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1.  IL13 gene polymorphisms modify the effect of exposure to tobacco smoke on persistent wheeze and asthma in childhood, a longitudinal study 
Respiratory Research  2008;9(1):2.
Background
Tobacco smoke and genetic susceptibility are risk factors for asthma and wheezing. The aim of this study was to investigate whether there is a combined effect of interleukin-13 gene (IL13) polymorphisms and tobacco smoke on persistent childhood wheezing and asthma.
Methods
In the Isle of Wight birth cohort (UK, 1989–1999), five IL13 single nucleotide polymorphisms (SNPs): rs1800925 (-1112C/T), rs2066960, rs1295686, rs20541 (R130Q) and rs1295685 were genotyped. Parents were asked whether their children had wheezed in the last 12 months at ages 1, 2, 4 and 10 years. Children who reported wheeze in the first 4 years of life and also had wheezing at age 10 were classified as early-onset persistent wheeze phenotype; non-wheezers never wheezed up to age 10. Persistent asthma was defined as having a diagnosis of asthma both during the first four years of life and at age 10. Logistic regression methods were used to analyze data on 791 children with complete information. Potential confounders were gender, birth weight, duration of breast feeding, and household cat or dog present during pregnancy.
Results
Maternal smoking during pregnancy was associated with early-onset persistent wheeze (OR 2.93, p < 0.0001); polymorphisms in IL13 were not (OR 1.15, p = 0.60 for the common haplotype pair). However, the effect of maternal smoking during pregnancy was stronger in children with the common IL13 haplotype pair compared to those without it (OR 5.58 and OR 1.29, respectively; p for interaction = 0.014). Single SNP analysis revealed a similar statistical significance for rs20541 (p for interaction = 0.02). Comparable results were observed for persistent childhood asthma (p for interaction = 0.03).
Conclusion
This is the first report that shows a combined effect of in utero exposure to smoking and IL13 on asthma phenotypes in childhood. The results emphasize that genetic studies need to take environmental exposures into account, since they may explain contradictory findings.
doi:10.1186/1465-9921-9-2
PMCID: PMC2265286  PMID: 18186920
2.  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
3.  Parental smoking and childhood asthma: longitudinal and case-control studies 
Thorax  1998;53(3):204-212.
BACKGROUND—The relation of parental smoking to wheezing and asthma occurring after the first year of life was assessed by a systematic quantitative review of case-control and longitudinal studies, complementing earlier reviews of cross sectional surveys and wheezing in early childhood.
METHODS—Fifty one relevant publications were identified after consideration of 1593 abstracts selected by electronic search of the Embase and Medline databases using keywords relevant to passive smoking in children. The search was completed in April 1997 and identified six studies of asthma incidence, seven of prognosis, 22 case-control studies, and 10 case series addressing disease severity.
RESULTS—Maternal smoking was associated with an increased incidence of wheezing illness up to age 6 (pooled odds ratio 1.31, 95% CI 1.22 to 1.41), but less strongly thereafter (1.13, 95% CI 1.04to 1.22). The long term prognosis of early wheezing illness was better if the mother smoked. The pooled odds ratio for asthma prevalence from 14 case-control studies was 1.37 (95% CI 1.15to 1.64) if either parent smoked. Four studies suggest that parental smoking is more strongly associated with wheezing among non-atopic children. Indicators of disease severity including symptom scores, attack frequency, medication use, hospital attendance, and life threatening bronchospasm were in general positively related to household smoke exposure.
CONCLUSIONS—The excess incidence of wheezing in smoking households appears to be largely non-atopic "wheezy bronchitis" with a relatively benign prognosis, but among children with established asthma, parental smoking is associated with more severe disease. This apparent paradox may be reconciled if environmental tobacco smoke is considered a co-factor provoking wheezing attacks, rather than a cause of the underlying asthmatic tendency.


PMCID: PMC1745164  PMID: 9659358
4.  Interleukin-13 Genetic Variants, Household Carpet Use and Childhood Asthma 
PLoS ONE  2013;8(1):e51970.
