Jonathan Grigg

Definition, assessment and treatment of wheezing disorders in preschool children: an evidence-based approach

There is poor agreement on definitions of different phenotypes of preschool wheezing disorders. The present Task Force proposes to use the terms episodic (viral) wheeze to describe children who wheeze intermittently and are well between episodes, and multiple-trigger wheeze for children who wheeze both during and outside discrete episodes. Investigations are only needed when in doubt about the diagnosis. Based on the limited evidence available, inhaled short-acting β2-agonists by metered-dose inhaler/spacer combination are recommended for symptomatic relief. Educating parents regarding causative factors and treatment is useful. Exposure to tobacco smoke should be avoided; allergen avoidance may be considered when sensitisation has been established. Maintenance treatment with inhaled corticosteroids is recommended for multiple-trigger wheeze; benefits are often small. Montelukast is recommended for the treatment of episodic (viral) wheeze and can be started when symptoms of a viral cold develop. Given the large overlap in phenotypes, and the fact that patients can move from one phenotype to another, inhaled corticosteroids and montelukast may be considered on a trial basis in almost any preschool child with recurrent wheeze, but should be discontinued if there is no clear clinical benefit. Large well-designed randomised controlled trials with clear descriptions of patients are needed to improve the present recommendations on the treatment of these common syndromes.

Oral Prednisolone for Preschool Children with Acute Virus-Induced Wheezing

BACKGROUND Attacks of wheezing induced by upper respiratory viral infections are common in preschool children between the ages of 10 months and 6 years. A short course of oral prednisolone is widely used to treat preschool children with wheezing who present to a hospital, but there is conflicting evidence regarding its efficacy in this age group. METHODS We conducted a randomized, double-blind, placebo-controlled trial comparing a 5-day course of oral prednisolone (10 mg once a day for children 10 to 24 months of age and 20 mg once a day for older children) with placebo in 700 children between the ages of 10 months and 60 months. The children presented to three hospitals in England with an attack of wheezing associated with a viral infection; 687 children were included in the intention-to-treat analysis (343 in the prednisolone group and 344 in the placebo group). The primary outcome was the duration of hospitalization. Secondary outcomes were the score on the Preschool Respiratory Assessment Measure, albuterol use, and a 7-day symptom score. RESULTS There was no significant difference in the duration of hospitalization between the placebo group and the prednisolone group (13.9 hours vs. 11.0 hours; ratio of geometric means, 0.90; 95% confidence interval, 0.77 to 1.05) or in the interval between hospital admission and signoff for discharge by a physician. In addition, there was no significant difference between the two study groups for any of the secondary outcomes or for the number of adverse events. CONCLUSIONS In preschool children presenting to a hospital with mild-to-moderate wheezing associated with a viral infection, oral prednisolone was not superior to placebo. (Current Controlled Trials number, ISRCTN58363576.)

Respiratory risks from household air pollution in low and middle income countries

A third of the worlds population uses solid fuel derived from plant material (biomass) or coal for cooking, heating, or lighting. These fuels are smoky, often used in an open fire or simple stove with incomplete combustion, and result in a large amount of household air pollution when smoke is poorly vented. Air pollution is the biggest environmental cause of death worldwide, with household air pollution accounting for about 3·5-4 million deaths every year. Women and children living in severe poverty have the greatest exposures to household air pollution. In this Commission, we review evidence for the association between household air pollution and respiratory infections, respiratory tract cancers, and chronic lung diseases. Respiratory infections (comprising both upper and lower respiratory tract infections with viruses, bacteria, and mycobacteria) have all been associated with exposure to household air pollution. Respiratory tract cancers, including both nasopharyngeal cancer and lung cancer, are strongly associated with pollution from coal burning and further data are needed about other solid fuels. Chronic lung diseases, including chronic obstructive pulmonary disease and bronchiectasis in women, are associated with solid fuel use for cooking, and the damaging effects of exposure to household air pollution in early life on lung development are yet to be fully described. We also review appropriate ways to measure exposure to household air pollution, as well as study design issues and potential effective interventions to prevent these disease burdens. Measurement of household air pollution needs individual, rather than fixed in place, monitoring because exposure varies by age, gender, location, and household role. Women and children are particularly susceptible to the toxic effects of pollution and are exposed to the highest concentrations. Interventions should target these high-risk groups and be of sufficient quality to make the air clean. To make clean energy available to all people is the long-term goal, with an intermediate solution being to make available energy that is clean enough to have a health impact.

Efficacy of a short course of parent-initiated oral prednisolone for viral wheeze in children aged 1-5 years: randomised controlled trial.

