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1.  Preterm Birth and Childhood Wheezing Disorders: A Systematic Review and Meta-Analysis 
PLoS Medicine  2014;11(1):e1001596.
In a systematic review and meta-analysis, Jasper Been and colleagues investigate the association between preterm birth and the development of wheezing disorders in childhood.
Please see later in the article for the Editors' Summary
Background
Accumulating evidence implicates early life factors in the aetiology of non-communicable diseases, including asthma/wheezing disorders. We undertook a systematic review investigating risks of asthma/wheezing disorders in children born preterm, including the increasing numbers who, as a result of advances in neonatal care, now survive very preterm birth.
Methods and Findings
Two reviewers independently searched seven online databases for contemporaneous (1 January 1995–23 September 2013) epidemiological studies investigating the association between preterm birth and asthma/wheezing disorders. Additional studies were identified through reference and citation searches, and contacting international experts. Quality appraisal was undertaken using the Effective Public Health Practice Project instrument. We pooled unadjusted and adjusted effect estimates using random-effects meta-analysis, investigated “dose–response” associations, and undertook subgroup, sensitivity, and meta-regression analyses to assess the robustness of associations.
We identified 42 eligible studies from six continents. Twelve were excluded for population overlap, leaving 30 unique studies involving 1,543,639 children. Preterm birth was associated with an increased risk of wheezing disorders in unadjusted (13.7% versus 8.3%; odds ratio [OR] 1.71, 95% CI 1.57–1.87; 26 studies including 1,500,916 children) and adjusted analyses (OR 1.46, 95% CI 1.29–1.65; 17 studies including 874,710 children). The risk was particularly high among children born very preterm (<32 wk gestation; unadjusted: OR 3.00, 95% CI 2.61–3.44; adjusted: OR 2.81, 95% CI 2.55–3.12). Findings were most pronounced for studies with low risk of bias and were consistent across sensitivity analyses. The estimated population-attributable risk of preterm birth for childhood wheezing disorders was ≥3.1%.
Key limitations related to the paucity of data from low- and middle-income countries, and risk of residual confounding.
Conclusions
There is compelling evidence that preterm birth—particularly very preterm birth—increases the risk of asthma. Given the projected global increases in children surviving preterm births, research now needs to focus on understanding underlying mechanisms, and then to translate these insights into the development of preventive interventions.
Review Registration
PROSPERO CRD42013004965
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Most pregnancies last around 40 weeks, but worldwide, more than 11% of babies are born before 37 weeks of gestation (the period during which a baby develops in its mother's womb). Preterm birth is a major cause of infant death—more than 1 million babies die annually from preterm birth complications—and the number of preterm births is increasing globally. Multiple pregnancies, infections, and chronic (long-term) maternal conditions such as diabetes can all cause premature birth, but the cause of many preterm births is unknown. The most obvious immediate complication that is associated with preterm birth is respiratory distress syndrome. This breathing problem, which is more common in early preterm babies than in near-term babies, occurs because the lungs of premature babies are structurally immature and lack pulmonary surfactant, a unique mixture of lipids and proteins that coats the inner lining of the lungs and helps to prevent the collapse of the small air sacs in the lungs that absorb oxygen from the air. Consequently, preterm babies often need help with their breathing and oxygen supplementation.
Why Was This Study Done?
Improvements in the management of prematurity mean that more preterm babies survive today than in the past. However, accumulating evidence suggests that early life events are involved in the subsequent development of non-communicable diseases (non-infectious chronic diseases). Given the increasing burden of preterm birth, a better understanding of the long-term effects of preterm birth is essential. Here, the researchers investigate the risks of asthma and wheezing disorders in children who are born preterm by undertaking a systematic review (a study that uses predefined criteria to identify all the research on a given topic) and a meta-analysis (a statistical method for combining the results of several studies). Asthma is a chronic condition that is caused by inflammation of the airways. In people with asthma, the airways can react very strongly to allergens such as animal fur and to irritants such as cigarette smoke. Exercise, cold air, and infections can also trigger asthma attacks, which can sometimes be fatal. The symptoms of asthma include wheezing (a high-pitched whistling sound during breathing), coughing, chest tightness, and shortness of breath. Asthma cannot be cured, but drugs can relieve its symptoms and prevent acute asthma attacks.
What Did the Researchers Do and Find?
The researchers identified 30 studies undertaken between 1995 and the present (a time span chosen to allow for recent changes in the management of prematurity) that investigated the association between preterm birth and asthma/wheezing disorders in more than 1.5 million children. Across the studies, 13.7% of preterm babies developed asthma/wheezing disorders during childhood, compared to only 8.3% of babies born at term. Thus, the risk of preterm babies developing asthma or a wheezing disorder during childhood was 1.71 times higher than the risk of term babies developing these conditions (an unadjusted odds ratio [OR] of 1.71). In analyses that allowed for confounding factors—other factors that affect the risk of developing asthma/wheezing disorders such as maternal smoking—the risk of preterm babies developing asthma or a wheezing disorder during childhood was 1.46 times higher than that of babies born at term (an adjusted OR of 1.46). Notably, compared to children born at term, children born very early (before 32 weeks of gestation) had about three times the risk of developing asthma/wheezing disorders in unadjusted and adjusted analyses. Finally, the population-attributable risk of preterm birth for childhood wheezing disorders was more than 3.1%. That is, if no preterm births had occurred, there would have been more than a 3.1% reduction in childhood wheezing disorders.
What Do These Findings Mean?
These findings strongly suggest that preterm birth increases the risk of asthma and wheezing disorders during childhood and that the risk of asthma/wheezing disorders increases as the degree of prematurity increases. The accuracy of these findings may be affected, however, by residual confounding. That is, preterm children may share other, unknown characteristics that increase their risk of developing asthma/wheezing disorders. Moreover, the generalizability of these findings is limited by the lack of data from low- and middle-income countries. However, given the projected global increases in children surviving preterm births, these findings highlight the need to undertake research into the mechanisms underlying the association between preterm birth and asthma/wheezing disorders and the need to develop appropriate preventative and therapeutic measures.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001596.
The March of Dimes, a nonprofit organization for pregnancy and baby health, provides information on preterm birth (in English and Spanish)
Nemours, another nonprofit organization for child health, also provides information (in English and Spanish) on premature babies and on asthma (including personal stories)
The UK National Health Service Choices website provides information about premature labor and birth and a real story about having a preterm baby; it provides information about asthma in children (including real stories)
The MedlinePlus Encyclopedia has pages on preterm birth, asthma, asthma in children, and wheezing (in English and Spanish); MedlinePlus provides links to further information on premature birth, asthma, and asthma in children (in English and Spanish)
doi:10.1371/journal.pmed.1001596
PMCID: PMC3904844  PMID: 24492409
2.  Effects of BMI, Fat Mass, and Lean Mass on Asthma in Childhood: A Mendelian Randomization Study 
PLoS Medicine  2014;11(7):e1001669.
In this study, Granell and colleagues used Mendelian randomization to investigate causal effects of BMI, fat mass, and lean mass on current asthma at age 7½ years in the Avon Longitudinal Study of Parents and Children (ALSPAC) and found that higher BMI increases the risk of asthma in mid-childhood.
Please see later in the article for the Editors' Summary
Background
Observational studies have reported associations between body mass index (BMI) and asthma, but confounding and reverse causality remain plausible explanations. We aim to investigate evidence for a causal effect of BMI on asthma using a Mendelian randomization approach.
Methods and Findings
We used Mendelian randomization to investigate causal effects of BMI, fat mass, and lean mass on current asthma at age 7½ y in the Avon Longitudinal Study of Parents and Children (ALSPAC). A weighted allele score based on 32 independent BMI-related single nucleotide polymorphisms (SNPs) was derived from external data, and associations with BMI, fat mass, lean mass, and asthma were estimated. We derived instrumental variable (IV) estimates of causal risk ratios (RRs). 4,835 children had available data on BMI-associated SNPs, asthma, and BMI. The weighted allele score was strongly associated with BMI, fat mass, and lean mass (all p-values<0.001) and with childhood asthma (RR 2.56, 95% CI 1.38–4.76 per unit score, p = 0.003). The estimated causal RR for the effect of BMI on asthma was 1.55 (95% CI 1.16–2.07) per kg/m2, p = 0.003. This effect appeared stronger for non-atopic (1.90, 95% CI 1.19–3.03) than for atopic asthma (1.37, 95% CI 0.89–2.11) though there was little evidence of heterogeneity (p = 0.31). The estimated causal RRs for the effects of fat mass and lean mass on asthma were 1.41 (95% CI 1.11–1.79) per 0.5 kg and 2.25 (95% CI 1.23–4.11) per kg, respectively. The possibility of genetic pleiotropy could not be discounted completely; however, additional IV analyses using FTO variant rs1558902 and the other BMI-related SNPs separately provided similar causal effects with wider confidence intervals. Loss of follow-up was unlikely to bias the estimated effects.
Conclusions
Higher BMI increases the risk of asthma in mid-childhood. Higher BMI may have contributed to the increase in asthma risk toward the end of the 20th century.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The global burden of asthma, a chronic (long-term) condition caused by inflammation of the airways (the tubes that carry air in and out of the lungs), has been rising steadily over the past few decades. It is estimated that, nowadays, 200–300 million adults and children worldwide are affected by asthma. Although asthma can develop at any age, it is often diagnosed in childhood—asthma is the most common chronic disease in children. In people with asthma, the airways can react very strongly to allergens such as animal fur or to irritants such as cigarette smoke, becoming narrower so that less air can enter the lungs. Exercise, cold air, and infections can also trigger asthma attacks, which can be fatal. The symptoms of asthma include wheezing, coughing, chest tightness, and shortness of breath. Asthma cannot be cured, but drugs can relieve its symptoms and prevent acute asthma attacks.
Why Was This Study Done?
We cannot halt the ongoing rise in global asthma rates without understanding the causes of asthma. Some experts think obesity may be one cause of asthma. Obesity, like asthma, is increasingly common, and observational studies (investigations that ask whether individuals exposed to a suspected risk factor for a condition develop that condition more often than unexposed individuals) in children have reported that body mass index (BMI, an indicator of body fat calculated by dividing a person's weight in kilograms by their height in meters squared) is positively associated with asthma. Observational studies cannot prove that obesity causes asthma because of “confounding.” Overweight children with asthma may share another unknown characteristic (confounder) that actually causes both obesity and asthma. Moreover, children with asthma may be less active than unaffected children, so they become overweight (reverse causality). Here, the researchers use “Mendelian randomization” to assess whether BMI has a causal effect on asthma. In Mendelian randomization, causality is inferred from associations between genetic variants that mimic the effect of a modifiable risk factor and the outcome of interest. Because gene variants are inherited randomly, they are not prone to confounding and are free from reverse causation. So, if a higher BMI leads to asthma, genetic variants associated with increased BMI should be associated with an increased risk of asthma.
What Did the Researchers Do and Find?
