Nikolaos Douladiris

Iron is essential for oxygen transport, energy metabolism, and immune regulation. Yet iron deficiency is the most common micronutrient disorder across all age groups, affecting nearly one quarter of the global population. Iron deficiency triggers nutritional immunity, a host defense mechanism that withholds and redistributes iron, contributing to increased morbidity and mortality. This review outlines normal iron physiology, distribution and absorption pathways and on the consequences of deficiency across body compartments, with particular attention to type 2–driven diseases. Beyond anemia, insufficient iron availability disrupts immune homeostasis by promoting type 2 inflammation, elevating IgE, and activating mast cells and eosinophils. Regulatory macrophages, the central hub of iron cycling, adopt an inflammatory, iron‐sequestering state that reinforces malabsorption and redistribution. Epidemiology studies show higher iron‐deficiency risk in allergic individuals; low maternal iron or early‐life iron predisposes to eczema, wheeze, and asthma, while food‐allergen elimination (notably cow's milk) further worsens anemia risk. Clinical evidence indicates that restoring iron status through diet, supplementation, or fortification lowers IgE levels, improves lung function, and alleviates symptoms of rhinitis, urticaria, and asthma. Iron may therefore represent a modifiable determinant of allergic disease development and severity. Integrating iron assessment and nutritional care into allergy management may reduce disease burden and slow the progression of allergic march.

Background: Food protein‐induced allergic proctocolitis (FPIAP) is the leading cause of rectal bleeding in infants. Tolerance is presumed to develop until the first year of age, although natural history studies are scarce, making the determination of the ideal duration for any intervention, challenging. Intestinal microbiota (IM) is crucial in food allergy development; however, data for FPIAP remain limited. This study aimed to assess FPIAP remission after 3 months of milk avoidance and its correlation with IM longitudinal changes.Methods: A prospective observational study of infants aged ≤6 months with a diagnosis of FPIAP. After 3 months of management according to a clinical algorithm, infants were subjected to a milk challenge using either a cow (CM) or a goat (GM) milk formula in a random order. Stool samples were collected longitudinally for microbiome analysis.Results: Out of 61 infants, 57 were challenged (29 with CM, 28 with GM). Of these, 55 (96.5%) achieved tolerance, with no difference in tolerance rates between CM (28/29) and GM (27/28). The average age of tolerance development was 6.3 months. Enterobacteriaceae clusters (Klebsiella‐ and Shigella‐dominated) were most often represented in samples from symptomatic infants. In contrast, Bacteroides and Bifidobacteria clusters emerged later, in apparently healthy infants.Conclusion: A 3‐month intervention was sufficient for almost all infants to achieve tolerance. GM was tolerated equally well to CM. Symptomatic FPIAP is associated with immature enterotypes, while disease remission coincides with microbiome changes in time.

Aim: To investigate the routine guidance provided by pediatricians concerning the timing of complementary feeding (CF) for both healthy infants and those at a heightened risk of allergies. Methods: A total of 233 pediatricians participated in an anonymous online survey that included questions about demographics and recommendations for CF. Specifically, they provided guidance on the types of foods, preparation methods, supplements, time intervals for introducing new foods to infants at low and high allergy risk, and delayed food introductions for high-risk cases. Results: The respondents advised introducing certain foods at specific ages: fruits, starchy non-gluten grains, vegetables, olive oil, and meat were appropriate at 6 months; gluten-rich grains at 7 months; yogurt, hard-boiled eggs, and legumes at 8 months; fish at 8.5 months; and nuts at 9 months. Pediatricians, especially those with less than 15 years of practice, often introduced egg, seafood, gluten-rich grains, legumes, and nuts earlier for high-risk infants. Parenthood and male gender were associated with the earlier introduction of eggs and grains. Conclusions: Greek pediatricians follow a structured food introduction schedule for CF in infants. Interestingly, they tend to delay the introduction of common food allergens and recommend longer intervals between introducing new foods, particularly for high-risk infants. Key Notes: Despite recent evidence-based indications on healthy complementary feeding strategies for infants, discrepancies persist among pediatricians regarding food choices and the order and timing of food introduction, both for healthy infants and those at risk of allergy. Guidance on complementary feeding by pediatricians is influenced by their individual characteristics. Pediatricians tend to delay the introduction of common food allergens and recommend longer intervals between introducing new foods, particularly for high-risk infants.

