IgE to cross-reactive carbohydrate determinants (CCD) in childhood: Prevalence, risk factors, putative origins.

BACKGROUND: IgE antibodies to cross-reactive carbohydrate determinants (CCD) are usually clinically irrelevant but they can be a cause of false positive outcomes of allergen-specific IgE tests in vitro. Their prevalence and levels have been so far cross-sectionally examined among adult allergic patients and much less is known about their origins and relevance in childhood. METHODS: We examined CCD with a cross-sectional approach in 1263 Italian pollen allergic children (Panallergen in Paediatrics, PAN-PED), as well as with a longitudinal approach in 612 German children (Multicenter Allergy Study, MAS), whose cutaneous and IgE sensitization profile to a broad panel of allergen extracts and molecules was already known. The presence and levels of IgE to CCD were examined in the sera of both cohorts using bromelain (MUXF3) as reagent and a novel chemiluminescence detection system, operating in a solid phase of fluorescently labelled and streptavidin-coated paramagnetic microparticles (NOVEOS, HYCOR, USA). RESULTS: IgE to CCD was found in 22% of the Italian pollen allergic children, mainly in association with an IgE response to grass pollen. Children with IgE to CCD had higher total IgE levels and were sensitized to more allergenic molecules of Phleum pratense than those with no IgE to CCD. Among participants of the German MAS birth cohort study, IgE to CCD emerged early in life (even at pre-school age), with IgE sensitization to group 1 and 4 allergen molecules of grasses, and almost invariably persisted over the full observation period. CONCLUSIONS: Our results contribute to dissect the immunological origins, onset, evolution and risk factors of CCD-sIgE response in childhood, and raise the hypothesis that group 1 and/or 4 allergen molecules of grass pollen are major inducers of these antibodies through an antigen-specific, T-B cell cognate interaction.

Primary Prevention of Pediatric Asthma through Nutritional Interventions.

Asthma is the most common chronic non-communicable disease in children, the pathogenesis of which involves several factors. The increasing burden of asthma worldwide has emphasized the need to identify the modifiable factors associated with the development of the disease. Recent research has focused on the relationship between dietary factors during the first 1000 days of life (including pregnancy)-when the immune system is particularly vulnerable to exogenous interferences-and allergic outcomes in children. Specific nutrients have been analyzed as potential targets for the prevention of childhood wheeze and asthma. Recent randomized controlled trials show that vitamin D supplementation during pregnancy, using higher doses than currently recommended, may be protective against early childhood wheezing but not school-age asthma. Omega-3 fatty acid supplementation during pregnancy and infancy may be associated with a reduced risk of childhood wheeze, although the evidence is conflicting. Data from observational studies suggest that some dietary patterns during pregnancy and infancy might also influence the risk of childhood asthma. However, the quality of the available evidence is insufficient to allow recommendations regarding dietary changes for the prevention of pediatric asthma. This review outlines the available high-quality evidence on the role of prenatal and perinatal nutritional interventions for the primary prevention of asthma in children and attempts to address unmet areas for future research in pediatric asthma prevention.

Lack of iron, zinc, and vitamins as a contributor to the etiology of atopic diseases.

Micronutritional deficiencies are common in atopic children suffering from atopic dermatitis, food allergy, rhinitis, and asthma. A lack of iron, in particular, may impact immune activation with prolonged deficiencies of iron, zinc, vitamin A, and vitamin D associated with a Th2 signature, maturation of macrophages and dendritic cells (DCs), and the generation of IgE antibodies. In contrast, the sufficiency of these micronutrients establishes immune resilience, promotion of regulatory cells, and tolerance induction. As micronutritional deficiencies mimic an infection, the body's innate response is to limit access to these nutrients and also impede their dietary uptake. Here, we summarize our current understanding of the physiological function of iron, zinc, and vitamins A and D in relation to immune cells and the clinical consequences of deficiencies in these important nutrients, especially in the perinatal period. Improved dietary uptake of iron is achieved by vitamin C, vitamin A, and whey compounds, whereas zinc bioavailability improves through citrates and proteins. The addition of oil is essential for the dietary uptake of beta-carotene and vitamin D. As for vitamin D, the major source comes via sun exposure and only a small amount is consumed via diet, which should be factored into clinical nutritional studies. We summarize the prevalence of micronutritional deficiencies of iron, zinc, and vitamins in the pediatric population as well as nutritional intervention studies on atopic diseases with whole food, food components, and micronutrients. Dietary uptake via the lymphatic route seems promising and is associated with a lower atopy risk and symptom amelioration. This review provides useful information for clinical studies and concludes/emphasizes that a healthy, varied diet containing dairy products, fish, nuts, fruits, and vegetables as well as supplementing foods or supplementation with micronutrients as needed is essential to combat the atopic march.