The researchers investigated causal effects of BMI, fat mass, and lean mass on current asthma at age 7½ years in 4,835 children enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC, a long-term health project that started in 1991). They calculated an allele score for each child based on 32 BMI-related genetic variants, and estimated associations between this score and BMI, fat mass and lean mass (both measured using a special type of X-ray scanner; in children BMI is not a good indicator of “fatness”), and asthma. They report that the allele score was strongly associated with BMI, fat mass, and lean mass, and with childhood asthma. The estimated causal relative risk (risk ratio) for the effect of BMI on asthma was 1.55 per kg/m2. That is, the relative risk of asthma increased by 55% for every extra unit of BMI. The estimated causal relative risks for the effects of fat mass and lean mass on asthma were 1.41 per 0.5 kg and 2.25 per kg, respectively.
What Do These Findings Mean?
These findings suggest that a higher BMI increases the risk of asthma in mid-childhood and that global increases in BMI toward the end of the 20th century may have contributed to the global increase in asthma that occurred at the same time. It is possible that the observed association between BMI and asthma reported in this study is underpinned by “genetic pleiotropy” (a potential limitation of all Mendelian randomization analyses). That is, some of the genetic variants included in the BMI allele score could conceivably also increase the risk of asthma. Nevertheless, these findings suggest that public health interventions designed to reduce obesity may also help to limit the global rise in asthma.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001669.
The US Centers for Disease Control and Prevention provides information on asthma and on all aspects of overweight and obesity (in English and Spanish)
The World Health Organization provides information on asthma and on obesity (in several languages)
The UK National Health Service Choices website provides information about asthma, about asthma in children, and about obesity (including real stories)
The Global Asthma Report 2011 is available
The Global Initiative for Asthma released its updated Global Strategy for Asthma Management and Prevention on World Asthma Day 2014
Information about the Avon Longitudinal Study of Parents and Children is available
MedlinePlus provides links to further information on obesity in children, on asthma, and on asthma in children (in English and Spanish
Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001669
PMCID: PMC4077660  PMID: 24983943
3.  Association of Secondhand Smoke Exposure with Pediatric Invasive Bacterial Disease and Bacterial Carriage: A Systematic Review and Meta-analysis 
PLoS Medicine  2010;7(12):e1000374.
Majid Ezzati and colleagues report the findings of a systematic review and meta-analysis that probes the association between environmental exposure to secondhand smoke and the epidemiology of pediatric invasive bacterial disease.
Background
A number of epidemiologic studies have observed an association between secondhand smoke (SHS) exposure and pediatric invasive bacterial disease (IBD) but the evidence has not been systematically reviewed. We carried out a systematic review and meta-analysis of SHS exposure and two outcomes, IBD and pharyngeal carriage of bacteria, for Neisseria meningitidis (N. meningitidis), Haemophilus influenzae type B (Hib), and Streptococcus pneumoniae (S. pneumoniae).
Methods and Findings
Two independent reviewers searched Medline, EMBASE, and selected other databases, and screened articles for inclusion and exclusion criteria. We identified 30 case-control studies on SHS and IBD, and 12 cross-sectional studies on SHS and bacterial carriage. Weighted summary odd ratios (ORs) were calculated for each outcome and for studies with specific design and quality characteristics. Tests for heterogeneity and publication bias were performed. Compared with those unexposed to SHS, summary OR for SHS exposure was 2.02 (95% confidence interval [CI] 1.52–2.69) for invasive meningococcal disease, 1.21 (95% CI 0.69–2.14) for invasive pneumococcal disease, and 1.22 (95% CI 0.93–1.62) for invasive Hib disease. For pharyngeal carriage, summary OR was 1.68 (95% CI, 1.19–2.36) for N. meningitidis, 1.66 (95% CI 1.33–2.07) for S. pneumoniae, and 0.96 (95% CI 0.48–1.95) for Hib. The association between SHS exposure and invasive meningococcal and Hib diseases was consistent regardless of outcome definitions, age groups, study designs, and publication year. The effect estimates were larger in studies among children younger than 6 years of age for all three IBDs, and in studies with the more rigorous laboratory-confirmed diagnosis for invasive meningococcal disease (summary OR 3.24; 95% CI 1.72–6.13).
Conclusions
When considered together with evidence from direct smoking and biological mechanisms, our systematic review and meta-analysis indicates that SHS exposure may be associated with invasive meningococcal disease. The epidemiologic evidence is currently insufficient to show an association between SHS and invasive Hib disease or pneumococcal disease. Because the burden of IBD is highest in developing countries where SHS is increasing, there is a need for high-quality studies to confirm these results, and for interventions to reduce exposure of children to SHS.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The deleterious health effects of smoking on smokers are well established, but smoking also seriously damages the health of nonsmokers. Secondhand smoke (SHS), which is released by burning cigarettes and exhaled by smokers, contains hundreds of toxic chemicals that increase the risk of adults developing lung cancer and heart disease. Children, however, are particularly vulnerable to the effects of SHS exposure (also known as passive smoking) because they are still developing physically. In addition, children have little control over their indoor environment and thus can be heavily exposed to SHS. Exposure to SHS increases the risk of ear infections, asthma, respiratory symptoms (coughing, sneezing, and breathlessness), and lung infections such as pneumonia and bronchitis in young children and the risk of sudden infant death syndrome during the first year of life.
Why Was This Study Done?
Several studies have also shown an association between SHS exposure (which damages the lining of the mouth, throat, and lungs and decreases immune defenses) and potentially fatal invasive bacterial disease (IBD) in children. In IBD, bacteria invade the body and grow in normally sterile sites such as the blood (bacteremia) and the covering of the brain (meningitis). Three organisms are mainly responsible for IBD in children—Streptococcus pneumoniae, Haemophilus influenzae type B (Hib), and Neisseria meningitidis. In 2000, S. pneumonia (pneumococcal disease) alone killed nearly one million children. Here, the researchers undertake a systematic review and meta-analysis of the association between SHS exposure in children and two outcomes—IBD and the presence of IBD-causing organisms in the nose and throat (bacterial carriage). A systematic review uses predefined criteria to identify all the research on a given topic; meta-analysis is a statistical method that combines the results of several studies. By combining data, it is possible to get a clearer view of the causes of a disease than is possible from individual studies.
What Did the Researchers Do and Find?
The researchers identified 30 case-control studies that compared the occurrence of IBD over time in children exposed to SHS with its occurrence in children not exposed to SHS. They also identified 12 cross-sectional studies that measured bacterial carriage at a single time point in children exposed and not exposed to SHS. The researchers used the data from these studies to calculate a “summary odds ratio” (OR) for each outcome—a measure of how SHS exposure affected the likelihood of each outcome. Compared with children unexposed to SHS, exposure to SHS doubled the likelihood of invasive meningococcal disease (a summary OR for SHS exposure of 2.02). Summary ORs for invasive pneumococcal disease and Hib diseases were 1.21 and 1.22, respectively. However, these small increases in the risk of developing these IBDs were not statistically significant unlike the increase in the risk of developing meningococcal disease. That is, they might have occurred by chance. For bacterial carriage, summary ORs for SHS exposure were 1.68 for N. meningitidis, 1.66 for S. pneumonia (both these ORs were statistically significant), and 0.96 for Hib (a nonsignificant decrease in risk).
What Do These Findings Mean?
These findings indicate that SHS exposure is significantly associated with invasive meningococcal disease among children. However, the evidence that SHS exposure is associated with invasive pneumococcal and Hib disease is only suggestive. These findings also indicate that exposure to SHS is associated with an increased carriage of N. meningitidis and S. pneumoniae. The accuracy and generalizability of these findings is limited by the small number of studies identified, by the lack of studies from developing countries where SHS exposure is increasing and the burden of IBD is high, and by large variations between the studies in how SHS exposure was measured and IBD diagnosed. Nevertheless, they suggest that, by reducing children's exposure to SHS (by, for example, persuading parents not to smoke at home), the illness and death caused by IBDs among children could be greatly reduced. Such a reduction would be particularly welcome in developing countries where vaccination against IBDs is low.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000374.
The US Centers for Disease Control and Prevention provides information on secondhand smoke, on children and secondhand smoke exposure, on meningitis, and on Hib infection
The US Environmental Protection Agency also provides information on the health effects of exposure to secondhand smoke (in English and Spanish) and a leaflet (also in English and Spanish) entitled Secondhand Tobacco Smoke and the Health of Your Family
The US Office of the Surgeon General provides information on the health consequences of involuntary exposure to tobacco smoke
The World Health Organization provides a range of information on the global tobacco epidemic
The World Health Organization has information on meningococcal disease (in English only) and on Hib (in several languages)
The US National Foundation for Infectious Diseases provides a fact sheet on pneumococcal disease
doi:10.1371/journal.pmed.1000374
PMCID: PMC2998445  PMID: 21151890
4.  Active or Passive Exposure to Tobacco Smoking and Allergic Rhinitis, Allergic Dermatitis, and Food Allergy in Adults and Children: A Systematic Review and Meta-Analysis 
PLoS Medicine  2014;11(3):e1001611.
In a systematic review and meta-analysis, Bahi Takkouche and colleagues examine the associations between exposure to tobacco smoke and allergic disorders in children and adults.
Please see later in the article for the Editors' Summary
Background
Allergic rhinitis, allergic dermatitis, and food allergy are extremely common diseases, especially among children, and are frequently associated to each other and to asthma. Smoking is a potential risk factor for these conditions, but so far, results from individual studies have been conflicting. The objective of this study was to examine the evidence for an association between active smoking (AS) or passive exposure to secondhand smoke and allergic conditions.
Methods and Findings
We retrieved studies published in any language up to June 30th, 2013 by systematically searching Medline, Embase, the five regional bibliographic databases of the World Health Organization, and ISI-Proceedings databases, by manually examining the references of the original articles and reviews retrieved, and by establishing personal contact with clinical researchers. We included cohort, case-control, and cross-sectional studies reporting odds ratio (OR) or relative risk (RR) estimates and confidence intervals of smoking and allergic conditions, first among the general population and then among children.
We retrieved 97 studies on allergic rhinitis, 91 on allergic dermatitis, and eight on food allergy published in 139 different articles. When all studies were analyzed together (showing random effects model results and pooled ORs expressed as RR), allergic rhinitis was not associated with active smoking (pooled RR, 1.02 [95% CI 0.92–1.15]), but was associated with passive smoking (pooled RR 1.10 [95% CI 1.06–1.15]). Allergic dermatitis was associated with both active (pooled RR, 1.21 [95% CI 1.14–1.29]) and passive smoking (pooled RR, 1.07 [95% CI 1.03–1.12]). In children and adolescent, allergic rhinitis was associated with active (pooled RR, 1.40 (95% CI 1.24–1.59) and passive smoking (pooled RR, 1.09 [95% CI 1.04–1.14]). Allergic dermatitis was associated with active (pooled RR, 1.36 [95% CI 1.17–1.46]) and passive smoking (pooled RR, 1.06 [95% CI 1.01–1.11]). Food allergy was associated with SHS (1.43 [1.12–1.83]) when cohort studies only were examined, but not when all studies were combined.
The findings are limited by the potential for confounding and bias given that most of the individual studies used a cross-sectional design. Furthermore, the studies showed a high degree of heterogeneity and the exposure and outcome measures were assessed by self-report, which may increase the potential for misclassification.
