Johan C. de Jongste

An Official American Thoracic Society/European Respiratory Society Statement: Asthma Control and Exacerbations Standardizing Endpoints for Clinical Asthma Trials and Clinical Practice

BACKGROUND The assessment of asthma control is pivotal to the evaluation of treatment response in individuals and in clinical trials. Previously, asthma control, severity, and exacerbations were defined and assessed in many different ways. PURPOSE The Task Force was established to provide recommendations about standardization of outcomes relating to asthma control, severity, and exacerbations in clinical trials and clinical practice, for adults and children aged 6 years or older. METHODS A narrative literature review was conducted to evaluate the measurement properties and strengths/weaknesses of outcome measures relevant to asthma control and exacerbations. The review focused on diary variables, physiologic measurements, composite scores, biomarkers, quality of life questionnaires, and indirect measures. RESULTS The Task Force developed new definitions for asthma control, severity, and exacerbations, based on current treatment principles and clinical and research relevance. In view of current knowledge about the multiple domains of asthma and asthma control, no single outcome measure can adequately assess asthma control. Its assessment in clinical trials and in clinical practice should include components relevant to both of the goals of asthma treatment, namely achievement of best possible clinical control and reduction of future risk of adverse outcomes. Recommendations are provided for the assessment of asthma control in clinical trials and clinical practice, both at baseline and in the assessment of treatment response. CONCLUSIONS The Task Force recommendations provide a basis for a multicomponent assessment of asthma by clinicians, researchers, and other relevant groups in the design, conduct, and evaluation of clinical trials, and in clinical practice.

Traffic-related Air Pollution and the Development of Asthma and Allergies during the First 8 Years of Life

RATIONALE The role of air pollution exposure in the development of asthma, allergies, and related symptoms remains unclear, due in part to the limited number of prospective cohort studies with sufficiently long follow-ups addressing this problem. OBJECTIVES We studied the association between traffic-related air pollution and the development of asthma, allergy, and related symptoms in a prospective birth cohort study with a unique 8-year follow-up. METHODS Annual questionnaire reports of asthma, hay fever, and related symptoms during the first 8 years of life were analyzed for 3,863 children. At age 8, measurements of allergic sensitization and bronchial hyperresponsiveness were performed for subpopulations (n = 1,700 and 936, respectively). Individual exposures to nitrogen dioxide (NO(2)), particulate matter (PM(2.5)), and soot at the birth address were estimated by land-use regression models. Associations between exposure to traffic-related air pollution and repeated measures of health outcomes were assessed by repeated-measures logistic regression analysis. Effects are presented for an interquartile range increase in exposure after adjusting for covariates. MEASUREMENTS AND MAIN RESULTS Annual prevalence was 3 to 6% for asthma and 12 to 23% for asthma symptoms. Annual incidence of asthma was 6% at age 1, and 1 to 2% at later ages. PM(2.5) levels were associated with a significant increase in incidence of asthma (odds ratio [OR], 1.28; 95% confidence interval [CI], 1.10-1.49), prevalence of asthma (OR, 1.26; 95% CI, 1.04-1.51), and prevalence of asthma symptoms (OR, 1.15; 95% CI, 1.02-1.28). Findings were similar for NO(2) and soot. Associations were stronger for children who had not moved since birth. Positive associations with hay fever were found in nonmovers only. No associations were found with atopic eczema, allergic sensitization, and bronchial hyperresponsiveness. CONCLUSIONS Exposure to traffic-related air pollution may cause asthma in children.

A summary of the new GINA strategy: a roadmap to asthma control

Over the past 20 years, the Global Initiative for Asthma (GINA) has regularly published and annually updated a global strategy for asthma management and prevention that has formed the basis for many national guidelines. However, uptake of existing guidelines is poor. A major revision of the GINA report was published in 2014, and updated in 2015, reflecting an evolving understanding of heterogeneous airways disease, a broader evidence base, increasing interest in targeted treatment, and evidence about effective implementation approaches. During development of the report, the clinical utility of recommendations and strategies for their practical implementation were considered in parallel with the scientific evidence. This article provides a summary of key changes in the GINA report, and their rationale. The changes include a revised asthma definition; tools for assessing symptom control and risk factors for adverse outcomes; expanded indications for inhaled corticosteroid therapy; a framework for targeted treatment based on phenotype, modifiable risk factors, patient preference, and practical issues; optimisation of medication effectiveness by addressing inhaler technique and adherence; revised recommendations about written asthma action plans; diagnosis and initial treatment of the asthma−chronic obstructive pulmonary disease overlap syndrome; diagnosis in wheezing pre-school children; and updated strategies for adaptation and implementation of GINA recommendations. This paper summarises key changes in the GINA global strategy report, a practical new resource for asthma care http://ow.ly/ObvYi

The Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort study: Design and first results

The Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort study was initiated in 1996. Children born to allergic mothers were enrolled in a double‐blind placebo‐controlled trial for evaluating the use of mite‐impermeable mattress and pillow covers. Children born to allergic and non‐allergic mothers were enrolled in a ‘natural history’ study to assess the role of environmental and dietary risk factors for the development of allergic disease in childhood. Recruitment started by distributing a validated screening questionnaire among >10,000 pregnant women during their first visit to a prenatal health clinic. Allergic mothers‐to‐be were invited to participate in the intervention study. Allergic, and a random sample of non‐allergic, mothers‐to‐be were invited to participate in the ‘natural history’ arm of the study. In the intervention study, homes were visited before birth, 3 months after birth, and 12 months after birth for the collection of dust samples from floors and mattresses. In addition, the homes of about one‐third of the children in the ‘natural history’ part of the study were visited for dust collection when the children were 3 months of age. The intervention study started with 855 participants and the ‘natural history’ study with 3,291 participants. Follow‐up at 3 years of age has now been completed with satisfactory compliance (>90%). A medical investigation and home visit at 4 years of age are nearing completion. Preliminary results show that mite‐allergen levels were lower than found in previous Dutch studies, and that the intervention measure had a significant effect on mite‐allergen levels, without important clinical benefits up to age 2 years old. The allergic families lived in homes with fewer ‘triggers’ such as pets, smoking and carpets than the non‐allergic families, regardless of the intervention. The ongoing PIAMA cohort study will probably reveal useful information concerning effects of allergen load and reduction in the setting of a relatively low mite‐allergen exposure, as well as other variables on the development of allergic manifestions and asthma.

Daily Telemonitoring of Exhaled Nitric Oxide and Symptoms in the Treatment of Childhood Asthma

RATIONALE Asthma treatment might improve when inhaled steroids are titrated on airway inflammation. Fractional exhaled nitric oxide (FeNO0.05), a marker of eosinophilic airway inflammation, can be measured at home. OBJECTIVES We assessed daily FeNO0.05 telemonitoring in the management of childhood asthma. METHODS Children with atopic asthma (n = 151) were randomly assigned to two groups: FeNO0.05 plus symptom monitoring, or monitoring of symptoms only. All patients scored asthma symptoms in an electronic diary over 30 weeks; 77 received a portable nitric oxide (NO) analyzer. Data were transmitted daily to the coordinating centers. Patients were phoned every 3 weeks and their steroid dose was adapted according to FeNO0.05 and symptoms, or according to symptoms. Children were seen at 3, 12, 21, and 30 weeks for examination and lung function testing. The primary end point was the proportion of symptom-free days in the last 12 study weeks. MEASUREMENTS AND MAIN RESULTS Telemonitoring was feasible with reliable FeNO0.05 data for 86% of days, and valid diary entries for 79% of days. Both groups showed an increase in symptom-free days, improvement of FEV1 and quality of life, and a reduction in steroid dose. None of the changes from baseline differed between groups. The difference in symptom-free days over the last 12 weeks was 0.3% (P = 0.95; 95% confidence interval, -10 to 11%). There was a trend for fewer exacerbations in the FeNO0.05 group. CONCLUSIONS Thirty weeks of daily FeNO0.05 and symptom telemonitoring was associated with improved asthma control and a lower steroid dose. We found no added value of daily FeNO0.05 monitoring compared with daily symptom monitoring only.

