Allergy and autoimmunity in children: non-mutually exclusive diseases. A narrative review.

In last decades a simultaneous increase in the prevalence of atopic and autoimmune disorders in pediatric population has been observed. Despite the Th1-Th2 paradigm, supporting the polarization of the immune system with Th1 response involved in autoimmune diseases and Th2 response leading to hypersensitivity reactions, recent evidence suggests a possible coexistence of common pathogenic pathways as result of shared immune dysregulation. Similar genes and other mechanisms such as epithelial barrier damage, gut microbiota dysbiosis and reduced number of T regs and IL-10 contribute to the onset of allergy and autoimmunity. IgA deficiency is also hypothesized to be the crosslink between celiac disease and allergy by lowering gut mucous membrane protection from antigens and allergens. The present narrative review aims to give an overview of the co-occurrence of allergic and autoimmune disorders (celiac disease, inflammatory bowel diseases, type 1 diabetes mellitus, thyroid disease, juvenile idiopathic arthritis) in pediatric population, based on the available evidence. We also highlighted the common pathogenic pathways that may underpin both. Our findings confirm that allergic and autoimmune diseases are commonly associated, and clinicians should therefore be aware of the possible coexistence of these conditions in order to ameliorate disease management and patient care. Particular attention should be paid to the association between atopic dermatitis or asthma and celiac disease or type 1 diabetes and vice versa, for therapeutic interventions. Further studies are needed to better clarify mechanisms involved in the pathogenesis and eventually identify new therapeutic strategies.

The role of the atopy patch test in the diagnostic work-up of non-IgE gastrointestinal food allergy in children: a systematic review.

The "Atopy Patch Test" (APT) has been proposed as a diagnostic tool for food allergies (FA), especially in children with FA-related gastrointestinal symptoms. However, its diagnostic accuracy is debated, and its usefulness is controversial. The aim of this systematic review was to evaluate the APT diagnostic accuracy compared with the diagnostic gold standard, i.e., the oral food challenge (OFC), in children affected by non-IgE mediated gastrointestinal food allergies, including the evaluation in milk allergic subgroup. Both classical non-IgE mediated clinical pictures and food induced motility disorders (FPIMD) were considered. The search was conducted in PubMed and Scopus from January 2000 to June 2022 by two independent researchers. The patient, intervention, comparators, outcome, and study design approach (PICOS) format was used for developing key questions, to address the APT diagnostic accuracy compared with the oral food challenge (OFC). The quality of the studies was assessed by the QUADAS-2 system. The meta-analysis was performed to calculate the pooled sensitivity, specificity, DOR (diagnostic odds ratio), PLR (positive likelihood ratio), and NLR (negative likelihood ratio) with their 95% confidence intervals (CI). Out of the 457 citations initially identified via the search (196 on PubMed and 261 on Scopus), 37 advanced to full-text screening, and 16 studies were identified to be included in the systematic review. Reference lists from relevant retrievals were searched, and one additional article was added. Finally, 17 studies were included in the systematic review. The analysis showed that APT has a high specificity of 94% (95%CI: 0.88-0.97) in the group of patients affected by FPIMD. Data showed a high pooled specificity of 96% (95% CI: 0.89-0.98) and the highest accuracy of APT in patients affected by cow's milk allergy (AUC = 0.93).      Conclusion: APT is effective in identifying causative food in children with food-induced motility disorders.  What is Known: • Atopy patch test could be a useful diagnostic test for diagnosing food allergy, especially in children with food allergy-related gastrointestinal symptoms. What is New: • Atopy patch test may be a useful tool in diagnosing non IgE food allergy, especially in children with food-induced gastrointestinal motility disorders and cow's milk allergy.

FDXR-associated disease: a challenging differential diagnosis with inflammatory peripheral neuropathy.

BACKGROUND AND AIMS: Mutations in FDXR gene, involved in mitochondrial pathway, cause a rare recessive neurological disorder with variable severity of phenotypes. The most common presentation includes optic and/or auditory neuropathy, variably associated to developmental delay or regression, global hypotonia, pyramidal, cerebellar signs, and seizures. The review of clinical findings in previously described cases from literature reveals also a significant incidence of sensorimotor peripheral polyneuropathy (22.72%) and ataxia (43.18%). To date, 44 patients with FDXR mutations have been reported. We describe here on two new patients, siblings, who presented with a quite different phenotype compared to previously described patients. METHODS: Clinical, neurophysiological, and genetic features of two siblings and a systematic literature review focused on the clinical spectrum of the disease are described. RESULTS: Both patients presented with an acute-sub-acute onset of peripheral neuropathy and only in later stages of the disease developed the typical features of FDXR-associated disease. INTERPRETATION: The peculiar clinical presentation at onset and the evolution of the disease in our patients and in some cases revised from the literature shed lights on a new possible phenotype of FDXR-associated disease: a peripheral neuropathy which can mimic an acute inflammatory disease.

