Disparities in pediatric anaphylaxis triggers and management across Asia.

BACKGROUND: The epidemiology and management of anaphylaxis are not well-reported in Asia. METHODS: A regional pediatric anaphylaxis registry was established by the Asia-Pacific Research Network for Anaphylaxis (APRA), using standardized protocols for prospective data collection, to evaluate the triggers and management of anaphylaxis in the Asia-Pacific region. Pediatric patients below 18 years presenting with anaphylaxis across four Asian countries/cities (Thailand, Singapore, Hong Kong (HK), and Qingdao) were included. Allergen triggers, symptoms, anaphylaxis severity, and management were compared. RESULTS: Between 2019 and 2022, 721 anaphylaxis episodes in 689 patients from 16 centers were identified. The mean age at anaphylaxis presentation was 7.0 years (SD = 5.2) and 60% were male. Food was the most common trigger (62%), particularly eggs and cow's milk in children aged 3 years and below. In school-age children, nut anaphylaxis was most common in HK and Singapore, but was rare in the other countries, and wheat was the top allergen in Bangkok. Shellfish anaphylaxis was most common in children aged 7-17. Adrenaline was administered in 60% of cases, with 9% given adrenaline before hospital arrival. Adrenaline devices were prescribed in up to 82% of cases in Thailand but none in Qingdao. CONCLUSIONS: The APRA identified food as the main trigger of anaphylaxis in children, but causative allergens differed even across Asian countries. Fewer than two-thirds of cases received adrenaline treatment, pre-hospital adrenaline usage was low, and adrenaline device prescription remained suboptimal. The registry recognizes an unmet need to strengthen anaphylaxis care and research in Asia-Pacific.

Immune modulation by rural exposures and allergy protection.

BACKGROUND: Growing up on traditional farms protects children from the development of asthma and allergies. However, we have identified distinct asthma-protective factors, such as poultry exposure. This study aims to examine the biological effect of rural exposure in China. METHODS: We recruited 67 rural children (7.4 ± 0.9 years) and 79 urban children (6.8 ± 0.6 years). Depending on the personal history of exposure to domestic poultry (DP), rural children were further divided into those with DP exposure (DP+ , n = 30) and those without (DP- , n = 37). Blood samples were collected to assess differential cell counts and expression of immune-related genes. Dust samples were collected from poultry stables inside rural households. In vivo activities of nasal administration of DP dust extracts were tested in an ovalbumin-induced asthma model. RESULTS: There was a stepwise increase in the percentage of eosinophils (%) from rural DP+ children (median = 1.65, IQR = [1.28, 3.75]) to rural DP- children (3.40, [1.70, 6.50]; DP+ vs. DP- , p = .087) and to the highest of their urban counterparts (4.00, [2.00, 7.25]; urban vs. DP+ , p = .017). Similarly, rural children exhibited reduced mRNA expression of immune markers, both at baseline and following lipopolysaccharide (LPS) stimulation. Whereas LPS stimulation induced increased secretion of Th1 and proinflammatory cytokines in rural DP+ children compared to rural DP- children and urban children. Bronchoalveolar lavage of mice with intranasal instillation of dust extracts from DP household showed a significant decrease in eosinophils as compared to those of control mice (p < .05). Furthermore, DP dust strongly inhibited gene expression of Th2 signature cytokines and induced IL-17 expression in the murine asthma model. CONCLUSIONS: Immune responses of rural children were dampened compared to urban children and those exposed to DP had further downregulated immune responsiveness. DP dust extracts ameliorated Th2-driven allergic airway inflammation in mice. Determining active protective components in the rural environment may provide directions for the development of primary prevention of asthma.

From preschool wheezing to asthma: Environmental determinants.

Wheezing is common among preschool children, representing a group of highly heterogeneous conditions with varying natural history. Several phenotypes of wheezing have been proposed to facilitate the identification of young children who are at risk of subsequent development of asthma. Epidemiological and immunological studies across different populations have revealed the key role of environmental factors in influencing the progression from preschool wheezing to childhood asthma. Significant risk factors include severe respiratory infections, allergic sensitization, and exposure to tobacco smoke. In contrast, a farming/rural environment has been linked to asthma protection in both human and animal studies. Early and intense exposures to microorganisms and microbial metabolites have been demonstrated to alter host immune responses to allergens and viruses, thereby driving the trajectory away from wheezing illness and asthma. Ongoing clinical trials of candidate microbes and microbial products have shown promise in shaping the immune function to reduce episodes of viral-induced wheezing. Moreover, restoring immune training may be especially important for young children who had reduced microbial exposure due to pandemic restrictions. A comprehensive understanding of the role of modifiable environmental factors will pave the way for developing targeted prevention strategies for preschool wheezing and asthma.