BACKGROUND Episodic wheeze triggered by viral colds is common in children aged between 1 and 5 years (preschool viral wheeze). Most affected children are asymptomatic by age 6 years. Persistence of wheeze is associated with above-average systemic eosinophil priming. Use of parental-initiated oral prednisolone is recommended at the first sign of preschool viral wheeze. However, evidence for this treatment strategy is conflicting. We therefore aimed to assess the efficacy of a short course of oral prednisolone for preschool viral wheeze, with stratification for systemic eosinophil priming. METHODS Children aged 1-5 years admitted to hospital with viral wheeze were allocated to either a high-primed or low-primed stratum according to amounts of serum eosinophil cationic protein and eosinophil protein X, and randomised to parent-initiated prednisolone (20 mg one daily for 5 days) or placebo for the next episode. The primary outcomes were the 7-day mean daytime and night-time respiratory symptom scores, which were analysed by mean differences between treatment groups. FINDINGS 108 children were randomised to placebo and 109 to prednisolone. Outcome data were available for 120 (78%) of 153 children who had a further episode of viral wheeze, of whom 51 received prednisolone and 69 placebo. Mean daytime (difference in means -0.01 [-0.22 to 0.20]) and night-time (0.10 [-0.12 to 0.32]) respiratory symptom scores and need for hospital admission did not differ between treatment groups. Within the high-primed (n=59) and low-primed (n=61) strata there was no difference in primary outcome between treatment groups. INTERPRETATION There is no clear benefit of a short course of parent-initiated oral prednisolone for viral wheeze in children aged 1-5 years even in those with above-average eosinophil priming.

Locally generated particulate pollution and respiratory symptoms in young children

Background: Particulate matter <10 μm (PM10) from fossil fuel combustion is associated with an increased prevalence of respiratory symptoms in children and adolescents. However, the effect of PM10 on respiratory symptoms in young children is unclear. Methods: The association between primary PM10 (particles directly emitted from local sources) and the prevalence and incidence of respiratory symptoms was studied in a random sample cohort of 4400 Leicestershire children aged 1–5 years surveyed in 1998 and again in 2001. Annual exposure to primary PM10 was calculated for the home address using the Airviro dispersion model and adjusted odds ratios (ORS) and 95% confidence intervals were calculated for each μg/m3 increase. Results: Exposure to primary PM10 was associated with the prevalence of cough without a cold in both 1998 and 2001, with adjusted ORs of 1.21 (1.07 to 1.38) and 1.56 (1.32 to 1.84) respectively. For night time cough the ORs were 1.06 (0.94 to 1.19) and 1.25 (1.06 to 1.47), and for current wheeze 0.99 (0.88 to 1.12) and 1.28 (1.04 to 1.58), respectively. There was also an association between primary PM10 and new onset symptoms. The ORs for incident symptoms were 1.62 (1.31 to 2.00) for cough without a cold and 1.42 (1.02 to 1.97) for wheeze. Conclusion: In young children there was a consistent association between locally generated primary PM10 and the prevalence and incidence of cough without a cold and the incidence of wheeze which was independent of potential confounders.

Particulate matter exposure in children: relevance to chronic obstructive pulmonary disease.

The effect of exposure to air pollution during childhood on the development of lung disease in adulthood remains to be defined. A common component of air pollution from fossil fuels, environmental tobacco smoke, and burning of solid fuels such as biomass is particulate matter (PM) less than 10 mum in aerodynamic diameter (PM(10)) consisting of aggregates of carbon spherules less than 10 nanometers. Epidemiologic studies suggest that the normal growth in lung function during childhood is impaired by long-term inhalation of carbonaceous PM(10). The most convincing evidence for an effect of PM on lung growth is from a longitudinal study performed in Southern California, where the majority of ambient PM is derived from fossil fuels. Whether exposure of children to high levels of PM from biomass fuel combustion also impairs lung function growth remains unclear. A direct link between exposure of children to PM and increased vulnerability to respiratory disease in adulthood is provided by studies showing an association between life-long biomass smoke and the development of chronic obstructive pulmonary disease (COPD) in non-cigarette-smoking women. Since carbonaceous PM is a component of mainstream cigarette smoke, there may be significant overlap in the cellular and molecular mechanisms underlying the adverse health effects of PM in children and the development of COPD in adult smokers. Studies of children, especially in the developing world, will therefore provide insights into the pathogenesis of COPD.

A cleaner burning biomass-fuelled cookstove intervention to prevent pneumonia in children under 5 years old in rural Malawi (the Cooking and Pneumonia Study): a cluster randomised controlled trial

