Immunol Allergy Clin N Am 28 (2008) xiii–xiv
Foreword
Environmental Factors in Asthma
Rafeul Alam, MD, PhD Consulting Editor
Whether you take the biblical quotationd‘‘for dust you are and to dust you will return’’ (Genesis 3:19)dor the theory of evolution, which implies that environmental changes triggered the biological evolution, it is all about environment. We as biologists have recognized the power of genes ever since Mendel demonstrated the principles of genetic inheritance, and Watson and Crick resolved the structure and beauty of the double helix. The driving power of genes in the expression of a phenotype is undeniable. Nonetheless, phenotype is not the same as genotype, and we are yet to fully understand the complexity of the gene–environment interaction. Our simple paradigm of promoter-driven exon-based gene expression is losing its ground. We now understand that the expression of a gene is far more complex. Gene expression is controlled by proximal and distant enhancers and silencers, epigenetic modulation of the gene locus, secondary regulation by microRNA, gene splicing, single nucleotide polymorphism, and other factors. Many of the foregoing processes are influenced by the environment. Asthma, being a polygenic disease, is far more susceptible to environmental changes. Thus, research in the environmental aspect of asthma is very important. A comprehensive understanding of the environmental contribution to asthma requires population-based case control and prospective epidemiologic studies, which are extremely difficult to conduct. Nonetheless, significant progress has been made in this field. We have observed continued evolution of the hygiene hypothesis. We have a better understanding of 0889-8561/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.iac.2008.04.002 immunology.theclinics.com
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FOREWORD
indoor pollution. We recognize the complex biologic effect of indoor allergens. To elaborate on the complexity of environmental factors, Dr. Mark Eisner, a leader in the field, has invited some of the top experts to contribute to this issue. The issue addresses such important areas as indoor allergens, indoor and outdoor pollution, hygiene hypothesis dealing with microbial environment, social environment that includes diet and obesity, and others. This will be an exciting reading. Rafeul Alam, MD, PhD Division of Allergy and Immunology National Jewish Medical and Research Center University of Colorado at Denver Health Sciences Center 1400 Jackson Street Denver, CO 80206, USA E-mail address:
[email protected] Immunol Allergy Clin N Am 28 (2008) xv–xvi
Preface
Mark D. Eisner, MD, MPH Guest Editor
The morbidity and mortality from asthma have increased greatly during the past few decades in the United States and most developed countries. Although recent developments in genetics have provided exciting breakthroughs in airway disease, genetic factors, by themselves, cannot explain the dramatic increases in asthma prevalence and severity. Dramatic changes in the environment have occurred concurrently with the asthma epidemic, raising the possibility that environmental factors may be responsible for the increased burden of asthma. Indeed, the alterations of the indoor and outdoor environment are dramatic features of the twentieth and twenty-first centuries. Changes in diet, body composition, and workplace conditions have also occurred. In this issue of the Immunology and Allergy Clinics of North America, we review recent epidemiologic studies that implicate the environment as a cause of asthma and its exacerbation. The term ‘‘environment’’ is broad and all encompassing. Indeed, it reflects all that is external to the human organism. For many, the term ‘‘environment’’ connotes the outdoor environment and its pollution by traffic, other sources of combustion, and industrial contamination. But for most residents of industrialized countries, the majority of time, in excess of 90%, is spent indoors. Consequently, the indoor environment, which includes homes, schools, workplaces, and other public places, becomes especially important. Although it is true that the outdoor (ambient) environment greatly influences the indoor one by entrainment of air and other substances, there are unique point sources of pollution, allergen exposure, and viral infection indoors. And finally, the social environment, which 0889-8561/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.iac.2008.04.001 immunology.theclinics.com
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reflects the broader context of our lives, may have important influences on asthma. Randomized controlled trials have become the gold standard for addressing many problems in clinical medicine and health. But such trials are not suited to studying most of the effects of environmental exposures on health. Although short-term exposure studies are conducted in highly controlled environments, they provide limited insight into the development of chronic diseases such as asthma, which have a long induction period (ie, develop over a long period of time). Ethical and logistic concerns preclude randomizing human subjects to potentially hazardous exposures over a longer time period. Therefore, epidemiologic methods are the best ones for assessing the impact of environmental exposures on health outcomes, such as asthma and other respiratory diseases. In this issue, we review the evidence that exposures to indoor pollution (passive smoking, indoor combustion), other indoor exposures (allergens, viral infections, occupational exposures, dampness, mold), and outdoor pollution (traffic, other ambient pollution) are important factors for the development and clinical course of asthma. The issue also considers the social environment and how it influences asthma status. The impact of diet and obesity, which have changed markedly during the past several decades, may also contribute substantively to the asthma epidemic. And living on a farm, with exposure to microbes and allergens, has fascinating, and sometimes counterintuitive, effects on asthma induction and course. Finally, an article on asthma and the inner city integrates the issues of pollutant and allergen exposure that often occur concurrently in the urban environment. Ultimately, the goal of epidemiology and public health is preventiondin this case, prevention of asthma incidence and exacerbation. This issue elucidates the impact of the environment, defined broadly, on asthma with the goal of highlighting possible areas in which exposure prevention or remediation might decrease the burden of asthma. Mark D. Eisner, MD, MPH University of California San Francisco 505 Parnassus Avenue, M1097 San Francisco, CA 94143, USA E-mail address:
[email protected] Immunol Allergy Clin N Am 28 (2008) 485–505
Dampness and Mold in the Indoor Environment: Implications for Asthma N.M. Sahakian, MD, MPH*, J.-H. Park, ScD, CIH, J.M. Cox-Ganser, PhD Centers for Disease Control and Prevention, National Institute of Occupational Health and Safety, Division of Respiratory Disease Studies, 1095 Willowdale Road, MS-H2800, Morgantown, WV 26505, USA
The National Institute for Occupational Safety and Health receives weekly requests to help with issues of indoor environmental quality in relation to illness in nonindustrial workplaces, such as office buildings and schools. Since the mid-1990s, there has been a marked increase in the number of these requests to the point where in 2007 they represented 57% of the total of 390 requests for evaluation of the workplace in relation to health and safety issues. As an example of requests concerning work-related asthma, from January 2007 through December 2007, there were 39 requests in relation to asthma, 34 (87%) from nonindustrial workplaces with workers concerned about indoor environmental quality. Of these 34 requests, 23 (68%) listed dampness or mold as exposures of concern. Thus, asthma in the nonindustrial environment accounts for the majority of the public’s concern for possible work-related asthma, and requesters have made the association between their work-related asthma symptoms and damp/moldy environments. A recent calculation estimates that 21% (95% confidence interval [CI], 12%–29%) of current asthma in the United States is attributable to dampness/mold in homes [1]. This article presents epidemiologic findings pertinent to asthma and asthma-like symptoms in relation to exposure to dampness/mold in homes, schools, and workplaces. With regard to specific agents found in damp indoor environments that may play a role in asthma, it concentrates on mold (used synonymously with fungi) and includes some findings on bacteria. The literature on asthma in relation to dust mite or cockroach allergens is not addressed. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the National Institute for Occupational Safety and Health. * Corresponding author. E-mail address:
[email protected] (N.M. Sahakian). 0889-8561/08/$ - see front matter. Published by Elsevier Inc. doi:10.1016/j.iac.2008.03.009
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Reviews of the epidemiologic literature up to 2003 A European review (NORDDAMP) of well-designed epidemiologic studies published prior to July 1998 found that odds ratios (ORs) for cough, wheeze, and asthma associated with indoor dampness ranged from 1.4 to 2.2 [2]. A subsequent review (EUROEXPO) of studies published from 1998 to 2000 confirmed indoor dampness as a risk factor for health effects, regardless of atopic status. The investigators concluded that additional prospective studies were needed [3]. In the United States, the Centers for Disease Control and Prevention asked the Institute of Medicine (IOM) to complete a review of the scientific literature. The IOM committee reviewed studies published up to late 2003 believed influential in shaping the scientific understanding of dampnessassociated health effects [4]. With respect to asthma and asthma-related symptoms, the IOM found that there was sufficient evidence for associations between exposure to damp indoor environments or mold or other agents in damp indoor environments and cough, wheeze, and asthma symptoms in asthmatic persons, and limited or suggestive evidence for associations with asthma development and dyspnea. They concluded that excessive indoor dampness is a public health problem and that prevention or reduction of this condition should be a public health goal. Among the research needs formulated by the committee were improved characterization of dampnessrelated microbial emissions and chemical emissions from building materials and furnishings and their roles in adverse health outcomes; studies on interaction effects of multiple exposure factors in damp indoor environments; and studies on intervention effectiveness. Meta-analysis in 2007 A meta-analysis of 33 peer-reviewed epidemiologic studies on respiratory health outcomes and home dampness or mold included studies published from 1989 to 2006 [5]. The estimated OR for cough in adults was 1.52 (95% CI, 1.18–1.96); for cough in children 1.75 (95% CI, 1.56–1.96); for wheeze in adults 1.39 (95% CI, 1.04–1.85); for wheeze in children 1.53 (95% CI, 1.39–1.68); for current asthma 1.56 (95% CI, 1.30–1.86); for ever-diagnosed asthma 1.37 (95% CI, 1.23–1.53); and for asthma development 1.34 (95% CI, 0.86–2.10). The investigators estimated that home dampness or mold is associated with a 30% to 50% increase in respiratory health outcomes. Dampness/mold and asthma developmentdrecent publications Recent research not included in the 2004 IOM report has increased the body of evidence regarding the association between dampness and asthma development (Tables 1 and 2).