Outcome context-dependence is not WEIRD: Comparing reinforcement- and description-based economic preferences worldwide.

Recent evidence indicates that reward value encoding in humans is highly context-dependent, leading to suboptimal decisions in some cases. But whether this computational constraint on valuation is a shared feature of human cognition remains unknown. To address this question, we studied the behavior of individuals from across 11 countries of markedly different socioeconomic and cultural makeup using an experimental approach that reliably captures context effects in reinforcement learning. Our findings show that all samples presented evidence of similar sensitivity to context. Crucially, suboptimal decisions generated by context manipulation were not explained by risk aversion, as estimated through a separate description-based choice task (i.e., lotteries) consisting of matched decision offers. Conversely, risk aversion significantly differed across countries. Overall, our findings suggest that context-dependent reward value encoding is a hardcoded feature of human cognition, while description-based decision-making is significantly sensitive to cultural factors.

MRSA Femoral Osteomyelitis from Superinfected Scabies Lesions: A Pediatric Case Report.

Scabies is a skin infestation from the Sarcoptes scabiei. It is considered a public health issue causing concern in developing countries and is considered a "neglected tropical disease" by the World Health Organization (WHO). Scabies skin lesions may cause severe itching and can be the portal of entry for opportunistic and pathogenic bacteria, which can cause serious systemic infections. We report the case of a 3-year-old boy with recurrent scabies infections who presented to the emergency department because of a fever and refusal to walk. Blood tests showed neutrophilic leukocytosis and significantly increased C reactive protein (CRP) and procalcitonin. Upon medical examination, his right thigh was extremely painful upon palpation, knee flexion was lost and he was unable to stand, so magnetic resonance imaging (MRI) was performed. MRI showed osteomyelitis of metaphysis and distal diaphysis of the right femur with associated subperiosteal purulent collection and concomitant pyomyositis and fasciitis of the distal right thigh. Blood cultures were positive for methicillin-resistant Staphylococcus aureus (MRSA). The patient received a long course of intravenous antibiotic therapy and his condition slowly improved. Follow-up femur X-ray showed a mixed pattern of erosion and sclerosis at the meta-diaphyseal region and periosteal reaction at the diaphyseal region. This case highlights the importance of early scabies diagnosis even in Western countries where poverty and household overcrowding are uncommon. Early diagnosis, timely initiation of proper treatment and evidence of clinical resolution are important elements to prevent recurrence of infection and serious systemic superinfections even from multi-drug resistant bacteria. Clinical consequences from unrecognized disease or inadequate eradication are preventable.

Late-Onset Pyloric Stenosis and Intussusception With Final Diagnosis of Food Proteins' Hypersensitivity in Schaaf-Yang Syndrome: A Case Report.

Schaaf-Yang syndrome (SYS) is a rare neurodevelopmental disorder whose clinical spectrum includes neurodevelopment delay, dysmorphic features, and gastrointestinal symptoms such as feeding difficulties, gastroesophageal reflux, and chronic constipation. Given the small number of patients diagnosed with this syndrome, our aim is to describe novel clinical features that have not yet been reported. The patient we are describing is a 14-year-old male affected by a severe form of SYS. Initial clinical presentation included respiratory distress at birth, feeding difficulties, and neurodevelopmental delay. Since the age of 8 months, he had been tube fed with a semi-elemental formula, and this was well tolerated. At 9 years of age, the pathological mutation (variant p.Val701fs in MAGEL2 gene) associated with SYS was diagnosed. At 13 years of age, he presented severe gastrointestinal symptoms associated to progressive feeding difficulties. He also suffered from recurrent pancreatitis, late-onset pyloric stenosis and intussusception. Histology showed duodenal villous atrophy with a negative serology for celiac disease. Food protein's hypersensitivity was diagnosed and symptoms resolved after starting an elemental formula.

Nutritional status of children and adolescents in three Serbian enclaves in Kosovo and Metohija.

