An integrated molecular risk score early in life for subsequent childhood asthma risk.

BACKGROUND: Numerous children present with early wheeze symptoms, yet solely a subgroup develops childhood asthma. Early identification of children at risk is key for clinical monitoring, timely patient-tailored treatment, and preventing chronic, severe sequelae. For early prediction of childhood asthma, we aimed to define an integrated risk score combining established risk factors with genome-wide molecular markers at birth, complemented by subsequent clinical symptoms/diagnoses (wheezing, atopic dermatitis, food allergy). METHODS: Three longitudinal birth cohorts (PAULINA/PAULCHEN, n = 190 + 93 = 283, PASTURE, n = 1133) were used to predict childhood asthma (age 5-11) including epidemiological characteristics and molecular markers: genotype, DNA methylation and mRNA expression (RNASeq/NanoString). Apparent (ap) and optimism-corrected (oc) performance (AUC/R2) was assessed leveraging evidence from independent studies (Naïve-Bayes approach) combined with high-dimensional logistic regression models (LASSO). RESULTS: Asthma prediction with epidemiological characteristics at birth (maternal asthma, sex, farm environment) yielded an ocAUC = 0.65. Inclusion of molecular markers as predictors resulted in an improvement in apparent prediction performance, however, for optimism-corrected performance only a moderate increase was observed (upto ocAUC = 0.68). The greatest discriminate power was reached by adding the first symptoms/diagnosis (up to ocAUC = 0.76; increase of 0.08, p = .002). Longitudinal analysis of selected mRNA expression in PASTURE (cord blood, 1, 4.5, 6 years) showed that expression at age six had the strongest association with asthma and correlation of genes getting larger over time (r = .59, p < .001, 4.5-6 years). CONCLUSION: Applying epidemiological predictors alone showed moderate predictive abilities. Molecular markers from birth modestly improved prediction. Allergic symptoms/diagnoses enhanced the power of prediction, which is important for clinical practice and for the design of future studies with molecular markers.

Electrical impedance spectroscopy detects skin barrier dysfunction in childhood atopic dermatitis.

BACKGROUND: Skin barrier dysfunction is associated with the development of atopic dermatitis (AD), however methods to assess skin barrier function are limited. We investigated the use of electrical impedance spectroscopy (EIS) to detect skin barrier dysfunction in children with AD of the CARE (Childhood AlleRgy, nutrition, and Environment) cohort. METHODS: EIS measurements taken at multiple time points from 4 months to 3-year-old children, who developed AD (n = 66) and those who did not (n = 49) were investigated. Using only the EIS measurement and the AD status, we developed a machine learning algorithm that produces a score (EIS/AD score) which reflects the probability that a given measurement is from a child with active AD. We investigated the diagnostic ability of this score and its association with clinical characteristics and age. RESULTS: Based on the EIS/AD score, the EIS algorithm was able to clearly discriminate between healthy skin and clinically unaffected skin of children with active AD (area under the curve 0.92, 95% CI 0.85-0.99). It was also able to detect a difference between healthy skin and AD skin when the child did not have active AD. There was no clear association between the EIS/AD score and the severity of AD or sensitisation to the tested allergens. The performance of the algorithm was not affected by age. CONCLUSIONS: This study shows that EIS can detect skin barrier dysfunction and differentiate skin of children with AD from healthy skin and suggests that EIS may have the ability to predict future AD development.

Systematic review of the association between short-chain fatty acids and allergic diseases.

We performed a systematic review to investigate the current evidence on the association between allergic diseases and short chain fatty acids (SCFAs), which are microbially produced and suggested as one mechanism on how gut microbiome affects the risk of allergic diseases. Medline, Embase and Web of Science were searched from data inception until September 2022. We identified 37 papers, of which 17 investigated prenatal or early childhood SCFAs and the development of allergic diseases in childhood, and 20 assessed SCFAs in patients with pre-existing allergic diseases. Study design, study populations, outcome definition, analysis method and reporting of the results varied between papers. Overall, there was some evidence showing that the three main SCFAs (acetate, propionate and butyrate) in the first few years of life had a protective effect against allergic diseases, especially for atopic dermatitis, wheeze or asthma and IgE-mediated food allergy in childhood. The association between each SCFA and allergic disease appeared to be different by disease and the age of assessment. Further research that can determine the potentially timing specific effect of each SCFA will be useful to investigate how SCFAs can be used in treatment or in prevention against allergic diseases.

Navigating the evolving landscape of atopic dermatitis: Challenges and future opportunities: The 4th Davos declaration.

