Ultra-processed foods, allergy outcomes and underlying mechanisms in children: An EAACI task force report.

BACKGROUND: Consumption of ultra-processed foods [UPFs] may be associated with negative health outcomes. Limited data exist regarding the potential role of UPFs in the occurrence of allergic diseases. The underlying mechanisms underpinning any such associations are also poorly elucidated. METHODS: We performed a systematic review and narrative evidence synthesis of the available literature to assess associations between UPF consumption and pediatric allergy outcomes (n = 26 papers), including data on the association seen with the gut microbiome (n = 16 papers) or immune system (n = 3 papers) structure and function following PRISMA guidelines. RESULTS: Dietary exposure to fructose, carbonated soft drinks, and sugar intake was associated with an increased risk of asthma, allergic rhinitis, and food allergies in children. Commercial baby food intake was associated with childhood food allergy. Childhood intake of fructose, fruit juices, sugar-sweetened beverages, high carbohydrate UPFs, monosodium glutamate, UPFs, and advanced glycated end-products (AGEs) was associated with the occurrence of allergic diseases. Exposure to UPFs and common ingredients in UPFs seem to be associated with increased occurrence of allergic diseases such as asthma, wheezing, food allergies, atopic dermatitis, and allergic rhinitis, in many, but not all studies. CONCLUSION: More preclinical and clinical studies are required to better define the link between UPF consumption and the risk of allergies and asthma. These observational studies ideally require supporting data with clearly defined UPF consumption, validated dietary measures, and mechanistic assessments to definitively link UPFs with the risk of allergies and asthma.

Effects of Mediterranean diet during pregnancy on the onset of overweight or obesity in the offspring: a randomized trial.

BACKGROUND/OBJECTIVES: The PREMEDI study was designed to assess the efficacy of nutritional counseling aimed at promoting Mediterranean Diet (MD) during pregnancy on the incidence of overweight or obesity at 24 months in the offspring. METHODS: PREMEDI was a parallel-arm randomized-controlled trial. 104 women in their first trimester of pregnancy were randomly assigned in a 1:1 ratio to standard obstetrical and gynecological care alone (CT) or with nutritional counseling promoting MD. Women enrolled in the MD arm were provided with 3 sessions of nutritional counseling (one session per trimester). The main outcome was the proportion of overweight or obesity among the offspring at the age of 24 months. Maternal MD-adherence and weight gain during pregnancy were also evaluated. Lastly, the evaluation of epigenetic modulation of metabolic pathways in the offspring was analyzed in cord blood. RESULTS: Five women in the MD arm and 2 in the CT arm were lost to follow-up, so a total of 97 completed the study. At 24 months, children of MD mothers were less likely to have overweight or obesity than those of the CT mothers (6% vs. 33%, absolute risk difference = -27%, 95% CI -41% to -12%, p < 0.001; number needed to treat 3, 95% CI 2 to 8, intention to treat analysis). A significantly higher increase of MD-adherence during the trial was observed in the MD arm compared to the CT arm. A similar body weight gain at the end of pregnancy was observed in the two arms. The mean (SD) methylation rate of the leptin gene in cord blood was 30.4 (1.02) % and 16.9 (2.99) % in the CT and MD mothers, respectively (p < 0.0001). CONCLUSIONS: MD during pregnancy could be an effective strategy for preventing pediatric overweight or obesity at 24 months. This effect involves, at least in part, an epigenetic modification of leptin expression.

Targeting Food Allergy with Probiotics.

The globally dramatic increase in food allergy prevalence and severity is demanding effective preventive and therapeutic strategies. Food allergy derives from a defect of immune tolerance mechanisms. Immune tolerance is modulated by gut microbiome composition and function, and gut microbiome dysbiosis has been associated with the development of food allergy. Selected probiotic strains could regulate immune tolerance mechanisms. The mechanisms are multiple and are still not completely defined. Increasing evidence is providing useful information on the choice of optimal bacterial species/strains, dosage, and timing for intervention. The increased knowledge on the crucial role played by postbiotic gut microbiome-derived metabolites, such as butyrate, is also opening the way to a post- biotic approach in the stimulation of immune tolerance.

The journey toward disease modification in cow milk protein allergy.