Summary Background WHO estimates exposure to air pollution from cooking with solid fuels is associated with over 4 million premature deaths worldwide every year including half a million children under the age of 5 years from pneumonia. We hypothesised that replacing open fires with cleaner burning biomass-fuelled cookstoves would reduce pneumonia incidence in young children. Methods We did a community-level open cluster randomised controlled trial to compare the effects of a cleaner burning biomass-fuelled cookstove intervention to continuation of open fire cooking on pneumonia in children living in two rural districts, Chikhwawa and Karonga, of Malawi. Clusters were randomly allocated to intervention and control groups using a computer-generated randomisation schedule with stratification by site, distance from health centre, and size of cluster. Within clusters, households with a child under the age of 4·5 years were eligible. Intervention households received two biomass-fuelled cookstoves and a solar panel. The primary outcome was WHO Integrated Management of Childhood Illness (IMCI)-defined pneumonia episodes in children under 5 years of age. Efficacy and safety analyses were by intention to treat. The trial is registered with ISRCTN, number ISRCTN59448623. Findings We enrolled 10 750 children from 8626 households across 150 clusters between Dec 9, 2013, and Feb 28, 2016. 10 543 children from 8470 households contributed 15 991 child-years of follow-up data to the intention-to-treat analysis. The IMCI pneumonia incidence rate in the intervention group was 15·76 (95% CI 14·89–16·63) per 100 child-years and in the control group 15·58 (95% CI 14·72–16·45) per 100 child-years, with an intervention versus control incidence rate ratio (IRR) of 1·01 (95% CI 0·91–1·13; p=0·80). Cooking-related serious adverse events (burns) were seen in 19 children; nine in the intervention and ten (one death) in the control group (IRR 0·91 [95% CI 0·37–2·23]; p=0·83). Interpretation We found no evidence that an intervention comprising cleaner burning biomass-fuelled cookstoves reduced the risk of pneumonia in young children in rural Malawi. Effective strategies to reduce the adverse health effects of household air pollution are needed. Funding Medical Research Council, UK Department for International Development, and Wellcome Trust.

Environmental toxins; their impact on children’s health

Contamination of the environment by man-made and natural toxins has a direct impact on the health of children. This review considers how toxic contamination is identified and regulated, and highlights specific hazards.

Combustion of dried animal dung as biofuel results in the generation of highly redox active fine particulates

BackgroundThe burning of biomass in the developing world for heating and cooking results in high indoor particle concentrations. Long-term exposure to airborne particulate matter (PM) has been associated with increased rates of acute respiratory infections, chronic obstructive lung disease and cancer. In this study we determined the oxidative activity of combustion particles derived from the biomass fuel dung cake by examining their capacity to deplete antioxidants from a model human respiratory tract lining fluid (RTLF). For comparison, the observed oxidative activity was compared with that of particles derived from industrial and vehicular sources.ResultsIncubation of the dung cake particle suspensions in the RTLF for 4 h resulted in a mean loss of ascorbate of 72.1 ± 0.7 and 89.7 ± 2.5% at 50 and 100 μg/ml, respectively. Reduced glutathione was depleted by 49.6 ± 4.3 and 63.5 ± 22.4% under the same conditions. The capacity of these samples to deplete ascorbate was in excess of that observed with diesel or gasoline particles, but comparable to that seen with residual oil fly ash and considerably in excess of all three control particles in terms of glutathione depletion. Co-incubation with the metal chelator diethylenetriaminepentaacetate inhibited these losses, whilst minimal inhibition was seen with superoxide dismutase and catalase treatment. The majority of the activity observed appeared to be contained within aqueous particle extracts.ConclusionThese data demonstrate that biomass derived particles have considerable oxidative activity, largely attributable to their transition metal content.

Double-blind randomised placebo-controlled trial of bolus-dose vitamin D3 supplementation in adults with asthma (ViDiAs)

Rationale Asthma exacerbations are commonly precipitated by viral upper respiratory infections (URIs). Vitamin D insufficiency associates with susceptibility to URI in patients with asthma. Trials of vitamin D in adults with asthma with incidence of exacerbation and URI as primary outcome are lacking. Objective To conduct a randomised controlled trial of vitamin D3 supplementation for the prevention of asthma exacerbation and URI (coprimary outcomes). Measurements and methods 250 adults with asthma in London, UK were allocated to receive six 2-monthly oral doses of 3 mg vitamin D3 (n=125) or placebo (n=125) over 1 year. Secondary outcomes included asthma control test and St Georges Respiratory Questionnaire scores, fractional exhaled nitric oxide and concentrations of inflammatory markers in induced sputum. Subgroup analyses were performed to determine whether effects of supplementation were modified by baseline vitamin D status or genotype for 34 single nucleotide polymorphisms in 11 vitamin D pathway genes. Main results 206/250 participants (82%) were vitamin D insufficient at baseline. Vitamin D3 did not influence time to first severe exacerbation (adjusted HR 1.02, 95% CI 0.69 to 1.53, p=0.91) or first URI (adjusted HR 0.87, 95% CI 0.64 to 1.16, p=0.34). No clinically important effect of vitamin D3 was seen on any of the secondary outcomes listed above. The influence of vitamin D3 on coprimary outcomes was not modified by baseline vitamin D status or genotype. Conclusions Bolus-dose vitamin D3 supplementation did not influence time to exacerbation or URI in a population of adults with asthma with a high prevalence of baseline vitamin D insufficiency. Trial registration number NCT00978315 (ClinicalTrials.gov).