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1.  Indigenous health and environmental risk factors: an Australian problem with global analogues? 
Global Health Action  2014;7:10.3402/gha.v7.23766.
Indigenous people experience poorer health than non-Indigenous people, and this well-described inequality has been observed in many countries. The contribution of different risk factors to the health ‘gap’ has understandably focussed on those factors for which there are sufficient data. However, this has precluded environmental risk factors – those present in air, water, food, and soil – due to a lack of data describing exposures and outcomes. These risk factors are demonstrably important at the global scale, as highlighted by the 2010 Global Burden of Disease study. Here, we describe how a greater focus on environmental risk factors is required in order to define their role in the Indigenous health gap. We use the Australian context as a case study of an issue we feel has global analogues and relevance. Suggestions for how and why this situation should be remedied are presented and discussed.
PMCID: PMC4007027  PMID: 24802385
environmental health; Indigenous peoples; Australia; health; environment
2.  Genome-wide association analysis identifies 11 risk variants associated with the asthma with hay fever phenotype 
To date, no genome-wide association study (GWAS) has considered the combined phenotype of asthma with hay fever. Previous analyses of family data from the Tasmanian Longitudinal Health Study provide evidence that this phenotype has a stronger genetic cause than asthma without hay fever.
We sought to perform a GWAS of asthma with hay fever to identify variants associated with having both diseases.
We performed a meta-analysis of GWASs comparing persons with both physician-diagnosed asthma and hay fever (n = 6,685) with persons with neither disease (n = 14,091).
At genome-wide significance, we identified 11 independent variants associated with the risk of having asthma with hay fever, including 2 associations reaching this level of significance with allergic disease for the first time: ZBTB10 (rs7009110; odds ratio [OR], 1.14; P = 4 × 10−9) and CLEC16A (rs62026376; OR, 1.17; P = 1 × 10−8). The rs62026376:C allele associated with increased asthma with hay fever risk has been found to be associated also with decreased expression of the nearby DEXI gene in monocytes. The 11 variants were associated with the risk of asthma and hay fever separately, but the estimated associations with the individual phenotypes were weaker than with the combined asthma with hay fever phenotype. A variant near LRRC32 was a stronger risk factor for hay fever than for asthma, whereas the reverse was observed for variants in/near GSDMA and TSLP. Single nucleotide polymorphisms with suggestive evidence for association with asthma with hay fever risk included rs41295115 near IL2RA (OR, 1.28; P = 5 × 10−7) and rs76043829 in TNS1 (OR, 1.23; P = 2 × 10−6).
By focusing on the combined phenotype of asthma with hay fever, variants associated with the risk of allergic disease can be identified with greater efficiency.
PMCID: PMC4280183  PMID: 24388013
Rhinitis; atopy; selection; genetic correlation; bivariate; single nucleotide polymorphism
3.  Early identification of children likely to develop persistent asthma: atopy is an integral component of the high risk phenotype 
Lancet  2008;372(9643):1100-1106.
There is a growing consensus that the long term solution to the asthma epidemic lies in prevention and not in treatment of established disease. Atopic asthma arises from gene x environment interactions which most commonly occur during a relatively narrow window period in pre- and postnatal development. These interactions are incompletely understood, and hence the holy grail of primary prevention remains an elusive goal. We contend that a lack of understanding of the role of atopy in early life in the development of persistent asthma in children exists amongst primary care physicians, paediatricians and specialists. In this review we argue that early identification of high risk children is feasible based on currently available technology, and worthwhile in relation to potential benefits to the children so identified. Knowledge of an asthmatic child's atopic status in early life has practical clinical and prognostic implications, as well as forming the basis for future preventative strategies.
PMCID: PMC4440493  PMID: 18805338
4.  The influence of sighing respirations on infant lung function measured using multiple breath washout gas mixing techniques 
Physiological Reports  2015;3(4):e12347.
There is substantial interest in studying lung function in infants, to better understand the early life origins of chronic lung diseases such as asthma. Multiple breath washout (MBW) is a technique for measuring lung function that has been adapted for use in infants. Respiratory sighs occur frequently in young infants during natural sleep, and in accordance with current MBW guidelines, result in exclusion of data from a substantial proportion of testing cycles. We assessed how sighs during MBW influenced the measurements obtained using data from 767 tests conducted on 246 infants (50% male; mean age 43 days) as part of a large cohort study. Sighs occurred in 119 (15%) tests. Sighs during the main part of the wash-in phase (before the last 5 breaths) were not associated with differences in standard MBW measurements compared with tests without sighs. In contrast, sighs that occurred during the washout were associated with a small but discernible increase in magnitude and variability. For example, the mean lung clearance index increased by 0.36 (95% CI: 0.11–0.62) and variance increased by a multiplicative factor of 2 (95% CI: 1.6–2.5). The results suggest it is reasonable to include MBW data from testing cycles where a sigh occurs during the wash-in phase, but not during washout, of MBW. By recovering data that would otherwise have been excluded, we estimate a boost of about 10% to the final number of acceptable tests and 6% to the number of individuals successfully tested.