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Adults In a study that investigated occupational exposures, researchers reviewed medical records at clinics in a Swedish town covering a 1.5-year period to identify cases of newly diagnosed asthma among 20 to 65 year olds [6]. Controls were randomly selected from the Swedish population registry, lived in the same town, and were matched by age and gender to cases. Response rates and study numbers for cases and controls were 90% (n ¼ 120) and 84% (n ¼ 446), respectively. The OR (adjusted for occupational exposure to dust, fumes, or vapors, childhood allergy symptoms, and ever smoking) for workplace exposure to building mold or moisture damage that lasted 3 or more years and occurred before the year of asthma diagnosis (for cases) or referent time (for controls) was 4.7 (95% CI, 1.5–14.3). Because this study included agricultural and maintenance workers whose exposure may differ in intensity and type from office workers in damp buildings, caution should be exercised when applying these findings to workers of nonindustrial indoor environments. A study by Gunnbjo¨rnsdo´ttir and colleagues used data from the 1990–1994 European Community Respiratory Health Surveys (ECRHS) and a followup survey conducted in 1999–2001 [7]. Participants from four Nordic countries were 20 to 44 years old at the time of the initial survey. Response rates and study numbers for the initial and follow-up surveys were 84% (n ¼ 21,802) and 74% (n ¼ 16,190). New-onset asthma was defined as an asthma attack or use of asthma medications during the past 12 months on the second survey with negative responses to both of these questions on the first survey. The OR (adjusted for age, study center, gender, body mass index, rhinitis, smoking status, type of housing, age of building, and socioeconomic status) for the association between the presence of home dampness anytime between the two surveys and new-onset asthma was 1.13 (95% CI, 0.92–1.40) and thus did not quite meet statistical significance. Associations for new-onset asthma symptoms were significant. Researchers also investigated the remission of asthma-like symptoms and found that presence of home dampness inbetween the two surveys significantly decreased remission of nocturnal dyspnea and nocturnal cough. Analysis of a subset (Swedish subjects, n ¼ 1854) of second survey, also by Gunnbjo¨rnsdo´ttir and colleagues, participants demonstrated significant positive associations between home dampness and dyspnea at rest, dyspnea after exertion, and nocturnal dyspnea [8]. A Finnish population-based incident case-control study compared 521 adults, who had newly diagnosed asthma (defined as reversible airways obstruction with at least one asthma-like symptom) identified over a 2.5-year period, to 932 randomly selected controls who did not have asthma [9]. Response rates for cases and controls were 90% and 80%, respectively. Cases and controls were 21 to 63 years old and lived within the same hospital district in South Finland. Workplace wall-to-wall carpeting and workplace mold independently increased the risk for new-onset asthma.
Study design
Environmental exposure
Health outcome
Odds ratio (95% CI)
Adults Flodin and Jo¨nsson [6]
Longitudinal case-control study (20–65 years old)
Reported workplace dampness (mold or moisture damage)a
New-onset physician-diagnosed asthma at age 20–65 years
4.7 (1.5–14.3)
Prospective study with a 7.9-year follow-up period (mean age at follow up: 40 years)
Reported dampness (water damage, leakage, or mold growth) in the homeb
New-onset asthma attack or current use of asthma medicationsc New-onset wheezec New-onset nocturnal dyspneac New-onset nocturnal coughc
1.1 (0.9–1.4)
Gunnbjo¨rnsdo´ttir et al [7]
Jaakkola et al [9]
Emenius et al [13]
Population-based incident case-control study (21–63 years old)
Reported visible mold or mold odor at workc and – No wall-to-wall carpet at work – Wall-to-wall carpet at work
New-onset physician-diagnosed asthma with both reversible airways obstruction and a history of at least one asthma-like symptom
Prospective study of a birth cohort from age 2 months to 2 years of age
Reported water damage, windowpane condensation, visible mold, or mold odor when child was 2 months of age
Three or more episodes of wheezing after age 3 months and either use of inhaled steroids or symptoms suggestive of bronchial hyper-reactivity
1.7 (1.3–2.4)
Nested case-control study of a birth cohort (2 years old)
One sign of dampness based on home inspection Three or more signs of dampness based on home inspection
Three or more episodes of wheezing after age 3 months and either use of inhaled steroids or symptoms suggestive of bronchial hyper-reactivity
1.3 (0.8–2.2)
1.4 (0.9–2.1) 4.6 (1.1–19.4)
2.7 (1.3–5.4)
et al
Children Wickman et al [12]
1.3 (1.1–1.5) 1.3 (1.1–1.6) 1.3 (1.1–1.4)
SAHAKIAN
Reference
488
Table 1 Epidemiologic studies investigating an association between indoor dampness or mold and new-onset asthma or new-onset asthma-like symptoms that use odds ratios as a measure of risk
Pekkanen et al [15]
b c
Mold odor based on current home inspection Visible mold based on current home inspection Visible mold in main living area based on current home inspection Water damage in main living area based on current home inspection
Present for 3 or more years and occurred at least 3 years before year of asthma diagnosis. Present any time in between the initial and follow-up survey. Present during the past year.
New-onset physician-diagnosed asthma or new referral to hospital after two or more attacks of wheezing
4.1 (0.6–26.0) 1.2 (0.7–2.1) 2.6 (1.2–5.8)
2.2 (1.2–4.0) DAMPNESS AND MOLD IN THE INDOOR ENVIRONMENT
a
Population-based incident case-control study (1–7 years old)
489
490 Table 2 Epidemiologic studies investigating an association between indoor dampness or mold and new-onset asthma that use incidence rate ratio as a measure of risk
Reference Adults Cox-Ganser et al [10]
a
Environmental exposure
Cross-sectional study with information on dates of hire and asthma diagnosis (mean age 46 years)
Office building with water damage and mold contamination based on building inspection
7.5 (no CI)
Cross-sectional study with information on dates of hire and asthma diagnosis (mean age 48 years)
School building with evidence of water damage and mold contamination based on building inspection
8.5 (no CI)
Population-based cohort study with a 6-year follow-up period (1–7 years old at baseline)
Reported mold odor in the homeb Reported visible mold in the homeb Reported moisture on surfaces in the homeb Reported water damage in the homeb Any of above dampness indicators
2.4 (1.1–5.6) 0.6 (0.2–1.7) 0.9 (0.5–1.5)
et al
Children Jaakkola et al [14]a
Study design
SAHAKIAN
White et al [11]
Incidence rate ratio (95% CI)
1.0 (0.4–2.3) 1.0 (0.7–1.5)
Cited in Fisk WJ, Lei-Gomez Q, Mendell MJ. Meta-analyses of the associations of respiratory health effects with dampness and mold in homes. Indoor Air 2007;17:284–96. b Present during the past year at time of initial survey.