Nutraceuticals in Viral Infections: An Overview of the Immunomodulating Properties.

Nutraceuticals, including vitamin D, vitamin A, zinc, lactoferrin, polyphenols coenzyme Q, magnesium, and selenium, are implicated in the modulation of the complex molecular pathways involved in the immune response against viral pathogens. A common element of the activity of nutraceuticals is their ability to enhance the innate immune response against pathogens by acting on the major cellular subsets and inducing the release of pro-inflammatory cytokines and antimicrobial peptides. In some cases, this action is accompanied by a direct antimicrobial effect, as evidenced in the specific case of lactoferrin. Furthermore, nutraceuticals act through complex molecular mechanisms to minimize the damage caused by the activation of the immune system against pathogens, reducing the oxidative damage, influencing the antigen presentation, enhancing the differentiation and proliferation of regulatory T cells, driving the differentiation of lymphocyte subsets, and modulating the production of pro-inflammatory cytokines. In this paper, we review the main molecular mechanisms responsible for the immunomodulatory function of nutraceuticals, focusing on the most relevant aspects for the prevention and treatment of viral infections.

Could nutritional supplements act as therapeutic adjuvants in COVID-19?

BACKGROUND: The role of the immune system and inflammatory response in the pathogenesis of the severe manifestations of coronavirus disease 2019 (COVID-19) is well known. Currently, different therapies active on the immune system are used for the management of COVID-19. The involvement of the immune system also opens the opportunity for the use of nutritional supplements with antimicrobial and immunomodulatory activity. MAIN ASPECTS: Nutritional supplements with antimicrobial and immunomodulatory activity are promising therapeutic adjuvants for the treatment of COVID-19, and also for the prevention of viral spreading. In particular, the role of vitamin D, probiotics, lactoferrin, and zinc is of significant clinical interest, although there are only a few data on their use in COVID-19 patients. Their molecular actions, together with the results of studies performed on other respiratory infections, strongly suggest their potential utility in COVID-19. This article discusses the main properties of these nutritional supplements and their potential applicability in the prevention and treatment of COVID-19. CONCLUSION: The supplementation with vitamin D, probiotics, lactoferrin and zinc could have a role both in preventing SARS-CoV-2 infection and in mitigating the clinical course in infected patients, contributing in the prevention of immune-mediated organ damage.

Dietary Interventions and Nutritional Factors in the Prevention of Pediatric Asthma.

Asthma is the most frequent chronic disease in children, and its pathogenesis involves genetic, epigenetic, and environmental factors. The rapid rise in the prevalence of asthma registered over the last few decades has stressed the need to identify the environmental and modifiable factors associated with the development of the disease. In particular, there is increasing interest in the role of modifiable nutritional factors specific to both the prenatal and post-natal early life as, during this time, the immune system is particularly vulnerable to exogenous interferences. Several dietary factors, including maternal diet during pregnancy, the duration of breastfeeding, the use of special milk formulas, the timing of the introduction of complementary foods, and prenatal and early life supplementation with vitamins and probiotics/prebiotics, have been addressed as potential targets for the prevention of asthma. In this review, we outline recent findings on the potential role of prenatal and perinatal dietary and nutritional interventions for the primary prevention of pediatric asthma. Moreover, we addressed unmet needs and areas for future research in the prevention of childhood-onset asthma.

EAACI Allergen Immunotherapy User's Guide.

