Bacteria and viruses and their role in the preschool wheeze to asthma transition.

Wheezing is the cardinal symptom of asthma; its presence early in life, mostly caused by viral infections, is a major risk factor for the establishment of persistent or recurrent disease. Early-life wheezing and asthma exacerbations are triggered by common respiratory viruses, mainly rhinoviruses (RV), and to a lesser extent, respiratory syncytial virus, parainfluenza, human metapneumovirus, coronaviruses, adenoviruses, influenza, and bocavirus. The excess presence of bacteria, several of which are part of the microbiome, has also been identified in association with wheezing and acute asthma exacerbations, including haemophilus influenza, streptococcus pneumoniae, moraxella catarrhalis, mycoplasma pneumoniae, and chlamydophila pneumonia. While it is not clear when asthma starts, its characteristics develop over time. Airway remodeling already appears between the ages of 1 and 3 years of age even prior to the presence of atopic inflammation or an asthma diagnosis. The role of genetic defect or variations hampering the airway epithelium in response to environmental stimuli and severe disease morbidity are now considered as major determinants for early structural changes. Repeated viral infections can induce and perpetuate airway hyperresponsiveness. Allergic sensitization, that often precedes infection-induced wheezing, shifts inflammation toward type-2, while common respiratory infections themselves promote type-2 inflammation. Nevertheless, most children who wheeze with viral infections during infancy and during preschool years do not develop persistent asthma. Multiple factors, including illness severity, viral etiology, allergic sensitization, and the exposome, are associated with disease persistence. Here, we summarize current knowledge and developments in infection epidemiology of asthma in children, describing the known impact of each individual agent and mechanisms of transition from recurrent wheeze to asthma.

Comorbidities of Chronic Urticaria: A glimpse into a complex relationship.

Chronic Urticaria (CU) is a chronic inflammatory, predominantly mast cell-driven disease, characterized by the development of wheals and/or angioedema for more than 6 weeks. It affects approximately 1%-5% of the total population worldwide and imposes a substantial burden on health-related quality of life, significantly affecting patients' daily life. The economic impact on the health system is also not negligible, with an estimated cost per patient per year of approximately 2.000 $ in the United States. Although the underlying pathophysiology is not fully explored, autoimmune mechanisms have been proposed, including type I ("autoallergy" by means of autoantibodies to self-antigens) and type IIb (autoimmunity). Atopic, autoimmune, and psychiatric disorders are prevalent comorbidities in both children and adults with Chronic Spontaneous Urticaria (CSU). Although malignancies, cardiovascular diseases and other comorbidities have also been reported as associated diseases in patients with CSU, data remain scarce. It is still unknown whether the aforementioned comorbidities share common pathophysiological mechanisms with specific endotypes of CSU. The current review aims to overview current data on comorbidities of CU, and furthermore to comment on the potential linked pathways underlying these diseases.

Targeted deletion of Interleukin-3 results in asthma exacerbations.

The cytokine interleukin-3 (IL-3) acts on early hematopoietic precursor cells. In humans, Treg cells secrete IL-3 and repress inflammatory cells except for basophils. The present study aims to elucidate the contribution of IL-3 in the development and the course of allergic asthma. We therefore analyzed the secretion of IL-3 in PBMCs and total blood cells in two cohorts of pre-school children with and without asthma. In a murine model of allergic asthma, we analyzed the phenotype of IL-3-/- mice compared to wild-type mice. PBMCs from asthmatic children showed increased IL-3 secretion, which directly correlated with improved lung function. IL-3-/- asthmatic mice showed increased asthmatic traits. Moreover, IL-3-deficient mice had a defect in T regulatory cells in the lung. In conclusion, IL-3 downregulation was found associated with more severe allergic asthma in pre-school children. Consistently, targeting IL-3 resulted in an induced pathophysiological response in a murine model of allergic asthma.

Development of an in vitro homeostasis model between airway epithelial cells, bacteria and bacteriophages: a time-lapsed observation of cell viability and inflammatory response.