Prospective study of disease persistence and lung function trajectories of childhood asthma.

BACKGROUND: A proportion of asthmatic children outgrow their disease by adulthood, but there are limited data on predictors for asthma persistence. This prospective study characterized the trajectory of spirometric indices and identified predictors for the persistence of childhood asthma. METHODS: Chinese asthmatic children aged 6-15 years from pediatric allergy clinic underwent annual visits for ≥5 years and until their adulthood. Pre-bronchodilator spirometry and anti-asthma medications were recorded at baseline and then at least annually. Asthma resolution was defined when patients were free from asthma symptoms and use of anti-asthma drugs for ≥2 years. Logistic regression was used to identify predictors for asthma persistence. Generalized estimating equation was used to analyze longitudinal changes in lung function parameters in relation to asthma persistence. RESULTS: 181 asthmatic children aged [mean (SD)] 10.0 (2.7) years were followed for [mean (SD)] 12.5 (2.8) years. One third of them outgrew asthma during follow-up. Female was 3.36 times more likely to have persistent asthma. Inhaled corticosteroid (ICS) treatment ever and frequent asthma exacerbation (AE) predicted asthma persistence with respective odds ratios of 3.19 (95% confidence interval [CI] 1.44-7.09) and 3.05 (95% CI 1.39-6.68). Persistent asthma was inversely associated with baseline forced expiratory volume in 1-second (FEV1 %) with an odds ratio of 0.96 (95% CI 0.93-1.00). Throughout follow-up, patients with persistent asthma had generally lower forced expiratory indices than those with asthma resolution. Children with persistent asthma experienced poorer lung function growth. CONCLUSIONS: Female, ICS ever, and frequent AE predicted persistent asthma. Patients with persistent asthma had lower forced expiratory indices and poorer lung function growth into adulthood.

Guidelines for the prevention and management of children and adolescents with COVID-19.

Children are the future of the world, but their health and future are facing great uncertainty because of the coronavirus disease 2019 (COVID-19) pandemic. In order to improve the management of children with COVID-19, an international, multidisciplinary panel of experts developed a rapid advice guideline at the beginning of the outbreak of COVID-19 in 2020. After publishing the first version of the rapid advice guideline, the panel has updated the guideline by including additional stakeholders in the panel and a comprehensive search of the latest evidence. All recommendations were supported by systematic reviews and graded using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. Expert judgment was used to develop good practice statements supplementary to the graded evidence-based recommendations. The updated guideline comprises nine recommendations and one good practice statement. It focuses on the key recommendations pertinent to the following issues: identification of prognostic factors for death or pediatric intensive care unit admission; the use of remdesivir, systemic glucocorticoids and antipyretics, intravenous immunoglobulin (IVIG) for multisystem inflammatory syndrome in children, and high-flow oxygen by nasal cannula or non-invasive ventilation for acute hypoxemic respiratory failure; breastfeeding; vaccination; and the management of pediatric mental health. CONCLUSION: This updated evidence-based guideline intends to provide clinicians, pediatricians, patients and other stakeholders with evidence-based recommendations for the prevention and management of COVID-19 in children and adolescents. Larger studies with longer follow-up to determine the effectiveness and safety of systemic glucocorticoids, IVIG, noninvasive ventilation, and the vaccines for COVID-19 in children and adolescents are encouraged. WHAT IS KNOWN: • Several clinical practice guidelines for children with COVID-19 have been developed, but only few of them have been recently updated. • We developed an evidence-based guideline at the beginning of the COVID-19 outbreak and have now updated it based on the results of a comprehensive search of the latest evidence. WHAT IS NEW: • The updated guideline provides key recommendations pertinent to the following issues: identification of prognostic factors for death or pediatric intensive care unit admission; the use of remdesivir, systemic glucocorticoids and antipyretics, intravenous immunoglobulin for multisystem inflammatory syndrome in children, and high-flow oxygen by nasal cannula or non-invasive ventilation for acute hypoxemic respiratory failure; breastfeeding; vaccination; and the management of pediatric mental health.