Allergen immunotherapy is a cornerstone in the treatment of allergic children. The clinical efficiency relies on a well-defined immunologic mechanism promoting regulatory T cells and downplaying the immune response induced by allergens. Clinical indications have been well documented for respiratory allergy in the presence of rhinitis and/or allergic asthma, to pollens and dust mites. Patients who have had an anaphylactic reaction to hymenoptera venom are also good candidates for allergen immunotherapy. Administration of allergen is currently mostly either by subcutaneous injections or by sublingual administration. Both methods have been extensively studied and have pros and cons. Specifically in children, the choice of the method of administration according to the patient's profile is important. Although allergen immunotherapy is widely used, there is a need for improvement. More particularly, biomarkers for prediction of the success of the treatments are needed. The strength and efficiency of the immune response may also be boosted by the use of better adjuvants. Finally, novel formulations might be more efficient and might improve the patient's adherence to the treatment. This user's guide reviews current knowledge and aims to provide clinical guidance to healthcare professionals taking care of children undergoing allergen immunotherapy.

Nutritional Factors in the Prevention of Atopic Dermatitis in Children.

Atopic dermatitis is one of the most frequent chronic skin diseases worldwide and often develops within the first few years of life. Recent advancements in our knowledge of its pathophysiology have brought to light the role of genetic predisposition and environmental triggers. With the increasing prevalence of allergic diseases, there is a strong need for a better understanding of the various modifiable eliciting factors of such conditions. The concomitant rise in food allergy and insights into the skin barrier function has highlighted the role of nutrition and diet in the prevention and modification of allergic disorders. Furthermore, the identification of the skin as an important route of sensitization, and the risk of progression to asthma later in life, stress the significance of optimizing our management of skin inflammation in the prevention of allergies. Many nutritional factors, including the type of maternal diet during pregnancy, the duration of breastfeeding, the epicutaneous exposure of allergenic food proteins in the first few years of life, the timing of the introduction of complementary foods, the supplementation of vitamins and probiotics/prebiotics during prenatal and early life, have been assessed as potential targets for the prevention of atopy and eczema. Here, we review the latest data addressing prenatal and perinatal nutritional and dietary interventions in the primary prevention of atopic dermatitis. Also, we define knowledge gaps and targets for future research in the prevention of atopic dermatitis.

Cow's Milk Substitutes for Children: Nutritional Aspects of Milk from Different Mammalian Species, Special Formula and Plant-Based Beverages.

Cow's milk and dairy are commonly consumed foods in the human diet and contribute to maintaining a healthy nutritional state, providing unique sources of energy, calcium, protein, and vitamins, especially during early childhood. Milk formula is usually made from cow's milk and represents the first food introduced into an infant's diet when breastfeeding is either not possible or insufficient to cover nutritional needs. Very recently, increased awareness of cow's milk protein allergy and intolerance, and higher preference to vegan dietary habits have influenced parents towards frequently choosing cows' milk substitutes for children, comprising other mammalian milk types and plant-based milk beverages. However, many of these milk alternatives do not necessarily address the nutritional requirements of infants and children. There is a strong need to promote awareness about qualitative and quantitative nutritional compositions of different milk formulas, in order to guide parents and medical providers selecting the best option for children. In this article, we sought to review the different compositions in terms of macronutrients and micronutrients of milk from different mammalian species, including special milk formulas indicated for cow's milk allergy, and of plant-based milk alternatives.

Levels of Growth Factors and IgA in the Colostrum of Women from Burundi and Italy.