Bacteriophages represent the most extensive group of viruses within the human virome and have a significant impact on general health and well-being by regulating bacterial population dynamics. Staphylococcus aureus, found in the anterior nostrils, throat and skin, is an opportunistic pathobiont that can cause a wide range of diseases, from chronic inflammation to severe and acute infections. In this study, we developed a human cell-based homeostasis model between a clinically isolated strain of S. aureus 141 and active phages for this strain (PYOSa141) isolated from the commercial Pyophage cocktail (PYO). The cocktail is produced by Eliava BioPreparations Ltd. (Tbilisi, Georgia) and is used as an add-on therapy for bacterial infections, mainly in Georgia. The triptych interaction model was evaluated by time-dependent analysis of cell death and inflammatory response of the nasal and bronchial epithelial cells. Inflammatory mediators (IL-8, CCL5/RANTES, IL-6 and IL-1ß) in the culture supernatants were measured by enzyme-linked immunosorbent assay and cell viability was determined by crystal violet staining. By measuring trans-epithelial electrical resistance, we assessed the epithelial integrity of nasal cells that had differentiated under air-liquid interface conditions. PYOSa141 was found to have a prophylactic effect on airway epithelial cells exposed to S. aureus 141 by effectively down-regulating bacterial-induced inflammation, cell death and epithelial barrier disruption in a time-dependent manner. Overall, the proposed model represents an advance in the way multi-component biological systems can be simulated in vitro.

Predictors of Food Sensitization in Children and Adults Across Europe.

BACKGROUND: The geographical variation and temporal increase in the prevalence of food sensitization (FS) suggest environmental influences. OBJECTIVE: To investigate how environment, infant diet, and demographic characteristics, are associated with FS in children and adults, focusing on early-life exposures. METHODS: Data on childhood and adult environmental exposures (including, among others, sibship size, day care, pets, farm environment, and smoking), infant diet (including breast-feeding and timing of introduction to infant formula and solids), and demographic characteristics were collected from 2196 school-age children and 2185 adults completing an extensive questionnaire and blood sampling in the cross-sectional pan-European EuroPrevall project. Multivariable logistic regression was applied to determine associations between the predictor variables and sensitization to foods commonly implicated in food allergy (specific IgE ≥0.35 kUA/L). Secondary outcomes were inhalant sensitization and primary (non-cross-reactive) FS. RESULTS: Dog ownership in early childhood was inversely associated with childhood FS (odds ratio, 0.65; 95% CI, 0.48-0.90), as was higher gestational age at delivery (odds ratio, 0.93 [95% CI, 0.87-0.99] per week increase in age). Lower age and male sex were associated with a higher prevalence of adult FS (odds ratio, 0.97 [95% CI, 0.96-0.98] per year increase in age, and 1.39 [95% CI, 1.12-1.71] for male sex). No statistically significant associations were found between other evaluated environmental determinants and childhood or adult FS, nor between infant diet and childhood FS, although early introduction of solids did show a trend toward prevention of FS. CONCLUSIONS: Dog ownership seems to protect against childhood FS, but independent effects of other currently conceived environmental and infant dietary determinants on FS in childhood or adulthood could not be confirmed.

Prevalence estimates and risk factors for early childhood wheeze across Europe: the EuroPrevall birth cohort.

BACKGROUND: Preschool wheeze is an important problem worldwide. No comparative population-based studies covering different countries have previously been undertaken. OBJECTIVE: To assess the prevalence of early childhood wheeze across Europe and evaluate risk factors focusing on food allergy, breast feeding and smoke exposure. METHODS: Infants from nine countries were recruited into the EuroPrevall birth cohort. At 12 and 24 months, data on wheeze, allergic signs/symptoms, feeding, smoke exposure, infections and day care attendance were collected using questionnaires. Poisson regression was used to assess risk factors for wheeze. RESULTS: 12 049 infants were recruited. Data from the second year of life were available in 8805 (73.1%). The prevalence of wheeze in the second year of life ranged from <2% in Lodz (Poland) and Vilnius (Lithuania) to 13.1% (95% CI 10.7% to 15.5%) in Southampton (UK) and 17.2% (95% CI 15.0% 19.5%) in Reykjavik (Iceland). In multivariable analysis, frequent lower respiratory tract infections in the first and second years of life (incidence rate ratio (IRR) 1.9 (95% CI 1.3 to 2.6) and 2.5 (95% CI 1.9 to3.4), respectively), postnatal maternal smoking (IRR 1.6, 95% CI 1.1 to 2.4), day care attendance (IRR 1.6, 95% CI 1.1 to 2.5) and male gender (IRR 1.3, 95% CI 1.0 to 1.7) were associated with wheeze. The strength of their association with wheeze differed between countries. Food allergy and breast feeding were not independently associated with wheeze. CONCLUSION: The prevalence of early childhood wheeze varied considerably across Europe. Lower respiratory tract infections, day care attendance, postnatal smoke exposure and male gender are important risk factors. Further research is needed to identify additional modifiable risk factors that may differ between countries.

Contribution of repeated infections in asthma persistence from preschool to school age: Design and characteristics of the PreDicta cohort.