PMCID: PMC4425956  PMID: 25847916
Infants; lung function; multiple breath washout; sighing respirations
5.  Assessment of bronchodilator responsiveness in preschool children using forced oscillations 
Thorax  2007;62(9):814-819.
The forced oscillation technique (FOT) requires minimal patient cooperation and is feasible in preschool children. Few data exist on respiratory function changes measured using FOT following inhaled bronchodilators (BD) in healthy young children, limiting the clinical applications of BD testing in this age group. A study was undertaken to determine the most appropriate method of quantifying BD responses using FOT in healthy young children and those with common respiratory conditions including cystic fibrosis, neonatal chronic lung disease and asthma and/or current wheeze.
A pseudorandom FOT signal (4–48 Hz) was used to examine respiratory resistance and reactance at 6, 8 and 10 Hz; 3–5 acceptable measurements were made before and 15 min after the administration of salbutamol. The post‐BD response was expressed in absolute and relative (percentage of baseline) terms.
Significant BD responses were seen in all groups. Absolute changes in BD responses were related to baseline lung function within each group. Relative changes in BD responses were less dependent on baseline lung function and were independent of height in healthy children. Those with neonatal chronic lung disease showed a strong baseline dependence in their responses. The BD response in children with cystic fibrosis, asthma or wheeze (based on both group mean data and number of responders) was not greater than in healthy children.
The BD response assessed by the FOT in preschool children should be expressed as a relative change to account for the effect of baseline lung function. The limits for a positive BD response of −40% and 65% for respiratory resistance and reactance, respectively, are recommended.
PMCID: PMC2117298  PMID: 17412777
6.  Respiratory function in healthy young children using forced oscillations 
Thorax  2007;62(6):521-526.
Monitoring of respiratory function is important in the diagnosis and management of respiratory disease. The forced oscillation technique requires minimal patient cooperation and is ideal for the determination of respiratory function in young children. This study aimed to develop reference ranges and to document the repeatability in healthy young children using commercially available forced oscillation equipment.
The forced oscillation technique, which uses a pseudo‐random noise forcing signal between 4 and 48 Hz, was used to measure respiratory function in healthy young children. Repeatability over a 15 min period was also assessed. Regression equations and standardised Z scores were determined for respiratory resistance (Rrs) and reactance (Xrs) at 6, 8 and 10 Hz.
Respiratory function was obtained in 158 healthy children aged two to seven years and between 92 and 127 cm in height. Oscillatory respiratory mechanics exhibited linear relationships with height. Within‐test variability for resistance ranged between 6% and 9% and between 17% and 20% for reactance. Resistance and reactance did not change significantly over a 15 min period.
Reference ranges for respiratory impedance variables in healthy children aged two to seven years are presented. The short‐term repeatability of forced oscillatory variables in this age group is reported, allowing appropriate cut‐off values for therapeutic interventions to be defined.
PMCID: PMC2117207  PMID: 17251315
7.  Indoor determinants of dustborne allergens in Mexican homes 
Allergy and Asthma Proceedings  2015;36(2):130-137.
Exposure to indoor allergens represents a significant risk factor for allergies and asthma in several parts of the world. In Mexico, few studies have evaluated indoor allergens, including cat, dog, and mouse allergens and the factors that predict their presence. This study evaluates the main environmental and household predictors of high prenatal allergen levels and multiple allergen exposures in a birth cohort from Mexico City. A cross-sectional study was conducted as part of a birth cohort study of 1094 infants recruited during pregnancy and followed until delivery. We collected dust samples in a subset of 264 homes and assessed environmental factors. Der p 1, Der f 1, dust mite group 2, Fel d 1, Can f 1, Rat n 1, Mus m 1, and Bla g 2 concentrations in dust samples were measured using immunoassays. To define detectable allergen levels, the lowest limits of detection for each allergen were taken as cutoff points. Overall allergen exposure was considered high when four or more allergens exceeded detectable levels in the same household. Logistic regression was used for predictive models. Eighty-five percent of homes had at least one allergen in dust over the detection limit, 52.1% had high exposure (four or more allergens above detectable limits), and 11.7% of homes had detectable levels for more than eight allergens. Der p 1, Der p 2, Mus m 1, and Fel d 1 were the most frequent allergens detected. Each allergen had both common and distinct predictors. The main predictors of a high multiple allergen index were the size of the home, pesticide use, mother's age, mother as homemaker, and season. Increased indoor environmental allergen exposure is mainly related to sociodemographic factors and household cleaning.
PMCID: PMC4338857  PMID: 25715241
Cat; environment; indoor exposure; Mexico; mouse
8.  Children’s Health in Latin America: The Influence of Environmental Exposures 
Environmental Health Perspectives  2014;123(3):201-209.
Chronic diseases are increasing among children in Latin America.
Objective and Methods
To examine environmental risk factors for chronic disease in Latin American children and to develop a strategic initiative for control of these exposures, the World Health Organization (WHO) including the Pan American Health Organization (PAHO), the Collegium Ramazzini, and Latin American scientists reviewed regional and relevant global data.