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Workplace wall-to-wall carpet together with workplace mold further increased the risk for new-onset asthma. Results were adjusted for gender, age, education, personal smoking, environmental tobacco smoke, water damage, and damp spots at home. It is possible that carpets acted as a reservoir for moisture and related contaminants. Two cross-sectional studies of United States office and school employees who worked in buildings with water damage and mold contamination found postoccupancy adult-onset asthma incidence densities to be 7.5 and 8.5 times greater than preoccupancy incidence densities, respectively [10,11]. Although, incidence rate ratios (IRRs) were not adjusted for demographic variables, pre- and postoccupancy asthma incidence densities were calculated for the same group of participants. These studies support a temporal association, which is important in establishing a causal association of exposure with disease. Children A birth cohort study of 4089 Swedish children at 2 months old and 1 and 2 years old found a positive association between damp home environment and asthma development 1.74 (95% CI, 1.28–2.39), adjusted for gender, parental history of allergic disease, socioeconomic status, maternal age, exclusive breastfeeding, maternal smoking, pet ownership, and age of building [12]. Data on damp home environment were taken from the first questionnaire when the children were 2 months old. Asthma was defined as at least three episodes of wheezing between 3 months and 2 years of age, in combination with treatment of inhaled glucocorticoids or signs of hyperreactivity without upper-respiratory infection. In a subsequent nested case-control study of the same birth cohort, 181 children who met the case definition were compared to 359 age-matched healthy controls [13]. Information on damp indoor conditions came from the baseline questionnaire and from home inspections in the first winter season after recruitment into the casecontrol study. There were consistent positive associations between indicators of dampness/mold in the home and being a case. A strong finding was that there was an increasing risk for recurrent wheezing with an increasing number of indicators of dampness found during the home inspections: one indicator of dampness was associated with an OR of 1.3 (95% CI, 0.8–2.2), whereas having three or more dampness indicators was associated with an OR of 2.7 (95% CI, 1.3–5.4). A cohort study of randomly selected children from the Finnish population registry used results from a survey at age 1 to 7 years and another survey 6 years later [14]. Response rates and study numbers for the initial and subsequent surveys were 80% (n ¼ 2568) and 77% (n ¼ 1984), respectively. Children were considered exposed if mold odor, visible mold, dampness, or water damage had been reported in the home prior to the baseline study. The IRR for asthma comparing children exposed (n ¼ 384) and nonexposed
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(n ¼ 1532) to mold odor was 2.44 (95% CI, 1.07–5.60) after adjustment for age, gender, duration of breastfeeding, parental education, single parent, maternal smoking during pregnancy, environmental tobacco smoke exposure, gas cooking, presence of furry or feathery pets, and type of child care. One of the major strengths of this study was its prospective study design, which eliminated over-reporting of pre-existing home mold based on newly diagnosed asthma and provided evidence for a temporal relationship between home mold and asthma. Other Finnish researchers conducted a case-control study of children newly diagnosed with asthma at the university hospital in Kuopio, Finland [15]. Cases were defined as children 1 to 7 years of age who had been referred to the hospital because of two or more attacks of wheezing within the past year or were newly diagnosed with asthma. Controls who did not have asthma were randomly drawn from the Finnish population registry and matched by age, gender, and municipality to cases. Cases and controls were required to have lived at least 2 years or at least 75% of their lifetime in their current homes. Participation rates and study numbers for cases and controls were 98% (n ¼ 121) and 84% (n ¼ 241). Homes were inspected for evidence of mold odor, visible mold, and water damage. Models adjusted for parental asthma, paternal education, number of siblings, indoor pets, and daycare attendance during the first year of life yielded significant results for water damage in the main living area (OR 2.24; 95% CI, 1.25–4.01) and visible mold in the main living area (OR 2.59; 95% CI, 1.15–5.85). The study found a trend for increased risk for newly diagnosed asthma with each additional square meter of observed home water damage (OR 1.36; 95% CI, 0.91–2.03). Dampness/mold and dyspneadrecent publications Recent studies have investigated associations with dyspnea, nocturnal dyspnea, dyspnea during exertion, dyspnea after exertion, and dyspnea at rest, with differing results. The findings of Gunnbjo¨rnsdo´ttir and colleagues in relation to dyspnea were discussed previously. Park and colleagues developed a grading system for visible water stains, visible mold, mold odor, and moisture, which they applied in an investigation of 1231 employees (mean age 51 years) of a United States community college that had several waterdamaged buildings [16]. Dampness indicators in models adjusted for age, gender, smoking, job status, year of hire, allergies, and use of latex gloves were shown to predict risk for dyspnea present during the past 12 months that improved away from the building. Others have compared the prevalence of work-related dyspnea among employees in water-damaged and mold-contaminated buildings to a United States survey of office workers in nonproblem buildings [10,17]. Workrelated dyspnea was defined as shortness of breath that occurred 1 or more days per week in the past 4 weeks and which improved away from
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work. Although analyses could not be controlled for demographic factors, researchers found significantly elevated prevalence rate ratios (2.2 to 4.6) that suggested an association between building dampness and dyspnea. Researchers in Norway studied 2819 randomly selected adults, ages 26 to 81 years, who resided 11 years earlier (time of first survey) in the same county in Western Norway [18]. Response rate for the survey was 89%. In logistic regression models adjusted for age, gender, smoking status, educational level, pack years, and occupational exposure to dust or fumes, visible mold in the home significantly increased the risks for dyspnea when climbing two flights of stairs at an ordinary pace and of attacks of dyspnea (OR 2.3 [95% CI, 1.35–3.85] and 1.7 [95% CI, 1.06–2.72], respectively). In summary, all nine studies (five adult studies and four pediatric studies) addressing environmental dampness and new-onset asthma published since the IOM report demonstrate some significant associations between environmental dampness and new-onset asthma or new-onset asthma-like symptoms. Additionally, all five adult studies investigating associations between environmental dampness and dyspnea found some significant associations between one or more measures of dyspnea and environmental dampness. Two of these studies showed an exposure-response relationship.
Microbial exposures in damp environments and asthma and asthma-like symptomsdrecent publications Recent research has advanced the knowledge on associations between asthma development or asthma-like symptoms and fungi and bacteria (Table 3). Limitations of sampling and analytic methods for microbial agents and lack of knowledge on which specific fungi or microbial agents are relevant measures of risk for respiratory illness have hampered exposure assessment. Such limitations include (1) lack of personal sampling methods for estimating long-term exposure to airborne microbes or microbial agents, (2) difficulty in accounting for the large temporal and spatial variability of airborne microbial agents with standard short-term sampling methods, (3) high sampling and analytic cost, and (4) lack of standardized analytic methods. Despite these limitations, measured exposure assessments are necessary to obtain evidence on possible etiologic agents of disease. Adults A longitudinal study of subjects who participated in the ECRHS in Melbourne, Australia, followed 360 adults (20 to 45 years old) over a 2-year period with regard to measured home exposures and the development and remission of asthma [19]. The investigators measured dust mite and cat allergens and ergosterol (the principal sterol in fungal membranes) in bedroom floor and bed dust samples and culturable fungi from bedroom air samples at the onset of the study and 2 years later. They found that
494
Table 3 Epidemiologic studies investigating an association between microbial agents and asthma and asthma-like symptoms Odds ratios Other fungi
Fungal biomass
Endotoxin Bacteria
MVOC
1.5 (a) 1.5 (a) 0.9 (a)
1.0 (Cla/a) 1.5 (Cla/a) 1.0 (a)
1.1 (a) 1.2 (a) 1.0 (a)
1.1 (Erg/fd) 1.0 (Erg/fd) 1.5 (Erg/fd)
– – –
– – –
– – –
1.2 (a) 1.0 (a) 1.0 (a)
1.1 (Cla/a) 1.0 (Cla/a) 1.0 (Cla/a)
0.9 (a) 1.0 (a) 0.9 (a)
1.1 (Erg/bd) – 0.8 (Erg/bd) – 0.9 (Erg/bd) –
– – –
– – –
Park et al [20]b Case-control study: Post-occupancy office (mean age 46 y) PD asthma PD asthma or asthma symptoms
1.6 1.7 1.7 1.6
2.2 1.9 1.8 1.6
0.7 1.3 1.1 1.3
1.4 1.6 1.6 1.5
(fd) (cd) (fd) (cd)
– – –
– – –
WR wheeze Park et al [21]c Cross sectional study: office (mean age 46 y) WR chest-tightness WR shortness of breath WR cough
2.0 (fd) d 1.9 (fd) d 2.4 (fd) d
d d d
d d d
2.5 (fd) 2.2 (fd) 1.9 (fd)
– – –
– – –
1.7 (fd) d
d
d
1.3 (fd)
–
–
–
–
–
–
–
–
Adults Matheson [19]a Longitudinal study: home (20–45 y)
c
Salo et al [22]
Cross sectional study: home (73% O18 y)
Health outcome Development: Current asthma Asthma attack PD asthma Remission: Current asthma Wheeze BHR
Current PD asthma
(fd) (cd) (fd) (cd)
(Hyd/fd) (Hyd/cd) (Hyd/fd) (Hyd/cd)
1.7 (Alt/sd)
(fd) (cd) (fd) (cd)
(Erg/fd) (Erg/cd) (Erg/fd) (Erg/cd)
1.4 1.2 1.5 1.1
et al
Specific fungi
Study design
SAHAKIAN
Total fungi
Reference
Children Douwes et al [26]d
Birth cohort study: home (1–4 y)
PD asthma by age 4 d
d
d
d
d
d
d
1.1 (Mes/hd) d 1.1 (Xer/hd)
0.4 0.7 0.4 0.4 1.1
(EPS/fd) 0.4 (fd) (Glu/fd) (EPS/fd) 0.7 (fd) (Glu/fd) (Erg/hd) 0.7 (hd)
d
d
d
d
Hyva¨rinen et al [27]e
Case-control study: home (1–7 y)
Persistent wheeze in past 4 years Development of asthma
van Strien et al [28]b
Cross-sectional study: home (6–14 y)
PD asthma Wheeze
d d
d d
d d
d d
d d
1.1 (Mur/bd) 0.6 (Mur/bd)
d d
Kim et al [29]f
Cross- sectional study: elementary school
PD asthma Nocturnal breathlessness Daytime breathlessness Wheeze
0.94 (a) d 0.84 (a) d
d d
d d
d d
0.97 (a) 0.92 (a)
2.1 (a) 5.2 (a)
0.94 (a) d
d
d
d
0.97 (a)
1.8 (a)
0.93 (a) d
d
d
d
0.99 (a)
1.4 (a)
1.2 (Mes, Act/hd) d 1.0 (Mes/hd) DAMPNESS AND MOLD IN THE INDOOR ENVIRONMENT
ORs in bold font are significant for P % 0.05. Underlined ORs are marginally significant for 0.05 ! P % 0.10. Abbreviations: a, airborne; act, actinomycetes; Alt, Alternaria; bd, bed dust; BHR, bronchial hyper-reactivity; cd, chair dust; Cla, Cladosporium; EPS, extracellular polysaccharide of Penicillium and Aspergillus species; Erg, ergosterol; fd, floor dust; Glu, glucan; hd, house dust; Hyd, hydrophilic; Mes, mesophilic; mur, muramic acid; PD, physician-diagnosed; sd, surface dust; WR, work-related; Xer, xerophilic. a ORs are for twofold increase of exposure in the second survey compared to the first survey. b ORs are for IQR increase (cfu/g dust) in exposure. c ORs are for highest tertile compared to lowest tertile exposure group. d ORs are ratios are for high compared to low exposure group. e ORs are for each 0.01 nm/mg increase of endotoxin, 105 cfu/g increase of mesophilic bacteria, 103 cfu/g increase of mesophilic actinomycetes, 103 pg/mg increase of ergosterol, 105 cfu/g increase of mesophilic fungi, and 105 cfu/g increase of xerophilic fungi. f ORs are for each 102/m3 increase of bacteria or mold and 1 mg/m3 increase of total MVOC.
