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Over the past year, studies into virus-induced wheeze in children have shifted towards investigations that examine the mechanisms by which respiratory viruses cause wheeze and an increase in studies examining the effects of novel interventions to reduce wheezing exacerbations. Studies on rhinovirus species (RV)-C infection have found that this is associated with a decrease in expression of CDHR3, the cellular receptor specific for this virus, and a decrease in interferon-β expression, both of which are likely to favour RV-C infection. Recent clinical trials in children have found a decrease in wheezing exacerbations with both anti-respiratory syncytial virus antibody and anti-immunoglobulin E antibody therapy, and a clinical trial of prednisolone in children with their first RV-induced wheeze showed that only those with an RV viral count >7000 copies·mL -1 responded. Further studies on the effects of bacterial lysates on immune system function continue to support the potential of this approach to reduce virus-induced wheezing exacerbations in children. These studies and many previous investigations into immunomodulation using bacterial lysates have led to the funding and commencement of a large study in which long-term administration of a bacterial lysate in young children will be assessed for its ability to prevent asthma., Competing Interests: Conflict of interest: None declared., (Copyright ©ERS 2018.)

Human rhinovirus (HRV) infections are now widely accepted as the commonest cause of acute respiratory illnesses (ARIs) in children. Advanced PCR techniques have enabled HRV infections to be identified as causative agents in most common ARIs in childhood including bronchiolitis, acute asthma, pneumonia and croup. However, the long-term implications of rhinovirus infections are less clear. The aim of this review is to examine the relationship between rhinovirus infections and disorders of the lower airways in childhood., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The aim of the present study was to measure airway, oropharyngeal and gastrointestinal deposition of (99m)Tc-labelled hydrofluoroalkane-beclomethasone dipropionate after inhalation via a pressurised metered-dose inhaler and spacer (Aerochamber Plus) in asthmatic children. A group of 24 children (aged 5-17 yrs) with mild asthma inhaled the labelled drug. A total of 12 children took five tidal breaths after each actuation (tidal group). The other 12 children used a slow maximal inhalation followed by a 5 - 10-s breath-hold (breath-hold group). Simultaneous anterior and posterior planar gamma-scintigraphic scans (120-s acquisition) were recorded. For the tidal group, mean+/-sd lung deposition (% ex-actuator, attenuation corrected) was 35.4+/-18.3, 47.5+/-13.0 and 54.9+/-11.2 in patients aged 5-7 (n = 4), 8-10 (n = 4) and 11-17 yrs (n = 4), respectively. Oropharyngeal and gastrointestinal deposition was 24.0+/-10.5, 10.3+/-4.4 and 10.1+/-6.2. With the breath-hold technique, lung deposition was 58.1+/-6.7, 56.6+/-5.2 and 58.4+/-9.2. Oropharyngeal and gastrointestinal deposition was 12.9+/-3.2, 20.1+/-9.5 and 20.8+/-8.8. Inhalation of the extrafine formulation with the breath-hold technique showed significantly improved lung deposition compared with tidal breathing across all ages. Oropharyngeal and gastrointestinal deposition was markedly decreased, regardless of which inhalation technique was applied, compared with a previous paediatric study using the same formulation delivered via a breath-actuated metered-dose inhaler.

Background: We have previously reported a relationship between increased airway responsiveness (AR) in infancy and reduced childhood lung function., Objective: The current study aimed to determine whether the Arg16Gly polymorphism of the beta2 adrenoceptor (beta2AR) gene was important to this relationship., Methods: A cohort that initially numbered 253 individuals underwent assessments of AR and lung function aged 1 month, 6 and 11 years; genotyping for polymorphisms of the beta(2)AR was performed., Results: At 1 month of age, the genotype homozygous Arg16 (n=24) was associated with a mean increase in log dose-response slope (AR) of 0.27 [95% confidence interval (CI) 0.07, 0.49] compared with the genotype homozygous Gly16 (n=58), P=0.01. At 11 years of age, the genotype homozygous Arg16 (n=35) was associated with a mean reduction in the percentage of forced expiratory volume in 1 s of 5.3% [95% CI 0.3, 10.2] compared with the genotype homozygous Gly16 (n=65), P=0.03. There was no association between the Arg16Gly polymorphism and atopy or diagnosed asthma. However, nine of 69 individuals with the genotype homozygous Gly16 were admitted to hospital with asthma compared with five out of 111 individuals with the remaining genotypes (P<0.05)., Conclusion: The Arg16Gly polymorphism may be important to the association between increased AR in infancy and reduced lung function in childhood and may also be a determinant of asthma severity in children but not asthma per se.