Colostrum is produced in the first days postpartum. It is a known source of immune mediators for a newborn within the first week of life. Although it is still unclear if colostrum composition varies between populations, recent data suggest differences. Hepatocyte growth factor (HGF); transforming growth factor-ß (TGF-ß) 1, 2, and 3; and immunoglobulin A (IgA) are key immunological components of colostrum that stimulate neonatal gastrointestinal and immune system development. We aimed to investigate the differences in the concentration between immune markers in the colostrum of mothers living in Burundi and Italy, and to identify the factors associated with differences. In this cross-sectional birth cohort study, a total of 99 colostrum samples from Burundian (n = 23) and Italian (n = 76) women were collected at 0 to 6 days postpartum. A clinical chemistry analyser was used for IgA quantification and electro-chemiluminescence, for HGF and TGFß1-3 assessment. A univariate analysis and multivariate linear regression model were used for statistical testing. The concentrations of TGF-ß2 (p = 0.01) and IgA (p < 0.01) were significantly higher in the colostrum from the women residing in Burundi than in Italy, both in a univariate analysis and upon the adjustment for confounding factors. A similar trend is seen for HGF, reaching statistical significance upon a multivariate analysis. We found a moderate to strong positive correlation between the TGF-ß isoforms and IgA concentration in both countries (p < 0.01), with stronger concentration in the colostrum from Burundi. The results of this study are in support of previous data, suggesting that concentration of the immune active molecules is higher in the human milk of women residing in developing countries. However, with a small sample size, caution must be applied, as the findings require further confirmation. Future work should also be focused on other factors (e.g., lipid and microbial composition), as well as the investigation into colostrum and between populations comparison, adjusting for potential confounders.

Impact of delivery mode on the colostrum microbiota composition.

BACKGROUND: Breast milk is a rich nutrient with a temporally dynamic nature. In particular, numerous alterations in the nutritional, immunological and microbiological content occur during the transition from colostrum to mature milk. The objective of our study was to evaluate the potential impact of delivery mode on the microbiota of colostrum, at both the quantitative and qualitative levels (bacterial abundance and microbiota network). METHODS: Twenty-nine Italian mothers (15 vaginal deliveries vs 14 Cesarean sections) were enrolled in the study. The microbiota of colostrum samples was analyzed by next generation sequencing (Ion Torrent Personal Genome Machine). The colostrum microbiota network associated with Cesarean section and vaginal delivery was evaluated by means of the Auto Contractive Map (AutoCM), a mathematical methodology based on Artificial Neural Network (ANN) architecture. RESULTS: Numerous differences between Cesarean section and vaginal delivery colostrum were observed. Vaginal delivery colostrum had a significant lower abundance of Pseudomonas spp., Staphylococcus spp. and Prevotella spp. when compared to Cesarean section colostrum samples. Furthermore, the mode of delivery had a strong influence on the microbiota network, as Cesarean section colostrum showed a higher number of bacterial hubs if compared to vaginal delivery, sharing only 5 hubs. Interestingly, the colostrum of mothers who had a Cesarean section was richer in environmental bacteria than mothers who underwent vaginal delivery. Finally, both Cesarean section and vaginal delivery colostrum contained a greater number of anaerobic bacteria genera. CONCLUSIONS: The mode of delivery had a large impact on the microbiota composition of colostrum. Further studies are needed to better define the meaning of the differences we observed between Cesarean section and vaginal delivery colostrum microbiota.

Prevalence and Clinical Relevance of IgE Sensitization to Profilin in Childhood: A Multicenter Study.

BACKGROUND: Little is known about the prevalence and clinical relevance of hypersensitivity to the plant panallergen profilin in children. OBJECTIVES: The present study aimed to investigate prevalence, risk factors and clinical relevance of profilin sensitization in a large cohort of Italian children of different ages living in different geographic areas. METHODS: Children with pollen allergy enrolled by 16 pediatric outpatient clinics sited in three main geographic areas of Italy were studied. SPT were carried out with commercial pollen extracts and a commercial purified date palm pollen profilin. IgE specific for allergenic pollen molecules, Phl p 12 (grass profilin) and Pru p 3 (peach lipid transfer protein) were tested by ImmunoCAP FEIA. RESULTS: IgE to Phl p 12 (≥0.35 kU/l) was observed in 296 of the 1,271 participants (23%), including 17 of the 108 (16%) preschool children. Profilin SPT was positive (≥3 mm) in 320/1,271 (25%) participants. The two diagnostic methods were concordant in 1,151 (91%, p < 0.0001) cases. Phl p 12 IgE prevalence declined from northern to southern Italy and was directly associated with IgE to Phl p 1 and/or Phl p 5 and Ole e 1. Among children with IgE to Phl p 12, OAS was provoked by kiwi, melon, watermelon, banana, apricot and cucumber. CONCLUSIONS: Profilin sensitization is very frequent among pollen-allergic children, occurs at a very young age and contributes to the development of childhood OAS with a typical pattern of offending foods. Pediatricians should always consider IgE sensitization to profilin while examining pollen-allergic children, even if they are at preschool age.