Background: Atopic dermatitis (AD) at a young age often precedes the development of food allergies. Although AD affects millions of infants worldwide, prenatal and postnatal risk factors, and their association with the development of food allergies later on, are not fully elucidated. This study seeks to investigate AD epidemiology in infancy and its risk factors, examining early-life factors (both prenatal and postnatal) that could contribute to the later development of food allergies. Methods: Between January 2019 and December 2019, 501 infants were included in this prospective cohort study. Longitudinal data collection was performed through maternal interviews, the first one conducted within three days after the delivery and the second within 24 to 36 months after the delivery, encompassing variables such as demographics, family history of atopy, maternal smoking, antibiotic use during pregnancy, the mode of delivery, breastfeeding history, food practices, and greenness exposure within 3 days from delivery, while they were still in the hospital. Results: Maternal smoking during pregnancy (p = 0.001) and an older sibling atopy history (p = 0.03) was significantly linked to AD incidence. Cesarean section delivery (p = 0.04) was associated with a higher risk of food allergies in infants with AD. Having a garden at home correlated with a higher likelihood of AD (p = 0.01), and food elimination without medical guidance (p = 0.02) due to AD correlated with an elevated risk of food allergies. Conclusions: Encouraging timely allergenic food introduction while promoting dietary diversity, rich in plant-based foods, maternal smoking cessation, and professional dietary guidance may help minimize AD and food allergy risk. Future studies should address the role of greenness in the development of AD and food allergies.

Background: Immunoglobulin-E(IgE)-mediated hypersensitivity to cow’s milk allergens is a frequent cause of severe and life-threatening anaphylactic reactions. Besides case histories and controlled food challenges, the detection of the IgE antibodies specific to cow’s milk allergens is important for the diagnosis of cow-milk-specific IgE sensitization. Cow´s milk allergen molecules provide useful information for the refined detection of cow-milk-specific IgE sensitization. Methods: A micro-array based on ImmunoCAP ISAC technology was developed and designated milk allergen micro-array (MAMA), containing a complete panel of purified natural and recombinant cow’s milk allergens (caseins, α-lactalbumin, β-lactoglobulin, bovine serum albumin-BSA and lactoferrin), recombinant BSA fragments, and α-casein-, α-lactalbumin- and β-lactoglobulin-derived synthetic peptides. Sera from 80 children with confirmed symptoms related to cow’s milk intake (without anaphylaxis: n = 39; anaphylaxis with a Sampson grade of 1–3: n = 21; and anaphylaxis with a Sampson grade of 4–5: n = 20) were studied. The alterations in the specific IgE levels were analyzed in a subgroup of eleven patients, i.e., five who did not and six who did acquire natural tolerance. Results: The use of MAMA allowed a component-resolved diagnosis of IgE sensitization in each of the children suffering from cow’s-milk-related anaphylaxis according to Sampson grades 1–5 requiring only 20–30 microliters of serum. IgE sensitization to caseins and casein-derived peptides was found in each of the children with Sampson grades of 4–5. Among the grade 1–3 patients, nine patients showed negative reactivity to caseins but showed IgE reactivity to alpha-lactalbumin (n = 7) or beta-lactoglobulin (n = 2). For certain children, an IgE sensitization to cryptic peptide epitopes without detectable allergen-specific IgE was found. Twenty-four children with cow-milk-specific anaphylaxis showed additional IgE sensitizations to BSA, but they were all sensitized to either caseins, alpha-lactalbumin, or beta-lactoglobulin. A total of 17 of the 39 children without anaphylaxis lacked specific IgE reactivity to any of the tested components. The children developing tolerance showed a reduction in allergen and/or peptide-specific IgE levels, whereas those remaining sensitive did not. Conclusions: The use of MAMA allows for the detection, using only a few microliters of serum, of IgE sensitization to multiple cow’s milk allergens and allergen-derived peptides in cow-milk-allergic children with cow-milk-related anaphylaxis.