Conclusions
We observed very modest associations between smoking and some allergic diseases among adults. Among children and adolescents, both active and passive exposure to SHS were associated with a modest increased risk for allergic diseases, and passive smoking was associated with an increased risk for food allergy. Additional studies with detailed measurement of exposure and better case definition are needed to further explore the role of smoking in allergic diseases.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The immune system protects the human body from viruses, bacteria, and other pathogens. Whenever a pathogen enters the body, immune system cells called T lymphocytes recognize specific molecules on its surface and release chemical messengers that recruit and activate other types of immune cells, which then attack the pathogen. Sometimes, however, the immune system responds to harmless materials (for example, pollen; scientists call these materials allergens) and triggers an allergic disease such as allergic rhinitis (inflammation of the inside of the nose; hay fever is a type of allergic rhinitis), allergic dermatitis (also known as eczema, a disease characterized by dry, itchy patches on the skin), and food allergy. Recent studies suggest that all these allergic (atopic) diseases are part of a continuous state called the “atopic march” in which individuals develop allergic diseases in a specific sequence that starts with allergic dermatitis during infancy, and progresses to food allergy, allergic rhinitis, and finally asthma (inflammation of the airways).
Why Was This Study Done?
Allergic diseases are extremely common, particularly in children. Allergic rhinitis alone affects 10%–30% of the world's population and up to 40% of children in some countries. Moreover, allergic diseases are becoming increasingly common. Allergic diseases affect the quality of life of patients and are financially costly to both patients and health systems. It is important, therefore, to identify the factors that cause or potentiate their development. One potential risk factor for allergic diseases is active or passive exposure to tobacco smoke. In some countries up to 80% of children are exposed to second-hand smoke so, from a public health point of view, it would be useful to know whether exposure to tobacco smoke is associated with the development of allergic diseases. Here, the researchers undertake a systematic review (a study that uses predefined criteria to identify all the research on a given topic) and a meta-analysis (a statistical approach for combining the results of several studies) to investigate this issue.
What Did the Researchers Do and Find?
The researchers identified 196 observational studies (investigations that observe outcomes in populations without trying to affect these outcomes in any way) that examined the association between smoke exposure and allergic rhinitis, allergic dermatitis, or food allergy. When all studies were analyzed together, allergic rhinitis was not associated with active smoking but was slightly associated with exposure to second-hand smoke. Specifically, compared to people not exposed to second-hand smoke, the pooled relative risk (RR) of allergic rhinitis among people exposed to second-hand smoke was 1.10 (an RR of greater than 1 indicates an increased risk of disease development in an exposed population compared to an unexposed population). Allergic dermatitis was associated with both active smoking (RR = 1.21) and exposure to second-hand smoke (RR = 1.07). In the populations of children and adolescents included in the studies, allergic rhinitis was associated with both active smoking and exposure to second-hand smoke (RRs of 1.40 and 1.09, respectively), as was allergic dermatitis (RRs of 1.36 and 1.06, respectively). Finally food allergy was associated with exposure to second-hand smoke (RR = 1.43) when cohort studies (a specific type of observational study) only were examined but not when all the studies were combined.
What Do These Findings Mean?
These findings provide limited evidence for a weak association between smoke exposure and allergic disease in adults but suggest that both active and passive smoking are associated with a modestly increased risk of allergic diseases in children and adolescents. The accuracy of these findings may be affected by the use of questionnaires to assess smoke exposure and allergic disease development in most of the studies in the meta-analysis and by the possibility that individuals exposed to smoke may have shared other characteristics that were actually responsible for their increased risk of allergic diseases. To shed more light on the role of smoking in allergic diseases, additional studies are needed that accurately measure exposure and outcomes. However, the present findings suggest that, in countries where many people smoke, 14% and 13% of allergic rhinitis and allergic dermatitis, respectively, among children may be attributable to active smoking. Thus, the elimination of active smoking among children and adolescents could prevent one in seven cases of allergic rhinitis and one in eight cases of allergic dermatitis in such countries.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001611.
The UK National Health Service Choices website provides information about allergic rhinitis, hay fever (including personal stories), allergic dermatitis (including personal stories), and food allergy (including personal stories)
The US National Institute of Allergy and Infectious Disease provides information about allergic diseases
The UK not-for-profit organization Allergy UK provides information about all aspects of allergic diseases and a description of the atopic march
MedlinePlus encyclopedia has pages on allergic rhinitis and allergic dermatitis (in English and Spanish)
MedlinePlus provides links to further resources about allergies, eczema, and food allergy (in English and Spanish)
doi:10.1371/journal.pmed.1001611
PMCID: PMC3949681  PMID: 24618794
5.  Environmental tobacco smoke, parental atopy, and childhood asthma. 
Environmental Health Perspectives  2001;109(6):579-582.
We hypothesized that the joint effect of genetic propensity to asthma and exposure to environmental tobacco smoke on the risk of childhood asthma is greater than expected on the basis of their independent effects. We performed a population-based 4-year cohort study of 2,531 children born in Oslo, Norway. We collected information on the child's health and environmental exposures at birth and when the child was 6, 12, 18, and 24 months and 4 years of age. The outcomes of interest were bronchial obstruction during the first 2 years and asthma at the age of 4 years. Parental atopy was defined as a history of maternal or paternal asthma or hay fever. Exposure to environmental tobacco smoke was defined on the basis of questionnaire information on household smokers at birth. In logistic regression analysis adjusting for confounding, parental atopy alone increased the risk of bronchial obstruction [odds ratio 1.62; 95% confidence interval (CI) 1.10-2.40] and asthma (1.66; 95% CI, 1.08-2.54). In children without parental atopy, there was little effect of exposure to environmental tobacco smoke on bronchial obstruction (1.29; 95% CI, 0.88-1.89) and asthma (0.84; 95% CI, 0.53-1.34). The presence of parental atopy and exposure had a substantial effect both on bronchial obstruction (2.88; 95% CI, 1.91-4.32) and asthma (2.68; 95% CI, 1.70-4.22). The results are consistent with the hypothesized joint effect of parental atopy and exposure to environmental tobacco smoke. This phenomenon--denoted as effect modification of environmental exposure by genetic constitution, or gene by environment interaction--suggests that some genetic markers could indicate susceptibility to environmental factors.
PMCID: PMC1240339  PMID: 11445511
6.  WHEEZING AND ASTHMA MAY BE ENHANCED BY BROAD SPECTRUM ANTIBIOTICS USED IN EARLY CHILDHOOD. CONCEPT AND RESULTS OF A PHARMACOEPIDEMIOLOGY STUDY 
One of the mechanisms supposed to explain the increasing prevalence of asthma, among children in particular, is the use of antibiotics because they may modify natural microbial exposure and development of the immune system in early childhood. The aim of this study is to investigate the association between the use of various classes of antibiotics (penicillin, cephalosporin and macrolide derivatives) in early childhood and the medical diagnosis of asthma or wheezing reported by mothers over the follow-up after adjustment for potential confounders and respiratory infections. In a population-based sample of 5-year-olds, a part of the ongoing birth cohort study, the standardized interviews on health outcomes, potential confounders (child’s gender, maternal atopy, parity, prenatal and postnatal environmental tobacco smoke) and the use of antibiotics were gathered from mothers of 310 children. While the overall use of antibiotics during the early childhood was insignificantly associated with asthma (adjusted OR = 1.65, 95%CI: 0.93 – 2.93), the risk estimates were significant both for macrolide antibiotics (adjusted OR=2.14, 95%CI: 1.16–3.95) and cephalosporins (OR=1.98, 95%CI: 1.14–3.37). The significant excess in IRR (incident risk ratio) of wheezing episodes was related only to the use of macrolide antibiotics (adjusted IRR=1.91, 95%CI: 1.12–3.27). The use of other classes of antibiotics was found not to be associated with the medical diagnosis of asthma or wheezing episodes recorded in the study period. Conclusion: as early childhood use of broad spectrum antibiotics is associated with an increased risk of developing asthma in 5-year-olds, it may be hypothesized that the antibiotic- related suppression of allergic inflammatory responses in the course of treatment may later lead to greater than before atopic immune response in Th2 children or an impairment of Th1 immune responses in early childhood.
PMCID: PMC3684948  PMID: 21673367
antibiotics; asthma; childhood; wheezing; Th1 immune responses; allergic reactions
7.  Association between breast feeding and asthma in 6 year old children: findings of a prospective birth cohort study 
BMJ : British Medical Journal  1999;319(7213):815-819.
Objectives
To investigate the association between the duration of exclusive breast feeding and the development of asthma related outcomes in children at age 6 years.
Design
Prospective cohort study.
Setting
Western Australia.
Subjects
2187 children ascertained through antenatal clinics at the major tertiary obstetric hospital in Perth and followed to age 6 years.
Main outcome measures
Unconditional logistic regression to model the association between duration of exclusive breast feeding and outcomes related to asthma or atopy at 6 years of age, allowing for several important confounders: sex, gestational age, smoking in the household, and early childcare.
Results
After adjustment for confounders, the introduction of milk other than breast milk before 4 months of age was a significant risk factor for all asthma and atopy related outcomes in children aged 6 years: asthma diagnosed by a doctor (odds ratio 1.25, 95% confidence interval 1.02 to 1.52); wheeze three or more times since 1 year of age (1.41, 1.14 to 1.76); wheeze in the past year (1.31, 1.05 to 1.64); sleep disturbance due to wheeze within the past year (1.42, 1.07 to 1.89); age when doctor diagnosed asthma (hazard ratio 1.22, 1.03 to 1.43); age at first wheeze (1.36, 1.17 to 1.59); and positive skin prick test reaction to at least one common aeroallergen (1.30, 1.04 to 1.61).
Conclusion
A significant reduction in the risk of childhood asthma at age 6 years occurs if exclusive breast feeding is continued for at least the 4 months after birth. These findings are important for our understanding of the cause of childhood asthma and suggest that public health interventions to optimise breast feeding may help to reduce the community burden of childhood asthma and its associated traits.
Key messagesAsthma is the leading cause of admission to hospital in Australian children and its prevalence is increasingWhether breast feeding protects against asthma or atopy, or both, is controversialAsthma is a complex disease, and the relative risks between breast feeding and asthma or atopy are unlikely to be large; this suggests the need for investigation in a large prospective birth cohort with timely assessment of atopic outcomes and all relevant exposuresExclusive breast feeding for at least 4 months is associated with a significant reduction in the risk of asthma and atopy at age 6 years and with a significant delay in the age at onset of wheezing and asthma being diagnosed by a doctorPublic health interventions to promote an increased duration of exclusive breast feeding may help to reduce the morbidity and prevalence of childhood asthma and atopy
PMCID: PMC314207  PMID: 10496824
8.  Association of Adenotonsillectomy with Asthma Outcomes in Children: A Longitudinal Database Analysis 
PLoS Medicine  2014;11(11):e1001753.
Rakesh Bhattacharjee and colleagues use data from a US private health insurance database to compare asthma severity measures in children one year before and one year after they underwent adenotonsillectomy with asthma measures in those who did not undergo adenotonsillectomy.