The 4th Davos Declaration was developed during the Global Allergy Forum in Davos which aimed to elevate the care of patients with atopic dermatitis (AD) by uniting experts and stakeholders. The forum addressed the high prevalence of AD, with a strategic focus on advancing research, treatment, and management to meet the evolving challenges in the field. This multidisciplinary forum brought together top leaders from research, clinical practice, policy, and patient advocacy to discuss the critical aspects of AD, including neuroimmunology, environmental factors, comorbidities, and breakthroughs in prevention, diagnosis, and treatment. The discussions were geared towards fostering a collaborative approach to integrate these advancements into practical, patient-centric care. The forum underlined the mounting burden of AD, attributing it to significant environmental and lifestyle changes. It acknowledged the progress in understanding AD and in developing targeted therapies but recognized a gap in translating these innovations into clinical practice. Emphasis was placed on the need for enhanced awareness, education, and stakeholder engagement to address this gap effectively and to consider environmental and lifestyle factors in a comprehensive disease management strategy. The 4th Davos Declaration marks a significant milestone in the journey to improve care for people with AD. By promoting a holistic approach that combines research, education, and clinical application, the Forum sets a roadmap for stakeholders to collaborate to improve patient outcomes in AD, reflecting a commitment to adapt and respond to the dynamic challenges of AD in a changing world.

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.

Trajectories of cough without a cold in early childhood and associations with atopic diseases.

BACKGROUND: Although children can frequently experience a cough that affects their quality of life, few epidemiological studies have explored cough without a cold during childhood. OBJECTIVES: The objective of the study was to describe the latent class trajectories of cough from one to 10 years old and analyse their association with wheezing, atopy and allergic diseases. METHODS: Questions about cough, wheeze and allergic diseases were asked at 1, 1.5, 2, 3, 4, 5, 6 and 10 years of age in the European prospective cohort of Protection against Allergy: STUdy in Rural Environment (PASTURE). Specific IgE assays were performed at 10 years of age. Questions regarding a cough without a cold were used to build a latent class model of cough over time. RESULTS: Among the 961 children included in the study, apart from the never/infrequent trajectory (59.9%), eight trajectories of cough without a cold were identified: five grouped acute transient classes (24.1%), moderate transient (6.8%), late persistent (4.8%) and early persistent (4.4%). Compared with the never/infrequent trajectory, the other trajectories were significantly associated with wheezing, asthma and allergic rhinitis. For asthma, the strongest association was with the early persistent trajectory (ORa  = 31.00 [14.03-68.51]), which was inversely associated with farm environment (ORa  = 0.39 [0.19-0.77]) and had a high prevalence of cough triggers and unremitting wheeze. Late and early persistent trajectories were also associated with food allergy. Atopic sensitization was only associated with the late persistent trajectory. CONCLUSION: Late and early persistent coughs without a cold are positively associated with atopic respiratory diseases and food allergy. Children having recurrent cough without a cold with night cough and triggers would benefit from an asthma and allergy assessment. Growing up on a farm is associated with reduced early persistent cough.

Immune Responsiveness to LPS Determines Risk of Childhood Wheeze and Asthma in 17q21 Risk Allele Carriers.

Rationale: In murine models, microbial exposures induce protection from experimental allergic asthma through innate immunity. Objectives: Our aim was to assess the association of early life innate immunity with the development of asthma in children at risk. Methods: In the PASTURE farm birth cohort, innate T-helper cell type 2 (Th2), Th1, and Th17 cytokine expression at age 1 year was measured after stimulation of peripheral blood mononuclear cells with LPS in n = 445 children. Children at risk of asthma were defined based on single-nucleotide polymorphisms at the 17q21 asthma gene locus. Specifically, we used the SNP rs7216389 in the GSDMB gene. Wheeze in the first year of life was assessed by weekly diaries and asthma by questionnaire at age 6 years. Measurements and Main Results: Not all cytokines were detectable in all children after LPS stimulation. When classifying detectability of cytokines by latent class analysis, carrying the 17q21 risk allele rs7216389 was associated with risk of wheeze only in the class with the lowest level of LPS-induced activation: odds ratio (OR), 1.89; 95% confidence interval [CI], 1.13-3.16; P = 0.015. In contrast, in children with high cytokine activation after LPS stimulation, no association of the 17q21 risk allele with wheeze (OR, 0.63; 95% CI, 0.29-1.40; P = 0.258, P = 0.034 for interaction) or school-age asthma was observed. In these children, consumption of unprocessed cow's milk was associated with higher cytokine activation (OR, 3.37; 95% CI, 1.56-7.30; P = 0.002), which was in part mediated by the gut microbiome. Conclusions: These findings suggest that within the 17q21 genotype, asthma risk can be mitigated by activated immune responses after innate stimulation, which is partly mediated by a gut-immune axis.