Interleukin (IL)-13 genetic polymorphisms have shown adverse effects on respiratory health. However, few studies have explored the interactive effects between IL-13 haplotypes and environmental exposures on childhood asthma. The aims of our study are to evaluate the effects of IL-13 genetic variants on asthma phenotypes, and explore the potential interaction between IL-13 and household environmental exposures among Taiwanese children. We investigated 3,577 children in the Taiwan Children Health Study from 14 Taiwanese communities. Data regarding children's exposure and disease status were obtained from parents using a structured questionnaire. Four SNPs were tagged accounting for 100% of the variations in IL-13. Multiple logistic regression models with false-discovery rate (FDR) adjustments were fitted to estimate the effects of IL-13 variants on asthma phenotypes. SNP rs1800925, SNP rs20541 and SNP rs848 were significantly associated with increased risks on childhood wheeze with FDR of 0.03, 0.04 and 0.04, respectively. Children carrying two copies of h1011 haplotype showed increased susceptibility to wheeze. Compared to those without carpet use and h1011 haplotype, children carrying h1011 haplotype and using carpet at home had significantly synergistic risks of wheeze (OR, 2.5; 95% CI, 1.4–4.4; p for interaction, 0.01) and late-onset asthma (OR, 4.7; 95% CI, 2.0–10.9; p for interaction, 0.02). In conclusions, IL-13 genetic variants showed significant adverse effects on asthma phenotypes among children. The results also suggested that asthma pathogenesis might be mediated by household carpet use.
doi:10.1371/journal.pone.0051970
PMCID: PMC3559736  PMID: 23382814
5.  Smoking and prevalence of allergic disorders in Japanese pregnant women: baseline data from the Kyushu Okinawa Maternal and Child Health Study 
Environmental Health  2012;11:15.
Background
Studies on the associations between smoking and allergic diseases have mostly focused on asthma. Epidemiological studies in adults on the effects of smoking on allergic diseases other than asthma, such as eczema and rhinoconjunctivitis, have been limited, and the information that is available has been inconsistent. The aim of this study was to investigate the association between smoking status and environmental tobacco smoke (ETS) exposure and the prevalence of allergic diseases.
Methods
Study subjects were 1743 pregnant Japanese women. The definitions of wheeze and asthma were based on criteria from the European Community Respiratory Health Survey whereas those of eczema and rhinoconjunctivitis were based on criteria from the International Study of Asthma and Allergies in Childhood. Adjustment was made for age; region of residence; family history of asthma, atopic eczema, and allergic rhinitis; household income; and education.
Results
Compared with never smoking, current smoking and ≥ 4 pack-years of smoking were independently positively associated with the prevalence of wheeze. There were no associations between smoking status and the prevalence of asthma, eczema, or rhinoconjunctivitis. When subjects who had never smoked were classified into four categories based on the source of ETS exposure (never, only at home, only at work, and both), exposure occurring both at home and at work was independently associated with an increased prevalence of two outcomes: wheeze and rhinoconjunctivitis. No relationships were observed between exposure to ETS and the prevalence of asthma or eczema.
Conclusions
Our results provide evidence that current smoking and ETS exposure may increase the likelihood of wheeze. The possibility of a positive association between ETS exposure and rhinoconjunctivitis was also suggested.
doi:10.1186/1476-069X-11-15
PMCID: PMC3317840  PMID: 22413964
Asthma; Cross-sectional studies; Eczema; Environmental tobacco smoke; Smoking; Wheeze; Rhinoconjunctivitis
6.  Pertussis vaccination and wheezing illnesses in young children: prospective cohort study 
BMJ : British Medical Journal  1999;318(7192):1173-1176.
Objectives
To examine the relation between pertussis vaccination and the prevalence of wheezing illnesses in young children.
Design
Prospective cohort study.
Setting
Three former health districts comprising Avon Health Authority.
Subjects
9444 of 14 138 children enrolled in the Avon longitudinal study of pregnancy and childhood and for whom data on wheezing symptoms, vaccination status, and 15 environmental and biological variables were available.
Main outcome measures
Episodes of wheezing from birth to 6 months, 7-18 months, 19-30 months, and 31-42 months. These time periods were used to derive five categories of wheezing illness: early wheezing (not after 18 months); late onset wheezing (after 18 months); persistent wheezing (at every time period); recurrent wheezing (any combination of two or more episodes for each period); and intermittent wheezing (any combination of single episodes of reported wheezing). These categories were stratified according to parental self reported asthma or allergy.
Results
Unadjusted comparisons of the defined wheezing illnesses in vaccinated and non-vaccinated children showed no significant association between pertussis vaccination and any of the wheezing outcomes regardless of stratification for parental asthma or allergy. Wheeze was more common in non-vaccinated children at 18 months, and there was a tendency for late onset wheezing to be associated with non-vaccination in children whose parents did not have asthma, but this was not significant. After adjustment for environmental and biological variables, logistic regression analyses showed no significant increased relative risk for any of the wheezing outcomes in vaccinated children: early wheezing (0.99, 95% confidence interval 0.80 to 1.23), late onset wheezing (0.85, 0.69 to 1.05), persistent wheezing (0.91, 0.47 to 1.79), recurrent wheezing (0.96, 0.72 to 1.26), and intermittent wheezing (1.06, 0.81 to 1.37).
