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Recurrent wheezing in preschool children is heterogeneous and results from numerous genetic and environmental risk factors, which result in the same final clinical manifestation of acute episodes of wheezing but have distinct underlying mechanisms. Effective disease-modifying approaches, therefore, need to target the pathways driving the symptoms. We have good evidence to show that targeting airway eosinophilia alone in early-life preschool wheezing and using inhaled corticosteroids is not disease-modifying. Although airway remodelling develops early in preschool wheezing, the challenge is identifying suitable treatments for structural airway changes. There is increasing evidence for the role of lower airway bacterial infection contributing to wheeze episodes, but clinical trials investigating the impact of targeted antibiotic treatment on disease modification are needed. There is also increasing data supporting an association between lower airway neutrophilia and wheezing in a subgroup of preschool children, but direct causation and the role of neutrophil function remain unknown. Finally, there is encouraging preliminary data for the role of inactivated mixed bacterial lysates in children with non-allergic, infection-associated wheeze episodes, but the impact on longer-term outcomes and their mechanism of action is unknown. This review outlines a range of potential novel targets and approaches that may enable secondary prevention of asthma from preschool wheezing. In parallel, the potential for harm when interventions are introduced indiscriminately is highlighted. Some of the challenges that need to be addressed, including trial designs allowing tailored interventions, the need for non-invasive biomarkers for targeted interventions, and ensuring extended and long-term follow-up after intervention, are highlighted.

BACKGROUND: Eosinophil-derived neurotoxin (EDN) is a biomarker for eosinophilic activation. Urinary (u) EDN may allow non-invasive monitoring of asthma, but clinical recommendations are lacking. We assessed the potential of uEDN as a marker of disease activity in pediatric asthma.
METHODS: We assessed urine samples of 371 children from the German ALLIANCE study cohort, from which we had: 169 preschool wheezers (<6 years), 80 asthmatics (≥6 years), and 122 healthy controls using the ImmunoCAP™ EDN Assay. Creatinine (Cr)-adjusted uEDN values were analyzed using correlations, association tests, (non) parametric statistics, multiple linear, and multivariable regression.
RESULTS: uEDN/uCr values were higher in atopic versus non-atopic preschool-aged subjects (p = .035) and associated with the sum of allergen-specific IgE in younger (r = 0.24, p = .003), and older subjects (r = 0.23, p = .043). uEDN/uCr was marginally a good determinant for atopy (p = .078, for subjects aged <6 years, and p = .058 for subjects ≥6 years). Children with the T2-high phenotype had higher uEDN/uCr (p < .001) versus T2-low-irrespective of using uEDN/uCr or blood eosinophils in combination to allergen sIgE for disease phenotyping. uEDN/uCr significantly correlated with reduced lung function among asthmatics (FEV1 z-scores: r = -0.30, p = .007, and FEV1/FVC z-scores: r = -0.24, p = .038). Using multivariable modeling, uEDN/uCr was an independent determinant of FEV1 (p = .038), and to a lesser extent, FEV1/FVC (p = .080).
CONCLUSIONS: uEDN/uCr may serve as a non-invasive biomarker for clinical features such as lung function in pediatric asthma. We highlight the utility of uEDN/uCr as a biomarker that can be easily assessed using widely available robust diagnostic immunoassays.

OBJECTIVE: This study explored whether early-life factors, such as rhinovirus-induced wheeze and allergic sensitisation, were related to asthma at 11 years of age.
METHODS: We focused on 107 children aged 6-48 months, who attended the paediatric emergency department at Astrid Lindgren\'s Children\'s Hospital in Stockholm, Sweden, with acute wheeze in 2008-2012. They also attended follow-up visits at 11 years of age and were compared with 46 age-matched healthy controls. Odds ratios (OR) with 95% confidence intervals (CI) were calculated with logistic regression.
RESULTS: We found that 62.6% of the acute wheeze cases had asthma at 11 years of age. Rhinoviruses at inclusion were the only common airway viruses associated with an increased asthma risk (OR 2.4, 95% CI 1.02-5.6). Other increased risks were parental heredity for asthma and/or allergies (adjusted OR 3.4, 95% CI 1.1-9.9) and allergic sensitisation at 2 years of age (adjusted OR 3.0, 95% CI 1.02-8.7). The highest prevalence of asthma was when children had both rhinovirus-induced wheeze at inclusion and allergic sensitisation at 7 years of age.
CONCLUSIONS: Our findings highlight the importance of hereditary factors and allergic sensitisation on the development of asthma and suggest that rhinoviruses are associated with asthma development in predisposed children.