Please see later in the article for the Editors' Summary
Background
Childhood asthma and obstructive sleep apnea (OSA), both disorders of airway inflammation, were associated in recent observational studies. Although childhood OSA is effectively treated by adenotonsillectomy (AT), it remains unclear whether AT also improves childhood asthma. We hypothesized that AT, the first line of therapy for childhood OSA, would be associated with improved asthma outcomes and would reduce the usage of asthma therapies in children.
Methods and Findings
Using the 2003–2010 MarketScan database, we identified 13,506 children with asthma in the United States who underwent AT. Asthma outcomes during 1 y preceding AT were compared to those during 1 y following AT. In addition, 27,012 age-, sex-, and geographically matched children with asthma without AT were included to examine asthma outcomes among children without known adenotonsillar tissue morbidity. Primary outcomes included the occurrence of a diagnostic code for acute asthma exacerbation (AAE) or acute status asthmaticus (ASA). Secondary outcomes included temporal changes in asthma medication prescriptions, the frequency of asthma-related emergency room visits (ARERs), and asthma-related hospitalizations (ARHs). Comparing the year following AT to the year prior, AT was associated with significant reductions in AAE (30.2%; 95% CI: 25.6%–34.3%; p<0.0001), ASA (37.9%; 95% CI: 29.2%–45.6%; p<0.0001), ARERs (25.6%; 95% CI: 16.9%–33.3%; p<0.0001), and ARHs (35.8%; 95% CI: 19.6%–48.7%; p = 0.02). Moreover, AT was associated with significant reductions in most asthma prescription refills, including bronchodilators (16.7%; 95% CI: 16.1%–17.3%; p<0.001), inhaled corticosteroids (21.5%; 95% CI: 20.7%–22.3%; p<0.001), leukotriene receptor antagonists (13.4%; 95% CI: 12.9%–14.0%; p<0.001), and systemic corticosteroids (23.7%; 95% CI: 20.9%–26.5%; p<0.001). In contrast, there were no significant reductions in these outcomes in children with asthma who did not undergo AT over an overlapping follow-up period. Limitations of the MarketScan database include lack of information on race and obesity status. Also, the MarketScan database does not include information on children with public health insurance (i.e., Medicaid) or uninsured children.
Conclusions
In a very large sample of privately insured children, AT was associated with significant improvements in several asthma outcomes. Contingent on validation through prospectively designed clinical trials, this study supports the premise that detection and treatment of adenotonsillar tissue morbidity may serve as an important strategy for improving asthma control.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The global burden of asthma has been rising steadily over the past few decades. Nowadays, about 200–300 million adults and children worldwide are affected by asthma, a chronic condition caused by inflammation of the airways (the tubes that carry air in and out of the lungs). Although asthma can develop at any age, it is often diagnosed in childhood—asthma is one of the commonest chronic diseases in children. In the US, for example, asthma affects around 7.1 million children under the age of 18 years and is the third leading cause of hospitalization of children under the age of 15 years. In people with asthma, the airways can react very strongly to allergens such as animal fur or to irritants such as cigarette smoke. Exercise, cold air, and infections can trigger asthma attacks, which can be fatal. The symptoms of asthma include wheezing, coughing, chest tightness, and shortness of breath. Asthma cannot be cured, but drugs can relieve its symptoms and prevent acute asthma attacks.
Why Was This Study Done?
Recent studies have found an association between severe childhood asthma and obstructive sleep apnea (OSA). In OSA, airway inflammation promotes hypertrophy (excess growth) of the adenoids and the tonsils, immune system tissues in the upper airway. During sleep, the presence of hypertrophic adenotonsillar tissues predisposes the walls of the throat to collapse, which results in apnea—a brief interruption in breathing. People with OSA often snore loudly and frequently wake from deep sleep as they struggle to breathe. Childhood OSA, which affects 2%–3% of children, can be effectively treated by removal of the adenoids and tonsils (adenotonsillectomy). Given the association between childhood OSA and severe asthma and given the involvement of airway inflammation in both conditions, might adenotonsillectomy also improve childhood asthma? Here, the researchers analyze data from the MarketScan database, a large database of US patients with private health insurance, to investigate whether adenotonsillectomy is associated with improvements in asthma outcomes and with reductions in the use of asthma therapies in children.
What Did the Researchers Do and Find?
The researchers used the database to identify 13,506 children with asthma who had undergone adenotonsillectomy and to obtain information about asthma outcomes among these children for the year before and the year after the operation. Because asthma severity tends to decrease with age, the researchers also used the database to identify 27,012 age-, sex-, and geographically matched children with asthma who did not have the operation so that they could examine asthma outcomes over an equivalent two-year period in the absence of complications related to adenotonsillar hypertrophy. Comparing the year after adenotonsillectomy with the year before the operation, adenotonsillectomy was associated with a 30% reduction in acute asthma exacerbations, a 37.9% reduction in acute status asthmaticus (an asthma attack that is unresponsive to the drugs usually used to treat attacks), a 25.6% reduction in asthma-related emergency room visits, and a 35.8% reduction in asthma-related hospitalizations. By contrast, among the control children, there was only a 2% reduction in acute asthma exacerbations and only a 7% reduction in acute status asthmaticus over an equivalent two-year period. Adenotonsillectomy was also associated with significant reductions (changes unlikely to have occurred by chance) in prescription refills for most types of drugs used to treat asthma, whereas there were no significant reductions in prescription refills among children with asthma who had not undergone adenotonsillectomy. The study was limited by the lack of measures of race and obesity, which are both associated with severity of asthma.
What Do These Findings Mean?
These findings show that in a large sample of privately insured children in the US, adenotonsillectomy was associated with significant improvements in several asthma outcomes. These results do not show, however, that adenotonsillectomy caused a reduction in the severity of childhood asthma. It could be that the children who underwent adenotonsillectomy (but not those who did not have the operation) shared another unknown factor that led to improvements in their asthma over time. To prove a causal link, it will be necessary to undertake a randomized controlled trial in which the outcomes of groups of children with asthma who are chosen at random to undergo or not undergo adenotonsillectomy are compared. However, with the proviso that there are some risks associated with adenotonsillectomy, these findings suggest that the detection and treatment of adenotonsillar hypertrophy may help to improve asthma control in children.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001753.
The US Centers for Disease Control and Prevention provides information on asthma, including videos, games, and links to other resources for children with asthma
The American Lung Association provides detailed information about asthma and a fact sheet on asthma in children; it also has information about obstructive sleep apnea
The National Sleep Foundation provides information on snoring and obstructive sleep apnea in children
The UK National Health Service Choices website provides information (including some personal stories) about asthma, about asthma in children, and about obstructive sleep apnea
The “Global Asthma Report 2014” will be available in October 2014
MedlinePlus provides links to further information on asthma, on asthma in children, on sleep apnea, and on tonsils and adenoids (in English and Spanish)
doi:10.1371/journal.pmed.1001753
PMCID: PMC4219664  PMID: 25369282
9.  Effects of In Utero and Childhood Tobacco Smoke Exposure and β2-Adrenergic Receptor Genotype on Childhood Asthma and Wheezing 
Pediatrics  2008;122(1):e107-e114.
Objective
Associations between single-nucleotide polymorphisms in the β2-adrenergic receptor gene and asthma and wheeze have been inconsistent. Recent studies indicated that tobacco smoke affects β2-adrenergic receptor gene expression and associations of β2-adrenergic receptor gene variants with asthma in adults. We aimed to investigate the joint effects of in utero and childhood secondhand tobacco smoke exposure and 2 well-characterized functional single-nucleotide polymorphisms (Arg16Gly and Glu27Gln) of β2-adrenergic receptor gene on asthma and wheezing in 3128 non-Hispanic and Hispanic white children of the Children's Health Study.
Methods
We fitted logistic regression models to estimate odds ratios and 95% confidence intervals for the independent and joint effects of these single-nucleotide polymorphisms and in utero and secondhand tobacco smoke exposure on asthma and wheeze outcomes.
Results
Exposures to in utero maternal smoking and secondhand tobacco smoke were associated with wheezing. Children who were homozygous for the Arg16 allele and were exposed to maternal smoking in utero were at a threefold increased risk for lifetime wheeze compared with children who were unexposed and had at least 1 Gly16 allele. We found similar joint effects of secondhand tobacco smoke and Arg16Gly with wheezing. The risk for lifetime, current, and nocturnal wheeze increased with the number of smokers at home among Arg16 homozygous children. The results were consistent in 2 cohorts of children recruited in 1993 and 1996. Diplotype-based analyses were consistent with the single-nucleotide polymorphism–specific results. No associations were found for Glu27Gln.
Conclusions
Both in utero and childhood exposure to tobacco smoke were associated with an increased risk for wheeze in children, and the risks were greater for children with the Arg16Arg genotype or 2 copies of the Arg16–Gln27 diplotype. Exposures to smoking need to be taken into account when evaluating the effects of β2-adrenergic receptor gene variants on respiratory health outcomes.
doi:10.1542/peds.2007-3370
PMCID: PMC2748980  PMID: 18558635
β-2 adrenergic receptor; prenatal exposure; secondhand-smoke exposure; asthma; wheeze
10.  Asthma and allergies in Jamaican children aged 2–17 years: a cross-sectional prevalence survey 
BMJ Open  2012;2(4):e001132.
Objective
To determine the prevalence and severity of asthma and allergies as well as risk factors for asthma among Jamaican children aged 2–17 years.
Design
A cross-sectional, community-based prevalence survey using the International Study of Asthma and Allergies in Childhood questionnaire. The authors selected a representative sample of 2017 children using stratified, multistage cluster sampling design using enumeration districts as primary sampling units.
Setting
Jamaica, a Caribbean island with a total population of approximately 2.6 million, geographically divided into 14 parishes.
Participants
Children aged 2–17 years, who were resident in private households. Institutionalised children such as those in boarding schools and hospitals were excluded from the survey.
Primary and secondary outcome measures
The prevalence and severity of asthma and allergy symptoms, doctor-diagnosed asthma and risk factors for asthma.
Results
Almost a fifth (19.6%) of Jamaican children aged 2–17 years had current wheeze, while 16.7% had self-reported doctor-diagnosed asthma. Both were more common among males than among females. The prevalence of rhinitis, hay fever and eczema among children was 24.5%, 25% and 17.3%, respectively. Current wheeze was more common among children with rhinitis in the last 12 months (44.3% vs 12.6%, p<0.001), hay fever (36.8% vs 13.8%, p<0.001) and eczema (34.1% vs 16.4%, p<0.001). Independent risk factors for current wheeze (ORs, 95% CI) were chest infections in the first year of life 4.83 (3.00 to 7.77), parental asthma 4.19 (2.8 to 6.08), rhinitis in the last 12 months 6.92 (5.16 to 9.29), hay fever 4.82 (3.62 to 6.41), moulds in the home 2.25 (1.16 to 4.45), cat in the home 2.44 (1.66 to 3.58) and dog in the home 1.81 (1.18 to 2.78).
Conclusions
The prevalence of asthma and allergies in Jamaican children is high. Significant risk factors for asthma include chest infections in the first year of life, a history of asthma in the family, allergies, moulds and pets in the home.