Conclusions
No evidence was found that pertussis vaccination increases the risk of wheezing illnesses in young children. Further follow up of this population with objective measurement of allergy and bronchial responsiveness is planned to confirm these observations.
Key messagesPertussis vaccination has been proposed as a risk factor for the development of asthma and atopyThere was no evidence for increased wheezing illnesses in young children who were vaccinated against pertussis compared with non-vaccinated childrenFollow up studies of this population will help to further clarify the relation between early infections and vaccination and the development of atopic diseases, including asthmaLarge scale longitudinal studies beginning in pregnancy offer the opportunity to examine complex interactions between genetics and the environment in the cause of common childhood diseases
PMCID: PMC27852  PMID: 10221941
7.  Do Grandmaternal Smoking Patterns Influence the Etiology of Childhood Asthma? 
Chest  2013;145(6):1213-1218.
Background:
Animal data suggest that tobacco smoke exposure of a mother when she is in utero influences DNA methylation patterns in her offspring and that there is an effect on the respiratory system, particularly airway responsiveness. The only study, to our knowledge, in humans suggests that there is a similar effect on asthma. The present study tests whether an association with respiratory problems can be confirmed in a large population study and aims to determine whether in utero exposure of the father has similar effects on his offspring.
Methods:
Information from the Avon Longitudinal Study of Parents and Children was used to compare the offspring of women and of men who had themselves been exposed to cigarette smoke in utero; separate analyses were performed for children of women smokers and nonsmokers. The outcome measures were trajectories of history of early wheezing, doctor-diagnosed asthma by age 7 years, and results of lung function and methacholine challenge tests at 8 years. A variety of social and environmental factors were taken into account; offspring sexes were examined separately.
Results:
There was no association with any outcome in relation to maternal prenatal exposure. There was some evidence of an increase in asthma risk with paternal prenatal exposure when the study mother was a nonsmoker (adjusted OR, 1.17; 95% CI, 0.97-1.41). This was particularly strong for girls (adjusted OR, 1.39; 95% CI, 1.04-1.86).
Conclusions:
We did not find that maternal prenatal exposure to her mother’s smoking had any effect on her children’s respiratory outcomes. There was suggestive evidence of paternal prenatal exposure being associated with asthma and persistent wheezing in the granddaughters.
doi:10.1378/chest.13-1371
PMCID: PMC4042509  PMID: 24158349
8.  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
9.  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
10.  The association between endotoxin and lung function among children and adolescents living in a rural area 
Increased levels of endotoxin found in rural and agricultural areas are an environmental exposure believed to cause a paradoxical proinflammatory effect on respiratory health that can exacerbate asthma. Previous studies involving adults have demonstrated an association between high endotoxin levels and lower lung function. Apart from occupational settings, however, few studies have investigated the relationship between lung function and endotoxin exposure, such as environmental tobacco smoke, especially in children. This study examined the modifying effects of sex, pre-existing asthma and other environmental exposures, including tobacco smoke, in children living in rural communities in Saskatchewan.
BACKGROUND/OBJECTIVES:
Knowledge of the effects of domestic endotoxin on children’s lung function is limited. The association between domestic endotoxin and asthma or wheeze and lung function among school-age children (six to 18 years of age) was examined. The interaction between endotoxin and other personal and environmental characteristics and lung function was also assessed.
METHODS:
A case-control study was conducted in and around the rural community of Humboldt, Saskatchewan, between 2005 and 2007. Parents of cases reported either doctor-diagnosed asthma or wheeze in the previous year. Controls were randomly selected from those not reporting these conditions. Data were collected by questionnaire to ascertain symptoms and conditions, while spirometry was used to measure lung function including forced vital capacity and forced expiratory volume in 1 s. Dust collected from the child’s play area floor and the child’s mattress was used to quantify endotoxin, and saliva was collected to quantify cotinine levels and assess tobacco smoke exposure.
RESULTS:
There were 102 cases and 207 controls included in the present study. Lower forced expiratory volume in 1 s was associated with higher mattress endotoxin load among female cases (beta=−0.25, SE=0.07 [P<0.01]). There was a trend toward lower forced vital capacity, which was associated with higher play area endotoxin load among cases with high tobacco smoke exposure (beta=−0.17, SE=0.09 [P<0.10]).
CONCLUSIONS:
Findings indicated that high endotoxin levels present in common household areas of rural children with asthma or wheeze may also affect their lung function. These associations may be potentiated by tobacco smoke exposure and female sex.