A Cystic Fibrosis Mutation Associated with Mild Lung Disease

BACKGROUND Cystic fibrosis is the most common lethal autosomal recessive disorder among whites. Among Dutch patients with cystic fibrosis, delta F508 is the most common mutation and A455E the second most common mutation of the cystic fibrosis transmembrane conductance regulator gene on chromosome 7. A455E is associated with preserved pancreatic function and residual secretion of chloride across membranes. We investigated whether it is also associated with less severe pulmonary disease in patients with cystic fibrosis. METHODS A total of 33 patients with compound heterozygosity for the A455E mutation were matched according to age and sex with patients who were homozygous for the delta F508 mutation. The pairs were analyzed with respect to the following outcome variables: age at diagnosis, pulmonary-function values, and the frequency of pseudomonas colonization, pancreatic sufficiency, and diabetes mellitus. RESULTS Cystic fibrosis was diagnosed at a later age in the patients with the A455E mutation than in the delta F508 homozygotes (mean age at diagnosis, 15.0 vs. 3.1 years; P < 0.001). Fewer patients with the A455E mutation had pancreatic insufficiency (21.2 percent vs. 93.9 percent, P < 0.001), and none had diabetes mellitus (0 percent vs. 27.3 percent, P = 0.004). Forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) were significantly higher in the patients with the A455E mutation (mean FEV1, 73.9 percent of the predicted value vs. 54.3 percent of the predicted value; P = 0.002; mean FVC, 88.7 percent of the predicted value vs. 76.3 percent of the predicted value; P = 0.04). Fewer patients with the A455E mutation were colonized with Pseudomonas aeruginosa (33.3 percent vs. 60.6 percent, P = 0.02). CONCLUSIONS A455E is a common mutation causing cystic fibrosis in the Netherlands. Although several mutations are known to be associated with less severe pancreatic disease, our findings demonstrate a correlation between the A455E mutation and mild pulmonary disease. Because mortality in this disease depends primarily on the progression of pulmonary disease, patients with the A455E mutation have a better prognosis than patients who are homozygous for the delta F508 mutation.

Air Pollution Exposure and Lung Function in Children: The ESCAPE Project.

Background: There is evidence for adverse effects of outdoor air pollution on lung function of children. Quantitative summaries of the effects of air pollution on lung function, however, are lacking due to large differences among studies. Objectives: We aimed to study the association between residential exposure to air pollution and lung function in five European birth cohorts with a standardized exposure assessment following a common protocol. Methods: As part of the European Study of Cohorts for Air Pollution Effects (ESCAPE) we analyzed data from birth cohort studies situated in Germany, Sweden, the Netherlands, and the United Kingdom that measured lung function at 6–8 years of age (n = 5,921). Annual average exposure to air pollution [nitrogen oxides (NO2, NOx), mass concentrations of particulate matter with diameters < 2.5, < 10, and 2.5–10 μm (PM2.5, PM10, and PMcoarse), and PM2.5 absorbance] at the birth address and current address was estimated by land-use regression models. Associations of lung function with estimated air pollution levels and traffic indicators were estimated for each cohort using linear regression analysis, and then combined by random effects meta-analysis. Results: Estimated levels of NO2, NOx, PM2.5 absorbance, and PM2.5 at the current address, but not at the birth address, were associated with small decreases in lung function. For example, changes in forced expiratory volume in 1 sec (FEV1) ranged from –0.86% (95% CI: –1.48, –0.24%) for a 20-μg/m3 increase in NOx to –1.77% (95% CI: –3.34, –0.18%) for a 5-μg/m3 increase in PM2.5. Conclusions: Exposure to air pollution may result in reduced lung function in schoolchildren. Citation: Gehring U, Gruzieva O, Agius RM, Beelen R, Custovic A, Cyrys J, Eeftens M, Flexeder C, Fuertes E, Heinrich J, Hoffmann B, de Jongste JC, Kerkhof M, Klümper C, Korek M, Mölter A, Schultz ES, Simpson A, Sugiri D, Svartengren M, von Berg A, Wijga AH, Pershagen G, Brunekreef B. 2013. Air pollution exposure and lung function in children: the ESCAPE project. Environ Health Perspect 121:1357–1364; http://dx.doi.org/10.1289/ehp.1306770

The acquisition of tolerance toward cow's milk through probiotic supplementation: a randomized, controlled trial.

