It is generally surmised that community stressors have an incubating effect for a variety of diagnoses on maternal and child health. This is of public health significance, as children of mothers facing long-term distress were found to have a 60% higher risk for asthma diagnosis at age 7 in Manitoba, Canada. Our objective was to determine the association of community stressors with childhood asthma prevalence in Winnipeg, Canada from participants who completed the Study of Asthma, Genes and the Environment (SAGE) survey administered in 2002–2003 to a birth cohort from 1995. Measures of community socioeconomic makeup and community disorder with rank ordinalized by quintile at the census tract level were obtained from the 1996 Canada Census. Crime data (annual incidence per 10,000 persons) by neighbourhood profile for 2001 was provided by the Winnipeg Police Service. Dichotomous caregiver report of child asthma along with other indicators from the geocoded SAGE survey allowed linkage to 23 neighbourhood profiles. Multilevel logistic regression analyses were performed to estimate the effect of community stressors on childhood asthma prevalence for birth and non-birth home children (N = 1472) and children resident of birth homes at age 7 or 8 (N = 698). After adjusting for individual risk factors, children resident of birth homes in a high thefts over $5,000 neighbourhood profile were twice as likely (Adjusted OR, 2.05; 95% CI, 1.11–3.81) to have report of asthma compared to children in a lower thefts over $5,000 profile, with community thefts over $5,000 explaining over half of the observed neighbourhood variation in asthma.

Background:

Few population studies have examined the psychiatric outcomes of children and adolescents in the child welfare system, and no studies have compared outcomes before and after entry into care. Our objective was to assess the relative rate (RR) of suicide, attempted suicide, admission to hospital and visits to physicians’ offices among children and adolescents in care compared with those not in care. We also examined these outcomes within the child welfare population before and after entry into care.

Methods:

We used population-level data to identify children and adolescents 5 to 17 years of age who were in care in Manitoba for the first time between Apr. 1, 1997, and Mar. 31, 2006, and a comparison cohort not in care. We compared the two cohorts to obtain RRs for the specified outcomes. We also determined RRs within the child welfare population relative to the same population two years before entry into care.

Results:

We identified 8279 children and adolescents in care for the first time and a comparison cohort of 353 050 children and adolescents not in care. Outcome rates were higher among those in care than in the comparison cohort for suicide (adjusted RR 3.54, 95% confidence interval [CI] 2.11–5.95), attempted suicide (adjusted RR 2.11, 95% CI 1.84–2.43) and all other outcomes. However, adjusted RRs for attempted suicide (RR 0.27, 95% CI 0.21–0.34), admissions to hospital and physician visits decreased after entry into care.

Interpretation:

Children and adolescents in care were at greater risk of suicide and attempting suicide than those who were not in care. Rates of suicide attempts and hospital admissions within this population were highest before entry into care and decreased thereafter.

Perinatal programming, a dominant theory for the origins of cardiovascular disease, proposes that environmental stimuli influence developmental pathways during critical periods of prenatal and postnatal development, inducing permanent changes in metabolism. In this paper, we present evidence for the perinatal programming of asthma via the intestinal microbiome. While epigenetic mechanisms continue to provide new explanations for the programming hypothesis of asthma development, it is increasingly apparent that the intestinal microbiota plays an independent and potentially interactive role. Commensal gut bacteria are essential to immune system development, and exposures disrupting the infant gut microbiota have been linked to asthma. This paper summarizes the recent findings that implicate caesarean delivery, breastfeeding, perinatal stress, probiotics, and antibiotics as modifiers of infant gut microbiota in the development of asthma.

Background

A broad variety of natural environmental stimuli, genotypic influences and timing all contribute to expression of protective versus maladaptive immune responses and the resulting clinical outcomes in humans. The role of commonly co-segregating Toll-like receptor 4 (TLR4) non-synonymous single nucleotide polymorphisms Asp299Gly and Thr399Ile in this process remains highly controversial. Moreover, what differential impact these polymorphisms might have in at risk populations with respiratory dysfunction, such as current asthma or a history of infantile bronchiolitis, has never been examined. Here we determine the importance of these polymorphisms in modulating LPS and respiratory syncytial virus (RSV) - driven cytokine responses. We focus on both healthy children and those with clinically relevant respiratory dysfunction.

Methodology

To elucidate the impact of TLR4 Asp299Gly and Thr399Ile on cytokine production, we assessed multiple immune parameters in over 200 pediatric subjects aged 7–9. Genotyping was followed by quantification of pro- and anti-inflammatory cytokine responses by fresh peripheral blood mononuclear cells upon acute exposure to LPS or RSV.