PMCID: PMC3267627  PMID: 22187693
Asthma; Endotoxin; Lung function; Rural; Tobacco smoke; Wheeze
11.  Wheeze associated with prenatal tobacco smoke exposure: a prospective, longitudinal study 
Archives of Disease in Childhood  2000;83(4):307-312.
AIMS—To determine whether maternal smoking during pregnancy is a risk factor for reported wheeze in early childhood that is independent of postnatal environmental tobacco smoke (ETS) exposure and other known risk factors.
METHODS—A total of 8561 mothers and infants completed questions about smoking during pregnancy, ETS exposure, and the mother's recall of wheeze during early childhood.
RESULTS—A total of 1869 (21.8%) children had reported wheeze between 18 and 30 months of age, and 3496 (40.8%) had reported wheeze in one or more of the three study periods (birth to 6 months, 6-18 months, 18-30 months). The risk of wheeze between 18 and 30 months of age was higher if the mother smoked during pregnancy. This relation did not show a dose-response effect and became less obvious after adjustment for the effects of other factors. Average daily duration of ETS exposure reported at 6 months of age showed a dose-response effect and conferred a similar risk of reported wheeze. Factors associated with early childhood wheeze had the following adjusted odds ratios: maternal history of asthma 2.03(1.74 to 2.37); preterm delivery 1.66 (1.30 to 2.13); male sex 1.42 (1.28 to 1.59); rented accommodation 1.29 (1.11 to 1.51); and each additional child in household 1.13 (1.04 to 1.24).
CONCLUSIONS—Maternal smoking during pregnancy may be a risk factor for reported wheeze during early childhood that is independent of postnatal ETS exposure. For wheeze between 18 and 30 months of age, light smoking during the third trimester of pregnancy appears to confer the same risk as heavier smoking.


doi:10.1136/adc.83.4.307
PMCID: PMC1718491  PMID: 10999864
12.  Health effects of passive smoking. 3. Parental smoking and prevalence of respiratory symptoms and asthma in school age children 
Thorax  1997;52(12):1081-1094.
BACKGROUND: A systematic quantitative review of the evidence relating parental smoking to the prevalence of asthma and respiratory symptoms was conducted amongst school age children. METHODS: Sixty relevant studies were identified after consideration of 1593 articles selected by electronic search of the Embase and Medline databases using keywords relevant to passive smoking in children. The search was completed in April 1997 and identified 25 studies of asthma, 41 of wheeze, 34 of chronic cough, seven of chronic phlegm and six of breathlessness which were included in a quantitative overview. RESULTS: The pooled odds ratios for either parent smoking were 1.21 (95% CI 1.10 to 1.34) for asthma, 1.24 (95% CI 1.17 to 1.31) for wheeze, 1.40 (95% CI 1.27 to 1.53) for cough, 1.35 (95% CI 1.13 to 1.62) for phlegm, and 1.31 (95% CI 1.08 to 1.59) for breathlessness. Adjustment for confounding had little effect. Evidence of heterogeneity between studies appeared largely explicable by publication bias with a superfluity of small studies with large odds ratios. However, excluding these had little effect on the pooled odds ratios. The prevalence of all symptoms increased with the number of parents who smoked. While maternal smoking had a greater effect than paternal smoking, the effect of father only was clearly significant. CONCLUSIONS: The relationship between parental smoking and respiratory symptoms seems very likely to be causal given statistical significance, robustness to adjustment for confounding factors, consistency of the findings in different countries, and evidence of dose response. The raised risk in households where the father, but not the mother, smoked argues for a postnatal effect. 



PMCID: PMC1758471  PMID: 9516904
13.  Presence of asthma risk factors and environmental exposures related to upper respiratory infection-triggered wheezing in middle school-age children. 
Environmental Health Perspectives  2003;111(4):657-662.
Viral respiratory infections and exposure to environmental constituents such as tobacco smoke are known or suspected to trigger wheezing/asthma exacerbations in children. However, few population-based data exist that examine the relationship between wheezing triggered by viral respiratory infections and environmental exposures. In this investigation we used population-based data to evaluate differences in exposures between symptomatic middle school-age children who did and did not report wheezing triggered by viral respiratory infections. As part of the North Carolina School Asthma Survey (NCSAS), a 66-question data instrument was used to collect information from children enrolled in North Carolina public middle schools during the 1999-2000 school year. Associations between exposures and upper respiratory infection-triggered wheezing (URI-TW) among symptomatic children were examined using adjusted prevalence odds ratios (PORs). Video methods developed for the International Study of Asthma and Allergies in Childhood were used to assess wheezing. Among the 33,534 NCSAS symptomatic participants, positive associations were observed between most exposures and URI-TW. Reported presence of all allergy variables (PORs ranging from 2.11 to 2.45) was more strongly associated with URI-TW than either smoking or other exposures. Presence of URI-TW was higher at increasing levels of tobacco smoke exposure, but no apparent dose-response effect was observed for other indoor air pollutants. URI-TW in middle school children is most associated with reported allergen sensitivity, relative to other asthma risk factors and environmental exposures. Data from this investigation may be useful in developing assessment, screening, and targeting strategies to improve asthma and wheezing management in children.