Background and Aims: We have previously shown an association between reduced premorbid lung function (V'maxFRC) and bronchiolitis. We hypothesised that individuals with bronchiolitis will go on to have reduced lung function and increased respiratory symptoms in childhood., Methods: V'maxFRC was measured at 1 month of age; individuals with bronchiolitis were prospectively identified. Annual symptom questionnaires were completed from 3 to 6 years. At 11 years of age, children underwent an assessment including questionnaire, lung function, airway response to histamine (AR), and skin prick testing., Results: Eighteen individuals with bronchiolitis were ascertained from 253 cohort members. Children with bronchiolitis had increased viral induced wheeze at 3 (OR 5.8, 95% CI 1.4 to 25.2; n = 103) and 5 years (OR 5.3, 95% CI 1.1 to 25.5; n = 101). At 11 years of age, 194 children were assessed including 16 with past bronchiolitis. These 16 individuals had reduced mean z scores for % V'maxFRC compared with other children (-0.56 and 0.06 respectively) and mean z scores for % FEF(25-75) at 11 years (-0.53 and 0.06 respectively). At 11 years, FEV(1), FVC PEF, AR, atopy, wheeze, and diagnosed asthma were not different between groups., Conclusions: Reduced lung function is present before and after bronchiolitis; the level of reduction is comparable. The mechanism for wheeze and reduced lung function after bronchiolitis appears to be related to premorbid lung function and not bronchiolitis per se.

Over the last half of the last century, classic studies established many features of the development of the lung in humans. Early studies relied on meticulous measurement and evaluation of lung morphology and physiology. In recent years, such studies have been supplemented by carefully conducted, longitudinal studies and by the use of molecular biological methodologies to determine more detailed aspects of lung development. In addition, factors affecting the growth of the lung have been evaluated including preterm delivery, antenatal steroids, environmental factors, asthma and asthma medications. In the future, further advances are likely to come from the molecular biological approach.

Infants who wheeze are likely to have narrowed or overly compliant airways rather than atopy. After around 3 years of age, airway responsiveness and atopy are associated with the development of wheeze and the diagnosis of asthma. Anti- or proinflammatory genes are likely to be responsible for at least part of the predisposition to wheeze seen in older children, but further studies are needed to clarify this situation.

For a physician to understand how to prescribe appropriate doses of drugs via aerosol requires a basic understanding of the technical issues involved. Drugs are usually prescribed in terms of "nominal dose" (total dose of drug prescribed). This dose is device-specific, as recommended doses are different for different devices. The effective component of the nominal dose is the "lung dose", which is the mass of drug delivered to the lung. A given clinical effect should, in general, be produced by a given lung dose irrespective of the delivery device. However, the effect of a lung dose depends on several factors, including: 1) site of deposition 2) rate of clearance of the drug from airway 3) site of action of the drug. Confirmation that a particular lung dose will produce a desired clinical effect usually requires that a clinical trial be performed. The lung dose should be reflected by data on lung deposition, but interpreting such data requires that the following are considered: 1) Lung deposition figures can be stated in different ways: a) percentage of the nominal dose b) percentage of the mass of drug leaving the aerosol-generating device c) percentage of the mass of drug entering the mouth or nose. 2) The radiation from an inhaled aerosol is attenuated as it leaves the lung. Approaches vary as to how this correction is done, affecting the quoted data on percent deposition. 3) In children, lung deposition is age-dependent, but the effect of age on delivery is different for different devices. There are major differences in the efficiency of delivery for different devices with a range of 6-60%. When "adaptive aerosol delivery" nebulizers become available, they should provide an accurate dose of drug to the lung with very low variability. In summary, the concept of lung dose is useful in understanding the related technical aspects, and it has the potential to allow drugs to be prescribed more accurately.