BACKGROUND: The PreDicta cohort was designed to prospectively evaluate wheeze/asthma persistence in preschoolers in association with viral/microbial exposures and immunological responses. We present the cohort design and demographic/disease characteristics and evaluate unsupervised and predefined phenotypic subgroups at inclusion. METHODS: PreDicta is a 2-year prospective study conducted in five European regions, including children 4-6 years with a diagnosis of asthma as cases and healthy age-matched controls. At baseline, detailed information on demographics, asthma and allergy-related disease activity, exposures, and lifestyle were recorded. Lung function, airway inflammation, and immune responses were also assessed. Power analysis confirmed that the cohort is adequate to answer the initial hypothesis. RESULTS: A total of 167 asthmatic children (102 males) and 66 healthy controls (30 males) were included. Groups were homogeneous in respect to most baseline characteristics, with the exception of male gender in cases (61%) and exposure to tobacco smoke. Comorbidities and number and duration of infections were significantly higher in asthmatics than controls. 55.7% of asthmatic children had at least one positive skin prick test to aeroallergens (controls: 33.3%, P = .002). Spirometric and exhaled nitric oxide values were within normal limits; only baseline FEV0.5 and FEV1 reversibility values were significantly different between groups. Viral infections were the most common triggers (89.2%) independent of severity, control, or atopy; however, overlapping phenotypes were also common. Severity and control clustered together in an unsupervised analysis, separating moderate from mild disease. CONCLUSIONS: The PreDicta cohort presented no differences in non-asthma related measures; however, it is well balanced regarding key phenotypic characteristics representative of "preschool asthma".

Papel de las infecciones virales en el asma / The role of viral infections in asthma

Respiratory viral infections have been implicated in the origin and exacerbation of asthma symptoms in a variety of ways. A growing body of evidence indicates that viral infections are closely linked to infantile wheezing and suggest that severe bronchiolitis in early infancy may predispose to chronic childhood asthma. Alternatively, it could represent a marker of susceptible individuals. In contrast, mild repetitive infections in early years may provide a protective role against the development of asthma or atopy by switching the immune system towards Th1 responses. However, evidence on this hypothesis is not consistent as far as viruses are concerned. On the other hand, in the presence of asthma, the role of viral infections on exacerbations is well established. Several factors, such as the presence of atopy, timing of the exposure and severity of the infections, interactively contribute to the asthma-infection relationship. In the present report, recent data on the involvement of viral infections in the development and progression of asthma are reviewed

Las infecciones virales respiratorias han sido involucradas en el origen y en las exacerbaciones de los síntomas del asma en una variedad de formas. Cada vez hay más indicios de que las infecciones virales están estrechamente relacionadas con sibilancias en la niñez y sugieren que la bronquiolitis grave en la primera infancia puede predisponer a asma crónica infantil; por otra parte, podría representar un marcador de individuos susceptibles. Por el contrario, las infecciones leves repetidas en los primeros años brindarían un efecto protector contra la aparición de asma o atopia mediante la desviación del sistema inmunitario hacia respuestas Th1. Sin embargo, la información relacionada con esta hipótesis no es firme en lo que a virus se refiere. Por otra parte, en presencia de asma, el papel de las infecciones virales sobre las exacerbaciones está bien establecido. Varios factores, como la presencia de atopia, el momento en el que se produce la exposición y la gravedad de las infecciones, interactúan en la relación entre asma e infección. En este artículo se revisan datos acerca de la participación de las infecciones virales en la aparición y progresión del asma

Association of passive exposure of pregnant women to environmental tobacco smoke with asthma symptoms in children.

Environmental tobacco smoke (ETS) is a significant risk factor for the presence and increased severity of asthma- and allergy-related symptoms in children. Smoking during pregnancy has detrimental effects on asthma-associated outcomes in childhood. Whether passive exposure of pregnant women to ETS may also lead to asthma in their offspring, is not known. The aim of this study was to investigate the association of passive exposure of pregnant women to ETS and asthma- and/or allergy-related symptoms in Preschool children. Cross-sectional data were collected with questionnaires from 2374 Preschool children, recruited from public and private nurseries and day-care centers. Parental smoking was significantly associated with wheezing symptoms in their children. Mother's active smoking during pregnancy significantly increased the risk for occurrence of asthma symptoms and/or medically diagnosed asthma in Preschool children in a dose-dependent manner. Passive exposure to ETS, mainly during the third trimester of pregnancy, was significantly associated with asthma- and allergy-related symptoms after adjusting for several confounders in a multivariate analysis (current wheeze: OR = 1.42, 95% CI = 1.06-1.91, pruritic rash ever: OR= 1.45, 95% CI = 1.01-2.08). Passive exposure of pregnant women to ETS during the third trimester is positively associated with asthma- and allergy-related symptoms in their Preschool age children. Public health policies should be oriented not only towards smoking cessation, but also reinforce elimination of ETS exposure of pregnant women.