PMCID: PMC1241460  PMID: 12676631
14.  Indoor risk factors for asthma and wheezing among Seattle school children. 
Environmental Health Perspectives  1997;105(2):208-214.
Indoor risk factors for physician-diagnosed asthma and wheezing in the past 12 months without previous asthma diagnosis were assessed in a survey of parents of 5-9-year-old Seattle primary school students. Among the 925 respondents, 106 (11%) reported a physician diagnosis of asthma, 66 (7%) had wheezing without diagnosis, and 753 (82%) were asymptomatic. After adjusting for age, sex, gender, ethnicity, medical history, socioeconomic status (SES) and parental asthma status, an increased risk of physician diagnosis of asthma was associated with household water damage, the presence of one or more household tobacco smokers, and at least occasional environmental tobacco smoke (ETS) exposure. Similarly, an increased risk of wheezing in the past 12 months among children without diagnosed asthma was associated with household water damage, presence of one or more household tobacco smokers, and occasional or more frequent ETS exposure. No increased risk of either condition was associated with gas, wood, or kerosene stove use, household mold, basement water, or wall/window dampness. Similarities in the indoor risk factors patterns between diagnosed asthma and wheezing without diagnosis suggested a similar etiology of these two conditions. The slightly higher association between ETS and asthma may indicate that parents of diagnosed asthmatics were more conscious of ETS, and were more likely to prohibit household smoking by resident smokers. Future research is needed to quantify which aspects of household water damage are related to respiratory illness.
PMCID: PMC1469795  PMID: 9105796
15.  Parental smoking and children's respiratory health: independent effects of prenatal and postnatal exposure 
Tobacco Control  2006;15(4):294-301.
Objectives
Adverse effects have been reported of prenatal and/or postnatal passive exposure to smoking on children's health. Uncertainties remain about the relative importance of smoking at different periods in the child's life. We investigate this in a pooled analysis, on 53 879 children from 12 cross‐sectional studies—components of the PATY study (Pollution And The Young).
Methods
Effects were estimated, within each study, of three exposures: mother smoked during pregnancy, parental smoking in the first two years, current parental smoking. Outcomes were: wheeze, asthma, “woken by wheeze”, bronchitis, nocturnal cough, morning cough, “sensitivity to inhaled allergens” and hay fever. Logistic regressions were used, controlling for individual risk factors and study area. Heterogeneity between study‐specific results, and mean effects (allowing for heterogeneity) were estimated using meta‐analytical tools.
Results
There was strong evidence linking parental smoking to wheeze, asthma, bronchitis and nocturnal cough, with mean odds ratios all around 1.15, with independent effects of prenatal and postnatal exposures for most associations.
Conclusions
Adverse effects of both pre‐ and postnatal parental smoking on children's respiratory health were confirmed. Asthma was most strongly associated with maternal smoking during pregnancy, but postnatal exposure showed independent associations with a range of other respiratory symptoms. All tobacco smoke exposure has serious consequences for children's respiratory health and needs to be reduced urgently.
doi:10.1136/tc.2005.015065
PMCID: PMC2563598  PMID: 16885578
tobacco smoke; fetus; child; respiratory symptoms; asthma
16.  Using latent class growth analysis to identify childhood wheeze phenotypes in an urban birth cohort 
Background
To advance asthma cohort research, we need a method that can use longitudinal data, including when collected at irregular intervals, to model multiple phenotypes of wheeze and identify both time-invariant (eg, sex) and time-varying (eg, environmental exposure) risk factors.
Objective
To demonstrate the use of latent class growth analysis (LCGA) in defining phenotypes of wheeze and examining the effects of causative factors, using repeated questionnaires in an urban birth cohort study.
Methods
We gathered repeat questionnaire data on wheeze from 689 children ages 3 through 108 months (n = 7,048 questionnaires) and used LCGA to identify wheeze phenotypes and model the effects of time-invariant (maternal asthma, ethnicity, prenatal environmental tobacco smoke, and child sex) and time-varying (cold/influenza [flu] season) risk factors on prevalence of wheeze in each phenotype.