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increase in exposure to airborne Cladosporium over the study period significantly increased the risk for an asthma attack (OR 1.52; 95% CI, 1.08– 2.13). An increase in airborne total culturable fungi over the study period also increased the risk for an asthma attack (OR 1.54; 95% CI, 0.98– 2.43) and the development of asthma (wheezing in the past 12 months with bronchial hyper-responsiveness) (OR 1.53; 95% CI, 0.93–2.53). Despite the use of short-term (1-minute) air samples for fungal measurements, positive associations were found. Conversely, although ergosterol levels in dust may better represent long-term exposure, the investigators found no associations. A case-control study was nested within the cross-sectional study (discussed previously) of 888 participants working in a large water-damaged building in the United States where there was a large increase of postoccupancy adult-onset asthma [10,20]. Fungal exposures for 49 cases of current physician-diagnosed postoccupancy asthma and 152 controls (who had no lower respiratory and systemic symptoms and no physician diagnosis of asthma, hypersensitivity pneumonitis, or sarcoidosis) were compared using logistic regression models (adjusted for age, gender, race, smoking status, and building occupancy period). Researchers found postoccupancy asthma significantly associated with dust-borne total and hydrophilic (water-loving) culturable fungi (yeasts, Phoma herbarum, Chaetomium globosum, Mucor plumbeus, Rhizopus stolonifer, and Stachybotrys chartarum) in a linear exposure-dependent manner. Interquartile ranges (IQRs) were calculated by subtracting the 25th percentile values from the 75th percentile values. ORs for the risk for postoccupancy onset asthma per IQR of total culturable fungi in floor and chair dust were 1.6 (95% CI, 0.96–2.53) and 1.7 (95% CI, 1.07–2.60), respectively. ORs for the risk for postoccupancy asthma per IQR of hydrophilic fungi in floor and chair dust were 2.2 (95% CI, 1.23– 3.89) and 1.9 (95% CI, 1.19–2.89), respectively. In a cross-sectional analysis using all 888 participants, the same floor dust samples (n ¼ 338) analyzed for culturable fungi and endotoxin (the biologically active lipopolysaccharide found in the cell walls of gram-negative bacteria) were used to establish low-, medium-, and high-exposure categories [21]. Symptoms were defined as building related if they improved when away from the building. The investigators found that fungi and endotoxin in dust were significantly associated with building-related asthma-like symptoms in an exposure-dependent manner (range of OR for wheeze, chest tightness, attacks of shortness of breath, and attacks of cough: 1.7 [95% CI, 1.02–2.77] to 2.4 [95% CI, 1.29–4.59] in the highest fungal exposure group compared to the lowest and 1.3 [95% CI, 0.77–2.19] to 2.5 [95% CI, 1.30–4.90] in the highest endotoxin exposure group compared to the lowest). The study also demonstrated that workers exposed to high levels of endotoxin and fungi showed much higher risks of building-related wheeze, chest tightness, and shortness of breath compared to workers exposed to high levels of fungi or endotoxin alone, implying a synergistic effect of endotoxin and fungi.
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A large United States cross-sectional study using a nationally representative sample of 831 residential homes (2456 residents) found that exposure to Alternaria alternata allergen in surface dust was associated with an increased risk for current asthma (physician-diagnosed asthma with asthma symptoms in the past year) [22]. The OR for the second tertile was 1.45 (95% CI, 0.88– 2.39) and for the third tertile was 1.73 (95% CI, 1.08–2.77), in models adjusted for age, gender, race, education, smoking, sampling season, dust mite allergens, cockroach allergen, cat and dog allergens, mouse urinary protein, dust weight, and endotoxin, suggesting a linear exposure-response relationship. In models with A alternata in dust as a continuous variable and which adjusted for demographics, smoking, and sampling season, the risk for current asthma increased by 31% with each twofold increase in A alternata allergen concentration. A United States study of 190 patients who had asthma and 36 patients who had rhinitis measured forced expiratory volume in 1 second (FEV1) and analyzed dust samples collected from the homes of patients for (1/3)-b-D-glucan (a major carbohydrate constituent of fungal cell walls) and endotoxin [23]. In unadjusted quartile models with mean levels of bed and floor dust endotoxin and (1/3)-b-D-glucan as the exposures and FEV1 percent predicted as the outcome, exposure to endotoxin was associated with a 3% to 6% decrease in FEV1 percent predicted (with a nonlinear relationship). Exposure to increased levels of (1/3)-b-D-glucan had no association with FEV1 percent predicted. A strength of this study was the use of objective pulmonary measurements. A possible limitation was that subjects who did not have asthma or rhinitis were not included for comparison. In a Turkish case-control study, researchers collected 4-hour airborne fungal samples from living rooms during the winter and compared the levels of culturable fungi in homes with adult patients who had asthma with those in homes of controls [24]. They found that the airborne fungal levels in homes of cases and controls were not different. A limitation of this study was the single measurement per home. Considering that temporal and spatial variations of the airborne fungal concentration are large and that asthma is a chronic disease, their negative finding might have resulted from exposure misclassification. In a cross-sectional study in Denmark of 522 teachers from 15 schools (8 wet and 7 dry), researchers estimated individual teacher exposures based on dust and air sample measurements from rooms (n ¼ 107) and the number of hours spent in these rooms [25]. Using multivariate logistic regression analyses with three categories of exposure (adjusted for demographics, psychosocial work conditions, and building characteristics), they did not find any significant associations between asthma or objective pulmonary measurements (FEV1, forced vital capacity, and methacholine challenge test results) and exposure to fungi in dust or endotoxin or other microbial agents in dust and air. Although the levels of fungi in dust from rooms in the wet and dry schools were not high, there was approximately a 150-fold
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difference between the highest and lowest exposure values in the classrooms. The researchers pointed out that the study was conducted in schools with no history of excessive indoor air problems or health concerns. Therefore, these schools did not represent worst-case scenarios. Children In a prospective birth cohort study in the Netherlands, researchers collected dust samples from homes of 696 healthy infants at age 3 months and assessed their respiratory health 4 years later [26]. Mothers of all infants had allergy or asthma. Eighteen percent of the infants developed physiciandiagnosed asthma. Dust samples were collected from living room floors and the infants’ mattresses and were analyzed for endotoxin, (1/3)-b-D-glucan, and extracellular polysaccharide (carbohydrate in fungal cell walls) of Aspergillus and Penicillium species (EPS-Pen/Asp). They found that exposure to increasing levels of living room endotoxin and EPS-Pen/Asp during the first 3 months of life had significant protective effects on development of asthma during the first 4 years of life. Using models adjusted for gender, region, parental education, exposure to indoor tobacco smoke, and number of children in the household, the protective effect in the medium exposure group for endotoxin (OR 0.47; 95% CI, 0.26–0.86) was stronger than in the medium exposure group for EPS-Pen/Asp (OR 0.78; 95% CI, 0.40–1.55); and the protective effect in the high exposure group for endotoxin (OR 0.40; 95% CI, 0.21–0.77) was similar in strength to the high exposure group for EPS-Pen/Asp (OR 0.42; 95% CI, 0.18–0.99). The investigators found no associations of exposure to (1/3)-b-D-glucan with asthma development. A case-control study in Finland investigated home characteristics and levels of various microbial agents, including endotoxin, 3-hydroxy fatty acids (a biomarker of lipopolysaccharide), ergosterol, fungi, and actinomycetes (a large group of gram-positive bacteria), in house dusts of 36 children who had newly diagnosed asthma or who were referred to a hospital because of a history of two or more attacks of wheezing and 36 control children (age range 1 to 7 years old) [27]. Researchers found an increased risk for developing asthma with exposure to higher concentrations of mesophilic actinomycetes, mesophilic and xerophilic fungi, and ergosterol (adjusted OR range 1.08–1.18). In this study, ORs were small and statistical significance was marginal, possibly because of small sample size. A cross-sectional study performed in rural areas of three countries in Europe collected dust samples from the mattresses of children and analyzed these samples for endotoxin and muramic acid (a sugar in the peptidoglycan layer of bacterial cell walls) [28]. They studied 241 farm and 311 non–farm school children through a questionnaire and a skin test for a mixture of aeroallergens (grass pollen, birch pollen, mugwort pollen, Der p1, cat dander, dog dander, and Cladosporium herbarum). In an analysis stratified by sensitization, they found that muramic acid had a protective effect on
