Update on the Role of Allergy in Pediatric Functional Abdominal Pain Disorders: A Clinical Perspective.

Both functional abdominal pain disorders (FAPDs) and food allergies are relatively common in children and adolescents, and most studies report an association between FAPDs and allergic conditions. FAPDs share pathophysiologic processes with allergies, including both immune and psychological processes interacting with the microbiome. No conclusive data are implicating IgE-mediated reactions to foods in FAPDs; however, there may be patients who have IgE reactions localized to the gastrointestinal mucosa without systemic symptoms that are not identified by common tests. In FAPDs, the data appears stronger for aeroallergens than for foods. It also remains possible that food antigens initiate an IgG reaction that promotes mast cell activation. If a food allergen is identified, the management involves eliminating the specific food from the diet. In the absence of systemic allergic symptoms or oral allergy syndrome, it appears unlikely that allergic triggers for FAPDs can be reliably identified by standard testing. Medications used to blunt allergic reactions or symptomatically treat allergic reactions may be useful in FAPDs. The purpose of the current manuscript is to review the current literature regarding the role of allergy in FAPDs from a clinical perspective, including how allergy may fit in the current model of FAPDs.

A putative anti-inflammatory role for TRPM8 in irritable bowel syndrome-An exploratory study.

BACKGROUND: Chronic and recurring pain is a characteristic symptom in irritable bowel syndrome (IBS). Altered signaling between immune cells and sensory neurons within the gut may promote generation of pain symptoms. As transient receptor potential melastatin 8 (TRPM8) agonists, such as L-menthol in peppermint oil, have shown to attenuate IBS pain symptoms, we began investigating potential molecular mechanisms. METHODS: Colonic biopsy tissues were collected from patients with IBS and controls, in two separate cohorts. Immunohistochemistry was performed to identify TRPM8 localization. Quantitative PCR was performed to measure mucosal mRNA levels of TRPM8. In addition, functional experiments with the TRPM8 agonist icilin were performed ex vivo to examine cytokine release from biopsies. Daily diaries were collected to ascertain pain symptoms. RESULTS: In biopsy tissue from IBS patients, we showed that TRPM8 immunoreactivity is colocalized with immune cells predominantly of the dendritic cell lineage, in close approximation to nerve endings, and TRPM8 protein and mRNA expression was increased in IBS patients compared to controls (p < 0.001). TRPM8 mRNA expression showed a significant positive association with abdominal pain scores (p = 0.015). Treatment of IBS patient biopsies with icilin reduced release of inflammatory cytokines IL-1ß, IL-6, and TNF-α (p < 0.05). CONCLUSIONS AND INFERENCES: These data indicate TRPM8 may have important anti-inflammatory properties and by this virtue can impact neuro-immune disease mechanisms in IBS.

Alpha-Gal Allergy as a Cause of Intestinal Symptoms in a Gastroenterology Community Practice.

OBJECTIVES: Immunoglobulin E (IgE) to galactose-α-1,3-galactose (alpha-gal) is a recently appreciated cause of allergic reactions to mammalian meat and dairy. In eastern North America Lone Star tick bites are the dominant mode of sensitization. Classically the alpha-gal syndrome manifests with urticaria, gastrointestinal symptoms, and/or anaphylaxis, but increasingly there are reports of isolated gastrointestinal symptoms without other common allergic manifestations. The objective of this retrospective study was to determine the frequency of IgE to alpha-gal in patients presenting with unexplained gastrointestinal symptoms to a community gastroenterology practice, and to evaluate the symptom response to the removal of mammalian products from the diet in alpha-gal-positive individuals. METHODS: An electronic medical record database was used to identify patients with alpha-gal IgE laboratory testing performed within the past 4 years. These charts were reviewed for alpha-gal test results, abdominal pain, diarrhea, nausea and vomiting, hives, bronchospasm, diagnosis of irritable bowel syndrome, postprandial exacerbation of symptoms, meat exacerbation of symptoms, patient recall of tick bite, other simultaneous gastrointestinal tract diagnoses, and clinical improvement with mammalian food product avoidance. RESULTS: A total of 1112 adult patients underwent alpha-gal IgE testing and 359 (32.3%) were positive. Gastrointestinal symptoms were similar in those positive and negative for alpha-gal seroreactivity. Of the 359 alpha-gal-positive patients, 122 had follow-up data available and 82.0% of these improved on a diet free of mammalian products. Few patients reported hives (3.9%) or bronchospasm (2.2%). Serum alpha-gal IgE titers ranged from 0.1 to >100 kU/L, with an average of 3.43 kU/L and a median of 0.94 kU/L. CONCLUSIONS: Clinicians practicing in the region of the Lone Star tick habitat need to be aware that patients with IgE to alpha-gal can manifest with isolated abdominal pain and diarrhea, and these patients respond well to dietary exclusion of mammalian products.

