Rossa Brugha

Intermittent montelukast in children aged 10 months to 5 years with wheeze (WAIT trial): a multicentre, randomised, placebo-controlled trial

Summary Background The effectiveness of intermittent montelukast for wheeze in young children is unclear. We aimed to assess whether intermittent montelukast is better than placebo for treatment of wheeze in this age group. Because copy numbers of the Sp1-binding motif in the arachidonate 5-lipoxygenase (ALOX5) gene promoter (either 5/5, 5/x, or x/x, where x does not equal 5) modifies response to montelukast in adults, we stratified by this genotype. Methods We did this multicentre, parallel-group, randomised, placebo-controlled trial between Oct 1, 2010, and Dec 20, 2013, at 21 primary care sites and 41 secondary care sites in England and Scotland. Children aged 10 months to 5 years with two or more wheeze episodes were allocated to either a 5/5 or 5/x+x/x ALOX5 promoter genotype stratum, then randomly assigned (1:1) via a permuted block schedule (size ten), to receive intermittent montelukast or placebo given by parents at each wheeze episode over a 12 month period. Clinical investigators and parents were masked to treatment group and genotype strata. The primary outcome was number of unscheduled medical attendances for wheezing episodes. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01142505. Findings We randomly assigned 1358 children to receive montelukast (n=669) or placebo (n=677). Consent was withdrawn for 12 (1%) children. Primary outcome data were available for 1308 (96%) children. There was no difference in unscheduled medical attendances for wheezing episodes between children in the montelukast and placebo groups (mean 2·0 [SD 2·6] vs 2·3 [2·7]; incidence rate ratio [IRR] 0·88, 95% CI: 0·77–1·01; p=0·06). Compared with placebo, unscheduled medical attendances for wheezing episodes were reduced in children given montelukast in the 5/5 stratum (2·0 [2·7] vs 2·4 [3·0]; IRR 0·80, 95% CI 0·68–0·95; p=0·01), but not in those in the 5/x+x/x stratum (2·0 [2·5] vs 2·0 [2·3]; 1·03, 0·83–1·29; p=0·79, pinteraction=0·08). We recorded one serious adverse event, which was a skin reaction in a child allocated to placebo. Interpretation Our findings show no clear benefit of intermittent montelukast in young children with wheeze. However, the 5/5 ALOX5 promoter genotype might identify a montelukast-responsive subgroup. Funding Medical Research Council (UK) and National Institute for Health Research.

Urban Air Pollution and Respiratory Infections

Public awareness of the impact of air quality on health is increasing worldwide. Indoor and outdoor air pollutants impair childrens growing lungs, and increase the risk of respiratory infections. In many cities, children face indoor air pollution from fuels used for cooking and heating, as well as outdoor pollution from vehicle exhausts. Research identifies at-risk groups and seeks to establish biological plausibility for the associations already observed; and looks towards identifying the harmful pollutants that are responsible for respiratory morbidity and mortality. These findings may then serve to influence public debate and future policy at national and international level to improve air quality in cities, and improve childrens health.

Carbon in airway macrophages from children with asthma

Background Airway macrophage (AM) phagocytosis is impaired in severe asthma. Prostaglandin (PG) E2 and D2 are increased in severe asthma and suppress AM phagocytic function in vitro. In this study, we sought evidence for PG-mediated impairment of phagocytosis of inhalable carbonaceous particulate matter (PM) by AM in children with severe asthma compared with mild asthmatics and healthy controls. Methods AM were obtained from children with asthma and healthy controls using induced sputum. AM carbon area (μm2) was assessed by image analysis. In a subgroup of asthmatics, urinary PGE2 and PGD2 metabolites were measured by high-performance liquid chromatography, and PM exposure at the home address was modelled. Phagocytosis of PM by human monocyte-derived macrophages and rat AM was assessed in vitro by image analysis. Results AM carbon was 51% lower in children with moderate-to-severe asthma (n=36) compared with mild asthmatics (n=12, p<0.01) and healthy controls (n=47, p<0.01). There was no association between modelled PM exposure and AM carbon in 33 asthmatics who had a urine sample, but there was an inverse association between AM carbon and urinary metabolites of PGE2 and D2 (n=33, rs=−0.40, p<0.05, and rs=−0.44, p<0.01). PGE2 10−6 M, but not PGD2 10−6 M, suppressed phagocytosis of PM10 by human macrophages in vitro (p<0.05 vs control). PGE2 10−6 M also suppressed phagocytosis of PM10 by rat AM in vitro (p<0.01 vs control). Conclusions Phagocytosis of inhaled carbonaceous PM by AMs is impaired in severe asthma. PGE2 may contribute to impaired AM phagocytic function in severe asthma.