OBJECTIVE: To evaluate nutritional status of children and adolescents living in three Serbian enclaves in Kosovo and Metohija. METHODS: We conducted an observational cross-sectional, population-based study, enrolling children and adolescents who underwent a pediatric screening performed in the three Serbian enclaves of Gracanica, Gornje Kusce and Velika Hoca in Kosovo and Metohija. Children and adolescents (5-19 years) of all ethnic groups were evaluated in one of the three free outpatient medical facilities in rural villages in Kosovo. Body weight and height were measured, height-for-age z- scores (HAZ) and BMI-for-age z-scores (BAZ) indicators were analyzed. The anthropometric indicators HAZ and BAZ distributions were compared between sex and ages using Fisher's exact test. A two-sample Z-test for proportions was used to detect differences in individual categories of height- and BMI-for-age categories across sexes and age classes. RESULTS: Three hundred twenty-eight children and adolescents (184 females, 56.1% and 144 males, 43.9%) aged between 5 and 19 years were enrolled in the study. 241/328 participants showed a normal linear growth; with significantly more girls (78.3%) than boys (67.4%) being in the normal category. Similarly, a significant difference in BAZ distribution between sexes was noted, with more females being in the normal BMI category compared to males (63.0% vs 50.0%, respectively). Underweight and severe underweight subjects showed a prevalence of 1.5 and 0.6%, respectively. Overweight and obesity prevalence was 19.5 and 9.1%, respectively, which was comparable to World Health Organization overweight and obesity prevalence data for Serbia. CONCLUSIONS: Prevalence of undernutrition and severe undernutrition in children and adolescents living in three Serbian enclaves in Kosovo and Metohija is small. By contrast, a tendency to an increase in overweight and obesity, especially in the male population, was noted.

Non-IgE- or Mixed IgE/Non-IgE-Mediated Gastrointestinal Food Allergies in the First Years of Life: Old and New Tools for Diagnosis.

non-IgE and mixed gastrointestinal food allergies present various specific, well-characterized clinical pictures such as food protein-induced allergic proctocolitis, food protein-induced enterocolitis and food protein-induced enteropathy syndrome as well as eosinophilic gastrointestinal disorders such as eosinophilic esophagitis, allergic eosinophilic gastroenteritis and eosinophilic colitis. The aim of this article is to provide an updated review of their different clinical presentations, to suggest a correct approach to their diagnosis and to discuss the usefulness of both old and new diagnostic tools, including fecal biomarkers, atopy patch tests, endoscopy, specific IgG and IgG4 testing, allergen-specific lymphocyte stimulation test (ALST) and clinical score (CoMiss).

Potential Role of Omega-3 Polyunsaturated Fatty Acids in Pediatric Food Allergy.

Polyunsaturated fatty acids (PUFAs) are involved both in immune system regulation and inflammation. In particular, within the PUFAs category, omega-3 (ω-3) may reduce inflammation, whereas omega-6 (ω-6) PUFAs are generally considered to have a proinflammatory effect. Recent evidence highlights an imbalance in the ω-3:ω-6 ratio with an increased intake of ω-6, as a consequence of the shift towards a westernized diet. In critical age groups such as infants, toddlers and young children, as well as pregnant and lactating women or fish allergic patients, ω-3 intake may be inadequate. This review aims to discuss the potential beneficial effects of PUFAs on pediatric food allergy prevention and treatment, both at prenatal and postnatal ages. Data from preclinical studies with PUFAs supplementation show encouraging effects in suppressing allergic response. Clinical studies results are still conflicting about the best timing and dosages of supplementation and which individuals are most likely to benefit; therefore, it is still not possible to draw firm conclusions. With regard to food-allergic children, it is still debated whether PUFAs could slow disease progression or not, since consistent data are lacking. In conclusion, more data on the effects of ω-3 PUFAs supplementation alone or in combination with other nutrients are warranted, both in the general and food allergic population.

Summation anaphylaxis: A challenging diagnosis.

Anaphylaxis is the most severe of allergic reactions. The most frequent triggers of anaphylaxis in childhood are food, insect venom, drugs, exercise, etc. In some cases, the presence of more than one trigger is necessary for the allergic reaction, while one trigger alone is tolerated. This rare condition is called summation anaphylaxis (SA). Food-dependent exercise-induced anaphylaxis is the most well-known SA. However, SA may also occur with the association between food and/or exercise plus one or more of the following other cofactors, such as drugs, especially non-steroidal anti-inflammatory (NSAID), alcohol, infections, temperature variation, and menstrual cycle. SA can explain some cases of idiopathic anaphylaxis, as well as cases of an apparent breakdown in a previously acquired tolerance for food, or finally, when faced with a suggestive clinical history of food allergy or exercise anaphylaxis and the provocation test is negative. In these situations, a more careful clinical history looking for other cofactors is necessary.

The Role of Diet Diversity and Diet Indices on Allergy Outcomes.