Article summary
Article focus
The prevalence of asthma and allergies in both developed and developing countries is continuing to rise.
In some Caribbean countries, asthma is a public health problem associated with high economic costs.
This study determined the prevalence of asthma, allergy symptoms and associated risk factors.
Key messages
We demonstrated that the prevalence of asthma and allergy symptoms among Jamaican children aged 2–17 years is high.
Both the prevalence and severity of asthma symptoms are comparable to that reported among children in high-income countries.
Current wheeze and doctor-diagnosed asthma were more common in males and in children with allergies.
A history of asthma in the family, chest infections in the first year of life, allergies, exposure to moulds and pets in the home were associated with significant risk for asthma.
Identifying children at high risk for asthma and controlling modifiable risk factors is important in reducing the prevalence and morbidity related to asthma.
Strengths and limitations of this study
This is the first national study on asthma and allergies in Jamaica using a nationally representative sample of children with a response rate of 80%.
We used a modified ISAAC protocol in which sampling was done by household rather than by school. Using a population-based sampling strategy; we sampled one child and one adult per household. This approach enabled us to obtain national prevalence estimates for both adults and children in one survey at a reduced cost.
Limitations of this study include the fact that the prevalence of asthma and allergies was based solely on self-reports, no objective measures were done. Also in younger children, caregivers responded to questionnaires.
doi:10.1136/bmjopen-2012-001132
PMCID: PMC3400072  PMID: 22798254
11.  Association of Birth Weight With Asthma-Related Outcomes at Age 2 Years 
Pediatric pulmonology  2006;41(7):643-648.
Summary. Background: Although lower birth weight associated with prematurity raises the risk of asthma in childhood, few prospective studies have examined higher birth weight, and few have separated the two components of birth weight, fetal growth and length of gestation.
Objective. To examine the associations of fetal growth and length of gestation with asthma-related outcomes by age 2 years.
Methods. We studied 1,372 infants and toddlers born after 34 weeks’ gestation in Project Viva, a prospective cohort study of pregnant mothers and their children. The main outcome measures were parent report of (1) any wheezing (or whistling in the chest) from birth to age 2 years, (2) recurrent wheezing during the first 2 years of life, and (3) doctor’s diagnosis of asthma, wheeze or reactive airwaydisease (“asthma”) by age 2. We calculated gestational age from the last menstrual period or ultrasound examination, and determined birth weight for gestational age z-value (“fetal growth”) using US national reference data.
Results. Infants’ mean birth weight was 3,527 (SD, 517; range, 1,559–5,528) grams. By age 2 years, 34% of children had any wheezing, 14% had recurrent wheezing, and 16% had doctor-diagnosed asthma. After adjusting for several parent, child, and household characteristics in logistic regression models, we found that infants with birth weight ≥4,000 g were not more likely to have any wheezing (odds ratio (OR), 0.91; 95% confidence interval (CI): 0.62, 1.34) or doctor-diagnosed asthma (OR, 0.80; 95% CI: 0.49, 1.31) than infants with birth weight 3,500–3,999 g. In models examining length of gestation and fetal growth separately, neither the highest nor the lowest groups of either predictor were associated with the three outcomes. Boys had a higher incidence of asthma-related outcomes than girls, and exposure to passive smoking, parental history of asthma, and exposure to older siblings were all associated with greater risk of recurrent wheeze or asthma-related outcomes at age 2 years.
Conclusion. Although male sex, exposure to smoking, parental history of asthma, and exposure to older siblingswere associated with increased riskof wheezing and asthma-related outcomes in this prospective study of children born after 34 weeks gestation, fetal growth and length of gestation were not.
doi:10.1002/ppul.20427
PMCID: PMC1488724  PMID: 16703577
asthma; birth weight; fetal growth; length of gestation; wheezing
12.  The Long-Term Health Consequences of Child Physical Abuse, Emotional Abuse, and Neglect: A Systematic Review and Meta-Analysis 
PLoS Medicine  2012;9(11):e1001349.
Rosana Norman and colleagues conduct a systematic review and meta-analysis to assess the relationship between child physical abuse, emotional abuse, and neglect, and subsequent mental and physical health outcomes.
Background
Child sexual abuse is considered a modifiable risk factor for mental disorders across the life course. However the long-term consequences of other forms of child maltreatment have not yet been systematically examined. The aim of this study was to summarise the evidence relating to the possible relationship between child physical abuse, emotional abuse, and neglect, and subsequent mental and physical health outcomes.
Methods and Findings
A systematic review was conducted using the Medline, EMBASE, and PsycINFO electronic databases up to 26 June 2012. Published cohort, cross-sectional, and case-control studies that examined non-sexual child maltreatment as a risk factor for loss of health were included. All meta-analyses were based on quality-effects models. Out of 285 articles assessed for eligibility, 124 studies satisfied the pre-determined inclusion criteria for meta-analysis. Statistically significant associations were observed between physical abuse, emotional abuse, and neglect and depressive disorders (physical abuse [odds ratio (OR) = 1.54; 95% CI 1.16–2.04], emotional abuse [OR = 3.06; 95% CI 2.43–3.85], and neglect [OR = 2.11; 95% CI 1.61–2.77]); drug use (physical abuse [OR = 1.92; 95% CI 1.67–2.20], emotional abuse [OR = 1.41; 95% CI 1.11–1.79], and neglect [OR = 1.36; 95% CI 1.21–1.54]); suicide attempts (physical abuse [OR = 3.40; 95% CI 2.17–5.32], emotional abuse [OR = 3.37; 95% CI 2.44–4.67], and neglect [OR = 1.95; 95% CI 1.13–3.37]); and sexually transmitted infections and risky sexual behaviour (physical abuse [OR = 1.78; 95% CI 1.50–2.10], emotional abuse [OR = 1.75; 95% CI 1.49–2.04], and neglect [OR = 1.57; 95% CI 1.39–1.78]). Evidence for causality was assessed using Bradford Hill criteria. While suggestive evidence exists for a relationship between maltreatment and chronic diseases and lifestyle risk factors, more research is required to confirm these relationships.
Conclusions
This overview of the evidence suggests a causal relationship between non-sexual child maltreatment and a range of mental disorders, drug use, suicide attempts, sexually transmitted infections, and risky sexual behaviour. All forms of child maltreatment should be considered important risks to health with a sizeable impact on major contributors to the burden of disease in all parts of the world. The awareness of the serious long-term consequences of child maltreatment should encourage better identification of those at risk and the development of effective interventions to protect children from violence.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Child maltreatment—the abuse and neglect of children—is a global problem. There are four types of child maltreatment—sexual abuse (the involvement of a child in sexual activity that he or she does not understand, is unable to give consent to, or is not developmentally prepared for), physical abuse (the use of physical force that harms the child's health, survival, development, or dignity), emotional abuse (the failure to provide a supportive environment by, for example, verbally threatening the child), and neglect (the failure to provide for all aspects of the child's well-being). Most child maltreatment is perpetrated by parents or parental guardians, many of whom were maltreated themselves as children. Other risk factors for parents abusing their children include poverty, mental health problems, and alcohol and drug misuse. Although there is considerable uncertainty about the frequency and severity of child maltreatment, according to the World Health Organization (WHO) about 20% of women and 5%–10% of men report being sexually abused as children, and the prevalence of physical abuse in childhood may be 25%–50%.
Why Was This Study Done?
Child maltreatment has a large public health impact. Sometimes this impact is immediate and direct (injuries and deaths), but, more often, it is long-term, affecting emotional development and overall health. For child sexual abuse, the relationship between abuse and mental disorders in adult life is well-established. Exposure to other forms of child maltreatment has also been associated with a wide range of psychological and behavioral problems, but the health consequences of physical abuse, emotional abuse, and neglect have not been systematically examined. A better understanding of the long-term health effects of child maltreatment is needed to inform maltreatment prevention strategies and to improve treatment for children who have been abused or neglected. In this systematic review and meta-analysis, the researchers quantify the association between exposure to physical abuse, emotional abuse, and neglect in childhood and mental health and physical health outcomes in later life. A systematic review uses predefined criteria to identify all the research on a given topic; a meta-analysis is a statistical approach that combines the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 124 studies that investigated the relationship between child physical abuse, emotional abuse, or neglect and various health outcomes. Their meta-analysis of data from these studies provides suggestive evidence that child physical abuse, emotional abuse, and neglect are causally linked to mental and physical health outcomes. For example, emotionally abused individuals had a three-fold higher risk of developing a depressive disorder than non-abused individuals (an odds ratio [OR] of 3.06). Physically abused and neglected individuals also had a higher risk of developing a depressive disorder than non-abused individuals (ORs of 1.54 and 2.11, respectively). Other mental health disorders associated with child physical abuse, emotional abuse, or neglect included anxiety disorders, drug abuse, and suicidal behavior. Individuals who had been non-sexually maltreated as children also had a higher risk of sexually transmitted diseases and/or risky sexual behavior than non-maltreated individuals. Finally, there was weak and inconsistent evidence that child maltreatment increased the risk of chronic diseases and lifestyle risk factors such as smoking.
What Do These Findings Mean?
By providing suggestive evidence of a causal link between non-sexual child maltreatment and mental health disorders, drug use, suicide attempts, and sexually transmitted diseases and risky sexual behavior, these findings contribute to our understanding of the non-injury health impacts of child maltreatment. Although most of the studies included in the meta-analysis were undertaken in high-income countries, the findings suggest that this link occurs in both high- and low-to-middle-income countries. They also suggest that neglect may be as harmful as physical and emotional abuse. However, they need to be interpreted carefully because of the limitations of this meta-analysis, which include the possibility that children who have been abused may share other, unrecognized factors that are actually the cause of their later mental health problems. Importantly, this confirmation that physical abuse, emotional abuse, and neglect in childhood are important risk factors for a range of health problems draws attention to the need to develop evidence-based strategies for preventing child maltreatment both to reduce childhood suffering and to alleviate an important risk factor for later health problems.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001349.
The World Health Organization provides information on child maltreatment and its prevention (in several languages); Preventing Child Maltreatment: A Guide to Taking Action and Generating Evidence is a 2006 report produced by WHO and the International Society for Prevention of Child Abuse and Neglect
The US Centers for Disease Control and Prevention provides information on child maltreatment and links to additional resources
The National Society for the Prevention of Cruelty to Children (NSPCC) is a not-for-profit organization that aims to end all cruelty to children in the UK; Childline is a resource provided by the NSPCC that provides help, information, and support to children who are being abused
The Hideout is a UK-based website that helps children and young people understand domestic abuse
Childhelp is a US not-for-profit organization dedicated to helping victims of child abuse and neglect; its website includes a selection of personal stories about child maltreatment
doi:10.1371/journal.pmed.1001349
PMCID: PMC3507962  PMID: 23209385
13.  “Efforts to Reprioritise the Agenda” in China: British American Tobacco's Efforts to Influence Public Policy on Secondhand Smoke in China 
PLoS Medicine  2008;5(12):e251.