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wheeze in the past 12 months and on physician-diagnosed asthma in a linear exposure-dependent manner among nonsensitized children. Among the sensitized children, however, no linear exposure-response relationship was found. In this analysis, they adjusted for age, gender, study area, family history of asthma or hay fever, educational level of parents, number of older siblings, living on a farm, and mattress dust endotoxin concentration. Thus the effect of muramic acid was independent of endotoxin and farming environments. This study suggests that the effect of exposure to specific microbial agents on asthma and asthma symptoms in children may be modified by sensitization status. A cross-sectional study of 1014 primary school children in Sweden analyzed culturable fungi and bacteria, microbial volatile organic compounds (MVOCs), plasticizers, and total fungal and bacterial counts in air samples collected from 23 classrooms in eight schools [29]. Researchers used school-specific mean values of each analyte as an average exposure for all participants in each school. In logistic regression models adjusted for age and gender, they found significant positive associations between exposure to several individual MVOCs and wheeze, nocturnal dyspnea, and physician-diagnosed asthma (OR range 1.03–3.41); total MVOCs and nocturnal dyspnea (OR 5.25; 95% CI, 1.82–15.18) and physician-diagnosed asthma (OR 2.07; 1.09–3.93); and a plasticizer (2,2,4-trimethyl-1,3-pentanediol diisobutyrate) and wheeze, daytime dyspnea, nocturnal dyspnea, and physician-diagnosed asthma (OR range 1.85– 5.71). One study limitation was the assumption that measured volatile organic compounds were of microbial origin. Significant but small protective effects were found for total fungal counts on wheeze in the past 12 months (OR 0.98; 95% CI, 0.96–1.00), total bacterial counts on nocturnal dyspnea in the past 12 months (OR 0.92; 95% CI, 0.87–0.98), total culturable bacteria on nocturnal dyspnea (OR 0.92; 95% CI, 0.87– 0.98), and total culturable bacteria on physician-diagnosed asthma (OR 0.97; 95% CI, 0.94–1.00). The investigators questioned these protective effects and discussed that exposure misclassification bias may have occurred due to restrictions on opening of windows during the sampling period; however, how this misclassification produced the small protective effects of fungal and bacterial exposure is not clear. A 1-year study followed 17 children who had asthma and rhinitis and two children who had rhinitis alone who had a positive skin test for one or more fungal allergens (Cladosporium, Alternaria, Penicillium, or Aspergillus) [30]. Over a 1-year period, researchers collected monthly air samples for culturable fungi from the homes of the children. The researchers did not find significant correlations between total or individual airborne culturable fungi and daily asthma score (based on symptoms, daily medication use) and morning or evening peak expiratory flow. Only simple correlations between mold levels and health outcomes were performed, however. Longitudinal data analysis accounting for correlations among
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repeated measurements adjusted for demographics and other potential confounding factors may have provided more reliable and complete results. These studies present evidence that exposures to specific microbial agents in damp indoor environments are associated with development of asthma and asthma-like symptoms in adults. In contrast, studies among infants and young children have found adverse and protective effects. This duality of response in infants and children to microbial exposures has been a topic of much discussion in the literature since the effects of unhygienic conditions in relation to the development of allergic illnesses were first published [31]. A recent editorial expands on the complexities of exposure characteristics and genetic factors that may influence health outcomes [32]. Intervention studies in relation to asthma and asthma-like symptoms Three damp/moldy building remediation health studies with some aspects pertinent to asthma or asthma-like symptoms were reviewed by the IOM; two were among children in Finnish schools [33,34] and one was among office workers [35]. All three studies reported some decrease in respiratory symptoms after remediation. Among the office workers, there was no new asthma after relocation or after return to the remediated building. Prevalences of chest tightness, shortness of breath, cough, and wheeze among office workers were not reduced by 4 months after relocation but were lower 4 years after relocation. Eight newer studies are discussed. Workplace intervention studies A Danish study of employees of a damp/moldy swimming pool complex (which included an office building), before and after remediation, indicated drops in irritative and nonspecific symptoms, but lower respiratory symptoms were not studied [36]. Remediation included replacement of the roof and damp insulation materials below the roof, replacement of portions of the ceiling that were water damaged or contaminated with mold, cleaning of the inner building surfaces, and cleaning of the ventilation system. Researchers were able to document a significant decline in peak flow variability (20% to 15%) based on 2-week peak flow monitoring results before and 6 months after remediation, indicating intervention effectiveness. A double-blind multiple crossover study in office workers in three Canadian office buildings investigated the effect of ultraviolet (UV) germicidal lights installed in the heating, ventilation, and air conditioning (HVAC) systems on symptoms [37]. Despite noninclusion of buildings with known outbreaks of building-related illness or which were known to have substantial microbial contamination, researchers found that the use of UV lights lowered the prevalence of cough, chest tightness, and difficulty breathing. This effect was seen most strongly among never-smokers. The UV lights led to a 99%
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reduction of microbial contamination on exposed surfaces within the HVAC system but had no effect on airborne microbial concentrations. School intervention studies A study of a Swedish school with moisture problems found a decrease in lower respiratory symptoms (including dyspnea and cough) among the staff 7 months after remediation. Remediation consisted of ventilation of the damp concrete slab foundation and replacement of interior walls that had sustained water damage during repair of a prior roof leak. There was no change in lower respiratory symptoms among pupils but there was a decrease in some upper respiratory symptoms [38]. A 3-year follow-up of Finnish teachers in a damp/moldy school with a cluster of eight asthma cases (26%) and a reference school found that before and after remediation wheezing and dyspnea was higher in the damp/moldy school and that the asthma cases were still on similar asthma medication after remediation [39]. Remediation included replacement of mold-contaminated materials and repair of water leaks. The study did find some beneficial effects in regards to no new diagnosis of asthma and significant decreases in conjunctivitis, bronchitis, and sinusitis in the teachers after remediation. A 5-year follow-up study of Finnish children in a damp/moldy school that underwent remediation found mixed results in terms of improvement in health after remediation [40]. Remediation included an improved rainwater drainage system, improved water barrier on the basement walls, replacement of waterpermeable materials with non–water-permeable materials in building locations prone to high moisture loads, improved ventilation in crawl spaces, replacement of damaged materials, and extensive cleaning and disinfection of all surfaces after remediation. There were decreasing trends over time for sinusitis, nocturnal cough, and asthma in all students and in a smaller group of students who participated in all three surveys. There was no clear trend in other respiratory or nonspecific symptoms. Prevalences of symptoms in students who first occupied the school after remediation were lower than in the students who had occupied the school before remediation. Another Finnish study of elementary students in a damp/moldy school and a reference school found that symptoms were higher in students in the damp/moldy school compared to the reference students before but not during remediation [41]. Researchers surmised that there could have been some over-reporting during the preremediation surveys. Remediation included correction of moisture problems, installation of a mechanical exhaust and supply ventilation system to replace the natural ventilation system, and thorough cleaning after remediation. After remediation, study symptoms prevalence at the two schools were similar (including lower respiratory symptoms of cough, wheeze, and dyspnea) indicating that remediation may have been effective in improving health.
