Lee Koh

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 Consent was withdrawn for 12 (1%) children.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.

Cigarette smoke and platelet-activating factor receptor dependent adhesion of Streptococcus pneumoniae to lower airway cells

Background Exposure to cigarette smoke (CS) is associated with increased risk of pneumococcal infection. The mechanism for this association is unknown. We recently reported that the particulate matter from urban air simulates platelet-activating factor receptor (PAFR)-dependent adhesion of pneumococci to airway cells. We therefore sought to determine whether CS stimulates pneumococcal adhesion to airway cells. Methods Human alveolar (A549), bronchial (BEAS2-B), and primary bronchial epithelial cells (HBEpC) were exposed to CS extract (CSE), and adhesion of Streptococcus pneumoniae determined. The role of PAFR in mediating adhesion was determined using a blocker (CV-3988). PAFR transcript level was assessed by quantitative real-time PCR, and PAFR expression by flow cytometry. Lung PAFR transcript level was assessed in mice exposed to CS, and bronchial epithelial PAFR expression assessed in active-smokers by immunostaining. Results In A549 cells, CSE 1% increased pneumococcal adhesion (p<0.05 vs control), PAFR transcript level (p<0.01), and PAFR expression (p<0.01). Pneumococcal adhesion to A549 cells was attenuated by CV-3988 (p<0.001). CSE 1% stimulated pneumococcal adhesion to BEAS2-B cells and HBEpC (p<0.01 vs control). CSE 1% increased PAFR expression in BEAS2-B (p<0.01), and in HBEpC (p<0.05). Lung PAFR transcript level was increased in mice exposed to CS in vivo (p<0.05 vs room air). Active smokers (n=16) had an increased percentage of bronchial epithelium with PAFR-positive cells (p<0.05 vs never smokers, n=11). Conclusion CSE stimulates PAFR-dependent pneumococcal adhesion to lower airway epithelial cells. We found evidence that CS increases bronchial PAFR in vivo.

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.

Air pollution, ethnicity and telomere length in east London schoolchildren: An observational study.

BACKGROUND Short telomeres are associated with chronic disease and early mortality. Recent studies in adults suggest an association between telomere length and exposure to particulate matter, and that ethnicity may modify the relationship. However associations in children are unknown. OBJECTIVES We examined associations between air pollution and telomere length in an ethnically diverse group of children exposed to high levels of traffic derived pollutants, particularly diesel exhaust, and to environmental tobacco smoke. METHODS Oral DNA from 333 children (8-9years) participating in a study on air quality and respiratory health in 23 inner city London schools was analysed for relative telomere length using monochrome multiplex qPCR. Annual, weekly and daily exposures to nitrogen oxides and particulate matter were obtained from urban dispersion models (2008-10) and tobacco smoke by urinary cotinine. Ethnicity was assessed by self-report and continental ancestry by analysis of 28 random genomic markers. We used linear mixed effects models to examine associations with telomere length. RESULTS Telomere length increased with increasing annual exposure to NOx (model coefficient 0.003, [0.001, 0.005], p<0.001), NO2 (0.009 [0.004, 0.015], p<0.001), PM2.5 (0.041, [0.020, 0.063], p<0.001) and PM10 (0.096, [0.044, 0.149], p<0.001). There was no association with environmental tobacco smoke. Telomere length was increased in children reporting black ethnicity (22% [95% CI 10%, 36%], p<0.001) CONCLUSIONS: Pollution exposure is associated with longer telomeres in children and genetic ancestry is an important determinant of telomere length. Further studies should investigate both short and long-term associations between pollutant exposure and telomeres in childhood and assess underlying mechanisms.

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