Cow milk protein allergy (CMPA) is one of the most common food allergies in the pediatric age worldwide. Prevalence, persistence, and severity of this condition are on the rise, with a negative impact on the health-related quality of life of the patients and families and on the costs related to its management. Another relevant issue is that CMPA in early life may be the first stage of the "allergic march," leading to the occurrence of other atopic manifestations later in life, especially asthma, atopic eczema, urticaria, and rhinoconjunctivitis. Thus, "disease modification" options that are able to modulate the disease course of pediatric patients affected by CMPA would be very welcomed by affected families and healthcare systems. In this review, we report the most relevant progress on this topic.

Epidemiology of Paediatric Italian Food Allergy: Results of the EPIFA study.

Background: Updated epidemiologic data are important for defining effective public health strategies for pediatric food allergy (FA). Objective: The Epidemiology of Paediatric Italian Food Allergy (EPIFA) study was designed to investigate the epidemiology of pediatric FA in one of the most heavily populated Italian regions. Methods: A retrospective cohort study was performed in collaboration with family pediatricians aimed at investigating the epidemiology of Italian pediatric FA during 2009 to 2021. Family pediatricians in the Campania region were invited to use the Google Forms platform for online compilation of data forms. Data forms were reviewed by experienced pediatric allergists at the coordinating center. Results: A total population of 105,151 subjects (aged 0-14 years) was screened during the study period. Data from 752 FA patients were evaluated. A progressive increase in FA incidence and prevalence was observed from 2009 to 2021, with a relative increase up to 34% and 113.6%, respectively, at the end of study period. The relative increase in FA prevalence was higher in the 0-3-year-old age group in the same study period (+120.8%). The most frequent allergens were cow's milk, hen's egg, and nuts. Conclusion: The results of the EPIFA study showed an increase in pediatric FA incidence and prevalence from 2009 to 2021 in Italy. These results underline the necessity of new effective strategies for preventing and managing these conditions.

Skin, gut, and lung barrier: Physiological interface and target of intervention for preventing and treating allergic diseases.

The epithelial barriers of the skin, gut, and respiratory tract are critical interfaces between the environment and the host, and they orchestrate both homeostatic and pathogenic immune responses. The mechanisms underlying epithelial barrier dysfunction in allergic and inflammatory conditions, such as atopic dermatitis, food allergy, eosinophilic oesophagitis, allergic rhinitis, chronic rhinosinusitis, and asthma, are complex and influenced by the exposome, microbiome, individual genetics, and epigenetics. Here, we review the role of the epithelial barriers of the skin, digestive tract, and airways in maintaining homeostasis, how they influence the occurrence and progression of allergic and inflammatory conditions, how current treatments target the epithelium to improve symptoms of these disorders, and what the unmet needs are in the identification and treatment of epithelial disorders.

Growth pattern of paediatric patients affected by cow milk protein allergy fed with rice hydrolyzed formula.

OBJECTIVES: Formulas made from hydrolyzed rice proteins (HRPF) are well-tolerated plant-based alternatives to cow's milk protein (CMP)-based formulas for the dietary management of paediatric patients with CMP allergy (CMPA). Growth in patients with CMPA fed with HRPF has been evaluated in several studies with conflicting results. The aim was to evaluate the growth pattern of children with CMPA over a 12-month follow-up period. METHODS: Prospective cohort study evaluating growth patterns in challenge proven CMPA paediatric patients receiving HRPF for 12 months. Outcomes were anthropometry (body weight, body length, head circumference), adherence to the study formula and occurrence of adverse events (AEs). RESULTS: Sixty-six children were included and completed the 12-month study. At baseline, all CMPA patients were weaned. For the entire CMPA pediatric patients' cohort, from baseline to the end of the study period, the growth pattern resulted within the normal range of World Health Organization (WHO) growth references. The formula was well tolerated. Adherence was optimal and no AEs related to HRPF use were reported. CONCLUSIONS: HRPF is well tolerated and can help support healthy growth and development in infants and young children with CMPA. These type of formula can be given with complementary foods in the dietary management of CMPA.

A Lipopolysaccharide-Enriched Cow's Milk Allergy Microbiome Promotes a TLR4-Dependent Proinflammatory Intestinal Immune Response.