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Home intervention studies A randomized controlled trial in the United States recruited children (2 to 17 years old) who had asthma from a pediatric hospital in Cleveland, Ohio. All children lived in a home with visible mold based on an inspection [42]. Children were randomized to remediation (n ¼ 29) and control groups (n ¼ 33). Home remediation included removal of mold from hard surfaces, elimination of rainwater intrusion, installation of ventilation systems to exhaust water vapor from kitchens and bathrooms, and repair of plumbing leaks. The two groups had a standardized treatment regimen and measures were taken to minimize treatment barriers. There was a significant reduction in symptomatic days per month for the remediation group compared to the control group during the 10th and 12th months of the study. In addition, there were significantly fewer emergency department visits or hospitalizations among children in the remediation group (4%) compared to the control group (33%). A randomized control trial in South Wales studied 164 houses with dampness/mold, each with at least one occupant who had asthma [43]. Asthmatic subjects (n ¼ 232) ranged in age from 3 to 61 years. Houses were randomly allocated to an intervention group or control group. Intervention consisted of visible mold removal, treatment with fungicide, and installation of a fan in the loft to improve ventilation. Over the 12 months of the study, asthma symptoms and asthma medication use declined in the intervention group, but no difference was found between intervention and control groups in changes in variability of peak flow. Summary Based on their review of the literature up to late 2003, the IOM concluded that there was sufficient evidence for associations between exposure to damp indoor environments or mold or other agents in damp indoor environments and asthma-like symptoms, and limited or suggestive evidence for associations with asthma development and dyspnea. They suggested that respiratory effects be studied through additional prospective and intervention studies. Recent epidemiologic studies not included in their report provide additional evidence for an association between damp indoor environments and asthma development and dyspnea. There is some evidence that remediation reduces respiratory health effects, but lower respiratory symptoms may take some time to resolve and dampness-related asthma among occupants may not completely resolve. Exposure to specific microbial agents, such as total fungi, hydrophilic fungi, Cladosporium, Alternaria, and endotoxin, in damp indoor environments is associated with development of asthma and asthma-like symptoms in adults; however, both adverse and protective effects have been identified in studies of infants and children.
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References [1] Mudarri D, Fisk WJ. Public health and economic impact of dampness and mold. Indoor Air 2007;17(3):226–35. [2] Bornehag CG, Blomquist G, Gyntelberg F, et al. Dampness in buildings and health: Nordic interdisciplinary review of the scientific evidence on associations between exposure to ‘‘dampness’’ in buildings and health effects (NORDDAMP). Indoor Air 2001;11:72–86. [3] Bornehag CG, Sundell J, Bonini S, et al. Dampness in buildings as a risk factor for health effects, EUROEXPO: a multidisciplinary review of the literature (1998–2000) on dampness and mite exposure in buildings and health effects. Indoor Air 2004;14:243–57. [4] Institute of Medicine. Damp indoor spaces and health. Washington, DC: National Academies Press; 2004. [5] Fisk WJ, Lei-Gomez Q, Mendell MJ. Meta-analyses of the associations of respiratory health effects with dampness and mold in homes. Indoor Air 2007;17:284–96. [6] Flodin U, Jo¨nsson P. Non-sensitising air pollution at workplaces and adult onset asthma. Int Arch Occup Environ Health 2004;77:17–22. [7] Gunnbjo¨rnsdo´ttir MI, Franklin KA, Norba¨ck D, et al. Prevalence and incidence of respiratory symptoms in relation to indoor dampness: the RHINE study. Thorax 2006;61:221–5. [8] Gunnbjo¨rnsdo´ttir MI, Norba¨ck D, Plaschke P, et al. The relationship between indicators of building dampness and respiratory health in young Swedish adults. Respir Med 2003;97: 302–7. [9] Jaakkola JJK, Ieromnimon A, Jaakkola MS. Interior surface materials and asthma in adults: a population-based incident case-control study. Am J Epidemiol 2006;164:742–9. [10] Cox-Ganser JM, White SK, Jones R, et al. Respiratory morbidity in office workers in a waterdamaged building. Environ Health Perspect 2005;113:485–90. [11] White SK, Cox-Ganser JM. NIOSH health hazard evaluation and technical assistance report: Samuel Staples Elementary School, Easton, CT. Cincinnati: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, NIOSH Report No. HETA#20040138-2967. Available at: http://www.cdc.gov/niosh/hhe/reports/pdfs/2004-0138-2967.pdf. Accessed April 1, 2008. [12] Wickman M, Mele´n E, Berglind N, et al. Strategies for preventing wheezing and asthma in small children. Allergy 2003;58:742–7. [13] Emenius G, Svartengren M, Korsgaard J, et al. Indoor exposures and recurrent wheezing in infants: a study in the BAMSE cohort. Acta Paediatr 2004;93:899–905. [14] Jaakkola JJK, Hwang B-F, Jaakkola N. Home dampness and molds, parental atopy, and asthma in childhood: a six-year population-based cohort study. Environ Health Perspect 2005;113:357–61. [15] Pekkanen J, Hyva¨rinen A, Haverinen-Shaughnessy U, et al. Moisture damage and childhood asthma: a population-based incident case-control study. Eur Respir J 2007;29:509–15. [16] Park JH, Schleiff PL, Attfield MD, et al. Building-related respiratory symptoms can be predicted with semi-quantitative indices of exposure to dampness and mold. Indoor Air 2004; 14:425–33. [17] Sahakian NM, White SK, Park JH, et al. Identification of mold and dampness-associated respiratory morbidity in 2 schools: comparison of questionnaire survey responses to national data. J Sch Health 2008;78:32–7. [18] Skorge TD, Eagan TM, Eide GE, et al. Indoor exposures and respiratory symptoms in a Norwegian community sample. Thorax 2005;60:937–42. [19] Matheson MC. Changes in indoor allergen and fungal levels predict changes in asthma activity among young adults. Clin Exp Allergy 2005;35(7):907–13. [20] Park JH, Cox-Ganser JM, Kreiss K, et al. Hydrophilic fungi and ergosterol associated with respiratory illness in a water-damaged building. Environ Health Perspect 2008;116(1):45–50.
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[21] Park JH, Cox-Ganser J, Rao C, et al. Fungal and endotoxin measurements in dust associated with respiratory symptoms in a water-damaged office building. Indoor Air 2006;16(3): 192–203. [22] Salo PM, Arbes SJ, Sever M, et al. Exposure to Alternaria alternata in US homes is associated with asthma symptoms. J Allergy Clin Immunol 2006;118(4):892–8. [23] Blanc PD, Eisner MD, Katz PP, et al. Impact of the home indoor environment on adult asthma and rhinitis. J Occup Environ Med 2005;47(4):362–72. [24] Ceylan E, Ozkutuk A, Ergor G, et al. Fungi and indoor conditions in asthma patients. J Asthma 2006;43(10):789–94. [25] Ebbehøj NE, Meyer HW, Wu¨rtz H, et al. Molds in floor dust, building-related symptoms, and lung function among male and female schoolteachers. Indoor Air 2005;15(Suppl 10): 7–16. [26] Douwes J, van Strien R, Doekes G, et al. Does early indoor microbial exposure reduce the risk of asthma? The prevention and incidence of asthma and mite allergy birth cohort study. J Allergy Clin Immunol 2006;117(5):1067–73. [27] Hyva¨rinen A, Sebastian A, Pekkanen J, et al. Characterizing microbial exposure with ergosterol, 3-hydroxy fatty acids, and viable microbes in house dust: determinants and association with childhood asthma. Arch Environ Occup Health 2006;61(4):149–57. [28] van Strien RT, Engel R, Holst O, et al. Microbial exposure of rural school children, as assessed by levels of N-acetyl-muramic acid in mattress dust, and its association with respiratory health. J Allergy Clin Immunol 2004;113(5):860–7. [29] Kim JL, Elfman L, Mi Y, et al. Indoor molds, bacteria, microbial volatile organic compounds and plasticizers in schools–associations with asthma and respiratory symptoms in pupils. Indoor Air 2007;17(2):153–63. [30] Inal A, Karakoc GB, Altintas DU, et al. Effect of indoor mold concentrations on daily symptom severity of children with asthma and/or rhinitis monosensitized to molds. J Asthma 2007;44(7):543–6. [31] Strachan DP. Hay fever, hygiene, and household size. Br Med J 1989;299:1259–60. [32] Liu AH, Leung DYM. Renaissance of the hygiene hypothesis. J Allergy Clin Immunol 2006; 117(5):1063–6. [33] Savilahti R, Uitti J, Laippala P, et al. Respiratory morbidity among children following remediation of a water-damaged school. Arch Environ Health 2000;55:405–10. [34] Meklin T, Husman T, Pekkanen J, et al. Effects of moisture damage repair on microbial exposure and health effects in schools. In: Levin H, editor. Proceedings of Indoor Air 2002d The 9th International Conference on Indoor Air Quality and Climate. Vol. 3. Santa Cruz (CA): Indoor Air; 2002. p. 416–20. [35] Jarvis J, Morey P. Allergic respiratory disease and fungal remediation in a building in a subtropical climate. Appl Occup Environ Hyg 2001;64:660–7. [36] Ebbehøj NE, Hansen MO, Sigsgaard T, et al. Building-related symptoms and molds: a twostep intervention study. Indoor Air 2002;12:273–7. [37] Menzies D, Popa J, Hanley JA, et al. Effect of ultraviolet germicidal lights installed in office ventilation systems on workers’ health and wellbeing: a double-blind multiple crossover trial. Lancet 2003;362(29):1785–91. [38] A˚hman M, Lundin A, Musabasˇ ic V, et al. Improved health after intervention in a school with moisture problems. Indoor Air 2000;10:57–62. [39] Patovirta R-L, Husman T, Haverinen U, et al. The remediation of mold damaged schoold a three-year follow-up study on teachers’ health. Cent Eur J Public Health 2004;12:36–42. [40] Haverinen-Shaughnessy U, Pekkanen J, Nevalainen A, et al. Estimating effects of moisture damage repairs on students’ health - a long-term intervention study. J Expo Anal Environ Epidemiol 2004;14:S58–64. [41] Lignell U, Meklin T, Putus T, et al. Effects of moisture damage and renovation on microbial conditions and pupils’ health in two schoolsda longitudinal analysis of five years. J Environ Monit 2007;9:225–33.