Industrial development and urbanization are proceeding rapidly in Latin America, and environmental pollution has become widespread. Environmental threats to children’s health include traditional hazards such as indoor air pollution and drinking-water contamination; the newer hazards of urban air pollution; toxic chemicals such as lead, asbestos, mercury, arsenic, and pesticides; hazardous and electronic waste; and climate change. The mix of traditional and modern hazards varies greatly across and within countries reflecting industrialization, urbanization, and socioeconomic forces.
To control environmental threats to children’s health in Latin America, WHO, including PAHO, will focus on the most highly prevalent and serious hazards—indoor and outdoor air pollution, water pollution, and toxic chemicals. Strategies for controlling these hazards include developing tracking data on regional trends in children’s environmental health (CEH), building a network of Collaborating Centres, promoting biomedical research in CEH, building regional capacity, supporting development of evidence-based prevention policies, studying the economic costs of chronic diseases in children, and developing platforms for dialogue with relevant stakeholders.
Laborde A, Tomasina F, Bianchi F, Bruné MN, Buka I, Comba P, Corra L, Cori L, Duffert CM, Harari R, Iavarone I, McDiarmid MA, Gray KA, Sly PD, Soares A, Suk WA, Landrigan PJ. 2015. Children’s health in Latin America: the influence of environmental exposures. Environ Health Perspect 123:201–209;
PMCID: PMC4348745  PMID: 25499717
9.  Prenatal determinants of cord blood total immunoglobulin E levels in Mexican newborns 
Allergy and Asthma Proceedings  2013;34(5):e27-e34.
Asthma and allergic diseases have increased worldwide; however, etilogic factors for this increase are still poor. Prenatal consumptions of fatty acids are hypothesized, although few clinical trials in developing countries have been performed. This study was designed to identify predictors of immunoglobulin E (IgE) levels in cord blood of Mexican newborns. Total IgE was measured in umbilical cord blood from 613 infants whose mothers participated in a double-blind randomized controlled trial of 400 mg of docosahexaenoic acid or placebo from 18 to 22 weeks gestation through delivery. During pregnancy, information on sociodemographic characteristics, environmental exposures, and perceived maternal stress were obtained; a maternal blood sample was also collected to determine atopy via specific IgE levels. Logistic regression models were used to identify the main prenatal predictors of detectable total IgE levels in cord blood. IgE was detectable in cord blood from 344 (53.7%) infants; the main predictors in multivariate analyses were maternal atopy (odds ratio [OR] = 1.69; 95% CI, 1.19–2.42; p < 0.05) and pesticide use in the home (OR = 1.49; 95% CI, 1.04–2.14; p < 0.05). When stratified by maternal atopy, season of birth was a significant predictor in the atopic group only (OR = 2.48; 95% CI, 1.00–6.16; p < 0.05), and pesticide use was a significant predictor for infants born to nonatopic mothers (OR = 1.64; 95% CI, 1.07–2.51; p < 0.05). No differences were seen in the proportion of infants with detectable IgE by treatment group. Prenatal supplementation with omega-3 polyunsaturated fatty acid did not alter the detectable cord blood IgE levels. Maternal atopy and pesticide use during pregnancy are strong predictors of cord blood IgE levels in newborns. Clinical trial NCT00646360,
PMCID: PMC3973815  PMID: 23998234
Clinical trial; cord blood; maternal atopy; newborn; omega-3 polyunsaturated fatty acid; pregnancy supplementation; total immunoglobulin E
10.  Rhinovirus Exacerbates House-Dust-Mite Induced Lung Disease in Adult Mice 
PLoS ONE  2014;9(3):e92163.
Human rhinovirus is a key viral trigger for asthma exacerbations. To date, murine studies investigating rhinovirus-induced exacerbation of allergic airways disease have employed systemic sensitisation/intranasal challenge with ovalbumin. In this study, we combined human-rhinovirus infection with a clinically relevant mouse model of aero-allergen exposure using house-dust-mite in an attempt to more accurately understand the links between human-rhinovirus infection and exacerbations of asthma. Adult BALB/c mice were intranasally exposed to low-dose house-dust-mite (or vehicle) daily for 10 days. On day 9, mice were inoculated with human-rhinovirus-1B (or UV-inactivated human-rhinovirus-1B). Forty-eight hours after inoculation, we assessed bronchoalveolar cellular inflammation, levels of relevant cytokines/serum antibodies, lung function and responsiveness/sensitivity to methacholine. House-dust-mite exposure did not result in a classical TH2-driven response, but was more representative of noneosinophilic asthma. However, there were significant effects of house-dust-mite exposure on most of the parameters measured including increased cellular inflammation (primarily macrophages and neutrophils), increased total IgE and house-dust-mite-specific IgG1 and increased responsiveness/sensitivity to methacholine. There were limited effects of human-rhinovirus-1B infection alone, and the combination of the two insults resulted in additive increases in neutrophil levels and lung parenchymal responses to methacholine (tissue elastance). We conclude that acute rhinovirus infection exacerbates house-dust-mite-induced lung disease in adult mice. The similarity of our results using the naturally occurring allergen house-dust-mite, to previous studies using ovalbumin, suggests that the exacerbation of allergic airways disease by rhinovirus infection could act via multiple or conserved mechanisms.