We have previously reported that the gut microbiota of healthy infants harbors allergy-protective bacteria taxa that are depleted in infants with cow's milk allergy (CMA). Few reports have investigated the role of the gut microbiota in promoting allergic responses. In this study we selected a CMA-associated microbiota with increased abundance of Gram-negative bacteria for analysis of its proinflammatory potential. LPS is the major component of the outer membrane of Gram-negative bacteria. Colonization of mice with a global or conditional mutation of the LPS receptor TLR4 with this CMA microbiota induced expression of serum amyloid A1 (Saa1) and other Th17-, B cell-, and Th2-associated genes in the ileal epithelium in a TLR4-dependent manner. In agreement with the gene expression data, mice colonized with the CMA microbiota have expanded populations of Th17 and regulatory T cells and elevated concentrations of fecal IgA. Importantly, we used both antibiotic-treated specific pathogen-free and germ-free rederived mice with a conditional mutation of TLR4 in the CD11c+ compartment to demonstrate that the induction of proinflammatory genes, fecal IgA, and Th17 cells is dependent on TLR4 signaling. Furthermore, metagenomic sequencing revealed that the CMA microbiota has an increased abundance of LPS biosynthesis genes. Taken together, our results show that a microbiota displaying a higher abundance of LPS genes is associated with TLR4-dependent proinflammatory gene expression and a mixed type 2/type 3 response in mice, which may be characteristic of a subset of infants with CMA.

How dietary advanced glycation end products could facilitate the occurrence of food allergy.

BACKGROUND: Food allergy (FA) is one of the most common chronic conditions in children with an increasing prevalence facilitated by the exposure to environmental factors in predisposed individuals. It has been hypothesized that the increased consumption of ultra-processed foods, containing high levels of dietary advanced glycation end products (AGEs), could facilitate the occurrence of FA. OBJECTIVE: We sought to provide preclinical and clinical evidence on the potential role of AGEs in facilitating the occurrence of FA. METHODS: Human enterocytes, human small intestine organ culture, and PBMCs from children at risk for allergy were used to investigate the direct effect of AGEs on gut barrier, inflammation, TH2 cytokine response, and mitochondrial function. Intake of the 3 most common glycation products in Western diet foods, Nε-(carboxymethyl) lysine, Nε-(1-carboxyethyl) lysin, and Nδ-(5-hydro-5- methyl-4-imidazolone-2-yl)-ornithine (MG-H1), and the accumulation of AGEs in the skin were comparatively investigated in children with FA and in age-matched healthy controls. RESULTS: Human enterocytes exposed to AGEs showed alteration in gut barrier, AGE receptor expression, reactive oxygen species production, and autophagy, with increased transepithelial passage of food antigens. Small intestine organ cultures exposed to AGEs showed an increase of CD25+ cells and proliferating crypt enterocytes. PBMCs exposed to AGEs showed alteration in proliferation rate, AGE receptor activation, release of inflammatory and TH2 cytokines, and mitochondrial metabolism. Significant higher dietary AGE intake and skin accumulation were observed children with FA (n = 42) compared with age-matched healthy controls (n = 66). CONCLUSIONS: These data, supporting a potential role for dietary AGEs in facilitating the occurrence of FA, suggest the importance of limiting exposure to AGEs children as a potential preventive strategy against this common condition.

ACR Appropriateness Criteria® Abnormal Liver Function Tests.

Liver function tests are commonly obtained in symptomatic and asymptomatic patients. Various overlapping lab patterns can be seen due to derangement of hepatocytes and bile ducts function. Imaging tests are pursued to identify underlying etiology and guide management based on the lab results. Liver function tests may reveal mild, moderate, or severe hepatocellular predominance and can be seen in alcoholic and nonalcoholic liver disease, acute hepatitis, and acute liver injury due to other causes. Cholestatic pattern with elevated alkaline phosphatase with or without elevated γ-glutamyl transpeptidase can be seen with various causes of obstructive biliopathy. Acute or subacute cholestasis with conjugated or unconjugated hyperbilirubinemia can be seen due to prehepatic, intrahepatic, or posthepatic causes. We discuss the initial and complementary imaging modalities to be used in clinical scenarios presenting with abnormal liver function tests. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

ACR Appropriateness Criteria® Left Lower Quadrant Pain: 2023 Update.

The differential diagnosis for left lower quadrant pain is wide and conditions range from the benign and self-limited to life-threatening surgical emergencies. Along with patient history, physical examination, and laboratory tests, imaging is often critical to limit the differential diagnosis and identify life-threatening abnormalities. This document will discuss the guidelines for the appropriate use of imaging in the initial workup for patients who present with left lower quadrant pain, patients with suspected diverticulitis, and patients with suspected complications from diverticulitis. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

The chemistry of gut microbiome-derived lipopolysaccharides impacts on the occurrence of food allergy in the pediatric age.