Respiratory tract dendritic cells in paediatric asthma.

Airway dendritic cells (DC) are critical mediators of lung inflammation in asthma, but the characteristics of DC in the airways of healthy children, and children with asthma, are currently unknown.

Genitopatellar syndrome: a further case.

Departments of General Paediatrics, Paediatric Neurology, Paediatric Endocrinology, Chelsea and Westminster Hospital, London and North West Thames Regional Genetics Service, NWLH NHS Trust, Harrow, UK Correspondence to Dr Sue E. Holder, North West Thames Regional Genetics Service, NWLH NHS Trust, Watford Road, Harrow HA1 3UJ, UK Tel: + 44 20 8869 2796; fax: + 44 20 8869 3106; e-mail: s.holder@imperial.ac.uk

Alveolar macrophages carbon load: a marker of exposure?

To the Editor: In the editorial accompanying our article reporting higher alveolar macrophage carbon in adults who cycled to work in London, Ackermann-Liebrich 1 speculated that “very short, high peaks of exposure contribute more to total load of inhaled pollutants and, thus, we ought to control not only the mean pollutant levels but avoid higher peaks.” In our initial analyses, we found no …

Urinary prostanoids in preschool wheeze

Acute episodes of wheeze in children of preschool age are frequently triggered by viral upper respiratory tract infections and result in a significant burden to health services [1]. However, to date, the inflammatory mechanisms underlying preschool wheeze remain unclear. Mediators that have not been studied in preschool wheeze, but are implicated in the pathogenesis of wheeze in adults with asthma, include the pro-inflammatory prostanoid prostaglandin D2 (PGD2) [2] and the anti-inflammatory prostanoid PGE2 [3, 4]. In this study, we sought evidence for either increased PGD2 biosynthesis or reduced PGE2 biosynthesis, or a combination of both in children with preschool wheeze. To achieve this, we measured the major metabolites of PGD2 and PGE2 in the urine: 9α-hydroxy-11,15-dioxo-2,3,4,5-tetranor-prostan-1,20-dioic acid (tetranor-PGDM) and 9,15-dioxo-11α-hydroxy-13,14-dihydro-2,3,4,5-tetranor-prostan-1,20-dioic acid (tetranor-PGEM), respectively [5, 6]. Tetranor PGDM, a urinary metabolite of prostaglandin D2, is increased in children with preschool wheeze http://ow.ly/Ynjy305ZY9L

DNA methylation profiles between airway epithelium and proxy tissues in children

Epidemiological studies of deoxyribonucleic acid (DNA) methylation in airway disease have largely been conducted using blood or buccal samples. However, given tissue specificity of DNA methylation, these surrogate tissues may not allow reliable inferences about methylation in the lung. We sought to compare the pattern of DNA methylation in blood, buccal and nasal epithelial cells to that in airway epithelial cells from children.