Background
Each year, 540 million Chinese are exposed to secondhand smoke (SHS), resulting in more than 100,000 deaths. Smoke-free policies have been demonstrated to decrease overall cigarette consumption, encourage smokers to quit, and protect the health of nonsmokers. However, restrictions on smoking in China remain limited and ineffective. Internal tobacco industry documents show that transnational tobacco companies (TTCs) have pursued a multifaceted strategy for undermining the adoption of restrictions on smoking in many countries.
Methods and Findings
To understand company activities in China related to SHS, we analyzed British American Tobacco's (BAT's) internal corporate documents produced in response to litigation against the major cigarette manufacturers to understand company activities in China related to SHS. BAT has carried out an extensive strategy to undermine the health policy agenda on SHS in China by attempting to divert public attention from SHS issues towards liver disease prevention, pushing the so-called “resocialisation of smoking” accommodation principles, and providing “training” for industry, public officials, and the media based on BAT's corporate agenda that SHS is an insignificant contributor to the larger issue of air pollution.
Conclusions
The public health community in China should be aware of the tactics previously used by TTCs, including efforts by the tobacco industry to co-opt prominent Chinese benevolent organizations, when seeking to enact stronger restrictions on smoking in public places.
Monique Muggli and colleagues study British American Tobacco (BAT) internal documents and find that from the mid 1990s BAT pursued a strategy aimed at influencing the public debate on secondhand smoke in China.
Editors' Summary
Background.
Each year, about one million people die in China from tobacco-caused diseases, including cancer, heart disease, and lung disease. Although most of these deaths occur among smokers—300 million people smoke in China, accounting for one-third of the global “consumption” of cigarettes—more than 100,000 deaths from tobacco-related causes occur annually among the 540 million Chinese people who are exposed to secondhand smoke. Tobacco smoke contains 4,000 known chemicals, 69 of which are known or probable carcinogens, and, when it is produced in enclosed spaces, both smokers and nonsmokers are exposed to its harmful effects. The only effective way to reduce tobacco smoke exposure indoors to acceptable levels is to implement 100% smoke-free environments—ventilation, filtration, and the provision of segregated areas for smokers and nonsmokers are insufficient. Importantly, as well as protecting nonsmokers from secondhand smoke, the implementation of smoke-free public places also reduces the number of cigarettes smoked among continuing smokers, increases the likelihood of smokers quitting, and reduces the chances of young people taking up smoking.
Why Was This Study Done?
Article 8 of the World Health Organization's Framework Convention on Tobacco Control (FCTC; an international public-health treaty that seeks to reduce tobacco-caused death and disease) calls on countries party to the treaty to protect their citizens from secondhand smoke exposure. China became a party to the FCTC in 2005 but restrictions on smoking in public places in China remain limited and ineffective. Previous analyses of internal tobacco industry documents have revealed that transnational tobacco companies (TTCs) have used a multifaceted approach to undermine the adoption of restrictions on smoking in many countries. TTCs have been shown to influence media coverage of secondhand smoke issues and to promote ineffective ventilation and separate smoking and nonsmoking areas in restaurants, bars, and hotels (so-called “resocalization of smoking” accommodation principles) with the aim of undermining smoke-free legislation. In addition, TTCs have created organizations interested in non-tobacco-related diseases to draw attention away from the public-health implications of secondhand smoke. In this study, the researchers ask whether TTCs have used a similar approach to undermine the adoption of restrictions on smoking in China, one of the most coveted cigarette markets in the world by the major TTCs.
What Did the Researchers Do and Find?
The researchers analyzed internal corporate documents produced by British American Tobacco (BAT; the predominant TTC in China) in response to litigation against major cigarette manufacturers stored in document depositories in Minnesota, USA and Guildford, UK. Among these documents, they found evidence that BAT had attempted to divert attention from secondhand smoke issues toward liver disease prevention by funding the Beijing Liver Foundation (BFL) from its inception in 1997 until at least 2002 (the most recent year that BAT's corporate records are available for public review). The researchers also found evidence that BAT had promoted “resocialization of smoking” accommodation principles as a “route to avoid smoking bans” and pushed ventilation and air filtration in airports and in establishments serving food and drink. Finally, the researchers found evidence that BAT had sought to “present the message that ‘tobacco smoke is just one of the sources of air polution [sic] and a very insignificant one compared with other pollutants'” through presentations given to the Chinese tobacco industry and media seminars aimed at Chinese journalists.
What Do These Findings Mean?
These findings indicate that, beginning in the mid 1990s and continuing until at least 2002, BAT has followed an intensive, multi-pronged strategy designed to undermine the health policy agenda on secondhand smoke in China. Given their findings, the researchers suggest that BFL and other charitable organizations in China must be wary of accepting tobacco money and that measures must be taken to improve the transparency and accountability of these and other public organizations. To meet FCTC obligations under Article 5.3 (industry interference), policy makers in China, they suggest, must be made aware of how BAT and other TTCs have repeatedly sought to influence health policy in China by focusing attention toward the adoption of ineffective air filtration and ventilation systems in hospitality venues rather than the implementation of 100% smoke-free environments. Finally, Chinese policy makers and the media need to be better informed about BAT's long-standing attempts to communicate misleading messages to them about the health effects of secondhand smoke.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050251.
The World Health Organization's Regional Office for the Western Pacific provides smoking statistics for China and other countries in the region
The World Health Organization provides information on the health problems associated with secondhand smoke, about its Tobacco Free Initiative (available in several languages), and about the Framework Convention on Tobacco Control (also available in several languages)
MedlinePlus provides links to information about the dangers of secondhand smoke (available in English and Spanish)
The UK National Health Service Smokefree Web site provides information about the advantages of giving up smoking, how to give up smoking, and the dangers associated with secondhand smoke
British American Tobacco documents stored in the Minnesota and Guildford Depositories, including those analyzed in this study, can be searched through the British American Tobacco Documents Archive
doi:10.1371/journal.pmed.0050251
PMCID: PMC2605899  PMID: 19108603
14.  Genome-Wide Association Study Implicates Chromosome 9q21.31 as a Susceptibility Locus for Asthma in Mexican Children 
PLoS Genetics  2009;5(8):e1000623.
Many candidate genes have been studied for asthma, but replication has varied. Novel candidate genes have been identified for various complex diseases using genome-wide association studies (GWASs). We conducted a GWAS in 492 Mexican children with asthma, predominantly atopic by skin prick test, and their parents using the Illumina HumanHap 550 K BeadChip to identify novel genetic variation for childhood asthma. The 520,767 autosomal single nucleotide polymorphisms (SNPs) passing quality control were tested for association with childhood asthma using log-linear regression with a log-additive risk model. Eleven of the most significantly associated GWAS SNPs were tested for replication in an independent study of 177 Mexican case–parent trios with childhood-onset asthma and atopy using log-linear analysis. The chromosome 9q21.31 SNP rs2378383 (p = 7.10×10−6 in the GWAS), located upstream of transducin-like enhancer of split 4 (TLE4), gave a p-value of 0.03 and the same direction and magnitude of association in the replication study (combined p = 6.79×10−7). Ancestry analysis on chromosome 9q supported an inverse association between the rs2378383 minor allele (G) and childhood asthma. This work identifies chromosome 9q21.31 as a novel susceptibility locus for childhood asthma in Mexicans. Further, analysis of genome-wide expression data in 51 human tissues from the Novartis Research Foundation showed that median GWAS significance levels for SNPs in genes expressed in the lung differed most significantly from genes not expressed in the lung when compared to 50 other tissues, supporting the biological plausibility of our overall GWAS findings and the multigenic etiology of childhood asthma.
Author Summary
Asthma is a leading chronic childhood disease with a presumed strong genetic component, but no genes have been definitely shown to influence asthma development. Few genetic studies of asthma have included Hispanic populations. Here, we conducted a genome-wide association study of asthma in 492 Mexican children with asthma, predominantly atopic by skin prick test, and their parents to identify novel genetic variation for childhood asthma. We implicated several polymorphisms in or near TLE4 on chromosome 9q21.31 (a novel candidate region for childhood asthma) and replicated one polymorphism in an independent study of childhood-onset asthmatics with atopy and their parents of Mexican ethnicity. Hispanics have differing proportions of Native American, European, and African ancestries, and we found less Native American ancestry than expected at chromosome 9q21.31. This suggests that chromosome 9q21.31 may underlie ethnic differences in childhood asthma and that future replication would be most effective in populations with Native American ancestry. Analysis of publicly available genome-wide expression data revealed that association signals in genes expressed in the lung differed most significantly from genes not expressed in the lung when compared to 50 other tissues, supporting the biological plausibility of the overall GWAS findings and the multigenic etiology of asthma.
doi:10.1371/journal.pgen.1000623
PMCID: PMC2722731  PMID: 19714205
15.  Indoor air pollution and childhood asthma: effective environmental interventions. 
Environmental Health Perspectives  1995;103(Suppl 6):55-58.
Exposure to indoor air pollutants such as tobacco smoke and dust mites may exacerbate childhood asthma. Environmental interventions to reduce exposures to these pollutants can help prevent exacerbations of the disease. Among the most important interventions is the elimination of environmental tobacco smoke from the environments of children with asthma. However, the effectiveness of reducing asthmatic children's exposure to environmental tobacco smoke on the severity of their symptoms has not yet been systematically evaluated. Dust mite reduction is another helpful environmental intervention. This can be achieved by enclosing the child's mattresses, blankets, and pillows in zippered polyurethane-coated casings. Primary prevention of asthma is not as well understood. It is anticipated that efforts to reduce smoking during pregnancy could reduce the incidence of asthma in children. European studies have suggested that reducing exposure to food and house dust mite antigens during lactation and for the first 12 months of life diminishes the development of allergic disorders in infants with high total IgE in the cord blood and a family history of atopy. Many children with asthma and their families are not receiving adequate counseling about environmental interventions from health care providers or other sources.
PMCID: PMC1518930  PMID: 8549490
16.  High prevalence of asthma symptoms in Warao Amerindian children in Venezuela is significantly associated with open-fire cooking: a cross-sectional observational study 
Respiratory Research  2013;14(1):76.
Background
The International Study on Asthma and Allergies in Childhood (ISAAC) reported a prevalence of asthma symptoms in 17 centers in nine Latin American countries that was similar to prevalence rates reported in non-tropical countries. It has been proposed that the continuous exposure to infectious diseases in rural populations residing in tropical areas leads to a relatively low prevalence of asthma symptoms. As almost a quarter of Latin American people live in rural tropical areas, the encountered high prevalence of asthma symptoms is remarkable. Wood smoke exposure and environmental tobacco smoke have been identified as possible risk factors for having asthma symptoms.
Methods
We performed a cross-sectional observational study from June 1, 2012 to September 30, 2012 in which we interviewed parents and guardians of Warao Amerindian children from Venezuela. Asthma symptoms were defined according to the ISAAC definition as self-reported wheezing in the last 12 months. The associations between wood smoke exposure and environmental tobacco smoke and the prevalence of asthma symptoms were calculated by means of univariate and multivariable logistic regression analyses.