PMCID: PMC3954893  PMID: 24632596
11.  Using Mathematical Transmission Modelling to Investigate Drivers of Respiratory Syncytial Virus Seasonality in Children in the Philippines 
PLoS ONE  2014;9(2):e90094.
We used a mathematical transmission model to estimate when ecological drivers of respiratory syncytial virus (RSV) transmissibility would need to act in order to produce the observed seasonality of RSV in the Philippines. We estimated that a seasonal peak in transmissibility would need to occur approximately 51 days prior to the observed peak in RSV cases (range 49 to 67 days). We then compared this estimated seasonal pattern of transmissibility to the seasonal patterns of possible ecological drivers of transmissibility: rainfall, humidity and temperature patterns, nutritional status, and school holidays. The timing of the seasonal patterns of nutritional status and rainfall were both consistent with the estimated seasonal pattern of transmissibility and these are both plausible drivers of the seasonality of RSV in this setting.
PMCID: PMC3937436  PMID: 24587222
12.  Airway, but not serum or urinary, levels of YKL-40 reflect inflammation in early cystic fibrosis lung disease 
Cystic fibrosis (CF) lung disease begins in early life and is progressive with the major risk factor being an exaggerated inflammatory response. Currently, assessment of neutrophilic inflammation in early cystic fibrosis (CF) lung disease relies on bronchoalveolar lavage (BAL). The chitinase-like protein YKL-40 is raised in sputum and serum of adults with CF. We investigated YKL-40 in BAL, serum and urine to determine whether this reflected inflammation and infection in young children with CF.
YKL-40 was measured in matched samples of BAL, serum and urine obtained from 36 infants and young children with CF participating in an early surveillance program. Levels were compared to clinical data and markers of inflammation detected in the lung.
YKL-40 in BAL correlated with pulmonary infection [β=1.30 (SE 0.34), p < 0.001] and BAL markers of inflammation [macrophage number: r2 = 0.34, p < 0.001; neutrophil number: r2 = 0.74, p < 0.001; neutrophil elastase: r2 = 0.47, p < 0.001; CXCL8: r2 = 0.45, p < 0.001; IL-β: r2 = 0.62, p < 0.001]. YKL-40 was detectable in serum but levels did not correlate with BAL levels in the same individuals (r2 = 0.04, p = 0.14) or with inflammatory markers. YKL-40 was below the limit of detection in urine (30 pg/ml).
This study demonstrates that levels of the chitinase-like protein YKL-40 reflect airway inflammation and infection in early CF lung disease. The lack of increased YKL-40 in serum in the absence of systemic inflammation limits the benefit of this potential biomarker in early disease.
PMCID: PMC3946043  PMID: 24576297
Cystic fibrosis; YKL-40; Biomarker; Lung disease
13.  Elucidation of Pathways Driving Asthma Pathogenesis: Development of a Systems-Level Analytic Strategy 
Asthma is a genetically complex, chronic lung disease defined clinically as episodic airflow limitation and breathlessness that is at least partially reversible, either spontaneously or in response to therapy. Whereas asthma was rare in the late 1800s and early 1900s, the marked increase in its incidence and prevalence since the 1960s points to substantial gene × environment interactions occurring over a period of years, but these interactions are very poorly understood (1–6). It is widely believed that the majority of asthma begins during childhood and manifests first as intermittent wheeze. However, wheeze is also very common in infancy and only a subset of wheezy children progress to persistent asthma for reasons that are largely obscure. Here, we review the current literature regarding causal pathways leading to early asthma development and chronicity. Given the complex interactions of many risk factors over time eventually leading to apparently multiple asthma phenotypes, we suggest that deeply phenotyped cohort studies combined with sophisticated network models will be required to derive the next generation of biological and clinical insights in asthma pathogenesis.
PMCID: PMC4172064  PMID: 25295037
allergy; asthma; systems biology; virus infection; birth cohort; childhood; immune function; epidemiology
14.  Early Life Arsenic Exposure and Acute and Long-term Responses to Influenza A Infection in Mice 
Environmental Health Perspectives  2013;121(10):1187-1193.
Background: Arsenic is a significant global environmental health problem. Exposure to arsenic in early life has been shown to increase the rate of respiratory infections during infancy, reduce childhood lung function, and increase the rates of bronchiectasis in early adulthood.
Objective: We aimed to determine if early life exposure to arsenic exacerbates the response to early life influenza infection in mice.
Methods: C57BL/6 mice were exposed to arsenic in utero and throughout postnatal life. At 1 week of age, a subgroup of mice were infected with influenza A. We then assessed the acute and long-term effects of arsenic exposure on viral clearance, inflammation, lung structure, and lung function.
Results: Early life arsenic exposure reduced the clearance of and exacerbated the inflammatory response to influenza A, and resulted in acute and long-term changes in lung mechanics and airway structure.
