Asthma is a serious health problem throughout the world During the past two decades, many scientific advances have improved our understanding of asthma and ability to manage and control it effectively However, recommendations for asthma care need to be adapted to local conditions, resources and services Since it was formed in 1993, the Global Initiative for Asthma, a network of individuals, organisations and public health officials, has played a leading role in disseminating information about the care of patients with asthma based on a process of continuous review of published scientific investigations A comprehensive workshop report entitled "A Global Strategy for Asthma Management and Prevention", first published in 1995, has been widely adopted, translated and reproduced, and forms the basis for many national guidelines The 2006 report contains important new themes First, it asserts that "it is reasonable to expect that in most patients with asthma, control of the disease can and should be achieved and maintained," and recommends a change in approach to asthma management, with asthma control, rather than asthma severity, being the focus of treatment decisions The importance of the patient-care giver partnership and guided self-management, along with setting goals for treatment, are also emphasised

https://erj.ersjournals.com/content/erj/31/1/143.full.pdf

Global strategy for asthma management and prevention: GINA executive summary.

Background: A rich microbial environment in infancy protects against asthma [1], [2] and infections precipitate asthma exacerbations [3]. We compared the airway microbiota at three levels in adult patients with asthma, the related condition of COPD, and controls. We also studied bronchial lavage from asthmatic children and controls. 

Principal Findings: We identified 5,054 16S rRNA bacterial sequences from 43 subjects, detecting >70% of species present. The bronchial tree was not sterile, and contained a mean of 2,000 bacterial genomes per cm2 surface sampled. Pathogenic Proteobacteria, particularly Haemophilus spp., were much more frequent in bronchi of adult asthmatics or patients with COPD than controls. We found similar highly significant increases in Proteobacteria in asthmatic children. Conversely, Bacteroidetes, particularly Prevotella spp., were more frequent in controls than adult or child asthmatics or COPD patients. 

Significance: The results show the bronchial tree to contain a characteristic microbiota, and suggest that this microbiota is disturbed in asthmatic airways.

https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0008578&type=printable

Disordered Microbial Communities in Asthmatic Airways

In two cross-sectional studies, we compared children living on farms with those in a reference group with respect to the prevalence of asthma and atopy and to the diversity of microbial exposure. In one study — PARSIFAL (Prevention of Allergy — Risk Factors for Sensitization in Children Related to Farming and Anthroposophic Lifestyle) — samples of mattress dust were screened for bacterial DNA with the use of single-strand conformation polymorphism (SSCP) analyses to detect environmental bacteria that cannot be measured by means of culture techniques. In the other study — GABRIELA (Multidisciplinary Study to Identify the Genetic and Environmental Causes of Asthma in the European Community [GABRIEL] Advanced Study) — samples of settled dust from children’s rooms were evaluated for bacterial and fungal taxa with the use of culture techniques. Results In both studies, children who lived on farms had lower prevalences of asthma and atopy and were exposed to a greater variety of environmental microorganisms than the children in the reference group. In turn, diversity of microbial exposure was inversely related to the risk of asthma (odds ratio for PARSIFAL, 0.62; 95% confidence interval [CI], 0.44 to 0.89; odds ratio for GABRIELA, 0.86; 95% CI, 0.75 to 0.99). In addition, the presence of certain more circumscribed exposures was also inversely related to the risk of asthma; this included exposure to species in the fungal taxon eurotium (adjusted odds ratio, 0.37; 95% CI, 0.18 to 0.76) and to a variety of bacterial species, including Listeria monocytogenes, bacillus species, corynebacterium species, and others (adjusted odds ratio, 0.57; 95% CI, 0.38 to 0.86). Conclusions Children living on farms were exposed to a wider range of microbes than were children in the reference group, and this exposure explains a substantial fraction of the inverse relation between asthma and growing up on a farm. (Funded by the Deutsche Forschungsgemeinschaft and the European Commission.)

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Exposure to Environmental Microorganisms and Childhood Asthma

Background It is unknown whether inhaled corticosteroids can modify the subsequent development of asthma in preschool children at high risk for asthma. Methods We randomly assigned 285 participants two or three years of age with a positive asthma predictive index to treatment with fluticasone propionate (at a dose of 88 μg twice daily) or masked placebo for two years, followed by a one-year period without study medication. The primary outcome was the proportion of episode-free days during the observation year. Results During the observation year, no significant differences were seen between the two groups in the proportion of episode-free days, the number of exacerbations, or lung function. During the treatment period, as compared with placebo use, use of the inhaled corticosteroid was associated with a greater proportion of episode-free days (P = 0.006) and a lower rate of exacerbations (P<0.001) and of supplementary use of controller medication (P<0.001). In the inhaled-corticosteroid group, as compared with the placebo group, the mean increase in height was 1.1 cm less at 24 months (P<0.001), but by the end of the trial, the height increase was 0.7 cm less (P = 0.008). During treatment, the inhaled corticosteroid reduced symptoms and exacerbations but slowed growth, albeit temporarily and not progressively. Conclusions In preschool children at high risk for asthma, two years of inhaled-corticosteroid therapy did not change the development of asthma symptoms or lung function during a third, treatment-free year. These findings do not provide support for a subsequent disease-modifying effect of inhaled corticosteroids after the treatment is discontinued. (ClinicalTrials.gov number, NCT00272441.)