Results
We included 630 children between two and ten years of age. Asthma symptoms were recorded in 164 of these children (26%). The prevalence of asthma symptoms was associated with the cooking method. Children exposed to the smoke produced by cooking on open wood fires were at higher risk of having asthma symptoms compared to children exposed to cooking with gas (AOR 2.12, 95% CI 1.18 - 3.84). Four percent of the children lived in a household where more than ten cigarettes were smoked per day and they had a higher risk of having asthma symptoms compared to children who were not exposed to cigarette smoke (AOR 2.69, 95% CI 1.11 - 6.48).
Conclusion
Our findings suggest that children living in rural settings in a household where wood is used for cooking or where more than ten cigarettes are smoked daily have a higher risk of having asthma symptoms.
doi:10.1186/1465-9921-14-76
PMCID: PMC3723947  PMID: 23870058
Asthma[Mesh]; Wheeze; Woodsmoke; Tobacco smoke pollution[Mesh]; Smoke[Mesh]; Indigenous children
17.  Respiratory symptoms in adults are related to impaired quality of life, regardless of asthma and COPD: results from the European community respiratory health survey 
Background
Respiratory symptoms are common in the general population, and their presence is related to Health-related quality of life (HRQoL). The objective was to describe the association of respiratory symptoms with HRQoL in subjects with and without asthma or COPD and to investigate the role of atopy, bronchial hyperresponsiveness (BHR), and lung function in HRQoL.
Methods
The European Community Respiratory Health Survey (ECRHS) I and II provided data on HRQoL, lung function, respiratory symptoms, asthma, atopy, and BHR from 6009 subjects. Generic HRQoL was assessed through the physical component summary (PCS) score and the mental component summary (MCS) score of the SF-36.
Factor analyses and linear regressions adjusted for age, gender, smoking, occupation, BMI, comorbidity, and study centre were conducted.
Results
Having breathlessness at rest in ECRHS II was associated with mean score (95% CI) impairment in PCS of -8.05 (-11.18, -4.93). Impairment in MCS score in subjects waking up with chest tightness was -4.02 (-5.51, -2.52). The magnitude of HRQoL impairment associated with respiratory symptoms was similar for subjects with and without asthma/COPD. Adjustments for atopy, BHR, and lung function did not explain the association of respiratory symptoms and HRQoL in subjects without asthma and/or COPD.
Conclusion
Subjects with respiratory symptoms had poorer HRQoL; including subjects without a diagnosis of asthma or COPD. These findings suggest that respiratory symptoms in the absence of a medical diagnosis of asthma or COPD are by no means trivial, and that clarifying the nature and natural history of respiratory symptoms is a relevant challenge.
Several community studies have estimated the prevalence of common respiratory symptoms like cough, dyspnoea, and wheeze in adults [1-3]. Although the prevalence varies to a large degree between studies and geographical areas, respiratory symptoms are quite common. The prevalences of respiratory symptoms in the European Community Respiratory Health Study (ECRHS) varied from one percent to 35% [1]. In fact, two studies have reported that more than half of the adult population suffers from one or more respiratory symptoms [4,5].
Respiratory symptoms are important markers of the risk of having or developing disease. Respiratory symptoms have been shown to be predictors for lung function decline [6-8], asthma [9,10], and even all-cause mortality in a general population study [11]. In patients with a known diagnosis of asthma or chronic obstructive pulmonary disease (COPD), respiratory symptoms are important determinants of reduced health related quality of life (HRQoL) [12-15]. The prevalence of respiratory symptoms exceeds the combined prevalences of asthma and COPD, and both asthma and COPD are frequently undiagnosed diseases [16-18]. Thus, the high prevalence of respipratory symptoms may mirror undiagnosed and untreated disease.
The common occurrence of respiratory symptoms calls for attention to how these symptoms affect health also in subjects with no diagnosis of obstructive airways disease. Impaired HRQoL in the presence of respiratory symptoms have been found in two population-based studies [6,19], but no study of respiratory sypmtoms and HRQoL have separate analyses for subjects with and without asthma and COPD, and no study provide information about extensive objective measurements of respiratory health.
The ECRHS is a randomly sampled, multi-cultural, population based cohort study. The ECRHS included measurements of atopy, bronchial hyperresponsiveness (BHR), and lung function, and offers a unique opportunity to investigate how respiratory symptoms affect HRQoL among subjects both with and without obstructive lung disease.
In the present paper we aimed to: 1) Describe the relationship between respiratory symptoms and HRQoL in an international adult general population and: 2) To assess whether this relationship varied with presence of asthma and/or COPD, or presence of objective functional markers like atopy and BHR.
doi:10.1186/1477-7525-8-107
PMCID: PMC2954977  PMID: 20875099
18.  Regular Smoking and Asthma Incidence in Adolescents 
Rationale: Although involuntary exposure to maternal smoking during the in utero period and to secondhand smoke are associated with occurrence of childhood asthma, few studies have investigated the role of active cigarette smoking on asthma onset during adolescence.
Objectives: To determine whether regular smoking is associated with the new onset of asthma during adolescence.
Methods: We conducted a prospective cohort study among 2,609 children with no lifetime history of asthma or wheezing who were recruited from fourth- and seventh-grade classrooms and followed annually in schools in 12 southern California communities. Regular smoking was defined as smoking at least seven cigarettes per day on average over the week before and 300 cigarettes in the year before each annual interview. Incident asthma was defined using new cases of physician-diagnosed asthma.
Measurements and Main Results: Regular smoking was associated with increased risk of new-onset asthma. Children who reported smoking 300 or more cigarettes per year had a relative risk (RR) of 3.9 (95% confidence interval [95% CI], 1.7–8.5) for new-onset asthma compared with nonsmokers. The increased risk from regular smoking was greater in nonallergic than in allergic children. Regular smokers who were exposed to maternal smoking during gestation had the largest risk from active smoking (RR, 8.8; 95% CI, 3.2–24.0).
Conclusions: Regular smoking increased risk for asthma among adolescents, especially for nonallergic adolescents and those exposed to maternal smoking during the in utero period.
doi:10.1164/rccm.200605-722OC
PMCID: PMC2648110  PMID: 16973983
asthma; epidemiology; smoking
19.  Is there an association between wheezing and constipation in preschool children? Explanations from a longitudinal birth cohort 
BMJ Open  2011;1(2):e000237.
Objective
To assess whether wheezing and atopic dermatitis were associated with constipation in preschool children and to what extent shared risk factors contribute to this relationship.
Methods
A population-based sample of 4651 preschool children was used. At the age of 24, 36 and 48 months, a parental report of functional constipation was available according to the Rome II criteria, and data on atopic dermatitis and wheezing were available using age-adapted questionnaires from the International Study of Asthma and Allergies in Childhood. Stepwise multivariate analyses were performed to assess whether body mass index, infection exposure, food allergy and infant nutrition, and parental stress explained the association between wheezing, atopic dermatitis and constipation.
Results
Out of 4651 children, 12–17% had functional constipation between 24 and 48 months. Symptoms of wheezing decreased from 20% to 12% and atopic dermatitis decreased from 30% to 18% at the age of 24 and 48 months respectively. Between the age of 24 and 48 months, wheezing symptoms were significantly associated with functional constipation (OR 1.17; 1.02 to 1.34) but these results were mainly explained by the child's exposure to infections and use of antibiotics (adjusted odds ratio 1.08; 95% CI 0.95 to 1.24). No significant association was found between symptoms of atopic dermatitis and functional constipation (OR 1.08; 95% CI 0.94 to 1.23).
Conclusions
These findings suggest that functional constipation coexists with wheezing in childhood but is mainly explained by the child's infection exposure and use of antibiotics. Therefore, an independent association between respiratory symptoms and functional bowel disorders as suggested in previous studies is questionable.
Article summary
Article focus
Constipation, wheezing and atopic dermatitis are common symptoms in children.
Functional bowel disorders are linked to asthma and atopy in adults.
Functional bowel disorders, asthma and atopic disease may share common risk-factors that may explain coexistence of these symptoms.
Key messages
Wheezing, but not atopic dermatitis, is associated with functional constipation in preschool children. The association is mainly explained by a history of infection exposure.
Hence, the association between wheezing and functional constipation is not independent. Further research is needed to explore whether this result also applies to the outcome of asthma.
Strengths and limitations of this study
Population-based study population. The study group were not selected according to medical care.
This study addresses a topical area that has not been studied sufficiently and can contribute to the discussion of how asthma or atopy may be associated with functional bowel disorders.
This study took into account multiple shared risk factors of wheezing and constipation to shed light on the suggested association in literature.
Symptoms were available only from parental-reported questionnaires. This may lead to misclassification of the symptoms.
Early wheezing in infancy is not a sufficient predictor of childhood asthma.
No data were available regarding parental concerns of the child's health status. Bias may occur when parents with high concerns are more likely to report symptoms in their child as wheezing, constipation and infectious disease.
No data were available on IgE sensitisation, thus conclusions on the assocation between allergic disease and constipation should be made with caution.
doi:10.1136/bmjopen-2011-000237
PMCID: PMC3191603  PMID: 22021889
20.  Allergic diseases and asthma in the family predict the persistence and onset-age of asthma: a prospective cohort study 
Respiratory Research  2014;15(1):152.
Background
Family history of asthma and other allergic diseases have been linked to the risk of childhood asthma previously, but little is known about their effect on the age-of-onset and persistency of asthma until young adulthood.
Methods
We assessed the effect of the family history of asthma and allergic diseases on persistent vs. transient, and early- vs. late-onset persistent asthma in The Espoo Cohort Study 1991–2011, a population-based cohort study of 1623 subjects (follow-up rate 63.2%). The determinants were any family history (any parent or sibling); maternal; paternal; siblings only; parents only; and both siblings and parents. Analyses were conducted separately for asthma and allergic diseases while taking the other disease into account as a confounding factor. The outcomes were persistent, transient, early-onset persistent (<13 years) and late-onset persistent asthma. Adjusted risk ratios (RR) were calculated applying Poisson regression. Q-statistics were used to assess heterogeneity between RRs.
Results
Family history was associated with the different subtypes but the magnitude of effect varied quantitatively. Any family history of asthma was a stronger determinant of persistent (adjusted RR = 2.82, 95% CI 1.99-4.00) than transient asthma (1.65, 1.03-2.65) (heterogeneity: P = 0.07) and on early-onset than late-onset persistent asthma. Also any family history of allergic diseases was a stronger determinant of persistent and early-onset asthma. The impact of paternal asthma continued to young adulthood (early-onset: 3.33, 1.57-7.06 vs. late-onset 2.04, 0.75-5.52) while the influence of maternal asthma decreased with age (Early-onset 3.94, 2.11-7.36 vs. Late-onset 0.88, 0.28-2.81). Paternal allergic diseases did not follow the pattern of paternal asthma, since they showed no association with late-onset asthma. Also the effect estimates for other subtypes were lower than in other hereditary groups (persistent 1.29, 0.75-2.22 vs. transient 1.20, 0.67-2.15 and early-onset 1.86, 0.95-3.64 vs. late-onset 0.64, 0.22-1.80).