Molecular and immunological characterization of grass carp (Ctenopharyngodon idella) parvalbumin Cten i 1: A major fish allergen in Hong Kong.

BACKGROUND: Grass carp is the most commonly consumed fish species in Hong Kong. The allergenicity of grass carp and its allergen content are yet to be reported. This study characterized the major allergen in grass carp and investigated its allergenicity. METHODS: Sixty-nine subjects with history of IgE-mediated allergic reaction to grass carp were recruited. The protein content in steamed grass carp extract was resolved by SDS-PAGE, and the major allergen was identified by immunoblotting with serum from subjects allergic to grass carp. The identity of allergen was elucidated by mass spectrometry and amino acid sequence obtained by amplifying the specific gene from cDNA library of grass carp. The cross-reactivity between parvalbumins from grass carp and other phylogenetically close (common carp) or commercially important (cod and salmon) species was investigated by competitive inhibition ELISA. RESULTS: A major IgE-binding protein was found at approximately 9 kDa and identified as parvalbumin by immunoblotting and mass spectrometry. Grass carp parvalbumin was more allergenic than common carp, salmon, and cod parvalbumins despite sharing high sequence homology. This newly identified major allergenic parvalbumin isoform from grass carp was registered as Cten i 1 in the World Health Organization and International Union of Immunological Societies allergen database. CONCLUSIONS: Grass carp parvalbumin is identified as the major fish allergen in Hong Kong. The strong allergenicity of Cten i 1 contributes to the high IgE reactivity of grass carp. Grass carp, among other fish species, should be considered when managing fish-allergic patients.

Cadherin-related family member 3 gene impacts childhood asthma in Chinese children.

BACKGROUND: A missense variant (rs6967330) of the gene encoding cadherin-related family member 3 (CDHR3) was associated with recurrent severe exacerbations in pre-schoolers. However, there were limited data on its relationship with pre-school lung function and school-age asthma. This study replicated the association between polymorphic markers at the region of CDHR3 around rs6967330 and wheezing phenotypes in two independent cohorts of Chinese children. METHODS: Ten tagging SNPs located 10 kb around rs6967330 were selected by HaploView 5.0 based on 1000 Genomes database for Southern Han Chinese. Their associations with wheezing and lung function were examined in 1341 Chinese pre-school children, while those for asthma phenotypes were examined in an independent group of 2079 school-age children. Genotypic and haplotypic associations were analyzed by multivariate regression, and generalized multifactor dimensionality reduction was used to examine epistatic interactions for wheezing traits. RESULTS: The mean (SD) age of pre-school cohort was 4.7 (1.0) years. Rs6967330 was associated with current wheeze (odds ratio [OR] 1.63, 95% confidence interval [CI] 1.09-2.43) and its severity (OR 1.64, 95% CI 1.10-2.44) among pre-school children. This SNP was also associated with school-age asthma (OR 1.32, 95% CI 1.04-1.69). The minor allele of rs408223 was associated with lower FEV0.5 (ß = -2.411, P = .004) and FEV0.5 /FVC (ß = -1.292, P = .015). Lower spirometric indices were also associated with minor allele of rs140154310. GAC haplotype from rs4730125, rs6967330, and rs408223 was associated with pre-school current wheeze and school-age asthma. Epistatic interaction was found between unrelated CDHR3 SNPs for FEV0.5 among pre-schoolers. CONCLUSION: CDHR3 is a candidate gene for early-life wheezing, school-age asthma, and lung function in Chinese children.

Genetic effects of multiple asthma loci identified by genomewide association studies on asthma and spirometric indices.