Conclusions: Increased susceptibility to respiratory infections combined with exaggerated inflammatory responses throughout early life may contribute to the development of bronchiectasis in arsenic-exposed populations.
Citation: Ramsey KA, Foong RE, Sly PD, Larcombe AN, Zosky GR. 2013. Early life arsenic exposure and acute and long-term responses to influenza A infection in mice. Environ Health Perspect 121:1187–1193;
PMCID: PMC3801203  PMID: 23968752
15.  Poor Growth and Pneumonia Seasonality in Infants in the Philippines: Cohort and Time Series Studies 
PLoS ONE  2013;8(6):e67528.
Children with poor nutrition are at increased risk of pneumonia. In many tropical settings seasonal pneumonia epidemics occur during the rainy season, which is often a period of poor nutrition. We have investigated whether seasonal hunger may be a driver of seasonal pneumonia epidemics in children in the tropical setting of the Philippines. In individual level cohort analysis, infant size and growth were both associated with increased pneumonia admissions, consistent with findings from previous studies. A low weight for age z-score in early infancy was associated with an increased risk of pneumonia admission over the following 12 months (RR for infants in the lowest quartile of weight for age z-scores 1.28 [95% CI 1.08 to 1.51]). Poor growth in smaller than average infants was also associated with an increased risk of pneumonia (RR for those in the lowest quartile of growth in early infancy 1.31 [95%CI 1.02 to 1.68]). At a population level, we found that seasonal undernutrition preceded the seasonal increase in pneumonia and respiratory syncytial virus admissions by approximately 10 weeks (pairwise correlation at this lag was −0.41 [95%CI −0.53 to −0.27] for pneumonia admissions, and −0.63 [95%CI −0.72 to −0.51] for respiratory syncytial virus admissions). This lag appears biologically plausible. These results suggest that in addition to being an individual level risk factor for pneumonia, poor nutrition may act as a population level driver of seasonal pneumonia epidemics in the tropics. Further investigation of the seasonal level association, in particular the estimation of the expected lag between seasonal undernutrition and increased pneumonia incidence, is recommended.
PMCID: PMC3695907  PMID: 23840731
16.  In utero exposure to low dose arsenic via drinking water impairs early life lung mechanics in mice 
Exposure to arsenic via drinking water is a significant environmental issue affecting millions of people around the world. Exposure to arsenic during foetal development has been shown to impair somatic growth and increase the risk of developing chronic respiratory diseases. The aim of this study was to determine if in utero exposure to low dose arsenic via drinking water is capable of altering lung growth and postnatal lung mechanics.
Pregnant C57BL/6 mice were given drinking water containing 0, 10 (current World Health Organisation (WHO) maximum contaminant level) or 100μg/L arsenic from gestational day 8 to birth. Birth outcomes and somatic growth were monitored. Plethysmography and the forced oscillation technique were used to collect measurements of lung volume, lung mechanics, pressure-volume curves and the volume dependence of lung mechanics in male and female offspring at two, four, six and eight weeks of age.
In utero exposure to low dose arsenic via drinking water resulted in low birth weight and impaired parenchymal lung mechanics during infancy. Male offspring were more susceptible to the effects of arsenic on growth and lung mechanics than females. All alterations to lung mechanics following in utero arsenic exposure were recovered by adulthood.
Exposure to arsenic at the current WHO maximum contaminant level in utero impaired somatic growth and the development of the lungs resulting in alterations to lung mechanics during infancy. Deficits in growth and lung development in early life may contribute to the increased susceptibility of developing chronic respiratory disease in arsenic exposed human populations.
PMCID: PMC3584853  PMID: 23419080
Animal model; Arsenic; Environmental exposure; Growth & development; Lung function
17.  In Utero Exposure to Arsenic Alters Lung Development and Genes Related to Immune and Mucociliary Function in Mice 
Environmental Health Perspectives  2012;121(2):244-250.
Background: Exposure to arsenic via drinking water is a global environmental health problem. In utero exposure to arsenic via drinking water increases the risk of lower respiratory tract infections during infancy and mortality from bronchiectasis in early adulthood.
Objectives: We aimed to investigate how arsenic exposure in early life alters lung development and pathways involved in innate immunity.
Methods: Pregnant BALB/c, C57BL/6, and C3H/HeARC mice were exposed to 0 (control) or 100 μg/L arsenic via drinking water from gestation day 8 until the birth of their offspring. We measured somatic growth, lung volume, and lung mechanics of mice at 2 weeks of age. We used fixed lungs for structural analysis and collected lung tissue for gene expression analysis by microarray.
Results: The response to arsenic was genetically determined, and C57BL/6 mice were the most susceptible. Arsenic-exposed C57BL/6 mice were smaller in size, had smaller lungs, and had impaired lung mechanics compared with controls. Exposure to arsenic in utero up-regulated the expression of genes in the lung involved in mucus production (Clca3, Muc5b, Scgb3a1), innate immunity (Reg3γ, Tff2, Dynlrb2, Lplunc1), and lung morphogenesis (Sox2). Arsenic exposure also induced mucous cell metaplasia and increased expression of CLCA3 protein in the large airways.