Results
LCGA identified four wheezing phenotypes: never/infrequent (47.1%), early-transient (37.5%), early-persistent (7.6%), and late-onset (7.8%). Compared with children in the never/infrequent phenotype, maternal asthma was a risk factor for the other 3 phenotypes; Dominican versus African American ethnicity was a risk factor for the early-transient phenotype; and male sex was a risk factor for the early-persistent phenotype. The prevalence of wheeze was higher during the cold/flu season than otherwise among children in the early-persistent phenotype (P = .08).
Conclusion
This is the first application of LCGA to identify wheeze phenotypes in asthma research. Unlike other methods, this modeling technique can accommodate questionnaire data collected at irregularly spaced age intervals and can simultaneously identify multiple trajectories of health outcomes and associations with time-invariant and time-varying causative factors.
doi:10.1016/j.anai.2012.02.016
PMCID: PMC3371648  PMID: 22541400
17.  Parental smoking patterns and their association with wheezing in children 
Clinics  2013;68(7):934-939.
OBJECTIVE:
To investigate parental smoking patterns and their association with wheezing in children.
METHODS:
We performed a case-control study that included 105 children between 6 and 23 months of age who were divided into two groups: cases (children with 3 previous episodes of wheezing) and controls (healthy children without wheezing). The children's exposure to cigarette smoking was estimated using a questionnaire completed by the mothers and by the children's urinary cotinine levels.
RESULTS:
Based on both the questionnaire results and cotinine levels, exposure to cigarette smoking was higher in the households of cases in which the incidence of maternal smoking was significantly higher than that of paternal smoking. Children in this group were more affected by maternal smoking and by the total number of cigarettes smoked inside the house. Additionally, the questionnaire results indicated that the risk of wheezing was dose dependent. The presence of allergic components, such as atopic dermatitis and siblings with allergic rhinitis and asthma, greatly increased the odds ratio when wheezing was associated with cotinine levels.
CONCLUSION:
Children exposed to tobacco smoke have an increased risk of developing wheezing syndrome. This risk increases in association with the number of cigarettes smoked inside the house and the presence of other allergic components in the family.
doi:10.6061/clinics/2013(07)08
PMCID: PMC3714778  PMID: 23917656
Air Pollution; Indoor/Adverse Effects; Bronchial Hyperactivity/Chemically Induced; Cotinine/Analysis; Child; Tobacco Smoke Pollution/Adverse Effects
18.  Influence of dog ownership and high endotoxin on wheezing and atopy during infancy 
Background
Increased exposure to microbial products early in life may protect from development of atopic disorders in childhood. Few studies have examined the relationship of endotoxin exposure and pet ownership on atopy and wheezing during infancy.
Objective
Evaluate relationships among high endotoxin exposure, pet ownership, atopy, and wheezing in high-risk infants.
Methods
Infants (n = 532; mean age, 12.5 ± 0.8 months) with at least 1 parent with confirmed atopy were recruited. A complete medical history and skin prick testing to foods and aeroallergens were performed at age 1 year. House dust samples were analyzed for endotoxin.
Results
Prevalences of wheezing were not independently associated with dog or cat ownership or endotoxin levels. Percutaneous reactivity to at least 1 allergen was observed in 28.6% of infants. Univariate analyses showed significant associations of any wheezing, recurrent wheezing, and recurrent wheezing with an event with daycare attendance, number of siblings, respiratory infections, maternal smoking, and history of parental asthma. Logistic regression adjusting for the latter variables showed that recurrent wheezing (odds ratio, 0.4; 95% CI, 0.1–0.9) as well as 2 other wheeze outcomes were significantly reduced in homes with high endotoxin exposure in the presence of 2 or more dogs.
Conclusion
Pet ownership or endotoxin did not independently modify aeroallergen sensitization or wheezing during infancy. However, high endotoxin exposure in the presence of multiple dogs was associated with reduced wheezing in infants. Clinical implications: A home environment with many dogs and high levels of endotoxin may be conducive to reduced wheezing in infancy.
doi:10.1016/j.jaci.2006.08.008
PMCID: PMC2233938  PMID: 17157656
Endotoxin; birth cohort; wheeze; house dust; pet ownership
19.  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
20.  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
21.  Maternal Smoking during Pregnancy, Prematurity and Recurrent Wheezing in Early Childhood 
Pediatric pulmonology  2012;47(7):666-673.
Summary
Background
Prenatal maternal smoking and prematurity independently affect wheezing and asthma in childhood.