Therapeutic Effects of Vitamin D in Asthma and Allergy.

In recent years, low vitamin D status has been proposed as a putative risk factor for allergic diseases. A growing body of literature reports low vitamin D levels in atopic patients and supports an association between vitamin D deficiency and risk of adverse asthma and allergies outcomes. Therefore, it has been speculated that vitamin D supplementation may either prevent or reduce the risk of allergic diseases. Birth cohort studies addressing the role of vitamin D intake during pregnancy have shown conflicting results regarding allergy outcomes in offspring. Currently, only a few studies have tried to supplement vitamin D in asthmatic patients, often as an add-on therapy to standard asthma controller medications, and results are not all consistent. There is emerging data to show that vitamin D can enhance the antiinflammatory effects of glucocorticoids and potentially be used as adjuvant therapy in steroid-resistant asthma. Recent in vivo data suggest that vitamin D supplementation may also reduce the severity of atopic dermatitis. This review examines the existing relevant literature focusing on vitamin D supplementation in the treatment of allergic diseases.

The effect of component-resolved diagnosis on specific immunotherapy prescription in children with hay fever.

BACKGROUND: Sensitization to profilins and other cross-reacting molecules might hinder proper specific immunotherapy (SIT) prescription in polysensitized patients with pollen-related allergic rhinitis (AR). In these patients, component-resolved diagnosis (CRD) might modify SIT prescription by improving the identification of the disease-eliciting pollen sources. OBJECTIVES: We sought to measure the effect of CRD on SIT prescription in children with pollen-related AR. METHODS: Children (n = 651) with moderate-to-severe pollen-related AR were recruited between May 2009 and June 2011 in 16 Italian outpatient clinics. Skin prick test (SPT) reactivity to grass, cypress, olive, mugwort, pellitory, and/or Betulaceae pollen was considered clinically relevant if symptoms occurred during the corresponding peak pollen season. IgE sensitization to Phl p 1, Phl p 5, Bet v 1, Cup a 1, Art v 1, Ole e 1, Par j 2, and Phl p 12 (profilin) was measured by using ImmunoCAP. SIT prescription was modeled on SPT responses first and then remodeled considering also CRD according to GA(2)LEN-European Academy of Allergology and Clinical Immunology guidelines and the opinions of 14 pediatric allergists. RESULTS: No IgE to the respective major allergens was detected in significant proportions of patients with supposed clinically relevant sensitization to mugwort (45/65 [69%]), Betulaceae (146/252 [60%]), pellitory (78/257 [30%]), olive (111/390 [28%]), cypress (28/184 [15%]), and grass (56/568 [10%]). IgE to profilins, polcalcins, or both could justify 173 (37%) of 464 of these SPT reactions. After CRD, the SPT-based decision on SIT prescription or composition was changed in 277 (42%) of 651 or 315 (48%) of 651 children according to the European or American approach, respectively, and in 305 (47%) of 651 children according to the opinion of the 14 local pediatric allergists. CONCLUSIONS: In children with pollen-related AR, applying CRD leads to changes in a large proportion of SIT prescriptions as opposed to relying on clinical history and SPT alone. The hypothesis that CRD-guided prescription improves SIT efficacy deserves to be tested.

Is vitamin D deficiency correlated with childhood wheezing and asthma?

There is increasing evidence that vitamin D regulates immune responses. There is also epidemiological evidence of a relationship between vitamin D deficiency and development of asthma. In addition, several epidemiological studies suggest that low levels of vitamin D during pregnancy and early life are inversely associated with the risk of developing respiratory infections and wheezing in childhood. Vitamin D also seems to reduce asthma exacerbation and increase the response to glucocorticoids. These findings have led to considering a possible link between the occurrence of allergic respiratory diseases and low levels of vitamin D. However, the precise role of vitamin D in the pathogenesis of asthma still remains unclear, emphasizing the need for well-designed trials on vitamin D supplementation to decipher its role in preventing and/or managing the disease. This review examines the relationship that exists between vitamin D deficiency and childhood wheezing and asthma.