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Long-term inhaled corticosteroids in preschool children at high risk for asthma.

Throughout the past century, we have seen the emergence of a large number of multifactorial diseases, including inflammatory, autoimmune, metabolic, neoplastic and neurodegenerative diseases, many of which have been recently associated with intestinal dysbiosis - that is, compositional and functional alterations of the gut microbiome. In linking the pathogenesis of common diseases to dysbiosis, the microbiome field is challenged to decipher the mechanisms involved in the de novo generation and the persistence of dysbiotic microbiome configurations, and to differentiate causal host-microbiome associations from secondary microbial changes that accompany disease course. In this Review, we categorize dysbiosis in conceptual terms and provide an overview of immunological associations; the causes and consequences of bacterial dysbiosis, and their involvement in the molecular aetiology of common diseases; and implications for the rational design of new therapeutic approaches. A molecular- level understanding of the origins of dysbiosis, its endogenous and environmental regulatory processes, and its downstream effects may enable us to develop microbiome-targeting therapies for a multitude of common immune-mediated diseases.

Dysbiosis and the immune system

Background Pathological features of the airway in young children with severe recurrent wheeze suggest an association between bacterial colonization and the initiating events of early asthma. We conducted a study to investigate a possible association between bacterial colonization of the hypopharynx in asymptomatic neonates and later development of recurrent wheeze, asthma, and allergy during the first 5 years of life. Methods The subjects were children from the Copenhagen Prospective Study on Asthma in Childhood birth cohort who were born to mothers with asthma. Aspirates from the hypopharyngeal region of asymptomatic 1-month-old infants were cultured for Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Staphylococcus aureus. Wheeze was monitored prospectively on diary cards during the first 5 years of life. Blood eosinophil count and total IgE and specific IgE were measured at 4 years of age. Lung function was measured and asthma was diagnosed at 5 years of age. Results Hypoph...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa052632

Childhood Asthma after Bacterial Colonization of the Airway in Neonates

Background We hypothesized that asthma is preceded by a stage of recurrent episodes of wheezing during the first years of life and that inhaled corticosteroid therapy during symptomatic episodes in this early phase may delay progression to persistent wheezing. Methods We assigned one-month-old infants to treatment with two-week courses of inhaled budesonide (400 μg per day) or placebo, initiated after a three-day episode of wheezing, in this single-center, randomized, double-blind, prospective study of three years’ duration. The primary outcome was the number of symptom-free days; key secondary outcomes were the time to discontinuation due to persistent wheezing and safety, as evaluated by height and bone mineral density at the end of the study. Results We enrolled 411 infants and randomly assigned 294 to receive budesonide at a first episode of wheezing. The proportion of symptom-free days was 83 percent in the budesonide group and 82 percent in the placebo group (absolute difference, 1 percent; 95 percent confidence interval, −4.8 to 6.9 percent). Twenty-four percent of children in the budesonide group had persistent wheezing, as compared with 21 percent in the placebo group (hazard ratio, 1.22; 95 percent confidence interval, 0.71 to 2.13) — a finding that was unaffected by the presence or absence of atopic dermatitis. The mean duration of the acute episodes was 10 days in both groups and was independent of respiratory viral status. Height and bone mineral density were not affected by treatment. Conclusions Intermittent inhaled corticosteroid therapy had no effect on the progression from episodic to persistent wheezing and no short-term benefit during episodes of wheezing in the first three years of life. (ClinicalTrials.gov number, NCT00234390.)

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Intermittent Inhaled Corticosteroids in Infants with Episodic Wheezing

Nitric oxide in exhaled air (F ENO ) is increased in asthmatic children, probably reflecting aspects of airway inflammation. We have studied the effect of the leukotriene receptor antagonist (LTRA) montelukast on F ENO with a view to elucidate potential anti-inflammatory properties of LTRAs. Twenty-six asthmatic children 6 to 15 yr of age completed a double-blind crossover trial of 2 wk of treatment with 5 mg montelukast once daily versus placebo. F ENO was measured during single-breath exhalation at a constant flow rate of 0.1 to 0.13 L/s against a resistance of 10 kPa/L/s. Eleven children were receiving maintenance treatment with inhaled steroids during the study (mean daily dose, 273 m g), whereas the other 15 used only inhaled b 2 -agonists as required. The within-subject coefficient of variation of F ENO over a 2-wk interval for the 26 children was 38%. F ENO was significantly reduced by 20% after the 2-wk treatment with montelukast as compared with placebo as well as compared with baseline. This effect occurred rapidly with a 15% fall in F ENO within 2 d. The effect of montelukast on F ENO was independent of concurrent steroid treatment. The effect on F ENO is probably not caused by bronchodilatation since F ENO increased significantly after inhalation of terbutaline. In conclusion, F ENO in asthmatic children was significantly decreased from montelukast, which corroborates antiinflammatory properties of LTRA. Bisgaard H, Loland L, Anhoj J. NO in exhaled air of asthmatic children is reduced by the leukotriene receptor antagonist montelukast. AM J RESPIR CRIT CARE MED 1999;160:1227‐1231.