BACKGROUND: Genomewide association study (GWAS) published by GABRIEL consortium identified 10 asthma-associated loci. However, their relationship with lung functions is unclear. This study investigated the association between asthma traits and single-nucleotide polymorphisms (SNPs) of these GWAS loci. METHODS: Rs3894194 and rs9273349 were not genotyped due to unavailable TaqMan assays. Genetic associations of remaining eight SNPs were investigated in 903 school-age asthmatics and 1205 non-allergic controls. Four significant SNPs were then replicated in 479 adult asthmatics and 746 adult controls, and 1341 Chinese preschool children. Meta-analyses were performed by combining data from school-age children and adults. Generalized multifactor dimensionality reduction (GMDR) was used to analyze their interactions for asthma traits. RESULTS: Childhood asthma was associated with GSDMB_rs2305480 (odds ratio [OR] 0.69, 95% confidence interval [CI] 0.57-0.83). IL13_rs1295686 was associated with all asthma (OR 1.64, 95% CI 1.16-2.32) and early-onset asthma (OR 1.92, 95% CI 1.20-3.06) in adults, whereas GSDMB_rs2305480 was only associated with early-onset asthma (OR 0.69, 95% CI 0.49-0.96). According to meta-analyses, the minor allele of rs2305480 was inversely associated with FEV1 , FVC, and FEV1 /FVC (p < 0.01). GMDR analyses revealed 2-locus models of SLC22A5 with SMAD3 to modulate FEVt /FVC in both preschool children and adults, with IL13 to determine FVC in both school-age children and adults, and with IL2RB to modulate FEV1 /FVC in school-age children. CONCLUSIONS: IL13 and GSDMB are replicated as asthma genes. Rs2305480 of GSDMB is also associated with low FEV1 , FVC, and FEV1 /FVC among asthmatics. Moreover, SLC22A5, IL13, SMAD3, and GSDMB interact to modulate spirometric indices.

Childhood asthma and spirometric indices are associated with polymorphic markers of two vitamin D 25-hydroxylase genes.

BACKGROUND: Polymorphic markers of vitamin D pathway genes have been associated with asthma traits in different White populations. This study investigated the relationship between asthma phenotypes and single nucleotide polymorphisms (SNPs) of vitamin D receptor (VDR), vitamin D binding protein (GC), two 25-hydroxylases (CYP2R1 and CYP27A1), and 1α-hydroxylase (CYP27B1) in Hong Kong Chinese children. METHODS: 23 SNPs of the five vitamin D pathway genes were successfully genotyped in 914 asthmatic children and 1231 non-allergic controls. Genotypic and haplotypic associations with asthma phenotypes (diagnosis, spirometric indices, total IgE, and eosinophil percentage) were analyzed by multivariate regression. Generalized multifactor dimensionality reduction was used to detect epistatic interactions between SNPs for asthma phenotypes. RESULTS: Several SNPs of CYP27A1, CYP27B1, GC, and CYP2R1 were associated with asthma or spirometric indices, although only the association between FEV1 and CYP2R1 rs7935792 passed Bonferroni correction (p = 2.73 × 10(-4) ). Patients with CC genotype of rs7935792 had higher FEV1 than those with the other two genotypes. Asthma was also associated with TT haplotype of CYP27A1 and AGGATA haplotype of CYP2R1 (p = 0.021 and 0.024, respectively). Besides, strong association was found between FEV1 and GATAG of CYP2R1 (ß = 13.37, p = 4.83 × 10(-4) ). GMDR failed to identify any 2-locus to 4-locus interaction that modulated asthma or spirometric indices. CONCLUSIONS: Several SNPs and haplotypes of CYP2R1 are associated with asthma diagnosis and FEV1 in children. Asthma is also modestly associated with a CYP27A1 haplotype. These two 25-hydroxylase genes may be genetic determinants for asthma phenotypes in children.

Case-control association study of polymorphisms in the voltage-gated sodium channel genes SCN1A, SCN2A, SCN3A, SCN1B, and SCN2B and epilepsy.

