhea, intermittent vomiting, and failure to thrive. FPIES typically presents in infancy and self-resolves by school age in most patients. Adult-onset FPIES is rare, but it has been reported. Cow’s milk and soy are the most common triggering foods in infants in the US, and as solids are introduced in the diet, FPIES reactions to grains (rice, oat) increase in prevalence. Variability in common trigger foods exists depending on the geographical origin—for example, fish is a frequent trigger in Spanish and Italian patients. Heavy reliance on a detailed history is required for the diagnosis as physical exam findings, laboratory tests, and/or imaging studies are suggestive and not specific for FPIES. Oral food challenges remain the gold standard for confirming diagnosis, and the challenge protocol may be for an individual depending on risk of reaction, prior reaction severity, and positive-specific IgE status. The recent development of diagnostic criteria in 2017 will serve to increase recognition of the disorder and allow for early implementation of management strategies. Acute management during reactions includes IV hydration, anti-emetics, and IV corticosteroids. Reaction prevention strategies include strict food avoidance until the physician deems a food reintroduction challenge clinically appropriate. Future efforts in FPIES research should be aimed at elucidating the underlying disease mechanisms and possible treatment targets.

Hirschsprung-associated enterocolitis (HAEC) is one of the most severe complications in patients with Hirschsprung's disease (HSCR). Previous research has indicated that acetylcholine (ACH) plays an anti-inflammatory role during inflammation by acting on the α7 nicotinic acetylcholine receptor(α7nAchR) to promote the secretion of anti-inflammatory factors. However, the specific role of ACH in HAEC remains unclear. This experiment aims to explore the sources of ACH in HSCR and its anti-inflammatory mechanisms, thereby identifying new directions for the prevention and treatment of HAEC. We analyzed single-cell transcriptome data from HSCR to identify cells that secrete ACH and observed their distribution using immunofluorescence. In mice, F4/80, iNOS, ARG-1 and CD206 were used to identify and locate M1 and M2 macrophages in different intestinal segments. Western blot, reverse transcription-quantitative polymerase chain reaction, and enzyme-linked immunosorbent assay were used to test the levels of IκBα, tumor necrosis factor-α, interleukin-10, and the macrophage activation pathway proteins JAK2 and STAT3 in different intestinal segments of mice. Organoid and cell culture techniques were used to verify the anti-inflammatory mechanism of ACH models. scRNA-seq analysis revealed that tuft cells expressed the CHAT protein. In HSCR, aganglionic segments exhibited heightened cholinergic activity compared with dilated ganglionic segments. In HAEC, inflammation was mainly concentrated in the dilated ganglionic segment and was associated with an increase in M1 macrophages, whereas the aganglionic segment showed less inflammation and was associated with an increase in M2 macrophages. Furthermore, experiments showed that intestinal organoids containing tuft cells promoted an increase in M2 macrophage markers, and ACH promoted M2 macrophage polarization. Differences in inflammation among various intestinal segments in HAEC may be linked to ACH secreted by tuft cells. Drugs targeting tuft cells have the potential to become important components of HAEC treatment in the future.

We report 14 cases of immune effector cell (IEC)-associated enterocolitis following chimeric antigen receptor T-cell (CAR-T) therapy in multiple myeloma, with a 1.2% incidence overall (0.2% for idecabtagene vicleucel and 2.2% for ciltacabtagene autoleucel). Patients developed acute-onset symptoms (typically non-bloody Grade 3+ diarrhea) with negative infectious workup beginning a median of 92.5 days (range: 22–210 days) after CAR-T therapy and a median of 85 days after cytokine release syndrome resolution. Gut biopsies uniformly demonstrated inflammation, including intra-epithelial lymphocytosis and villous blunting. In one case where CAR-specific immunofluorescence stains were available, CAR T-cell presence was confirmed within the lamina propria. Systemic corticosteroids were initiated in 10 patients (71%) a median of 25.5 days following symptom onset, with symptom improvement in 40%. Subsequent infliximab or vedolizumab led to improvement in 50% and 33% of corticosteroid-refractory patients, respectively. Five patients (36%) have died from bowel perforation or treatment-emergent sepsis. In conclusion, IEC-associated enterocolitis is a distinct but rare complication of CAR-T therapy typically beginning 1–3 months after infusion. Thorough diagnostic workup is essential, including evaluation for potential T-cell malignancies. The early use of infliximab or vedolizumab may potentially hasten symptom resolution and lower reliance on high-dose corticosteroids during the post-CAR-T period.