Nutrients in foods are not eaten in isolation and food intake interacts in a complex manner, affecting health and disease outcomes. For this reason, focusing on the whole "pattern" of dietary intake instead of the single nutrients or groups of nutrients when studying diseases outcomes is increasingly appealing and growing. Diet diversity refers to the variety of foods being eaten, and the terms, diversity or variety, are often used interchangeably. When the overall diet is characterized by healthy foods, diet diversity will reflect a diversity/variety of healthy foods eaten over a period of time. The introduction of solid foods in the 1st year of life is considered a measure of increased diet diversity. Consuming a diverse range of foods and food allergens in the first year of life may increase intake of important nutrients and positively affect the gut microbiome structure and function. Intake of omega-3 fatty acids and fibers/prebiotics may be particularly important but more information is required about dose and which individuals are most likely to benefit. Increased diet diversity in the first year of life is also associated with reduced food allergy outcomes. In addition to diet diversity, diet indices are considered measures of overall diet quality and can be used as a simple assessment of dietary intake. The focus of this paper is to review and critically address the current knowledge of the association between diet diversity and diet indices and allergy outcomes. Based on the current evidence, we recommend the introduction of solid foods, including common allergenic solids, during the 1st year of life, according to the infant's neuro-developmental abilities and familial or cultural habits. For infants with severe AD and/or FA, medical assessment may be advisable before introducing common food allergens into the diet. Limited evidence exist about the role of diet indices in pregnancy and allergic disease in the offspring, and the most promising results indicate a reduction in childhood wheeze and/or asthma intake.

COVID-19 and food allergy in children.

In children with food allergy the visits should be limited to those that are unequivocally needed on clinical basis. Food challenge can be performed in selected situations, taking a more detailed history to make sure that patients provide whatever information we need. The maintenance of a safe diet can be hampered by several factors. Nutritional supplementation may be necessary.

Rotavirus vaccines in clinical development: Current pipeline and state-of-the-art.

Rotavirus (RV) disease is a leading cause of mortality and morbidity, especially in children under 5 years of age. The introduction of the two oral rotavirus vaccines Rotarix® and RotaTeq® has shown significant reductions in RV-related mortality, severe RV disease, and hospitalizations. However, some barriers, including a reduced efficacy in low-income countries, safety issues regarding the intussusception risk, age restrictions on vaccine use, the live-attenuated nature itself, and the substantial vaccine costs, currently restrict the full potential of RV disease prevention. Therefore, research is now focusing on the implementation of new oral vaccines and the development of parenteral vaccines to overcome these limits. This review provides an overview of the new rotavirus vaccines in clinical development and the ongoing clinical trials on new RV vaccines in the pediatric age.

Cow's Milk Allergy: Immunomodulation by Dietary Intervention.

Cow's milk proteins cause allergic symptoms in 2% to 3% of all infants. In these individuals, the physiological mechanism of tolerance is broken with subsequent possible sensitization to antigens, which can lead eventually to allergic responses. The present review aims to provide an overview of different aspects of immune modulation by dietary intervention in cow's milk allergy (CMA). It focuses on pathogenetic mechanisms of different CMA related disorders, e.g., gastroesophageal reflux and eosinophilic esophagitis, highlighting the role of dietary management on innate and adaptive immune systems. The traditional dietary management of CMA has greatly changed in the last years, moving from a passive approach, consisting of an elimination diet to relieve symptoms, to a "proactive" one, meaning the possibility to actively modulate the immune system. Thus, new insights into the role of hydrolysates and baked milk in immunomodulation are addressed here. Additionally, nutritional components, such as pre- and probiotics, may target the immune system via microbiota, offering a possible road map for new CMA prevention and treatment strategies.

Growth Pattern, Resting Energy Expenditure, and Nutrient Intake of Children with Food Allergies.

Growth impairment has been reported in children with food allergies (FA). However, the available data on the dietary intake of FA children are controversial, and no data are available on their resting energy expenditure (REE). The aim of this study was to test whether REE differs between FA and healthy children. In this study, 30 FA children were matched by sex and age, with 31 healthy controls using coarsened exact matching (CEM). Their REE was measured by indirect calorimetry (IC). Energy and macronutrient intake were evaluated using a three-day dietary record. Between-group comparisons were performed by robust median regression using CEM-related weights. The association of REE with allergies was also evaluated using robust median regression models. Anthropometric measurements, REE, and nutrient intake were similar in FA children and matched controls. Taking into account the association of REE with gender and age, a statistically significant but biologically negligible association was detected between median REE and allergy status (+9% in FA children). In conclusion, we did not find any biologically relevant difference in REE, anthropometry, and dietary intake in children with FA compared to healthy children.