Conclusions: Alterations in somatic growth, lung development, and the expression of genes involved in mucociliary clearance and innate immunity in the lung are potential mechanisms through which early life arsenic exposure impacts respiratory health.
PMCID: PMC3569690  PMID: 23221970
gene expression; growth and development; innate immunity; mucociliary clearance; toxicity
Inhaled corticosteroid use reduces respiratory symptoms in young children with recurrent wheeze. Delivery of steroids with pressurised metered dose inhalers and spacers is influenced by children’s proficiency/technique in using delivery devices.
To investigate the influence of an incentive device, the Funhaler®, on spacer technique and symptom control in young children with asthma and recurrent wheeze.
Randomised controlled trial where 132 2–6 year old asthmatic children received regular inhaled fluticasone through Aerochamber Plus®, or Funhaler®. The setting was a research clinic at Princess Margaret Hospital for Children, Perth, Australia. Subjects were followed up for a year. The main outcome measure was asthma symptoms. Proficiency in spacer technique was measured as salbutamol inhaled from spacer onto filter. Quality of life was measured three-monthly. Groups were compared in terms of spacer technique, symptoms and quality of life. The relationship between spacer technique and clinical outcome was examined.
There was no difference between Funhaler and Aerochamber groups in wheeze free days, cough free days, bronchodilator free days or quality of life (p = 0.90, 0.87, 0.74 and 0.11 respectively). Spacer technique was better in the Funhaler group (p = 0.05), particularly in subjects younger than 4 years of age (p = 0.002). Drug dose on filter (as the mean of five 100μg doses) ranged from zero to 136μg.
Use of Funhaler® incentive device does not improve clinical outcome, but improves spacer technique in children younger than 4 years. Variability in drug delivery is large in young children using pMDI-spacers.
PMCID: PMC3261303  PMID: 22040259
Asthma; wheeze; children; preschool; spacer technique; device technique; inhaled corticosteroids
19.  Respiratory viral infections in children with asthma: do they matter and can we prevent them? 
BMC Pediatrics  2012;12:147.
Asthma is a major public health problem with a huge social and economic burden affecting 300 million people worldwide. Viral respiratory infections are the major cause of acute asthma exacerbations and may contribute to asthma inception in high risk young children with susceptible genetic background. Acute exacerbations are associated with decreased lung growth or accelerated loss of lung function and, as such, add substantially to both the cost and morbidity associated with asthma.
While the importance of preventing viral infection is well established, preventive strategies have not been well explored. Good personal hygiene, hand-washing and avoidance of cigarette smoke are likely to reduce respiratory viral infections. Eating a healthy balanced diet, active probiotic supplements and bacterial-derived products, such as OM-85, may reduce recurrent infections in susceptible children. There are no practical anti-viral therapies currently available that are suitable for widespread use.
Hand hygiene is the best measure to prevent the common cold. A healthy balanced diet, active probiotic supplements and immunostimulant OM-85 may reduce recurrent infections in asthmatic children.
PMCID: PMC3471019  PMID: 22974166
Acute respiratory infections; Childhood asthma; Common cold; Acute exacerbations; Rhinovirus
20.  Genome-wide association and large scale follow-up identifies 16 new loci influencing lung function 
Artigas, María Soler | Loth, Daan W | Wain, Louise V | Gharib, Sina A | Obeidat, Ma’en | Tang, Wenbo | Zhai, Guangju | Zhao, Jing Hua | Smith, Albert Vernon | Huffman, Jennifer E | Albrecht, Eva | Jackson, Catherine M | Evans, David M | Cadby, Gemma | Fornage, Myriam | Manichaikul, Ani | Lopez, Lorna M | Johnson, Toby | Aldrich, Melinda C | Aspelund, Thor | Barroso, Inês | Campbell, Harry | Cassano, Patricia A | Couper, David J | Eiriksdottir, Gudny | Franceschini, Nora | Garcia, Melissa | Gieger, Christian | Gislason, Gauti Kjartan | Grkovic, Ivica | Hammond, Christopher J | Hancock, Dana B | Harris, Tamara B | Ramasamy, Adaikalavan | Heckbert, Susan R | Heliövaara, Markku | Homuth, Georg | Hysi, Pirro G | James, Alan L | Jankovic, Stipan | Joubert, Bonnie R | Karrasch, Stefan | Klopp, Norman | Koch, Beate | Kritchevsky, Stephen B | Launer, Lenore J | Liu, Yongmei | Loehr, Laura R | Lohman, Kurt | Loos, Ruth JF | Lumley, Thomas | Al Balushi, Khalid A | Ang, Wei Q | Barr, R Graham | Beilby, John | Blakey, John D | Boban, Mladen | Boraska, Vesna | Brisman, Jonas | Britton, John R | Brusselle, Guy G | Cooper, Cyrus | Curjuric, Ivan | Dahgam, Santosh | Deary, Ian J | Ebrahim, Shah | Eijgelsheim, Mark | Francks, Clyde | Gaysina, Darya | Granell, Raquel | Gu, Xiangjun | Hankinson, John L | Hardy, Rebecca | Harris, Sarah E | Henderson, John | Henry, Amanda | Hingorani, Aroon D | Hofman, Albert | Holt, Patrick G | Hui, Jennie | Hunter, Michael L | Imboden, Medea | Jameson, Karen A | Kerr, Shona M | Kolcic, Ivana | Kronenberg, Florian | Liu, Jason Z | Marchini, Jonathan | McKeever, Tricia | Morris, Andrew D | Olin, Anna-Carin | Porteous, David J | Postma, Dirkje S | Rich, Stephen S | Ring, Susan M | Rivadeneira, Fernando | Rochat, Thierry | Sayer, Avan Aihie | Sayers, Ian | Sly, Peter D | Smith, George Davey | Sood, Akshay | Starr, John M | Uitterlinden, André G | Vonk, Judith M | Wannamethee, S Goya | Whincup, Peter H | Wijmenga, Cisca | Williams, O Dale | Wong, Andrew | Mangino, Massimo | Marciante, Kristin D | McArdle, Wendy L | Meibohm, Bernd | Morrison, Alanna C | North, Kari E | Omenaas, Ernst | Palmer, Lyle J | Pietiläinen, Kirsi H | Pin, Isabelle | Polašek, Ozren | Pouta, Anneli | Psaty, Bruce M | Hartikainen, Anna-Liisa | Rantanen, Taina | Ripatti, Samuli | Rotter, Jerome I | Rudan, Igor | Rudnicka, Alicja R | Schulz, Holger | Shin, So-Youn | Spector, Tim D | Surakka, Ida | Vitart, Veronique | Völzke, Henry | Wareham, Nicholas J | Warrington, Nicole M | Wichmann, H-Erich | Wild, Sarah H | Wilk, Jemma B | Wjst, Matthias | Wright, Alan F | Zgaga, Lina | Zemunik, Tatijana | Pennell, Craig E | Nyberg, Fredrik | Kuh, Diana | Holloway, John W | Boezen, H Marike | Lawlor, Debbie A | Morris, Richard W | Probst-Hensch, Nicole | Kaprio, Jaakko | Wilson, James F | Hayward, Caroline | Kähönen, Mika | Heinrich, Joachim | Musk, Arthur W | Jarvis, Deborah L | Gläser, Sven | Järvelin, Marjo-Riitta | Stricker, Bruno H Ch | Elliott, Paul | O’Connor, George T | Strachan, David P | London, Stephanie J | Hall, Ian P | Gudnason, Vilmundur | Tobin, Martin D
Nature Genetics  2011;43(11):1082-1090.
Pulmonary function measures reflect respiratory health and predict mortality, and are used in the diagnosis of chronic obstructive pulmonary disease (COPD). We tested genome-wide association with the forced expiratory volume in 1 second (FEV1) and the ratio of FEV1 to forced vital capacity (FVC) in 48,201 individuals of European ancestry, with follow-up of top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P<5×10−8) with pulmonary function, in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1, and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.
PMCID: PMC3267376  PMID: 21946350
21.  Air Trapping on Chest CT Is Associated with Worse Ventilation Distribution in Infants with Cystic Fibrosis Diagnosed following Newborn Screening 
PLoS ONE  2011;6(8):e23932.
In school-aged children with cystic fibrosis (CF) structural lung damage assessed using chest CT is associated with abnormal ventilation distribution. The primary objective of this analysis was to determine the relationships between ventilation distribution outcomes and the presence and extent of structural damage as assessed by chest CT in infants and young children with CF.
Data of infants and young children with CF diagnosed following newborn screening consecutively reviewed between August 2005 and December 2009 were analysed. Ventilation distribution (lung clearance index and the first and second moment ratios [LCI, M1/M0 and M2/M0, respectively]), chest CT and airway pathology from bronchoalveolar lavage were determined at diagnosis and then annually. The chest CT scans were evaluated for the presence or absence of bronchiectasis and air trapping.
Matched lung function, chest CT and pathology outcomes were available in 49 infants (31 male) with bronchiectasis and air trapping present in 13 (27%) and 24 (49%) infants, respectively. The presence of bronchiectasis or air trapping was associated with increased M2/M0 but not LCI or M1/M0. There was a weak, but statistically significant association between the extent of air trapping and all ventilation distribution outcomes.
These findings suggest that in early CF lung disease there are weak associations between ventilation distribution and lung damage from chest CT. These finding are in contrast to those reported in older children. These findings suggest that assessments of LCI could not be used to replace a chest CT scan for the assessment of structural lung disease in the first two years of life. Further research in which both MBW and chest CT outcomes are obtained is required to assess the role of ventilation distribution in tracking the progression of lung damage in infants with CF.
PMCID: PMC3158781  PMID: 21886842
22.  Ethical Issues in Measuring Biomarkers in Children’s Environmental Health 
Environmental Health Perspectives  2009;117(8):1185-1190.