Objective
We sought to evaluate the interactive effects of maternal smoking and prematurity upon the development of early childhood wheezing.
Methods
We evaluated 1448 children with smoke exposure data from a prospective urban birth cohort in Boston. Maternal antenatal and postnatal exposure was determined from standardized questionnaires. Gestational age was assessed by the first day of the last menstrual period and early prenatal ultrasound (preterm<37 weeks gestation). Wheezing episodes were determined from medical record extraction of well and ill/unscheduled visits. The primary outcome was recurrent wheezing, defined as ≥ 4 episodes of physician documented wheezing. Logistic regression models and zero inflated negative binomial regression (for number of episodes of wheeze) assessed the independent and joint association of prematurity and maternal antenatal smoking on recurrent wheeze, controlling for relevant covariates.
Results
In the cohort, 90 (6%) children had recurrent wheezing, 147 (10%) were exposed to in utero maternal smoke and 419 (29%) were premature. Prematurity (odds ratio [OR] 2.0; 95% CI, 1.3-3.1) was associated with an increased risk of recurrent wheezing, but in utero maternal smoking was not (OR 1.1, 95% CI 0.5-2.4). Jointly, maternal smoke exposure and prematurity caused an increased risk of recurrent wheezing (OR 3.8, 95% CI 1.8-8.0). There was an interaction between prematurity and maternal smoking upon episodes of wheezing (p=0.049).
Conclusions
We demonstrated an interaction between maternal smoking during pregnancy and prematurity on childhood wheezing in this urban, multiethnic birth cohort.
doi:10.1002/ppul.22501
PMCID: PMC3756665  PMID: 22290763
Smoking; Prematurity; Wheeze
22.  Wheeze, asthma diagnosis and medication use: a national adult survey in a developing country 
Thorax  2005;60(11):895-901.
Background: As relatively little is known about adult wheeze and asthma in developing countries, this study aimed to determine the predictors of wheeze, asthma diagnosis, and current treatment in a national survey of South African adults.
Methods: A stratified national probability sample of households was drawn and all adults (>14 years) in the selected households were interviewed. Outcomes of interest were recent wheeze, asthma diagnosis, and current use of asthma medication. Predictors of interest were sex, age, household asset index, education, racial group, urban residence, medical insurance, domestic exposure to smoky fuels, occupational exposure, smoking, body mass index, and past tuberculosis.
Results: A total of 5671 men and 8155 women were studied. Although recent wheeze was reported by 14.4% of men and 17.6% of women and asthma diagnosis by 3.7% of men and 3.8% of women, women were less likely than men to be on current treatment (OR 0.6; 95% confidence interval (CI) 0.5 to 0.8). A history of tuberculosis was an independent predictor of both recent wheeze (OR 3.4; 95% CI 2.5 to 4.7) and asthma diagnosis (OR 2.2; 95% CI 1.5 to 3.2), as was occupational exposure (wheeze: OR 1.8; 95% CI 1.5 to 2.0; asthma diagnosis: OR 1.9; 95% CI 1.4 to 2.4). Smoking was associated with wheeze but not asthma diagnosis. Obesity showed an association with wheeze only in younger women. Both wheeze and asthma diagnosis were more prevalent in those with less education but had no association with the asset index. Independently, having medical insurance was associated with a higher prevalence of diagnosis.
Conclusions: Some of the findings may be to due to reporting bias and heterogeneity of the categories wheeze and asthma diagnosis, which may overlap with post tuberculous airways obstruction and chronic obstructive pulmonary disease due to smoking and occupational exposures. The results underline the importance of controlling tuberculosis and occupational exposures as well as smoking in reducing chronic respiratory morbidity. Validation of the asthma questionnaire in this setting and research into the pathophysiology of post tuberculous airways obstruction are also needed.
doi:10.1136/thx.2004.030932
PMCID: PMC1747242  PMID: 16263947
23.  Lower respiratory tract symptoms in Queensland schoolchildren: risk factors for wheeze, cough and diminished ventilatory function. 
Thorax  1993;48(10):1021-1024.