Drug delivery to patients using dry powder inhalers, such as the Turbuhaler, is believed to be influenced by the inspiratory flow used. Clinical studies have indicated that this delivery system can be used effectively by children. However, it is not known how the total and weight-corrected dose delivered to the airways varies with age. A deposition study using technetium-99m (99mTc)-labelled budesonide was performed in order to determine the effect of age on delivery. Twenty one children with cystic fibrosis, aged 4-16 yrs, were recruited. They were clinically stable with normal lung function. Initially, a gamma camera scan was taken in front of a flood source containing 37 MBq of 99mTc. Subsequently, subjects inhaled through a low resistance inspiratory filter connected to a commercially available Turbuhaler. Immediately afterwards they inhaled from a noncommercial Turbuhaler containing budesonide labelled with 99mTc, and then underwent anterior and posterior gamma camera scans. Both Turbuhaler inhalers were attached to a portable spirometer and the peak inspiratory flow through the Turbuhaler was recorded for each inhalation. The total body dose was calculated from the dose deposited on the inspiratory filter connected to the commercial Turbuhaler. Analysis of the gamma camera images provided information on the proportion of the radiolabel delivered to the lungs compared to that deposited in the upper airway and stomach. As expected, a highly significant positive correlation was noted between the peak inspiratory flow generated by the patient through the Turbuhaler and the dose delivered to the lung. Similarly, there was a highly significant positive correlation between age and "total lung dose". However, when total lung dose was corrected for body weight, there was a nonsignificant negative correlation with age. This study suggests that the "weight-corrected lung dose" achieved when children aged > 6 yrs use the Turbuhaler, is largely independent of age. It would appear that the flow-dependent properties of this device are such that the reduced peak inspiratory flow generated by younger children results in a lower dose to the lungs, but that this is off-set by their lower body weight. This is unlikely to be a property of other devices with different flow/drug delivery characteristics.

An inflatable cuff was used to generate partial forced expiratory flow-volume (FEFV) curves in 36 infants with and without obstructive airway disease. Curves were recorded in each infant over a range of compression pressures as high as and exceeding the pressure required for the maximal partial FEFV curve. The maximal curves were quantitated and compared with passive compliance and conductance of the respiratory system and absolute lung volume measured by whole-body plethysmography. In some infants, the transmission of pressure between cuff and pleural space was determined. Partial FEFV curve shapes generated with a standardized compression pressure calculated from the transmission of pressure data to give an increase in pleural pressure at FRC of 10 cm H2O were compared between infants. For these standardized compressions, infants with convex curves tended to have better respiratory function than did those with concave curves. The combination of a concave curve and flow limitation during tidal expiration was associated with the worst function. Two parameters, the ratio of forced maximal expiratory flow (measured from the maximal partial FEFV curve) to tidal expiratory flow (measured from the expiratory flow-volume curve of tidal breathing) at midtidal volume (Vm1d(forced/tidal] and the minimal compression pressure required to generate maximal expiratory flow at FRC (Pmin), satisfactorily quantified respiratory function without the need for size correction with absolute lung volume. In addition, Vm1d(forced/tidal) provides an index of expiratory flow reserve. We conclude that useful information can be provided from the shape of a partial FEFV curve in an infant, provided that curves are generated by a standardized compression pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Population-based birth cohorts on asthma and allergies increasingly provide new insights into the development and natural history of the diseases. Over 130 birth cohorts focusing on asthma and allergy have been initiated in the last 30 years. A NIAID (National Institute of Allergy and Infectious Diseases), NHLBI (National Heart Lung and Blood Institute), MeDALL (Mechanisms of the Development of Allergy, Framework Programme 7 of the European Commission) joint workshop was held in Bethesda, MD, USA September 11–12, 2012 with 3 objectives (1) documenting the knowledge that asthma/allergy birth cohorts have provided, (2) identifying the knowledge gaps and inconsistencies and (3) developing strategies for moving forward, including potential new study designs and the harmonization of existing asthma birth cohort data. The meeting was organized around the presentations of 5 distinct workgroups: (1) clinical phenotypes, (2) risk factors, (3) immune development of asthma and allergy, (4) pulmonary development and (5) harmonization of existing birth cohorts. This manuscript presents the workgroup reports and provides web links (AsthmaBirthCohorts.niaid.nih.gov or www.medall-fp7.eu) where the reader will find tables describing the characteristics of the birth cohorts included in this report, type of data collected at differing ages, and a selected bibliography provided by the participating birth cohorts.