Studying the impact of environmental exposures is important in children because they are more vulnerable to adverse effects on growth, development, and health. Assessing exposure in children is difficult, and measuring biomarkers is potentially useful. Research measuring biomarkers in children raises a number of ethical issues, some of which relate to children as research subjects and some of which are specific to biomarker research.
As an international group with experience in pediatric research, biomarkers, and the ethics of research in children, we highlight the ethical issues of undertaking biomarker research in children in these environments.
Significant issues include undertaking research in vulnerable communities, especially in developing countries; managing community expectations; obtaining appropriate consent to conduct the research; the potential conflicts of obtaining permission from an ethics review board in an economically developed country to perform research in a community that may have different cultural values; returning research results to participants and communities when the researchers are uncertain of how to interpret the results; and the conflicting ethical obligations of maintaining participant confidentiality when information about harm or illegal activities mandate reporting to authorities.
None of these challenges are insurmountable and all deserve discussion. Pediatric biomarker research is necessary for advancing child health.
PMCID: PMC2721859  PMID: 19672395
biobanks; biomarkers; children; environmental exposure; genetics; infants; informed consent; research ethics
23.  Children's environmental health: an under-recognised area in paediatric health care 
BMC Pediatrics  2009;9:10.
The knowledge that the environment in which we live, grow and play, can have negative or positive impacts on our health and development is not new. However the recognition that adverse environments can significantly and specifically affect the growth and development of a child from early intrauterine life through to adolescence, as well as impact their health later in adulthood, is relatively recent and has not fully reached health care providers involved in paediatric care.
Over the past 15 years, world declarations and statements on children's rights, sustainable development, chemical safety and most recently climate change, have succeeded in cultivating a global focus on children's health and their right to a healthy environment. Many international calls for research in the area, have also been able to identify patterns of environmental diseases in children, assess children's exposures to many environmental toxicants, identify developmental periods of vulnerability, and quantify the cost benefits to public health systems and beyond, of addressing environmentally related diseases in children. Transferring this information to front-line health care providers and increasing their awareness about the global burden of disease attributed to the environment and children's especial vulnerability to environmental threats is the salient aim of this commentary.
PMCID: PMC2645393  PMID: 19196484
24.  Reversal of airway hyperresponsiveness by induction of airway mucosal CD4+CD25+ regulatory T cells 
The Journal of Experimental Medicine  2006;203(12):2649-2660.
An important feature of atopic asthma is the T cell–driven late phase reaction involving transient bronchoconstriction followed by development of airways hyperresponsiveness (AHR). Using a unique rat asthma model we recently showed that the onset and duration of the aeroallergen-induced airway mucosal T cell activation response in sensitized rats is determined by the kinetics of functional maturation of resident airway mucosal dendritic cells (AMDCs) mediated by cognate interactions with CD4+ T helper memory cells. The study below extends these investigations to chronic aeroallergen exposure. We demonstrate that prevention of ensuing cycles of T cell activation and resultant AHR during chronic exposure of sensitized rats to allergen aerosols is mediated by CD4+CD25+Foxp3+LAG3+ CTLA+CD45RC+ T cells which appear in the airway mucosa and regional lymph nodes within 24 h of initiation of exposure, and inhibit subsequent Th-mediated upregulation of AMDC functions. These cells exhibit potent regulatory T (T reg) cell activity in both in vivo and ex vivo assay systems. The maintenance of protective T reg activity is absolutely dependent on continuing allergen stimulation, as interruption of exposure leads to waning of T reg activity and reemergence of sensitivity to aeroallergen exposure manifesting as AMDC/T cell upregulation and resurgence of T helper 2 cytokine expression, airways eosinophilia, and AHR.
PMCID: PMC2118157  PMID: 17088431
25.  Dendritic Cell Immaturity during Infancy Restricts the Capacity To Express Vaccine-Specific T-Cell Memory  
Infection and Immunity  2006;74(2):1106-1112.
The capacity of the immune system in infants to develop stable T-cell memory in response to vaccination is attenuated, and the mechanism(s) underlying this developmental deficiency in humans is poorly understood. The present study focuses on the capacity for expression of in vitro recall responses to tetanus and diphtheria antigens in lymphocytes from 12-month-old infants vaccinated during the first 6 months of life. We demonstrate that supplementation of infant lymphocytes with “matured” dendritic cells (DC) cultured from autologous CD14+ precursors unmasks previously covert cellular immunity in the form of Th2-skewed cytokine production. Supplementation of adult lymphocytes with comparable prematured autologous DC also boosted vaccine-specific T-cell memory expression, but in contrast to the case for the infants, these cytokine responses were heavily Th1 skewed. Compared to adults, infants had significantly fewer circulating myeloid DC (P < 0.0001) and plasmacytoid DC (P < 0.0001) as a proportion of peripheral blood mononuclear cells. These findings suggest that deficiencies in the numbers of antigen-presenting cells and their functional competence at 12 months of age limit the capacity to express effector memory responses and are potentially a key factor in reduced vaccine responsiveness in infants.
PMCID: PMC1360347  PMID: 16428758

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