Introduction: Food allergy (FA) in children is a major health concern. A better definition of the pathogenesis of the disease could facilitate effective preventive and therapeutic measures. Gut microbiome alterations could modulate the occurrence of FA, although the mechanisms involved in this phenomenon are poorly characterized. Gut bacteria release signaling byproducts from their cell wall, such as lipopolysaccharides (LPSs), which can act locally and systemically, modulating the immune system function. Methods: In the current study gut microbiome-derived LPS isolated from fecal samples of FA and healthy children was chemically characterized providing insights into the carbohydrate and lipid composition as well as into the LPS macromolecular nature. In addition, by means of a chemical/MALDI-TOF MS and MS/MS approach we elucidated the gut microbiome-derived lipid A mass spectral profile directly on fecal samples. Finally, we evaluated the pro-allergic and pro-tolerogenic potential of these fecal LPS and lipid A by harnessing peripheral blood mononuclear cells from healthy donors. Results: By analyzing fecal samples, we have identified different gut microbiome-derived LPS chemical features comparing FA children and healthy controls. We also have provided evidence on a different immunoregulatory action elicited by LPS on peripheral blood mononuclear cells collected from healthy donors suggesting that LPS from healthy individuals could be able to protect against the occurrence of FA, while LPS from children affected by FA could promote the allergic response. Discussion: Altogether these data highlight the relevance of gut microbiome-derived LPSs as potential biomarkers for FA and as a target of intervention to limit the disease burden.

Nutritional Strategies for the Prevention and Management of Cow's Milk Allergy in the Pediatric Age.

Cow's milk allergy (CMA) is one of the most common pediatric food allergies. The prevalence and severity of CMA have increased dramatically in the last decades, under the pressure of environmental factors in genetically predisposed individuals. Among the environmental influences, nutritional factors play a crucial role. Diet is the most modifiable factor, representing a potential target for the prevention and treatment of CMA. In this review, we report the most scientific-based nutritional strategies for preventing and managing pediatric CMA. In addition, we propose the most complete supplement of compounds able to prevent nutrient deficiencies in CMA pediatric patients and to positively influence the disease course.

Food allergy: cause or consequence of pediatric eosinophilic esophagitis? Potential implications of ultraprocessed foods in prevention and management.

Eosinophilic esophagitis (EoE) is a chronic, immune-mediated disease characterized by eosinophilic infiltration, leading to esophageal dysfunction, inflammation, and fibrotic remodeling. In the last few decades, there has been an increased prevalence of EoE at an alarming rate in the pediatric age. The pathogenesis of EoE is still largely undefined, and this limits the definition of effective strategies for the prevention and management of this condition. EoE is considered a multifactorial disease arising from a negative interaction between environmental factors and genetic background, causing an impaired esophageal epithelial barrier with subsequent abnormal allergen exposure activating type 2 (Th2) inflammation. Food antigens have been suggested as key players in Th2 inflammation in pediatric patients with EoE, but emerging evidence suggests a potential role of other dietary factors, including ultraprocessed foods, as possible triggers for the occurrence of EoE. In this paper, we discuss the potential role of these dietary factors in the development of the disease, and we propose a new approach for the management of pediatric patients with EoE.

ACR Appropriateness Criteria® Right Upper Quadrant Pain: 2022 Update.

Acute right upper quadrant pain is one of the most common presenting symptoms in hospital emergency departments, as well as outpatient settings. Although gallstone-related acute cholecystitis is a leading consideration in diagnosis, a myriad of extrabiliary sources including hepatic, pancreatic, gastroduodenal, and musculoskeletal should also be considered. This document focuses on the diagnostic accuracy of imaging studies performed specifically to evaluate acute right upper quadrant pain, with biliary etiologies including acute cholecystitis and its complications being the most common. An additional consideration of extrabiliary sources such as acute pancreatitis, peptic ulcer disease, ascending cholangitis, liver abscess, hepatitis, and painful liver neoplasms remain a diagnostic consideration in the right clinical setting. The use of radiographs, ultrasound, nuclear medicine, CT, and MRI for these indications are discussed. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

The step-down approach in children with cow's milk allergy: Results of a randomized controlled trial.