https://www.atsjournals.org/doi/pdf/10.1164/ajrccm.160.4.9903004

NO in exhaled air of asthmatic children is reduced by the leukotriene receptor antagonist montelukast.

Objectives To describe the development of atopic dermatitis (AD) during the first 3 years of life and identify the localization of the early skin lesions that predicts the development of AD Design Prospective, longitudinal, birth cohort study of children born to mothers with a history of asthma, followed up for 3 years with scheduled visits every 6 months as well as visits for onset or acute exacerbations of skin symptoms Setting The cohort was recruited from greater Copenhagen, Denmark, and followed up at a clinical research unit, which controlled all diagnoses and treatment of skin diseases Participants A total of 411 infants were enrolled in the cohort; 55 had incomplete follow-up and were excluded from certain analyses Main Outcome Measures Atopic dermatitis was defined based on the criteria of Hanifin and Rajka, and severity was assessed by the SCORAD (Scoring Atopic Dermatitis) index Predictive odds ratios of early skin lesions for those who developed AD vs those who did not were calculated Results The cumulative incidence of AD by age 3 years was 44% (155/356) The prevalence rate peaked at age 2 years for boys and at age 25 years for girls, but there were no other sex differences in the proportion of children developing AD Skin involvement in infants with AD was found to begin at the scalp, forehead, ear, and neck in a balaclava-like pattern and continue to the extensor sides and trunk, finally affecting the flexor sides of the extremities Early skin lesions of arms and joints best predicted AD at age 3 years Conclusions Atopic dermatitis begins at the scalp, forehead, ear, and neck in a balaclava-like pattern Eczema at the arms and joints provides the highest predictive value for the development of AD at age 3 years This may be used for early prediction and intervention of AD

https://jamanetwork.com/journals/jamadermatology/articlepdf/405221/DST50061.pdf

Development of atopic dermatitis during the first 3 years of life: the Copenhagen prospective study on asthma in childhood cohort study in high-risk children.

Background Neonatal lung function is suspected to be associated with wheezy disorders, but little is known about risk factors for the early lung function. Objectives To study prenatal determinants of neonatal lung function. Methods This is a clinical, prospective birth cohort study of 411 newborns, the Copenhagen Prospective Study on Asthma in Childhood, in a single-center research clinic dedicated solely to this longitudinal birth cohort study. Lung function was determined at 1 month of age by infant spirometry (the raised volume rapid thoraco-abdominal compression technique) and bronchial responsiveness to methacholine by transcutaneous oxygen measurements. Risk factor analyses included anthropometrics; demographics; socioeconomic factors; parental atopic history; previous deliveries; exposures during the third trimester to the mother's smoking, alcohol, and medicines; third trimester pregnancy complications including mother's asthma status; and mode of delivery. Results Lung function was determined in 404 neonates, age 6 weeks. Neonates with body mass index in the upper quartile had 14% lower baseline forced expiratory volume at 0.5 second, and neonates of mothers smoking during the third trimester had 7% lower baseline forced expiratory volume at 0.5 second. Sex or parental atopic disease did not affect the neonatal lung function and bronchial responsiveness. Maternal intake of paracetamol during the third trimester was associated with doubling of the bronchial responsiveness in the neonates, but the statistical significance may have been driven by outliers. Bronchial responsiveness exhibited a parabola development with tripling of bronchial responsiveness reaching the nadir at 3 months of age, but this needs replication in a study with repetitive measurements within individuals. Conclusion High body mass index in newborns and mothers smoking is associated with reduced neonatal lung function. This suggests that the association between body proportion and wheezing disorders may be a result of shared genes or prenatal nutrition.

Lotte Loland

Papers

Childhood Asthma after Bacterial Colonization of the Airway in Neonates

Intermittent Inhaled Corticosteroids in Infants with Episodic Wheezing

NO in exhaled air of asthmatic children is reduced by the leukotriene receptor antagonist montelukast.

Development of atopic dermatitis during the first 3 years of life: the Copenhagen prospective study on asthma in childhood cohort study in high-risk children.

Prenatal determinants of neonatal lung function in high-risk newborns