Phagocytosis of fossil fuel particulates by macrophages in children with asthma

Abstract Background Airway macrophages clear inhaled soot (black carbon) from traffic fumes. Macrophages from children with asthma have impaired phagocytosis of bacteria, and prostaglandin E2 (PGE2) is associated with impaired phagocytosis by macrophages. We sought to assess whether macrophage phagocytosis of soot was impaired, and to measure prostanoid metabolites, in children with asthma. Methods In this cross-sectional study, airway macrophages were obtained from 72 children aged 7–14 years by sputum induction with nebulised 4·5% saline. Children were classified as: healthy controls (n=39); mild asthma, defined as British Thoracic Society (BTS) step 1–2 (n=13); or moderate-to-severe asthma (BTS step 3–5) (n=20), and recruited from a UK paediatric outpatient clinic. Healthy controls were recruited as part of the London Low Emission Zone study. Macrophage black carbon was assessed with image analysis by an assessor masked to asthma severity. Exposure to air pollution was calculated by means of the London Air Quality Toolkit. Urinary PGE2 metabolites were measured with high performance liquid chromatography-tandem mass spectrometry. The effect of PGE2 on phagocytosis of black carbon by rat airway macrophages was assessed with an in-vitro phagocytosis assay using urban particulate matter collected from air filters placed at city centre sites in Leicester, UK. Written informed consent was obtained from children and parents (Research Ethics Committee reference 11-LO-1732 and 08/H0704/139). Findings Children with moderate-to-severe asthma had lower airway macrophage black carbon than did controls (median 0·19 mm 2 [IQR 0·11–0·26] vs 0·35 [0·16–0·49], p U test). Airway macrophage black carbon in children with mild asthma was much the same as in controls. Air pollution exposure at the home address did not differ between groups. Moderate to severe asthma was associated with an increase in the urinary PGE2 metabolite, 13,14-dihydro-15-keto-tetranor-PGE2 (median 668 pg/mg creatinine [IQR 293–937] vs 471 [315–623], p U test). In the 33 children with asthma, this urinary PGE2 metabolite was inversely associated with macrophage carbon (Spearman r =−0·47, p Interpretation Macrophage phagocytosis of black carbon derived from fossil fuel is impaired in moderate-to-severe childhood asthma. This process is associated with raised urinary concentrations of 13,14-dihydro-15-keto-tetranor-PGE2. PGE2 also impairs phagocytosis of black carbon and urban particulate matter by rat airway macrophages in vitro, and is therefore a plausible mediator underlying the impaired phagocytosis seen in macrophages from children with asthma. We now aim to replicate these findings in differentiated human macrophages and to establish airway concentrations of PGE2 from exhaled breath condensate samples taken from these children. Our results suggest a possible mechanism underlying the observation that traffic-derived air pollution adversely affects children with asthma, because they may be less able to clear inhaled particles effectively. Funding Barts and The London Charity.

G95 Particulate air pollution exposure using modes of urban transport

Aims/background Particulate air pollution from fossil fuel combustion is associated with impaired lung growth. In highly polluted cities there may be a health benefit in avoiding high particulate exposures. We sought to measure which modes of urban transport result in the lowest exposure of black carbon (soot) exposure to individuals. Method An aethalometer (MicroAeth AE51) was used to measure black carbon (BC) mass per minute. A standard route was devised between Whitechapel and Westminster using different modes of transport (walking, bus and underground railway). Total exposure (ng per m3/min) and exposure “peaks” (events exceeding 10000 ng per m3/min) were calculated for each mode of transport. Results were compared by Mann-Whitney U test. Results Total BC exposure is highest on the underground (16020 (12647–27451) ng per m3/min, median (IQR)) relative to walking (4053 (2980–6825) ng per m3/min) and buses (5466 (4497–6184) ng per m3/min, *p = 0.02, Kruskal Wallis test with Dunn’s multiple comparisons, Figure 1). There was no significant difference in mean BC exposure between walking and bus use. Number of exposure “peaks” was significantly higher on the underground compared to bus, with median 23 (15–36) peaks vs 2 (0.25–4.5), and 35 (6–45) for walking (p < 0.05 underground vs bus, Kruskal Wallis test with Dunn’s multiple comparisons, n = 4 journeys on each mode of transport). Abstract G95 Figure 1 Results of Kruskal Wallis test with Dunns multiple comparisons. Conclusion Particulate exposures are highest on underground transport in comparison to buses or walking on this route. Exposures to high peaks of black carbon are decreased while on a bus. Children and families may wish to take particulate exposure into account when planning how to move around highly polluted urban environments. The particles in overground air are well characterised but work is needed on the origin and health effects on growing lungs of black particles in the underground.