High-frequency action potentials are mediated by voltage-gated sodium channels, composed of one large α subunit and two small ß subunits, encoded mainly by SCN1A, SCN2A, SCN3A, SCN1B, and SCN2B genes in the brain. These play a key role in epilepsy, with the most commonly mutated gene in epilepsy being SCN1A. We examined whether polymorphisms in the above genes affect epilepsy risk in 1,529 epilepsy patients and 1,935 controls from four ethnicities or locations: Malay, Indian, and Chinese, all from Malaysia, and Chinese from Hong Kong. Of patients, 19 % were idiopathic, 42 % symptomatic, and 40 % cryptogenic. We genotyped 43 polymorphisms: 27 in Hong Kong, 28 in Malaysia, and 12 in both locations. The strongest association with epilepsy was rs3812718, or SCN1A IVS5N+5G>A: odds ratio (OR) = 0.85 for allele G (p = 0.0009) and 0.73 for genotype GG versus AA (p = 0.003). The OR was between 0.76 and 0.87 for all ethnicities. Meta-analysis confirmed the association (OR = 0.81 and p = 0.002 for G, and OR = 0.67 and p = 0.007 for GG versus AA), which appeared particularly strong for Indians and for febrile seizures. Allele G affects splicing and speeds recovery from inactivation. Since SCN1A is preferentially expressed in inhibitory neurons, G may decrease epilepsy risk. SCN1A rs10188577 displayed OR = 1.20 for allele C (p = 0.003); SCN2A rs12467383 had OR = 1.16 for allele A (p = 0.01), and displayed linkage disequilibrium with rs2082366 (r (2) = 0.67), whose genotypes tended toward association with SCN2A brain expression (p = 0.10). SCN1A rs2298771 was associated in Indians (OR = 0.56, p = 0.005) and SCN2B rs602594 with idiopathic epilepsy (OR = 0.62, p = 0.002). Therefore, sodium channel polymorphisms are associated with epilepsy.

Vitamin D deficiency is associated with diagnosis and severity of childhood atopic dermatitis.

BACKGROUND: Recent studies implicated the importance of vitamin D in innate immune defense and pathogenesis of allergic diseases. However, the impact of vitamin D deficiency on atopic dermatitis (AD) diagnosis and severity remains unclear. This case-control study investigated such relationship in Hong Kong Chinese children. METHODS: Serum 25-hydroxyvitamin D [25(OH)D] levels of 498 AD children and 328 non-allergic controls were measured by immunoassay. Subjects were categorized into deficient (< 25 nm), insufficient (25-49.9 nm), and sufficient (≥ 50 nm) groups. Short-term and long-term AD severity was evaluated by physician-diagnosed SCORing Atopic Dermatitis (SCORAD) and Nottingham Eczema Severity Score (NESS), respectively. Atopy biomarkers were also measured for analysis. RESULTS: The mean (s.d.) serum 25(OH)D levels in AD patients and controls were 28.9 (15.3) and 34.2 (14.5) nm, respectively (p < 0.001). More patients had serum 25(OH)D levels <25 nm than controls (47.8% vs. 26.6%). AD severity as indicated by both SCORAD and NESS showed inverse associations with serum 25(OH)D levels (respective p = 3.6 × 10(-4) and 0.004 when adjusted for age, sex, month of assessment, and immunoassay batch as covariates). Vitamin D-deficient patients (3.08 ± 0.76) had higher logarithm-transformed total IgE than those with insufficient (2.74 ± 0.69) and sufficient (2.72 ± 0.72) serum 25(OH)D levels (p < 0.001). The proportion of subjects with elevated IgE was higher in vitamin D-deficient (43.2%) than vitamin D-sufficient (20.0%) groups. CONCLUSIONS: Vitamin D deficiency and insufficiency are prevalent in Hong Kong Chinese children. Vitamin D deficiency is associated with childhood AD and high total IgE. Serum 25(OH)D levels correlate inversely with both long- and short-term AD severity.

Food allergies around the world.

The increase in the prevalence of food allergy has been considered as the second wave in the allergy epidemic following the first wave of increase in asthma and allergic rhinitis. It is well known that the prevalence of allergic conditions would follow economic development and urbanization in many countries or regions. In developed countries, one in three children suffered from at least one allergic disorder and these conditions include food allergy, eczema, allergic rhinitis and asthma. Food allergy is very often the first allergic manifestation affecting infants and young children. The exact etiologies are not known. The clinical manifestations ranged from a simple rash or an itch around the mouth, to the more severe manifestations of angioedema and potentially fatal anaphylaxis. Among all cases of childhood anaphylaxis, food is the most common cause. The common allergens resulting in food allergies in developed countries include egg, milk, fish, wheat, peanuts and tree nuts. However, there are marked variations in the patterns of food allergens in developing countries. In line with the epidemiology of asthma, food allergy is also much less common in rural areas. Clear understanding of reasons explaining the disparity of food allergies between urban and rural population would pave the way to the development of effective primary prevention for food allergy.