Rationale: The strongest genetic risk factor for childhood-onset asthma, the 17q21 locus, is associated with increased viral susceptibility and disease-promoting processes.Objectives: To identify biological targets underlying the escalated viral susceptibility associated with the clinical phenotype mediated by the 17q21 locus.Methods: Genome-wide transcriptome analysis of nasal brush samples from 261 children (78 healthy, 79 with wheezing at preschool age, 104 asthmatic) within the ALLIANCE (All-Age-Asthma) cohort, with a median age of 10.0 (range, 1.0-20.0) years, was conducted to explore the impact of their 17q21 genotype (SNP rs72163891). Concurrently, nasal secretions from the same patients and visits were collected, and high-sensitivity mesoscale technology was employed to measure IFN protein levels.Measurements and Main Results: This study revealed that the 17q21 risk allele induces a genotype- and asthma/wheeze phenotype-dependent enhancement of mucosal GSDMB expression as the only relevant 17q21-encoded gene in children with preschool wheeze. Increased GSDMB expression correlated with the activation of a type-1 proinflammatory, cell-lytic immune, and natural killer signature, encompassing key genes linked to an IFN type-2-signature (IFNG, CXCL9, CXCL10, KLRC1, CD8A, GZMA). Conversely, there was a reduction in IFN type 1 and type 3 expression signatures at the mRNA and protein levels.Conclusions: This study demonstrates a novel disease-driving mechanism induced by the 17q21 risk allele. Increased mucosal GSDMB expression is associated with a cell-lytic immune response coupled with compromised airway immunocompetence. These findings suggest that GSDMB-related airway cell death and perturbations in the mucosal IFN signature account for the increased vulnerability of 17q21 risk allele carriers to respiratory viral infections during early life, opening new options for future biological interventions.The All-Age-Asthma (ALLIANCE) cohort is registered at www.clinicaltrials.gov (pediatric arm, NCT02496468).

BACKGROUND: Preschool wheeze is a risk factor for asthma development. However, the molecular mechanism behind a wheezing episode is not well understood.
OBJECTIVE: Our aims were to assess the association of plasma proteins with acute preschool wheeze and to study the proteins with differential expression at the acute phase at revisit after 3 months. Additionally, to investigate the relationship between protein expression and clinical parameters.
METHODS: We measured 92 inflammatory proteins in plasma and clinical parameters from 145 children during an episode of preschool wheeze (PW) and at the revisit after 3 months (PW-R, n = 113/145) and 101 healthy controls (HC) aged 6-48 months in the GEWAC cohort using the antibody-mediated proximity extension-based assay (Olink Proteomics, Uppsala).
RESULTS: Of the 74 analysed proteins, 52 were differentially expressed between PW and HC. The expression profiles of the top 10 proteins, Oncostatin M (OSM), IL-10, IL-6, Fibroblast growth factor 21 (FGF21), AXIN1, CXCL10, SIRT2, TNFSF11, Tumour necrosis factor β (TNF-β) and CASP8, could almost entirely separate PW from HC. Five out of 10 proteins were associated with intake of oral corticosteroids (OCS) 24 h preceding blood sampling (OSM, CASP8, IL-10, TNF-β and CXCL10). No differences in protein expression were seen between PWs with or without OCS in comparison to HC. At the revisit after 3 months, differential protein expressions were still seen between PW-R and HC for three (IL-10, SIRT2 and FGF21) of the 10 proteins.
CONCLUSIONS: Our results contribute to unravelling potential immunopathological pathways shared between preschool wheeze and asthma.