Principal Findings

In contrast to early reports, neither SNP influenced immune responses evoked by LPS exposure or RSV infection, as measured by the intermediate phenotype of pro- and anti-inflammatory cytokine responses to these ubiquitous agents. There is no evidence of altered sensitivity in populations with “at risk” clinical phenotypes.

Conclusions/Significance

Genomic medicine seeks to inform clinical practice. Determination of the TLR4 Asp299Gly/Thr399Ile haplotype is of no clinical benefit in predicting the nature or intensity of cytokine production in children whether currently healthy or among specific at-risk groups characterized by prior infantile broncholitis or current asthma.

The objective of this study was to determine the risk of peanut allergy in siblings of peanut-allergic children. In 2005-2006, 560 households of children born in 1995 in the province of Manitoba, Canada, were surveyed. The index children (8-to 10-year-olds) were assessed by a pediatric allergist and had skin-prick testing and/or capRAST for peanut allergy. Surveys were completed by parents for siblings to determine the presence of peanut allergy. Of 560 surveys, 514 (92%) were completed. Twenty-nine (5.6%) index children were peanut allergic. Fifteen of 900 (1.7%) siblings had peanut allergy. Four of 47 (8.5%) were siblings of peanut-allergic children and 11 of 853 (1.3%) were siblings of non-peanut-allergic children. The risk of peanut allergy was markedly increased in siblings of a peanut-allergic child (odds ratio 6.72, 95% confidence interval 2.04-22.12). Siblings of peanut-allergic children are much more likely to be allergic to peanut. An allergy assessment by a qualified allergist should be routinely recommended before feeding peanut to these children.

BACKGROUND:

Ideally, on diagnosis of asthma in a child, parents are counselled to decrease environmental tobacco smoke exposure to their children.

OBJECTIVE:

To determine whether a diagnosis of asthma in children altered parental smoking behaviour toward a reduction in environmental tobacco smoke exposure.

METHODS:

In 2002/2003, a survey was sent to 12,556 households with children born in 1995 in Manitoba. Parents were asked whether their seven-year-old child had asthma, and whether smokers were present in the home in 1995 and/or currently. The likelihood (OR) of a change in parental smoking behaviour was determined according to the presence of asthma in their child, a family history of asthma, the location of residence (rural or urban) and their socioeconomic status.

RESULTS:

A total of 3580 surveys (28.5%) were returned. The overall prevalence of parental smoking in 1995 and 2002/2003 was 32.2% and 23.4%, respectively (31.9%/23.2% and 32.3%/23.6% in rural and urban environments, respectively). In 2002/2003, the prevalence of parental smoking in homes with asthmatic children was 29.8%. Parents were not more likely to quit smoking (OR=1.01, 95% CI 0.66 to 1.54) or smoke outside (OR=1.02, 95% CI 0.56 to 1.83) if their child developed asthma. Parental smoking behaviour (quit smoking or smoked outside) did not change if there was a positive family history of asthma (OR=1.04, 95% CI 0.78 to 1.37), if they lived in a rural or urban location (OR=0.94, 95% CI 0.71 to 1.23), or if they were from a low- or high-income household (OR=1.12, 95% CI 0.85 to 1.47).

CONCLUSIONS:

The likelihood of altering parental smoking behaviour occurred independently of a diagnosis of asthma in their child, a family history of asthma, the location of residence and their socioeconomic status.

Background

Regulatory bodies worldwide, including Health Canada, have issued warnings about prescribing antidepressants to children and adolescents. We sought to determine whether the Health Canada warning had the desired effects on prescribing patterns and outcomes and whether it had any unintended health consequences.

Methods

We examined data from prescription and health care databases representing more than 265 000 children, adolescents and young adults annually to determine changes in the rates of antidepressant prescription, use of health services and outcomes in these populations in the 9 years before and the 2 years after the Health Canada warning. We also examined the data for unintended changes in these rates among patients with anxiety disorders. We used young adults as the comparison group because they were not targeted by the warning.

Results

Following the warning, the rate of antidepressant prescriptions decreased among children and adolescents (relative risk [RR] 0.86, 95% confidence interval [CI] 0.81–0.91) and among young adults (RR 0.90, 95% CI 0.86–0.93). Ambulatory visits because of depression decreased among children and adolescents (RR 0.90, 95% CI 0.85–0.96) and young adults (RR 0.91, 95% CI 0.87–0.96). The rate of completed suicides among children and adolescents rose significantly after the warning (RR 1.25, 95% CI 1.08–1.44; annual rate per 1000 = 0.04 before and 0.15 after the warning). There was no equivalent change in the rate of completed suicides among young adults (RR 1.01, 95% CI 0.93–1.10; annual rate per 1000 = 0.15 before and 0.22 after the warning). Among patients with an anxiety disorder, the prescription rates did not change among children and adolescents, except for a decrease in the use of selective serotonin reuptake inhibitors other than fluoxetine, but the rates among young adults changed similar to the pattern of changes in the overall prescribing of antidepressants. There was also a significant decrease in the rate of physician visits because of anxiety disorders among young adults after the warning.