The abundance of Ruminococcus bromii is associated with faecal butyrate levels and atopic dermatitis in infancy.

BACKGROUND: Impaired microbial development and decreased levels of short chain fatty acids, particularly butyrate, is suggested to have a role in the development of atopic dermatitis (AD). METHODS: Faecal microbiota composition, abundance of selected bacterial groups and fermentation metabolites were compared at 90, 180 and 360 days of life between 27 children who developed AD by age one (AD group), and 39 controls (non-AD group) among the CARE (Childhood AlleRgy, nutrition and Environment) study cohort. RESULTS: Diversity within the Firmicutes and Bacteroidetes phylum in the faecal microbiota was lower in the AD group compared to the non-AD group. Longitudinal analysis showed multiple amplicon sequence variants (ASV) within the same bacterial family to be differentially abundant. Namely, Ruminococcus bromii, a keystone primary starch degrader, and Akkermansia muciniphila, a mucin-utilizer, had lower abundance among the AD group. Children with AD were less likely to have high levels of faecal butyrate at 360 days compared to those without AD (11.5% vs 34.2%). At 360 days, children with high abundance of R. bromii had higher level of butyrate as well as lower proportion of children with AD compared to children with low abundance of R. bromii (11.1-12.5% vs 44.4-52.5%), which was independent of the abundance of the major butyrate producers. CONCLUSION: Our results suggested that R. bromii and other primary degraders might play an important role in the differences in microbial cross-feeding and metabolite formation between children with and without AD, which may influence the risk of developing the disease.

Nutrient supplementation for prevention of viral respiratory tract infections in healthy subjects: A systematic review and meta-analysis.

It remains uncertain as to whether nutrient supplementation for the general population considered healthy could be useful in the prevention of RTIs, such as COVID-19. In this systematic review and meta-analysis, the evidence was evaluated for primary prevention of any viral respiratory tract infection (RTI) such as SARS-CoV-2, through supplementation of nutrients with a recognized role in immune function: multiple micronutrients, vitamin A, folic acid, vitamin B12, C, D, E, beta-carotene, zinc, iron and long-chain polyunsaturated fatty acids. The search produced 15,163 records of which 93 papers (based on 115 studies) met the inclusion criteria, resulting in 199,055 subjects (191,636 children and 7,419 adults) from 37 countries. Sixty-three studies were included in the meta-analyses, which was performed for children and adults separately. By stratifying the meta-analysis by world regions, only studies performed in Asia showed a significant but heterogeneous protective effect of zinc supplementation on RTIs (RR 0.86, 95% CI 0.7-0.96, I2  = 79.1%, p = .000). Vitamin D supplementation in adults significantly decreased the incidence of RTI (RR 0.89, 95% CI 0.79-0.99, p = .272), particularly in North America (RR 0.82 95% CI 0.68-0.97), but not in Europe or Oceania. Supplementation of nutrients in the general population has either no or at most a very limited effect on prevention of RTIs. Zinc supplementation appears protective for children in Asia, whilst vitamin D may protect adults in the USA and Canada. In 10/115 (8.7%) studies post-hoc analyses based on stratification for nutritional status was performed. In only one study zinc supplementation was found to be more effective in children with low zinc serum as compared to children with normal zinc serum levels.

Role of dietary fiber in promoting immune health-An EAACI position paper.

Microbial metabolism of specific dietary components, such as fiber, contributes to the sophisticated inter-kingdom dialogue in the gut that maintains a stable environment with important beneficial physiological, metabolic, and immunological effects on the host. Historical changes in fiber intake may be contributing to the increase of allergic and hypersensitivity disorders as fiber-derived metabolites are evolutionarily hardwired into the molecular circuitry governing immune cell decision-making processes. In this review, we highlight the importance of fiber as a dietary ingredient, its effects on the microbiome, its effects on immune regulation, the importance of appropriate timing of intervention to target any potential window of opportunity, and potential mechanisms for dietary fibers in the prevention and management of allergic diseases. In addition, we review the human studies examining fiber or prebiotic interventions on asthma and respiratory outcomes, allergic rhinitis, atopic dermatitis, and overall risk of atopic disorders. While exposures, interventions, and outcomes were too heterogeneous for meta-analysis, there is significant potential for using fiber in targeted manipulations of the gut microbiome and its metabolic functions in promoting immune health.