Local immune response to food antigens drives meal-induced abdominal pain.

Up to 20% of people worldwide develop gastrointestinal symptoms following a meal1, leading to decreased quality of life, substantial morbidity and high medical costs. Although the interest of both the scientific and lay communities in this issue has increased markedly in recent years, with the worldwide introduction of gluten-free and other diets, the underlying mechanisms of food-induced abdominal complaints remain largely unknown. Here we show that a bacterial infection and bacterial toxins can trigger an immune response that leads to the production of dietary-antigen-specific IgE antibodies in mice, which are limited to the intestine. Following subsequent oral ingestion of the respective dietary antigen, an IgE- and mast-cell-dependent mechanism induced increased visceral pain. This aberrant pain signalling resulted from histamine receptor H1-mediated sensitization of visceral afferents. Moreover, injection of food antigens (gluten, wheat, soy and milk) into the rectosigmoid mucosa of patients with irritable bowel syndrome induced local oedema and mast cell activation. Our results identify and characterize a peripheral mechanism that underlies food-induced abdominal pain, thereby creating new possibilities for the treatment of irritable bowel syndrome and related abdominal pain disorders.

Case of multisystem inflammatory syndrome in children presenting as fever and abdominal pain.

This case aims to remind all providers to scrutinise for atypical presentations of multisystem inflammatory syndrome in children (MIS-C) which may mimic a more routine diagnosis. In the absence of mucocutaneous symptoms, the diagnosis of MIS-C can be missed. Given the potential for rapid deterioration of patients with MIS-C, early treatment and inpatient interventions are necessary.

Immune checkpoint inhibitor-associated celiac disease.

BACKGROUND: Rare cases of immune checkpoint inhibitor (ICI)-associated celiac disease (ICI-CeD) have been reported, suggesting that disruption of tolerance mechanisms by ICIs can unmask celiac disease (CeD). This study aims to characterize the clinicopathological and immunophenotypic features of ICI-CeD in comparison to ICI-associated duodenitis (ICI-Duo) and usual CeD. METHODS: A medical and pathological records search between 2015 and 2019 identified eight cases of ICI-CeD, confirmed by tTG-IgA. Nine cases of ICI-Duo, 28 cases of moderate CeD, as well as 5 normal controls were used as comparison groups. Clinical information was collected from the electronic medical records. Immunohistochemistry for CD3, CD8, T-cell receptor gamma/delta (γδ), programmed death ligand 1 (PD-L1), and programmed death 1 (PD-1) were performed, with quantification of intraepithelial lymphocyte (IEL) subsets in three well-oriented villi. CD68, PD-L1, and PD-1 were assessed as a percentage of lamina propria surface area infiltrated by positive cells. Statistical significance was calculated by the Student's t-test and Fisher's exact test. RESULTS: The eight patients with ICI-CeD (F:M=1:3) and nine patients with ICI-Duo (F:M=5:4) presented similarly with diarrhea (13/17) and abdominal pain (11/17) after a median of 1.6 months on ICI therapy. In patients with ICI-CeD, tTG-IgA ranged from 104 to >300 IU/mL. Histological findings in ICI-CeD and ICI-Duo were similar and included expansion of the lamina propria, active neutrophilic duodenitis, variably increased IELs, and villous blunting. Immunohistochemistry showed that the average number of IELs per 100 enterocytes is comparable between ICI-CeD and ICI-Duo, with increased CD3+ CD8+ T cells compared with normal duodenum but decreased γδ T cells compared with CeD. Average PD-L1 percentage was 9% in ICI-CeD and 18% in ICI-Duo, in comparison to <1% in CeD and normal duodenum; average PD-1 percentage was very low to absent in all cases (<3%). On follow-up, five patients with ICI-CeD improved on a gluten-free diet (GFD) as the sole therapeutic intervention (with down-trending tTG-IgA) while the other three required immunosuppression. All patients who developed ICI-Duo received immunosuppression with variable improvement in symptoms. CONCLUSIONS: ICI-CeD resembles ICI-Duo clinically and histologically but shares the serological features and response to gluten withdrawal with classic CeD. Immunophenotyping of IELs in ICI-CeD and ICI-Duo also shows similar CD3, CD8, γδ T cell subsets, and PD-L1 populations, all of which differed quantitatively from usual CeD. We conclude that ICI-CeD is biologically similar to ICI-Duo and is likely a variant of ICI-Duo, but treatment strategies differ, with ICI-CeD often improving with GFD alone, whereas ICI-Duo requires systemic immunosuppression.

Clinical and anatomopathological features of eosinophilic oesophagitis in children and adults.