BACKGROUND Cows milk allergy (CMA) is the most frequently diagnosed food allergy in infancy. In general, patients have a good prognosis because the majority acquire tolerance within the first years. Interventions have been proposed to accelerate tolerance and reduce morbidity. Probiotic supplementation could be effective through modulation of the immune system. OBJECTIVE We sought to determine whether supplementation with a combination of probiotics (Lactobacillus casei CRL431 and Bifidobacterium lactis Bb-12) accelerates tolerance to cows milk (CM) in infants with CMA. METHODS We performed a double-blind, randomized, placebo-controlled trial in 119 infants with CMA. Infants received CRL431 and Bb-12 supplemented to their standard treatment of extensively hydrolyzed formula for 12 months. Primary outcome was clinical tolerance to CM at 6 and 12 months of treatment. Furthermore, we analyzed T- and B-lymphocyte subsets (CD3(+), CD3(+)CD4(+), CD3(+)CD8(+), and CD20(+)) in peripheral blood at randomization and at 12 months with flow cytometry and examined the presence of viable probiotic strains in fecal samples. RESULTS The cumulative percentage of tolerance to CM at 6 and 12 months was similar in both groups: 56 (77%) in the probiotics group versus 54 (81%) in the placebo group. Infants in the placebo group had higher percentages of CD3(+) and CD3(+)CD4(+) lymphocytes compared with those seen in probiotic-treated infants. Probiotic intake was confirmed because probiotics were isolated from feces more often in treated infants than in the placebo group. CONCLUSION Supplementation of CRL431 and Bb-12 to extensively hydrolyzed formula does not accelerate CM tolerance in infants with CMA.

Maternal Food Consumption during Pregnancy and the Longitudinal Development of Childhood Asthma

RATIONALE Maternal diet during pregnancy has the potential to affect airway development and to promote T-helper-2-cell responses during fetal life. This might increase the risk of developing childhood asthma or allergy. OBJECTIVES We investigated the influence of maternal food consumption during pregnancy on childhood asthma outcomes from 1 to 8 years of age. METHODS A birth cohort study consisting of a baseline of 4,146 pregnant women (1,327 atopic and 2,819 nonatopic). These women were asked about their frequency of consumption of fruit, vegetables, fish, egg, milk, milk products, nuts, and nut products during the last month. Their children were followed until 8 years of age. Longitudinal analyses were conducted to assess associations between maternal diet during pregnancy and childhood asthma outcomes over 8 years. MEASUREMENTS AND MAIN RESULTS Complete data were obtained for 2,832 children. There were no associations between maternal vegetable, fish, egg, milk or milk products, and nut consumption and longitudinal childhood outcomes. Daily consumption of nut products increased the risk of childhood wheeze (odds ratio [OR] daily versus rare consumption, 1.42; 95% confidence interval [95% CI], 1.06-1.89), dyspnea (OR, 1.58; 95% CI, 1.16-2.15), steroid use (OR, 1.62; 95% CI, 1.06-2.46), and asthma symptoms (OR, 1.47; 95% CI, 1.08-1.99). CONCLUSIONS Results of this study indicate an increased risk of daily versus rare consumption of nut products during pregnancy on childhood asthma outcomes. These findings need to be replicated by other studies before dietary advice can be given to pregnant women.

The Generation R Study: Biobank update 2015

The Generation R Study is a population-based prospective cohort study from fetal life until adulthood. The study is designed to identify early environmental and genetic causes and causal pathways leading to normal and abnormal growth, development and health from fetal life, childhood and young adulthood. In total, 9,778 mothers were enrolled in the study. Data collection in children and their parents include questionnaires, interviews, detailed physical and ultrasound examinations, behavioural observations, Magnetic Resonance Imaging and biological samples. Efforts have been conducted for collecting biological samples including blood, hair, faeces, nasal swabs, saliva and urine samples and generating genomics data on DNA, RNA and microbiome. In this paper, we give an update of the collection, processing and storage of these biological samples and available measures. Together with detailed phenotype measurements, these biological samples provide a unique resource for epidemiological studies focused on environmental exposures, genetic and genomic determinants and their interactions in relation to growth, health and development from fetal life onwards.