BACKGROUND--The occurrence of respiratory symptoms and abnormal lung function in children is known to be influenced by genetic and many environmental factors. The association between specific respiratory symptoms in children of school age and their parents has been examined. METHODS--Respiratory symptoms and ventilatory function were recorded for 4549 schoolchildren in Queensland, Australia. RESULTS--The cumulative prevalence of wheezing was 23.1% of 8 year olds and 20.8% of 12 year olds, and the prevalence of wheezing within the previous 12 months was 13.9% and 10.5% respectively. A parental history of asthma or wheeze and hayfever was associated with wheeze in the child, but did not affect either the age of onset or frequency of episodes. A history of frequent cough in children who had never wheezed was associated with a parental history of frequent bronchitis, but less strongly with parental wheeze. These familial aggregations were not mediated by common exposure to cigarette smoke. Both a history of parental wheeze and maternal cigarette use were associated with a decrease in FEF25-75 in the child and these effects were additive. CONCLUSIONS--The association of specific symptoms (wheeze and cough without wheeze) in parent and offspring is interpreted as evidence for different mechanisms of familial transmission, which may be genetic.
PMCID: PMC464820  PMID: 8256232
24.  Consumption of fresh fruit rich in vitamin C and wheezing symptoms in children 
Thorax  2000;55(4):283-288.
BACKGROUND—A beneficial effect of fresh fruit consumption on lung function has been observed in several studies. The epidemiological evidence of the effect on respiratory symptoms and asthma is limited. The consumption of fruit rich in vitamin C was examined in relation to wheezing and other respiratory symptoms in cross sectional and follow up studies of Italian children.
METHODS—Standardised respiratory questionnaires were filled in by parents of 18 737 children aged 6-7 years living in eight areas of Northern and Central Italy. The winter intake of citrus fruit and kiwi fruit by the children was categorised as less than once per week, 1-2 per week, 3-4 per week, and 5-7 per week. A subset of 4104 children from two areas was reinvestigated after one year using a second parental questionnaire to record the occurrence of wheezing symptoms over the intervening period.
RESULTS—In the cross sectional analysis, after controlling for several confounders (sex, study area, paternal education, household density, maternal smoking, paternal smoking, dampness or mould in the child's bedroom, parental asthma), intake of citrus fruit or kiwi fruit was a highly significant protective factor for wheeze in the last 12 months (odds ratio (OR) = 0.66, 95% confidence intervals (CI) 0.55 to 0.78, for those eating fruit 5-7 times per week compared with less than once per week), shortness of breath with wheeze (OR = 0.68, 95% CI 0.56 to 0.84), severe wheeze (OR = 0.59, 95% CI 0.40 to 0.85), nocturnal cough (OR = 0.73,95% CI 0.65 to 0.83), chronic cough (OR = 0.75, 95% CI 0.65 to 0.88), and non-coryzal rhinitis (OR = 0.72, 95% CI 0.63 to 0.83). In the follow up study fruit intake recorded at baseline was a strong and independent predictor of all symptoms investigated except non-coryzal rhinitis. In most cases the protective effect was evident even among children whose intake of fruit was only 1-2 times per week and no clear dose-response relationship was found. The effect was stronger (although not significantly so (p = 0.13)) in subjects with a history of asthma; those eating fresh fruit at least once a week experienced a lower one year occurrence of wheeze (29.3%) than those eating fruit less than once per week (47.1%) (OR = 0.46, 95% CI 0.27 to 0.81).
CONCLUSIONS—Although the effect of other dietary components cannot be excluded, it is concluded that the consumption of fruit rich in vitamin C, even at a low level of intake, may reduce wheezing symptoms in childhood, especially among already susceptible individuals.


doi:10.1136/thorax.55.4.283
PMCID: PMC1745721  PMID: 10722767
25.  Effects of active tobacco smoking on the prevalence of asthma-like symptoms in adolescents 
The prevalence of asthma in adolescents markedly varies between different localities as found by the International Study of Asthma and Allergies in Childhood (ISAAC) and this may be due to environmental factors. Although tobacco smoke exposure is related to an increase in the prevalence of asthma, there is lack of information on that respect in children from developing countries, where active tobacco smoking usually starts early in adolescence. This study was undertaken to assess the effect of tobacco smoking on the prevalence of asthma symptoms in a random sample of 4738 adolescents aged 13.4 ± 1.05 years who responded the ISAAC video questionnaires plus questions on tobacco smoking. The prevalence of tobacco smoking in the last 12 months was 16.2%, with significant female predominance. The persistent smokers had a significantly higher prevalence of asthma-like symptoms ever and in the last 12 months (wheezing, wheezing with exercise, nocturnal wheezing, severe wheezing, and dry nocturnal cough) than ex-smokers and nonsmokers. More than 27% of asthma symptoms in our adolescents are attributable to active tobacco consumption (population attributable risk). This study strongly suggests that potent and more effective campaigns against tobacco smoking should be implemented in developing countries, where active tobacco smoking is dramatically increasing in children.
PMCID: PMC2692110  PMID: 18044067
asthma; prevalence; ISAAC; tobacco; video questionnaires

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