INTRODUCTION: Eosinophilic oesophagitis (EoE) is a chronic clinical-pathological disorder with an immunological basis characterised by symptoms of oesophageal dysfunction and, histologically, eosinophilic inflammation. OBJECTIVE: To evaluate the clinical characteristics and differences in children and adults diagnosed with EoE in a tertiary level hospital. METHOD: Descriptive, retrospective and cross-sectional study. We randomly selected 40 children and 40 adults diagnosed with EoE between 2009 and 2016. The patient characteristics were analysed by means of epidemiological, clinical, diagnostic and therapeutic variables. RESULTS: The average age at diagnosis was 10 years (children) and 34 years (adults), with a higher frequency in males. The majority were sensitised to aeroallergens (77.5% children vs. 82.5% adults) and foods (75% children vs. 82.5% adults). Statistically significant differences were detected in sensitisation to fruits (p=0.007) and grains (p<0.001). Differences were observed in impaction (22.5% children vs. 82.5% adults), dysphagia (42.5% children vs. 77.5% adults) and abdominal pain (25% children vs. 7.5% adults). Endoscopy showed that children had a higher frequency of exudates (92.5%) and adults, trachealisation (50% vs. 5%) and stenosis (17.5% vs. 2.5%). Statistically significant differences were found in treatment with topical corticosteroids (30% children vs. 77.5% adults), with a variable positive response. 77.5% of the patients received elimination diets. CONCLUSIONS: Statistically significant differences were observed between the paediatric and adult populations in the food sensitisation profiles, clinical manifestations, endoscopic findings and treatments received. This is a complex pathology that calls for a multidisciplinary team and would require new non-invasive techniques to facilitate its management.

Towards evidence-based and personalised care of acute pancreatitis.

Acute pancreatitis is a heterogeneous illness. Most patients experience a mild course of disease, but one third will develop local complications and/or organ failure associated with increased morbidity and risk of mortality. Diagnosis of acute pancreatitis is based on typical epigastric pain, elevation of serum lipase or amylase levels, and/or characteristic findings on imaging. Personalised management is needed in patients with acute pancreatitis. Currently, analgesia, Ringer's lactate solution-based goal-directed fluid resuscitation and early oral refeeding providing enteral nutrition if not tolerated are the cornerstones for early management. Prophylactic antibiotics or endoscopic retrograde cholangiopancreatography in the absence of cholangitis are considered to be futile. Future clinical trials should address optimal fluid resuscitation, the early administration of anti-inflammatory drugs and the exact role of nutritional support in severe acute pancreatitis. Here, we present a patient case and review the diagnosis, treatment and prognosis of acute pancreatitis.

Mast cell-nerve interactions correlate with bloating and abdominal pain severity in patients with non-celiac gluten / wheat sensitivity.

BACKGROUND: Gastrointestinal (GI) and extra-GI symptoms/manifestations represent key clinical features of patients with non-celiac gluten/wheat sensitivity (NCG/WS). This study aimed to investigate neuro-immune (focusing on mast cells, MCs) interactions in the duodenal submucosa of patients with NCG/WS. METHODS: Submucosal whole mounts from duodenal biopsies of 34 patients with self-reported NCG/WS, 28 with celiac disease (CD), 13 with functional dyspepsia (FD), and 24 healthy controls (HC) were analyzed by immunohistochemistry. Quantitative data on neuronal and MCs density and the percentage of MCs in close vicinity to nerves were obtained, and correlations among neurons, MC density and MC-nerve distance (D), and symptoms were assessed in the three groups. KEY RESULTS: The number of submucosal neurons was not different among groups. In NCG/WS, MC density was not different from HC, while it was slightly increased vs. CD (P = .07) and significantly decreased vs. FD (P < .05). The percentage of MCs close to nerves (D < 15 µm) was similarly increased in all three pathological groups vs. HC (P < .001). In NCG/WS, MC infiltration correlated with bloating (P = .001) and abdominal pain severity (P = .03) and the percentage of MCs in proximity to neurons correlated with the number of GI symptoms (D < 5 µm; P = .05), bloating and abdominal pain severity (D < 15um; P = .01). CONCLUSIONS AND INFERENCES: Submucosal MC infiltration and the close (within 15 µm) MC-to-nerve proximity in the duodenum of NCG/WS patients are features providing a histopathological basis to better understand GI symptoms in this condition.

Duodenal eosinophilia is associated with functional dyspepsia and new onset gastro-oesophageal reflux disease.