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[42] Kercsmar CM, Dearborn D, Schluchter M, et al. Reduction in asthma morbidity in children as a result of home remediation aimed at moisture sources. Environ Health Perspect 2006; 114:1574–80. [43] Burr ML, Matthews IP, Arthur RA, et al. Effects on patients with asthma of eradicating visible indoor mould: a randomized controlled trial. Thorax 2007;62:767–72.
Immunol Allergy Clin N Am 28 (2008) 507–519
Indoor Combustion and Asthma Kathleen Belanger, PhD*, Elizabeth W. Triche, PhD Yale University School of Medicine, Department of Epidemiology and Public Health, Center for Perinatal, Pediatric & Environmental Epidemiology, One Church Street, 6th Floor, New Haven, CT 06510, USA
Combustion indoors produces both gases (eg, nitrogen dioxide, carbon monoxide) and particulate matter that may affect the development or exacerbation of asthma. Sources in the home include both heating devices (eg, fireplaces, woodstoves, kerosene heaters, flued [ie, vented] or nonflued gas heaters) and gas stoves for cooking. Home heating devices include both those used as the primary heating source and those used as a secondary source. In areas where central heating is the norm (ie, most of the United States), woodstoves, kerosene heaters, or gas space heaters may be used as a secondary source, allowing the family to heat a specific room or to lower the thermostat and reduce the cost of central heating. Some sources may be used only occasionally, such as fireplaces used for ambiance or space heaters used in case of power failure. In other parts of the world such as parts of Europe and China, burning wood or coal within the living space of a home may represent a primary method of heating. These differences in source use (eg, daily versus infrequently, primary versus secondary) lead to considerable variability in exposures. Gas stoves are another common source of indoor combustion. Exposures to emissions from stoves can also vary considerably depending on stove and household characteristics. Older stoves with continuously burning pilot lights produce significantly more exposure to nitrogen dioxide and particulate matter than stoves with electronic ignition. Other gas appliances, including gas dryers and hot water heaters, may also be sources of exposure to nitrogen dioxide and other pollutants, although exposures tend to be lower from these sources. In the Netherlands, exposure to gas geysers (a type of hot water heater) is common and their effect on respiratory symptoms has been studied [1].
Supported by grants ES05410 and ES011013 from the National Institute of Environmental Health Sciences. * Corresponding author. E-mail address:
[email protected] (K. Belanger). 0889-8561/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.iac.2008.03.011 immunology.theclinics.com
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Although previous reviews [2] have considered the association of indoor combustion sources with respiratory symptoms in general, this article highlights the recent literature, focusing specifically on exposure to indoor combustion in association with either the development or exacerbation of asthma. Studies of both the incidence and prevalence of asthma in association with indoor combustion sources are included. Severity of asthma will be measured by increases in asthma symptoms (eg, wheeze, persistent cough, chest tightness and shortness of breath) as well as increases in medication use, physician visits, emergency room visits, and hospitalization. Since asthma is a chronic condition affecting both children and adults, both age groups are included in this review. Heating and cooking devices will be considered separately. Generally, exposure in the home has been investigated. The few studies of children exposed at school [3] are also reviewed. The following questions are considered in this article: Is indoor combustion associated with asthma development, or with exacerbation of symptoms among asthmatics? Is exposure from heating devices more harmful than exposure from cooking devices? Are specific fuels (eg, coal), more likely to be associated with risk than others (eg, wood)? Are children more at risk than adults? Is the association of indoor combustion and asthma confounded by poverty or environmental factors associated with substandard housing or older appliances that burn inefficiently?
Heating sources Woodstoves Wood smoke includes a vast array of constituents forming a complex mix of particles of varying chemical and physical composition, making it difficult to identify any individual harmful constituent [4]. Thus, some have argued that it is best to examine the entire mixture rather than its individual constituents [4]. Factors such as frequency of use, whether the woodburning stove is a primary or secondary heater, ventilation, age, type and condition of the device, and size of home influence concentrations of emissions within the home. Four studies examined the association of asthma with exposure to a woodstove [5–8]. Of these, only Thorn and colleagues [5] reported a positive association (odds ratio [OR] ¼ 1.7, 95% CI 1.2–2.5). This study compared 174 cases of adult-onset asthma (after age 16 years) with 870 controls randomly selected from a population sample in Sweden. Additional risk factors related to adult-onset asthma in this study were environmental tobacco smoke (OR ¼ 2.4, CI 1.4–4.1), visible mold growth (OR ¼ 2.2, CI 1.4–3.5), and visible dampness with mold growth (OR ¼ 1.8, CI 1.1–3.1). Information about frequency of stove use was not available. No association with asthma was noted for exposure to an open fireplace, tiled stove, or iron stove, although nearly half of the study population reported these exposures.
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Three additional studies did not find any association between woodstove exposure and asthma [6–8]. Eisner and colleagues [7] followed 349 adult asthmatics in northern California for 18 months to assess asthma severity. Woodstove exposure was not associated with any of the health indicators that included: asthma severity; general physical health; asthma quality of life; and medical care (emergency department visits or hospital admissions). More frequent use of the woodstove was also not associated with any particular health outcome. A survey of 10,667 Finnish university students did not find any association of asthma prevalence with exposure to a woodstove for heating in the first six years of life (OR ¼ 0.99, CI 0.65–1.53) [6]. In this study, woodstove heating was associated with living on a farm. Similarly, a survey of 397 school children in Libby, Montana, did not find an association between using a woodstove as the main source of heat, and prevalence of recent wheeze (OR ¼ 1.07, CI 0.47–2.39) [8]. Recent wheeze was analyzed because half of the children with wheeze in the past four weeks did not have an asthma diagnosis. In both Finland and Montana, woodstoves were identified as the main source of heat, reducing the likelihood that negative findings resulted from infrequent use of the stoves. Coal stoves Coal is composed primarily of carbon, but it also contains sulfur, oxygen and hydrogen. Emissions from coal combustion include a large number of air pollutants such as particulate matter, carbon monoxide, sulfur dioxide, nitrogen oxides, and organic toxics. A handful of studies have examined the association between coal stove use and asthma in children. In Belfast, Northern Ireland, 2574 children whose names were selected from general practitioners’ lists were studied [9]. Those exposed to glassfronted solid fuel fires (GFF) dusually burning anthracitedwere compared to children in homes with other heating types (primarily oil fired furnaces). Exposure to GFF was associated with all four of these health outcomes: wheeze during the past 12 months (OR ¼ 2.47, CI 1.83–3.30); cough during the past 12 months (OR ¼ 2.20, CI 1.65–2.80); ever used an inhaler (OR ¼ 1.80, CI 1.30–2.30); and diagnosed asthma (OR ¼ 1.81, CI 1.40–2.40). This study also controlled for exposure to environmental tobacco smoke, deprivation score, and crowding. In Munster, Germany, a small number of children (26 out of 3467) who had coal space heaters in their homes [10] were at increased risk for wheeze and asthma; the correlation was made for both boys and girls, although not consistently due to the small sample size. Use of coal stoves for heating was recently studied with other potential asthma risk factors in China [11]. The International Study of Asthma and Allergies in Children (ISAAC) questionnaire was distributed to all children 6–10 years of age attending 25 randomly selected schools in suburban Beijing. The survey identified 403 children with asthma; 806 controls were
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matched for gender, age and class in school. Compared to the use of steam heat, exposure to a coal stove for heating increased the risk of asthma (OR ¼ 1.5, CI 1.1–1.9). Cooking with coal, without a ventilation fan, was associated with an even higher increased risk for asthma (OR ¼ 2.3, CI 1.5–3.5). A second study investigated household factors and asthma in four Chinese cities (Lanzou, Chongquig, Wuhan, and Gangzhou) [12]. In each city, one urban area with high ambient pollution and one suburban area with low ambient pollution were chosen. Parents of children (n ¼ 7754) attending one school in each area answered a questionnaire. Heating with coal was associated with cough with phlegm (OR ¼ 1.29, CI 1.11–1.50), wheeze (OR ¼ 1.22, CI 1.02–1.45), and asthma, with risks similar to the previous study (OR ¼ 1.52, CI 1.06–2.15). However, cooking with coal was not associated with any health outcome. Gas heaters Gas space heaters have nitrogen dioxide (NO2) emission rates similar to gas stoves. However, because they are used for longer periods of time in living and sleeping areas, there is typically less of a spatial gradient within the home. When they are not vented, use of these heaters can result in NO2 concentrations four or more times higher than gas stoves used for cooking [13]. A study in Tasmania, Australia investigated exposure to portable or fixed gas space heaters in the first year of life [14]. Data was linked between an infant study of risk factors for SIDS in 1988, and a school study of asthma in 1995. Of 1111 parents who participated in the infant study, 863 also participated in the asthma study. Children exposed to gas heaters in infancy were more likely to develop asthma (RR ¼ 1.95, CI 1.16–3.29) and somewhat more likely to have recent wheeze at age 7 years (RR ¼ 1.63, CI 0.96–2.74), adjusted for smoking in the home and gas cooking. Effects did not differ for children exposed to flued versus nonflued gas heaters. Current exposure to gas heaters at age 7 years was also associated with asthma (RR ¼ 1.33, CI 1.12–1.57) and recent wheeze (RR ¼ 1.41, CI 1.17–1.71). Among infants living in a home with a living room gas heater, those who slept in a room with the door always closed at night had a lower risk of asthma than those who slept with the bedroom door open (RR ¼ 0.26, CI 0.07–0.97). A major strength of this study was the availability of prospective infant data. The relationship between residential exposures and asthma was also examined in National Health and Nutrition Examination Survey (NHANES) III, a cross sectional study (n ¼ 8257) of a representative sample of children less than six years old in the US [15]. Children in homes where a gas stove or oven was used for heat were more likely to have physician-diagnosed asthma (OR ¼ 1.8, CI 1.02–3.1). Since these stoves are designed for cooking, rather than heating, they are not vented when used as a source of heat.