Background: Schoolchildren are likely to consume meals and snacks at school, with a possibility of allergic food reactions and anaphylaxis in the school environment. The school personnel should be informed of the presence of schoolchildren with food allergy (FA) and need to be trained in the management of allergic reactions, as to prepare them to intervene appropriately when necessary. Limited knowledge of FA and its management is documented globally among school staff and there is no uniform protocol in schools. Methods: In this observational cross-sectional study, teachers at state schools throughout Greece completed an online anonymous questionnaire on their awareness of FA reactions and the plans for the management of medical emergencies in their schools of employment. Results: Among the 289 teachers who responded the online invitation, 203 (70.24%) were female and 157 (54%) were aged under 40 years. Females expressed a higher level of concern about the presence of school personnel trained to manage FA symptoms (p = 0.001), written instructions, and the availability of adrenaline (epinephrine) at school (p < 0.001). A younger age was associated with a higher level of both interest and knowledge on FA management in schools. School directors were more certain about the availability of a special record of children with FA at school (p = 0.01), the availability of adrenaline (p = 0.006), and written guidelines on the management of serious health incidents at school (p = 0.04). Written guidelines instructing children to avoid sharing cutlery, glasses, home-prepared meals, and snacks bought from the school canteen were more common in schools in urban areas (p = 0.015). Only 20% of respondents could confirm with certainty that adrenaline autoinjectors (AAIs) were available at their schools, for the purpose of administering to children in the case of a severe FA reaction. Approximately 3/4 of the participating teachers stated that completion of this questionnaire raised their awareness of the risk of FA reactions in children at school. Conclusions: This study, the first in Greece to explore the knowledge of teachers about FA in schoolchildren, revealed the following absences in many schools: a process for identifying children with FA, a written emergency treatment plan, and immediate access to emergency AAI. School FA guidelines are necessary in Greece, and training, which includes the use of AAIs, is required to prepare teachers to manage FA reactions in children at school.

Since the discovery of immunoglobulin E (IgE) as a mediator of allergic diseases in 1967, our knowledge about the immunological mechanisms of IgE‐mediated allergies has remarkably increased. In addition to understanding the immune response and clinical symptoms, allergy diagnosis and management depend strongly on the precise identification of the elicitors of the IgE‐mediated allergic reaction. In the past four decades, innovations in bioscience and technology have facilitated the identification and production of well‐defined, highly pure molecules for component‐resolved diagnosis (CRD), allowing a personalized diagnosis and management of the allergic disease for individual patients. The first edition of the “EAACI Molecular Allergology User's Guide” (MAUG) in 2016 rapidly became a key reference for clinicians, scientists, and interested readers with a background in allergology, immunology, biology, and medicine. Nevertheless, the field of molecular allergology is moving fast, and after 6 years, a new EAACI Taskforce was established to provide an updated document. The Molecular Allergology User's Guide 2.0 summarizes state‐of‐the‐art information on allergen molecules, their clinical relevance, and their application in diagnostic algorithms for clinical practice. It is designed for both, clinicians and scientists, guiding health care professionals through the overwhelming list of different allergen molecules available for testing. Further, it provides diagnostic algorithms on the clinical relevance of allergenic molecules and gives an overview of their biology, the basic mechanisms of test formats, and the application of tests to measure allergen exposure.