BACKGROUND: It is unexplained why functional dyspepsia and gastro-oesophageal reflux disease (GERD) overlap more often than expected by chance. Post-prandial distress syndrome has been linked to impaired gastric fundic accommodation which may induce increased transient lower oesophageal sphincter relaxations and consequent GERD. Duodenal eosinophilia has been linked to functional dyspepsia and post-prandial distress syndrome. AIM: To identify if there is an association between duodenal eosinophilia in functional dyspepsia and symptoms of GERD and whether post-prandial distress syndrome or epigastric pain syndrome are associated with new onset GERD. METHODS: Participants (n = 1000) were randomly selected from the national Swedish population register and surveyed by questionnaires and oesophagogastroduodenoscopy in 1999-2001. All eligible subjects (n = 887) were invited to a follow-up study in 2010 (response rate 79%). In a case-control study of 213 subjects (functional dyspepsia vs healthy controls), histology from the duodenum was evaluated at baseline and the possible association of eosinophilia to new onset GERD symptoms was analysed. RESULTS: Functional dyspepsia (OR 7.6; 95% CI 2.93-19.4, P < 0.001) and post-prandial distress syndrome at baseline (OR 9.0, 95% CI 3.36-24.0, P < 0.001) were associated with an increased risk of GERD at follow-up. Eosinophilia in the second part of duodenum only was independently associated with an increased risk of GERD amongst those with functional dyspepsia (OR 4.2; 95% CI 1.2-4.77, P = 0.024) and post-prandial distress syndrome at baseline (OR 6.0; 95% CI 1.50-23.6, P = 0.011), respectively. CONCLUSIONS: Duodenal eosinophilia is associated with increased risk of GERD at 10-year follow-up in those with functional dyspepsia and post-prandial distress syndrome at baseline. Duodenal eosinophilia may explain the link between GERD and functional dyspepsia, suggesting subsets of functional dyspepsia and GERD may be part of the same disease spectrum.

Protease Activated Receptor-2 Induces Immune Activation and Visceral Hypersensitivity in Post-infectious Irritable Bowel Syndrome Mice.

BACKGROUND: The role of protease activated receptor-2 (PAR-2) in the pathogenesis of abdominal pain in irritable bowel syndrome (IBS) is not well defined. AIMS: To investigate the role of PAR-2-mediated visceral hypersensitivity in a post-infectious IBS (PI-IBS) mouse model. METHODS: T. spiralis-infected PI-IBS mouse model was used. Fecal serine protease activity and intestinal mast cells were evaluated. Intestinal permeability was assessed by urine lactulose/mannitol ratio, and colonic expressions of PAR-2 and tight junction (TJ) proteins were examined by Western blot. Intestinal immune profile was assessed by measuring Th (T helper) 1/Th2 cytokine expression. Visceral sensitivity was evaluated by abdominal withdrawal reflex in response to colorectal distention. RESULTS: Colonic PAR-2 expression as well as fecal serine protease activity and intestinal mast cell counts were elevated in PI-IBS compared to the control mice. Decreased colonic TJ proteins expression, increased lactulose/mannitol ratio, elevated colonic Th1/Th2 cytokine ratio, and visceral hypersensitivity were observed in PI-IBS compared to the control mice. Administration of PAR-2 agonist in control mice demonstrated similar changes observed in PI-IBS mice, while PAR-2 antagonist normalized the increased intestinal permeability and reduced visceral hypersensitivity observed in PI-IBS mice. CONCLUSIONS: PAR-2 activation increases intestinal permeability leading to immune activation and visceral hypersensitivity in PI-IBS mouse model.

Cow's Milk Protein Allergy in Infancy: A Risk Factor for Functional Gastrointestinal Disorders in Children?

The role and prevalence of cow's milk protein allergy (CMA) in functional gastrointestinal disorders remains unclear. The aim of this review is to update knowledge on the relationship between CMA and functional abdominal pain disorders (FAPDs) in children. Cochrane Database and Pubmed were searched from inception using general and specific terms for CMA and functional gastrointestinal disorders. CMA is reported as a predisposing or coexisting factor in a wide range of functional gastrointestinal disorders in infants and children. Pathogenesis of both conditions is complex and multiple mechanisms including dysmotility and hypersensitivity might contribute to the clinical manifestations. Data supporting the possible role of food allergies in the pathogenesis of FAPDs are limited. CMA may predispose to early life inflammation and visceral hypersensitivity, which in turn might manifest as FAPDs. The diagnosis of either CMA or FAPDs and distinction between them is challenging because of nonspecific and overlapping symptoms. Lack of accurate allergy tests in non-IgE (immunoglobulin E) mediated cases is also problematic. Oral food challenge, following an elimination diet, should be performed to diagnose a suspected non-IgE CMA allergy in children with FAPDs. In the management of FAPDs, an elimination diet should be considered for a limited period to verify if the symptoms improve or resolve.

Abdominal pain, unconsciousness, and skin rash after lung transplantation.

Long-term success of lung transplantation is limited by allograft dysfunction and frequent infections. Varicella zoster virus infection (VZV) is one of the most common opportunistic infections among solid organ transplantation recipients. However the occurrence of visceral involvement or disseminated disease, as seen after bone marrow transplantation, is rare. We report a case of a 59-year-old woman who underwent double-lung transplantation with a fatal visceral and disseminated varicella zoster virus infection.