BACKGROUND: The Step-Down Approach for Cow's Milk Allergy (SDACMA) trial evaluated the tolerability and the rate of immune tolerance acquisition in CMA children starting dietary treatment with amino acid-based formula (AAF) and then switching to EHCF containing the probiotic Lacticaseibacillus rhamnosus GG (EHCF + LGG). METHODS: Randomized controlled trial involving IgE-mediated CMA children receiving AAF from at least 4 weeks. EHCF + LGG tolerance was evaluated by the results of double-blind placebo-controlled food challenge (DBPCFC). Subjects tolerating EHCF + LGG were randomly allocated to remain on AAF, or to switch to EHCF + LGG. Immune tolerance acquisition to cow's milk proteins was evaluated with DBPCFC after 12 months of treatment. Allergy screening tests and body growth were also monitored. RESULTS: Sixty IgE-mediated CMA children were enrolled. The proportion of children treated with AAF who resulted tolerant to the first exposure of EHCF + LGG was 0.98 (exact 95% CI 0.91-0.99). The rate of the immune tolerance acquisition to cow milk proteins after 12 months treatment was higher in the EHCF + LGG (0.48, 95% exact CI 0.29-0.67, n/N = 14/29) than in the AAF group (0.03, 95% exact CI 0.001-0.17, n/N = 1/30). There was an absolute benefit increase (ABI) of tolerance rate equal to 0.45 (95% CI 0.23-0.63, Newcombe method 10) for EHCF + LGG versus AAF, corresponding to a NNT of 2 (2-4, Bender's method). A normal body growth pattern was observed in the two study groups. CONCLUSION: In IgE-mediated CMA children the step-down from AAF to EHCF + LGG is well tolerated and could facilitate the immune tolerance acquisition.

Imaging of Small-Bowel Neuroendocrine Neoplasms: AJR Expert Panel Narrative Review.

Neuroendocrine neoplasms (NENs) of the small bowel are typically slow-growing lesions that remain asymptomatic until reaching an advanced stage. Imaging modalities for lesion detection, staging, and follow-up in patients with known or suspected NEN include CT enterography, MR enterography, and PET/CT using a somatostatin receptor analog. FDG PET/CT may have a role in the evaluation of poorly differentiated NENs. Liver MRI, ideally with a hepatocyte-specific contrast agent, should be used in the evaluation of hepatic metastases. Imaging informs decisions regarding both surgical approaches and systematic therapy (specifically, peptide receptor radionuclide therapy). This AJR Expert Panel Narrative Review describes the multimodality imaging features of small-bowel NENs; explores the optimal imaging modalities for their diagnosis, staging, and follow-up; and discusses how imaging may be used to guide therapy.

The potential role of preventive and therapeutic immunonutrition strategies for pediatric food allergy: A mini-review.

Food allergy (FA) represents one of the main chronic conditions of the pediatric population. The gut microbiome (GM)-immune system axis is a milestone in affecting FA susceptibility. The dynamic and bidirectional crosstalk between the GM and immune system starts early in life, and it is deeply modulated during the first 1,000 days of life. Nutritional factors during this crucial period mainly influence the proper GM-immune system development and function across the lifespan, with potential beneficial or detrimental effects on health status. Immunonutrition strategies, applied from conception, could represent an innovative target for prevention and treatment of pediatric FA. Here we described the potential role of preventive and therapeutic immunonutrition strategies for pediatric FA, highlighting putative future perspectives in this field.

ACR Appropriateness Criteria® Hernia.

Abdominopelvic hernias are common clinical entities composed of a wide variety of congenital, traumatic, and iatrogenic etiologies. Any weakness in the body wall may result in hernia of cavity contents with concomitant risks of morbidity and mortality. Presentations may be specific, palpable body wall mass/bulge, or vague, nonspecific pain through bowel obstruction. This document focuses on initial imaging of the adult population with signs of symptoms prompting suspicion of abdominopelvic hernia. Imaging of the abdomen and pelvis to evaluate defects is essential for prompt diagnosis and treatment. Often CT and ultrasound are the first-line modalities to quickly evaluate the abdomen and pelvis, providing for accurate diagnoses and management of patients. MRI protocols may be useful as first-line imaging studies, especially in patients with orthopedic instrumentation. Although often performed, abdominal radiographs and fluorographic procedures may provide indirect evidence of hernias but are usually not indicated for initial diagnosis of hernia. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer-reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances in which peer-reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.