Water is a vital nutrient with innumerable functions for every living cell. The functions of human skin include protection against dehydration of the body. Atopic dermatitis (AD) is a chronic pruritic inflammatory skin disease that presents with dry skin, erythematous and eczematous lesions, and lichenification. This paper discusses the question of whether extra water intake in children with AD affects skin hydration and the skin barrier function. Among the methods used to treat dry skin, topical leave-on products are the first-line treatment, intended to improve hydration and the skin barrier function. The effectiveness of adequate water intake as a measure to treat dry skin is still under debate. Normal skin hydration increases with dietary water intake, particularly in those with prior lower water consumption. Skin dryness in AD is instrumental to the itch and inflammation cycle, contributing to barrier impairment and aggravating disease severity and flares. Certain emollients provide significant hydration to AD skin, with relief of dryness and reduction in barrier impairment, disease severity, and flares. Further investigations are needed to evaluate the optimum water intake levels in children with AD, as important questions remain unanswered, namely, does oral hydration provide relief of skin dryness and reduce barrier impairment, disease severity, and flares; is there any additional benefit from using mineral or thermal spring water; or is there a need to specifically study the fluid/water intake in children with AD and food allergy (FA) restrictions?

Background: Dietary and environmental factors may influence tolerance acquisition in food protein-induced allergic proctocolitis (FPIAP). This retrospective observational study explored the role of maternal diet during pregnancy and breastfeeding in tolerance acquisition in infantile FPIAP. Methods: Breastfed infants with FPIAP from six diverse regions in Greece were divided into two groups, based on development of tolerance to the trigger food: Group A (n = 43), before, and Group B (n = 53), after, the 6th month of age. Maternal diet during pregnancy and breastfeeding was elicited using the Mediterranean Diet Score Questionnaire and the Mediterranean Oriented Culture Specific Semi-Quantitative Food Frequency Questionnaire. Results: Mean age at diagnosis of FPIAP (1.5 months) and weaning (5.5 months) were the same in both groups. The main trigger was cow’s milk. Group A received infant milk formula earlier than Group B. Group B had a higher incidence of asthma/wheeze, siblings with milk allergy, maternal smoking and rural residence. On multivariate analysis, earlier resolution of FPIAP was associated with higher maternal education and with salt intake and consumption of goat/sheep cheese during pregnancy and olive oil during breastfeeding. Consumption of multivitamins during pregnancy and meat, winter fruits, green vegetables, butter, salt, “ready-to-eat” meals and pastries during breastfeeding were correlated with longer duration of symptoms. Conclusions: Mothers of children with FPIAP to cow’s milk protein can be advised to eat more yogurt, cheese and olive oil during subsequent pregnancies, and avoid multivitamins, grilled food, “ready-to-eat” meals, pastries, meat and alcohol during breastfeeding, to reduce the duration of FPIAP presenting in future infants.

Background: Immunoglobulin E (IgE)-mediated cow’s milk allergy (CMA) can be life-threatening and affects up to 3% of children. Hypoallergenic infant formulas based on hydrolyzed cow’s milk protein are increasingly considered for therapy and prevention of cow’s milk allergy. The aim of this study was to investigate the allergenic activity and ability to induce T cell and cytokine responses of an infant formula based on extensively hydrolyzed cow’s milk protein (whey) (eHF, extensively hydrolyzed formula) supplemented with Galactooligosaccharides (GOS) and Limosilactobacillus fermentum CECT5716 (LF) to determine its suitability for treatment and prevention of CMA. Methods: eHF and standard protein formula based on intact cow’s milk proteins (iPF) with or without Galactooligosaccharide (GOS) and Limosilactobacillus fermentum CECT5716 (LF) were investigated with allergen-specific antibodies and tested for IgE reactivity and allergenic activity in basophil degranulation assays with sera from cow’s milk (CM)-allergic infants/children. Their ability to stimulate T cell proliferation and cytokine secretion in cultured peripheral blood mononuclear cells (PBMC) from CM-allergic infants and children was studied with a FACS-based carboxyfluorescein diacetate succinimidyl ester (CFSE) dilution assay and xMAP Luminex fluorescent bead-based technology, respectively. Results: An eHF supplemented with GOS and LF exhibiting almost no IgE reactivity and allergenic activity was identified. This eHF induced significantly lower inflammatory cytokine secretion as compared to an intact protein-based infant formula but retained T cell reactivity. Conclusions: Due to strongly reduced allergenic activity and induction of inflammatory cytokine secretion but retained T cell reactivity, the identified eHF may be used for treatment and prevention of CMA by induction of specific T cell tolerance.