Interpretation

Health advisories and warnings issued by regulatory bodies may have unintended consequences on the provision of care, delivery of health services and clinical outcomes. Further efforts are required to ensure that health warnings do not result in unexpected harm.

Background

Evidence-based guidelines for antibiotic use are well established, but nonadherence to these guidelines continues. This study was undertaken to determine child, household and physician factors predictive of nonadherence to evidence-based antibiotic prescribing in children.

Methods

The prescription and health care records of 20 000 Manitoba children were assessed for 2 criteria of nonadherence to evidence-based antibiotic prescribing during the period from fiscal year 1996 (April 1996 to March 1997) to fiscal year 2000: receipt of an antibiotic for a viral respiratory tract infection (VRTI) and initial use of a second-line agent for acute otitis media, pharyngitis, pneumonia, urinary tract infection or cellulitis. The likelihood of nonadherence to evidence-based prescribing, according to child demographic characteristics, physician factors (specialty and place of training) and household income, was determined from hierarchical linear modelling. Child visits were nested within physicians, and the most parsimonious model was selected at p < 0.05.

Results

During the study period, 45% of physician visits for VRTI resulted in an antibiotic prescription, and 20% of antibiotic prescriptions were for second-line antibiotics. Relative to general practitioners, the odds ratio for antibiotic prescription for a VRTI was 0.51 (95% confidence interval [CI] 0.42–0.62) for pediatricians and 1.58 (95% CI 1.03–2.42) for other specialists. The likelihood that an antibiotic would be prescribed for a VRTI was 0.99 for each successive $10 000 increase in household income. Pediatricians and other specialists were more likely than general practitioners to prescribe second-line antibiotics for initial therapy. Both criteria for nonadherence to evidence-based prescribing were 40% less likely among physicians trained in Canada or the United States than among physicians trained elsewhere.

Interpretation

The links that we identified between nonadherence to evidence-based antibiotic prescribing in children and physician specialty and location of training suggest opportunities for intervention. The independent effect of household income indicates that parents also have an important role.

Background

Decreases in antibiotic use were widely reported in the 1990s. This study was undertaken to determine trends in the use of antibiotics from fiscal year (FY) 1995 (April 1995 to March 1996) to FY 2001 in a complete population of Manitoba children.

Methods

Using Manitoba's health care databases, we determined annual population-based rates of antibiotic prescription among children by antibiotic class (narrow-spectrum and broader-spectrum antibiotics), age group, physician diagnosis (e.g., otitis media or bronchitis) and neighbourhood income in urban areas (derived from the 1996 census). Antibiotic prescription rates were generated within a generalized linear model framework with general estimating equations, and differences between FY 2001 and FY 1995 were tested. Differences in antibiotic use over time were compared across antibiotic classes, age groups, diagnoses and income neighbourhoods.

Results

The overall antibiotic prescription rate decreased by almost one-third, from 1.2 prescriptions per child in FY 1995 to 0.9 prescriptions in FY 2001. Total antibiotic use declined for all respiratory tract infections; decreases were greatest for the sulfonamides (decrease to less than one-third the FY 1995 rate) and narrow-spectrum macrolides (decrease to less than half the FY 1995 rate). In contrast, the FY 2001 rate for broader-spectrum macrolides was as much as 12.5 times the FY 1995 rate. Otitis media accounted for one-quarter of the use of the latter agents. Preschool children and low-income children received the greatest number of antibiotic prescriptions. Declines in antibiotic prescriptions were of a lesser magnitude for low-income children (for whom rates in FY 2001 were four-fifths the rates in FY 1995) than for higher-income children (for whom rates in FY 2001 were about two-thirds the rates in FY 1995).

Interpretation

Overall, antibiotic use declined over the late 1990s in this population of Canadian children, but the increasing use of broader-spectrum macrolides and higher rates of antibiotic use among preschool and low-income children may have implications for antibiotic resistance.

Background

Drug benefit policies are an important determinant of a population's use of prescription drugs. This study was undertaken to determine whether a change in a provincial drug benefit policy, from a fixed deductible and copayment system to an income-based deductible system, resulted in changes in receipt of prescriptions for inhaled corticosteroids by Manitoba children with asthma.