Conclusions
Family history of asthma and allergic diseases are strong determinants of asthma, but the magnitude of effect varies according to the hereditary group so that some subtypes have a stronger hereditary component, and others may be more strongly related to environmental exposures. Our results provide useful information for assessing the prognosis of asthma based on a thorough family history.
doi:10.1186/s12931-014-0152-8
PMCID: PMC4255429  PMID: 25427760
Asthma; Allergic diseases; Family history; Heredity; Cohort study; Risk ratio; Longitudinal study; Heterogeneity; Epidemiology; Age of onset
21.  GSTP1 and TNF Gene Variants and Associations between Air Pollution and Incident Childhood Asthma: The Traffic, Asthma and Genetics (TAG) Study 
Environmental Health Perspectives  2014;122(4):418-424.
Background: Genetics may partially explain observed heterogeneity in associations between traffic-related air pollution and incident asthma.
Objective: Our aim was to investigate the impact of gene variants associated with oxidative stress and inflammation on associations between air pollution and incident childhood asthma.
Methods: Traffic-related air pollution, asthma, wheeze, gene variant, and potential confounder data were pooled across six birth cohorts. Parents reported physician-diagnosed asthma and wheeze from birth to 7–8 years of age (confirmed by pediatric allergist in two cohorts). Individual estimates of annual average air pollution [nitrogen dioxide (NO2), particulate matter ≤ 2.5 μm (PM2.5), PM2.5 absorbance, ozone] were assigned to each child’s birth address using land use regression, atmospheric modeling, and ambient monitoring data. Effect modification by variants in GSTP1 (rs1138272/Ala114Val and rs1695/IIe105Val) and TNF (rs1800629/G-308A) was investigated.
Results: Data on asthma, wheeze, potential confounders, at least one SNP of interest, and NO2 were available for 5,115 children. GSTP1 rs1138272 and TNF rs1800629 SNPs were associated with asthma and wheeze, respectively. In relation to air pollution exposure, children with one or more GSTP1 rs1138272 minor allele were at increased risk of current asthma [odds ratio (OR) = 2.59; 95% CI: 1.43, 4.68 per 10 μg/m3 NO2] and ever asthma (OR = 1.64; 95% CI: 1.06, 2.53) compared with homozygous major allele carriers (OR = 0.95; 95% CI: 0.68, 1.32 for current and OR = 1.20; 95% CI: 0.98, 1.48 for ever asthma; Bonferroni-corrected interaction p = 0.04 and 0.01, respectively). Similarly, for GSTP1 rs1695, associations between NO2 and current and ever asthma had ORs of 1.43 (95% CI: 1.03, 1.98) and 1.36 (95% CI: 1.08, 1.70), respectively, for minor allele carriers compared with ORs of 0.82 (95% CI: 0.52, 1.32) and 1.12 (95% CI: 0.84, 1.49) for homozygous major allele carriers (Bonferroni-corrected interaction p-values 0.48 and 0.09). There were no clear differences by TNF genotype.
Conclusions: Children carrying GSTP1 rs1138272 or rs1695 minor alleles may constitute a susceptible population at increased risk of asthma associated with air pollution.
Citation: MacIntyre EA, Brauer M, Melén E, Bauer CP, Bauer M, Berdel D, Bergström A, Brunekreef B, Chan-Yeung M, Klümper C, Fuertes E, Gehring U, Gref A, Heinrich J, Herbarth O, Kerkhof M, Koppelman GH, Kozyrskyj AL, Pershagen G, Postma DS, Thiering E, Tiesler CM, Carlsten C, TAG Study Group. 2014. GSTP1 and TNF gene variants and associations between air pollution and incident childhood asthma: the traffic, asthma and genetics (TAG) Study. Environ Health Perspect 122:418–424; http://dx.doi.org/10.1289/ehp.1307459
doi:10.1289/ehp.1307459
PMCID: PMC3984232  PMID: 24465030
22.  Endotoxin as a determinant of asthma and wheeze among rural dwelling children and adolescents: A case–control study 
Background
The association between endotoxin exposure and asthma is complex and has been associated with rural living. We examined the relationship between domestic endotoxin and asthma or wheeze among rural school-aged children (6–18 years) and assessed the interaction between endotoxin and other characteristics with these outcomes.
Methods
Between 2005 and 2007 we conducted a case–control study of children 6–18 years in the rural region of Humboldt, Canada. Cases (n = 102) reported doctor-diagnosed asthma or wheeze in the past year. Controls (n = 208) were randomly selected from children without asthma or wheeze. Data were collected to ascertain symptoms, asthma history and indoor environmental exposures (questionnaire), endotoxin (dust collection from the play area floor and child’s mattress), and tobacco smoke exposure (saliva collection). Statistical testing was completed using multiple logistic regression to account for potential confounders and to assess interaction between risk factors. A stratified analysis was also completed to examine the effect of personal history of allergy.
Results
Among children aged 6–12 years, mattress endotoxin concentration (EU/mg) and load (EU/m2) were inversely associated with being a case [odds ratio (OR) = 0.44, 95% confidence interval (CI) = 0.20-0.98; and OR = 0.38, 95% CI = 0.20-0.75, respectively]. These associations were not observed in older children or with play area endotoxin.
Conclusions
Our results suggest that endotoxin exposure might be protective for asthma or wheeze. The protective effect is found in younger school-aged, non-allergic children. These results may help explain the inconsistencies in previous studies and suggest that the protective effects of endotoxin in the prevention of atopy and asthma or wheeze are most effective earlier in life.
doi:10.1186/1471-2466-12-56
PMCID: PMC3545854  PMID: 22966977
Asthma; Children; Endotoxin; Wheeze; Pediatrics; Allergy
23.  Ambient Air Toxics and Asthma Prevalence among a Representative Sample of US Kindergarten-Age Children 
PLoS ONE  2013;8(9):e75176.
Background
Criteria pollutants have been associated with exacerbation of children’s asthma, but the role of air toxics in relation to asthma is less clear. Our objective was to evaluate whether exposure to outdoor air toxics in early childhood increased asthma risk or severity.
Methods
Air toxics exposure was estimated using the 2002 National Air toxics Assessment (NATA) and linked to longitudinal data (n=6950) from a representative sample of US children born in 2001 and followed through kindergarten-age in the Early Child Longitudinal Study - Birth Cohort (ECLS-B).
Results
Overall, 17.7% of 5.5 year-olds had ever been told by a healthcare professional they had asthma, and 6.8% had been hospitalized or visited an emergency room for an asthma attack. Higher rates of asthma were observed among boys (20.1%), low-income (24.8%), and non-Hispanic black children (30.0%) (p≤0.05). Air toxics exposure was greater for minority race/ethnicity (p<0.0001), low income (p<0.0001), non-rural area (p<0.001). Across all analyses, greater air toxics exposure, as represented by total NATA respiratory hazard index, or when limited to respiratory hazard index from onroad mobile sources or diesel PM, was not associated with a greater prevalence of asthma or hospitalizations (p trend >0.05). In adjusted logistic regression models, children exposed to the highest respiratory hazard index were not more likely to have asthma compared to those exposed to the lowest respiratory hazard index of total, onroad sources, or diesel PM.
Conclusions
Early childhood exposure to outdoor air toxics in a national sample has not previously been studied relative to children’s asthma. Within the constraints of the study, we found no evidence that early childhood exposure to outdoor air toxics increased risk for asthma. As has been previously reported, it is evident that there are environmental justice and disparity concerns for exposure to air toxics and asthma prevalence in US children.
doi:10.1371/journal.pone.0075176
PMCID: PMC3776728  PMID: 24058662
24.  A systematic review of associations between environmental exposures and development of asthma in children aged up to 9 years 
BMJ Open  2014;4(11):e006554.
Objectives
Childhood asthma is a complex condition where many environmental factors are implicated in causation. The aim of this study was to complete a systematic review of the literature describing associations between environmental exposures and the development of asthma in young children.
Setting
A systematic review of the literature up to November 2013 was conducted using key words agreed by the research team. Abstracts were screened and potentially eligible papers reviewed. Papers describing associations between exposures and exacerbation of pre-existing asthma were not included. Papers were placed into the following predefined categories: secondhand smoke (SHS), inhaled chemicals, damp housing/mould, inhaled allergens, air pollution, domestic combustion, dietary exposures, respiratory virus infection and medications.
Participants
Children aged up to 9 years.
Primary outcomes
Diagnosed asthma and wheeze.
Results
14 691 abstracts were identified, 207 papers reviewed and 135 included in the present review of which 15 were systematic reviews, 6 were meta-analyses and 14 were intervention studies. There was consistent evidence linking exposures to SHS, inhaled chemicals, mould, ambient air pollutants, some deficiencies in maternal diet and respiratory viruses to an increased risk for asthma (OR typically increased by 1.5–2.0). There was less consistent evidence linking exposures to pets, breast feeding and infant dietary exposures to asthma risk, and although there were consistent associations between exposures to antibiotics and paracetamol in early life, these associations might reflect reverse causation. There was good evidence that exposures to house dust mites (in isolation) was not associated with asthma risk. Evidence from observational and intervention studies suggest that interactions between exposures were important to asthma causation, where the effect size was typically 1.5–3.0.
Conclusions
There are many publications reporting associations between environmental exposures and modest changes in risk for asthma in young children, and this review highlights the complex interactions between exposures that further increase risk.
doi:10.1136/bmjopen-2014-006554
PMCID: PMC4244417  PMID: 25421340
PAEDIATRICS; PUBLIC HEALTH
25.  Active and uncontrolled asthma among children exposed to air stack emissions of sulphur dioxide from petroleum refineries in Montreal, Quebec: A cross-sectional study 
BACKGROUND:
Little attention has been devoted to the effects on children’s respiratory health of exposure to sulphur dioxide (SO2) in ambient air from local industrial emissions. Most studies on the effects of SO2 have assessed its impact as part of the regional ambient air pollutant mix.
OBJECTIVE:
To examine the association between exposure to stack emissions of SO2 from petroleum refineries located in Montreal’s (Quebec) east-end industrial complex and the prevalence of active asthma and poor asthma control among children living nearby.
METHODS:
The present cross-sectional study used data from a respiratory health survey of Montreal children six months to 12 years of age conducted in 2006. Of 7964 eligible households that completed the survey, 842 children between six months and 12 years of age lived in an area impacted by refinery emissions. Ambient SO2 exposure levels were estimated using dispersion modelling. Log-binomial regression models were used to estimate crude and adjusted prevalence ratios (PRs) and 95% CIs for the association between yearly school and residential SO2 exposure estimates and asthma outcomes. Adjustments were made for child’s age, sex, parental history of atopy and tobacco smoke exposure at home.
RESULTS:
The adjusted PR for the association between active asthma and SO2 levels was 1.14 (95% CI 0.94 to 1.39) per interquartile range increase in modelled annual SO2. The effect on poor asthma control was greater (PR=1.39 per interquartile range increase in modelled SO2 [95% CI 1.00 to 1.94]).
CONCLUSIONS:
Results of the present study suggest a relationship between exposure to refinery stack emissions of SO2 and the prevalence of active and poor asthma control in children who live and attend school in proximity to refineries.
PMCID: PMC3373279  PMID: 22536578
Asthma; Children; Cross-sectional study; Dispersion modelling; Point source emissions; Sulphur dioxide

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