Roles of pollution in the prevalence and exacerbations of allergic diseases in Asia.

The prevalence of asthma and allergic diseases has been found to be increasingly rapidly, especially in developing countries. Environmental factors have been found to be important contributors to the manifestations of allergic diseases. Air pollution has been extensively studied in different regions of the world. The levels of ambient air pollutants in many Asian countries are very high when compared with those in developed Western countries. However, the prevalence of asthma was relatively low across many Asian countries. Many studies have clearly documented that environmental air pollution is an important factor resulting in exacerbations of asthma. In particular, levels of traffic-related pollutants are increasing rapidly across many Asian countries in parallel with the level of urbanization and economic development. The loss of protective factors associated with a rural environment will further contribute to the adverse effect on patients with allergic diseases such as asthma. In this review the roles of air pollution were examined in relation to the inception and exacerbations of allergic diseases in Asia.

A systematic review of quality and consistency of clinical practice guidelines on the primary prevention of food allergy and atopic dermatitis.

Background and aims: With an increasing number of Clinical Practice Guidelines (CPGs) addressing primary prevention of food allergy and atopic dermatitis, it is timely to undertake a comprehensive assessment of the quality and consistency of recommendations and evaluation of their implementability in different geographical settings. Methods: We systematically reviewed CPGs from 8 international databases and extensive website searches. Seven reviewers screened records in any language and then used the AGREE II and AGREE REX instruments to critically appraise CPGs published between January 2011 and April 2022. Results: Our search identified 2138 relevant articles, of which 30 CPGs were eventually included. Eight (27%) CPGs were shortlisted based on our predefined quality criteria of achieving scores >70% in the "Scope and Purpose" and "Rigour of Development" domains of the AGREE II instrument. Among the shortlisted CPGs, scores on the "Applicability" domain were generally low, and only 3 CPGs rated highly in the "Implementability" domain of AGREE-REX, suggesting that the majority of CPGs fared poorly on global applicability. Recommendations on maternal diet and complementary feeding in infants were mostly consistent, but recommendations on use of hydrolysed formula and supplements varied considerably. Conclusion: The overall quality of a CPG for Food Allergy and Atopic Dermatitis prevention did not correlate well with its global applicability. It is imperative that CPG developers consider stakeholders' preferences, local applicability, and adapt existing recommendations to each individual population and healthcare system to ensure successful implementation. There is a need for development of high-quality CPGs for allergy prevention outside of North America and Europe. PROSPERO registration number: CRD42021265689.

Environmental Influences and Allergic Diseases in the Asia-Pacific Region: What Will Happen in Next 30 Years?

Asia-Pacific is a populous region with remarkable variations in socioeconomic development and environmental exposure among countries. The prevalence rates of asthma and allergic rhinitis appear to have recently reached a plateau in Western countries, whereas they are still increasing in many Asian countries. Given the large population in Asia, even a slight increase in the prevalence rate will translate into an overwhelming number of patients. To reduce the magnitude of the increase in allergic diseases in next few decades in Asia, we must understand the potential factors leading to the occurrence of these disorders and the development of potential preventive strategies. The etiology of allergic disorders is likely due to complex interactions among genetic, epigenetic, and environmental factors for the manifestations of inappropriate immune responses. As urbanization and industrialization inevitably progress in Asia, there is an urgent need to curtail the upcoming waves of the allergy epidemic. Potentially modifiable risk exposure, such as air pollution, should be minimized through timely implementation of effective legislations. Meanwhile, re-introduction of protective factors that were once part of the traditional farming lifestyle might give new insight into primary prevention of allergy.

Temporal Dynamics of the Nasopharyngeal Microbiome and its Relationship with Childhood Asthma Exacerbation.