Wheezing disorders in preschool children are common. Current treatment approaches assume all preschool wheezers are the same and will respond to a short course of oral corticosteroids (OCS) during acute attacks and subsequent maintenance inhaled corticosteroids (ICS) to prevent future attacks. But we have increasing evidence showing preschool wheezing disorders are markedly heterogeneous and the response to corticosteroids either during acute attacks or as maintenance therapy can be variable between patients and is determined by disease severity and underlying pathological phenotype.
The aim of this review is to discuss recent evidence which will help to explain a few critical pathophysiological concepts that are often misunderstood, thus helping to demystify the controversies that often surround preschool wheezing disorders and can contribute to ineffective management.
Preschool wheezing disorders are distinct from school-age allergic asthma. There is little evidence to support the use of oral corticosteroids for acute attacks. A staged approach to confirm the diagnosis, and objective tests to determine the pathological phenotype of preschool wheeze is essential prior to initiating maintenance therapy to control symptoms and prevent attacks in children with recurrent preschool wheeze.

Preschool wheeze (PSW) is a significant public health issue, with a high presentation rate to emergency departments, recurrent symptoms, and severe exacerbations. A heterogenous condition, PSW comprises several phenotypes that may relate to a range of pathobiological mechanisms. However, treating PSW remains largely generalized to inhaled corticosteroids and a short acting beta agonist, guided by symptom-based labels that often do not reflect underlying pathways of disease.
We review the observable features and characteristics used to ascribe phenotypes in children with PSW and available pathobiological evidence to identify possible endotypes. These are considered in the context of treatment options and future research directions. The role of machine learning (ML) and modern analytical techniques to identify patterns of disease that distinguish phenotypes is also explored.
Distinct clusters (phenotypes) of severe PSW are characterized by different underlying mechanisms, some shared and some unique. ML-based methodologies applied to clinical, biomarker, and environmental data can help design tools to differentiate children with PSW that continues into adulthood, from those in whom wheezing resolves, identifying mechanisms underpinning persistence and resolution. This may help identify novel therapeutic targets, inform mechanistic studies, and serve as a foundation for stratification in future interventional therapeutic trials.

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Allergic sensitization in early life has been identified as a strong risk factor for subsequent asthma in childhood. It is still unclear why only a part of sensitized children develop asthma, and the role of specific allergen molecules in asthma pathogenesis is ambiguous [Pharmacol Ther. 2009 Feb;121(2):174-84]. We assessed the sensitization to multiple allergen molecules longitudinally and explored its relation to persistent asthma at 7 years.
Seventy-two children included during an acute wheezing episode (cases) were followed prospectively from early preschool age (EPA) to age 7, and compared to 43 healthy controls at EPA. Allergen molecules were analyzed at EPA and age 7 using ImmunoCAP Solid-phase Allergen Chip (ISAC). Asthma diagnosis at 7 years was based on symptoms, medication, and spirometry.
At EPA, cases compared to controls showed a tendency toward having a higher prevalence of allergic sensitization (23.6% vs. 9.3%, p = 0.055). The prevalence of sensitization increased in cases from EPA to 7 years (23.6% vs. 38.9%; p = 0.048) as well as the median number (range) of immunoglobulin E (IgE)-reactive molecules 3 (3-14) versus 6.5 (1-21); p = 0.024. Sensitization to each additional molecule from EPA to the age of 7 was significantly related to asthma at 7 (OR = 1.25, 95% confidence interval [1.01, 1.54]).
Polysensitization, assessed by allergen molecules, had a significant impact on persistent asthma at school age. The extent of sensitization, illustrated by molecular spreading from preschool to school age, was related to asthma diagnosis at 7 years in children with a history of wheezing at early life.