Methods

Using Manitoba's health care administrative databases, we identified a population-based cohort of 10 703 school-aged children who met our case definition for asthma treatment before and after the province's drug benefit policy was changed in April 1996. The effects of the program change on the probability of receiving a prescription for an inhaled corticosteroid and on the mean number of inhaled corticosteroid doses dispensed were compared between a group of children insured under other drug programs (the comparison group) and 2 groups of children insured under the deductible program: those living in low-income neighbourhoods and those living in higher-income neighbourhoods. All analyses were adjusted for a measure of asthma severity.

Results

For higher-income children with severe asthma who were covered by the deductible program, the probability of receiving an inhaled corticosteroid prescription and the mean annual number of inhaled corticosteroid doses declined after the change to the drug policy. A trend toward a decrease in receipt of prescriptions was also observed for low-income children, but receipt of prescriptions was unaltered in the comparison group. Before the policy change, among children with severe asthma, the mean annual number of inhaled corticosteroid doses was lowest for low-income children, and this pattern persisted after the change. Among children with mild to moderate asthma, those covered by the deductible program (both low income and higher income) were less likely to receive prescriptions for inhaled corticosteroids than those in the comparison group, and this difference was statistically significant for the higher-income children.

Interpretation

The change to an income-based drug benefit policy was associated with a decrease in the use of inhaled corticosteroids by higher-income children with severe asthma and did not improve use of these drugs by low- income children.

Objectives

Lower socioeconomic status (SES) is consistently associated with poor health, yet little is known about the biological mechanisms underlying this inequality. In children, we examined the impact of early-life SES trajectories on the intensity of global innate immune activation, recognizing that excessive activation can be a precursor to inflammation and chronic disease.

Methods

Stimulated interleukin-6 production, a measure of immune responsiveness, was analyzed ex vivo for 267 Canadian schoolchildren from a 1995 birth cohort in Manitoba, Canada. Childhood SES trajectories were determined from parent-reported housing data using a longitudinal latent-class modeling technique. Multivariate regression was conducted with adjustment for potential confounders.

Results

SES was inversely associated with innate immune responsiveness (p = 0.003), with persistently low-SES children exhibiting responses more than twice as intense as their high-SES counterparts. Despite initially lower SES, responses from children experiencing increasing SES trajectories throughout childhood were indistinguishable from high-SES children. Low-SES effects were strongest among overweight children (p<0.01). Independent of SES trajectories, immune responsiveness was increased in First Nations children (p<0.05) and urban children with atopic asthma (p<0.01).

Conclusions

These results implicate differential immune activation in the association between SES and clinical outcomes, and broadly imply that SES interventions during childhood could limit or reverse the damaging biological effects of exposure to poverty during the preschool years.

Background

Genetic variants at the vitamin D receptor (VDR) locus are associated with asthma and atopy. We hypothesized that polymorphisms in other genes of the vitamin D pathway are associated with asthma or atopy.

Methods

Eleven candidate genes were chosen for this study, five of which code for proteins in the vitamin D metabolism pathway (CYP27A1, CYP27B1, CYP2R1, CYP24A1, GC) and six that are known to be transcriptionally regulated by vitamin D (IL10, IL1RL1, CD28, CD86, IL8, SKIIP). For each gene, we selected a maximally informative set of common SNPs (tagSNPs) using the European-derived (CEU) HapMap dataset. A total of 87 SNPs were genotyped in a French-Canadian family sample ascertained through asthmatic probands (388 nuclear families, 1064 individuals) and evaluated using the Family Based Association Test (FBAT) program. We then sought to replicate the positive findings in four independent samples: two from Western Canada, one from Australia and one from the USA (CAMP).

Results

A number of SNPs in the IL10, CYP24A1, CYP2R1, IL1RL1 and CD86 genes were modestly associated with asthma and atopy (p < 0.05). Two-gene models testing for both main effects and the interaction were then performed using conditional logistic regression. Two-gene models implicating functional variants in the IL10 and VDR genes as well as in the IL10 and IL1RL1 genes were associated with asthma (p < 0.0002). In the replicate samples, SNPs in the IL10 and CYP24A1 genes were again modestly associated with asthma and atopy (p < 0.05). However, the SNPs or the orientation of the risk alleles were different between populations. A two-gene model involving IL10 and VDR was replicated in CAMP, but not in the other populations.

Conclusion

A number of genes involved in the vitamin D pathway demonstrate modest levels of association with asthma and atopy. Multilocus models testing genes in the same pathway are potentially more effective to evaluate the risk of asthma, but the effects are not uniform across populations.