Despite distinct nasopharyngeal microbiome (NPM) profiles between asthmatics and healthy subjects, little is known about the NPM dynamics and its relation to childhood asthma exacerbation (AE). We investigated NPM changes by longitudinally collecting 135 flocked nasopharyngeal swabs (FNPSs) from 33 school-age asthmatic children at six time points (2 to 4-week intervals) from September to December 2017 in Hong Kong. Subjects were categorized into AE and stable asthma (AS) groups according to whether they experienced any exacerbation during follow-up. One-off FNPSs from nine nonasthmatic children were included as controls. Microbiota profiles were analyzed using 16S rRNA gene sequencing. All 144 NPMs were classified into six microbiome profile groups (MPGs), each dominated by Moraxella, Corynebacterium 1, Dolosigranulum, Staphylococcus, Streptococcus, or Anoxybacillus. The microbial diversity and compositions of NPM in exacerbation samples were different from both baseline samples and those from healthy controls. Moraxella and Dolosigranulum-dominated NPM exhibited high temporal stability revealed by MPG transition analysis. NPM diversity decreased whereas microbial composition remained similar over time. The relative abundances of Moraxella increased while Corynebacterium 1, Anoxybacillus, and Pseudomonas decreased longitudinally. However, these temporal patterns did not differ between AE and AS groups, suggesting that short-term dynamic patterns were not sufficient to predict AE occurrence. Asthmatic NPM underwent Moraxella expansion during AE and presented a high microbiome resilience (recovery potential) after AE resolution. Microbial pathways involved in methane, ketone bodies, and vitamin B3 metabolisms were enhanced during AE and primarily contributed by Moraxella. IMPORTANCE Evidence on the dynamic changes of NPM in asthmatic patients remains limited. Here, we present that asthmatic NPMs deviating from a healthy status still showed resilience after disturbance. Our data imply from a longitudinal perspective that Moraxella increase is closely related to AE occurrence. The finding of functional dysbiosis (imbalance) during AE offers a plausible explanation for the known association between nasopharyngeal Moraxella expansion and increased AE risk. This work serves as a basis for future long-term prospective studies leveraging multiomics approaches to elucidate the temporal association between NPM and pediatric AE.

Meteorin-ß/Meteorin like/IL-41 attenuates airway inflammation in house dust mite-induced allergic asthma.

We sought to examine the regulatory effect of Meteorin-ß (Metrnß)/Meteorin like (Metrnl)/IL-41 on lung inflammation in allergic asthma. We found that Metrnß was elevated significantly in asthmatic patients and in mice with allergic asthma induced by house dust mite (HDM) extract. Upon exposure to HDM, Metrnß was secreted predominantly by airway epithelial cells and inflammatory cells, including macrophages and eosinophils. The increased Metrnß effectively blocked the development of airway hyperreactivity (AHR) and decreased inflammatory cell airway infiltration and type 2 cytokine production, which was associated with downregulated DC-mediated adaptive immune responses. Moreover, Metrnß impaired the maturation and function of bone marrow-derived dendritic cells in vitro. Asthmatic mice adoptively transferred with dendritic cells isolated from Metrnß-treated allergic mice displayed decreased AHR, airway inflammation, and lung injury. Metrnß also displayed anti-inflammatory properties in immunodeficient SCID mice with allergic asthma and in in vitro 3D ALI airway models. Moreover, blockade of Metrnß by anti-Metrnß antibody treatment promoted the development of allergic asthma. These results revealed the unappreciated protective roles of Metrnß in alleviating DC-mediated Th2 inflammation in allergic asthma, providing the novel treatment strategy of therapeutic targeting of Metrnß in allergic asthma.

Quality and consistency of clinical practice guidelines on the prevention of food allergy and atopic dermatitis: Systematic review protocol.

Background and aims: Allergy prevention strategies have gained significant traction as a means to attenuate the growing burden of allergic diseases over the past decade. As the evidence base for primary prevention of food allergy (FA) and atopic dermatitis (AD) is constantly advancing, clinical practice guideline (CPG) recommendations on interventions for FA and AD prevention vary in quality and consistency among professional organizations. We present a protocol for a systematic review of CPGs on primary prevention of FA and AD. Methods: We will systematically review and appraise all CPGs addressing primary prevention of FA and AD and report our findings according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Electronic databases and manual website searches from January 2011 to March 2021 without language or geographical restrictions, and supplemented by author contact, will generate the list of potentially relevant CPGs to screen. Evaluation of the methodological quality, consistency, and global applicability of shortlisted CPGs will be performed by members of the Allergy Prevention Work Group of the World Allergy Organization (WAO) using the Appraisal of Guidelines for Research and Evaluation (AGREE) II and AGREE-REX (Recommendations EXcellence). instruments. Guideline contents, consistency, and quality of the recommendations will be summarised in tabular and narrative formats. We aim to present consolidated recommendations from international guidelines of the highest methodological quality and applicability, as determined by AGREE II and AGREE-REX. Dissemination: This systematic review will provide a succinct overview of the quality and consistency of recommendations across all existing CPGs for FA and AD prevention, as well as crucial perspectives on applicability of individual recommendations in different geographical contexts. Results from this systematic review will be reported in a peer-reviewed journal. It will also inform a position statement by WAO to provide a practical framework to guide the development of future guidelines for allergy prevention worldwide. Prospero registration number: CRD42021265689.

Whole-Genome Shotgun Sequencing for Nasopharyngeal Microbiome in Pre-school Children With Recurrent Wheezing.

Microbiome mediates early life immune deviation in asthma development. Recurrent wheeze (RW) in pre-school years is a risk factor for asthma diagnosis in school-age children. Dysbiosis exists in asthmatic airways, while its origin in pre-school years and relationship to RW is not clearly defined. This study investigated metagenomics of nasopharyngeal microbiome in pre-school children with RW. We applied whole-genome shotgun sequencing and human rhinovirus (HRV) detection on nasopharyngeal samples collected from three groups of pre-school children: (i) RW group: 16 children at-risk for asthma who were hospitalized for RW, (ii) inpatient control (IC): 18 subjects admitted for upper respiratory infection, and (iii) community control (CC): 36 children without respiratory syndromes. Sequence reads were analyzed by MetaPhlAn2 and HUMAnN2 algorithm for taxonomic and functional identification. Linear discriminant analysis effect size (LEfSe) analysis was used to identify discriminative features. We identified that Moraxella catarrhalis and Dolosigranulum pigrum were predominant species in nasopharynx. RW had lower alpha diversity (Shannon diversity index) than CC (0.48 vs. 1.07; P adj = 0.039), characterized by predominant Proteobacteria. LEfSe analysis revealed D. pigrum was the only discriminative species across groups (LDA = 5.57, P = 0.002), with its relative abundance in RW, IC, and CC being 9.6, 14.2, and 37.3%, respectively (P < 0.05). LEfSe identified five (ribo)nucleotides biosynthesis pathways to be group discriminating. Adjusting for HRV status, pre-school children with RW have lower nasopharyngeal biodiversity, which is associated with Proteobacteria predominance and lower abundance of D. pigrum. Along with discriminative pathways found in RW and CC, these microbial biomarkers help to understand RW pathogenesis.

Consensus on DEfinition of Food Allergy SEverity (DEFASE) an integrated mixed methods systematic review.

BACKGROUND AND AIMS: The term "Food Allergy" refers to a complex global health problem with a wide spectrum of severity. However, a uniform definition of severe food allergy is currently missing. This systematic review is the preliminary step towards a state-of-the-art synopsis of the current evidence relating to the severity of IgE-mediated food allergy; it will inform attempts to develop a consensus to define food allergy severity by clinicians and other stakeholders. METHODS: We undertook a mixed-methods systematic review, which involved searching 11 international biomedical databases for published studies from inception to 31 December 2019. Studies were independently screened against pre-defined eligibility criteria and critically appraised by established instruments. The substantial heterogeneity of included studies precluded meta-analyses and, therefore, narrative synthesis of quantitative and qualitative data was performed. RESULTS: We found 23 studies providing eligible primary data on symptom-specific severity of food allergic reactions, and 31 previously published symptom-severity scoring systems referred to food allergic reactions. There were seven studies which assessed quality-of-life measures in patients (and family members) with different food allergy severity and two studies that investigated the economic burden of food allergy severity. Overall, the quality and the global rating of all included studies were judged as being moderate. CONCLUSIONS: There is heterogeneity among severity scoring systems used and even outcomes considered in the context of severity of food allergy. No score has been validated. Our results will be used to inform the development of an international consensus to define the severity of food allergy. SYSTEMATIC REVIEW REGISTRATION: A protocol was prospectively registered with the International Prospective Register of Systematic Reviews (PROSPERO) database with the registration number CRD42020183103 (https://www.crd.york.ac.uk/prospero/#recordDetails).