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Fume-emitting heaters Another study combined different types of heating into two categories: ‘‘fume-emitting’’ and ‘‘nonfume-emitting.’’ In this cross-sectional study of 627 school children (ages 8–11) in Belmont, Australia (a coastal suburb of Sydney), the association between housing characteristics and prevalence of asthma was examined [16]. Questionnaires were completed by parents; airway hyper-responsiveness in the child was measured by histamine challenge; and atopy in the child was measured by skin prick testing to six common allergens. Fume-emitting heating systems included flued gas (4%), nonflued gas (14%), open fire (9%), woodstove (14%), and kerosene (1%); Nonfume-emitting heating systems included central heating (8%), electric heat (47%), and reverse cycle heating (15%). Use of fume-emitting heaters during the first year of the child’s life was associated with airway hyper-responsiveness, (OR ¼ 1.47, CI 1.06–2.03), recent wheeze (OR ¼ 1.44, CI 1.11–1.86), and current asthma (OR ¼ 2.08, CI 1.31–3.31) defined as airway hyper-responsiveness plus recent wheeze. Use of fume-emitting heaters in the first year of life was not associated with asthma when it was alternately defined as a physician diagnosis of asthma (OR ¼ 0.93, 0.74–1.17). In this study, current use of fume-emitting heaters was not associated with any of the asthma-related health outcomes examined. Strengths of this study are: the use of histamine challenge and skin prick testing to obtain objective outcome measures; and adjusting for smoking in the home. In addition, it is unlikely that bias would result in positive associations for exposure in the first year of a child’s life and negative associations with current exposure. Intervention studies Two studies have evaluated interventions designed to reduce asthma severity by changing heating systems in children’s homes. In Cornwall, UK, funds from the National Health Service were used to install central heating in the homes of children with asthma to eliminate dampness and increase energy efficiency [17]. Seventy-two children living in 59 homes where the heating system was replaced participated in an evaluation study. There were no control homes. Thirty-three homes previously had coal fires, and 26 homes had other forms of space heating. Central gas furnaces were installed in 37 homes and electric heat in 22. Respiratory symptoms and the number of days lost from school were assessed before and after the intervention. All respiratory symptoms (wheeze, cough, breathlessness) declined after the change in heating system, with the largest decline in cough at night. Days of school lost due to asthma also significantly improved, from a rate of 9.3 per 100 school days to 2.1 per 100 school days. The limitation of this study is the lack of a comparison group, and the possibility that parents were inclined to think their child’s asthma had improved after the change
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in heating system and report symptoms differently. The authors attributed the improvement in asthma symptoms to a reduction in dampness in the home (children sleeping in a damp bedroom 61% before, 21% after; children sleeping in a moldy bedroom 43% before, 6% after). However, the intervention also removed coal fires from the homes. Pilotto and colleagues [3] reported a randomized controlled trial from Adelaide, Australia that studied the effect of replacing nonflued gas heaters in schools. Of 18 schools using nonflued gas heaters, eight were randomized to the intervention group that received flued gas (n ¼ 4) or electric heat (n ¼ 4) depending on cost, and 10 were randomized to the control group with no heater replacement. To maintain blinding of teachers, parents and children, changes to the heating system were disguised as routine maintenance. Asthmatic children, who did not have nonflued gas heaters at home, were eligible for the study (n ¼ 118) and they recorded daily symptoms in a diary for the winter period. Lung function tests (before and after the study period) and skin prick tests were also carried out. Children in the intervention group experienced a reduction in the following symptoms: difficulty breathing during the day (RR ¼ 0.41, CI 0.07–0.98), difficulty breathing at night (RR ¼ 0.32, CI 0.14–0.69), chest tightness during the day (RR ¼ 0.45, CI 0.25–0.81), and asthma attacks during the day (RR ¼ 0.39, CI 0.17–0.93). Results of lung function testing did not differ between the two groups. Nitrogen dioxide levels measured in the intervention classrooms (mean 15.5, SD 6.6) were significantly lower than in control classrooms (mean 47.0, SD 26.8). Because this study was both randomized and blinded, it provides some of the strongest evidence of an association between indoor combustion (and NO2) and symptoms in asthmatic children.
Cooking appliances Gas cooking stoves Gas cooking stoves are an important source of indoor NO2. However, gas stoves tend to be used for shorter periods of time and are limited to the kitchen, resulting in a strong spatial gradient within the home. A large number of studies have investigated the relationship between gas cooking stoves and asthma prevalence or asthma symptoms. Both adults and children have been studied. Results are inconsistent, but exposure of children appears to be more consistent with risk than exposure of adults. Because gas stoves are used in the kitchen, women are thought to have a much higher exposure on average than men; some studies have considered these gender differences. Adult exposure Eisner and colleagues reported two studies of adult exposure to gas cooking and asthma [7,18]. Among 349 adult asthmatics in California, there was no
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apparent association of gas cooking with any of the health outcomes: asthma severity; physical health status; asthma quality of life; emergency department visits; or hospital admissions [7]. In NHANES III, 445 adult asthmatics completed pulmonary function testing [18]. There was no association between gas cooking and FEV1, FVC, FEV1/FVC ratio, or FEF25%–75%, nor was there any association with symptoms (cough, phlegm, dyspnea, or wheeze). However, in a cross sectional study (n ¼ 1159) in East Anglia, UK, gas cooking was positively associated with asthma symptoms and asthma attacks among women: wheeze (OR ¼ 2.07, CI 1.41–3.05); waking with shortness of breath (OR ¼ 2.32, CI 1.24–4.34); asthma attacks (OR ¼ 2.60, CI 1.20–5.65); and use of asthma medication (OR ¼ 2.88, 1.46–5.70) [19]. Women exposed to gas stoves also had lower lung function (% reduction in FEV1 ¼ 3.51 Standard Error [SE] 1.2, % FEV1/FVC ¼ 3.07 SE 1.21). No effects were seen in men. The authors argue that women spend more time cooking than men, and short-term ‘‘peak’’ exposures may be more harmful than exposures averaged over longer time periods. Moreover, when all of the European Community Respiratory Health (ECRHS) centers were examined in a subsequent study, the impact of gas stoves was much more variable and inconsistent. Child exposure Several studies have examined the impact of gas stove use on asthma in children. A case-control study of Dutch and German children investigated exposure to gas stoves and gas geysers (a type of unvented hot water heater) [1]. Cases (children with asthmatic symptoms) and controls were part of a larger longitudinal study. Parents of 1191 children (age 7–8 years) answered a questionnaire about housing characteristics. Gas cooking with a hood was not associated with asthma status (OR ¼ 0.94, CI 0.60–1.46), but use of an unvented gas geyser significantly increased the risk of asthma symptoms (OR ¼ 3.01, CI 1.21–7.56). In Victoria, Australia, parents of 148 children (including 53 asthmatics) were interviewed and nitrogen dioxide levels were measured in their homes [20]. Gas stove exposure was associated with asthma diagnosis (OR ¼ 2.23, CI 1.06–4.72) and respiratory symptoms (OR ¼ 2.32, CI 1.04–5.18). The association of gas stoves with respiratory symptoms remained significant (OR ¼ 2.24, CI 1.04–4.82) even after adjusting for measured NO2 concentration. This suggests several possibilities: that other pollutants from gas stoves are responsible for the health effects; that metrics other than average exposure are important; or that unmeasured confounders associated with gas stove use explain the association. As part of the Yale Childhood Asthma Study, exposures to NO2 and gas appliances were investigated as risk factors for exacerbations of asthma [21]. Children (n ¼ 728) less than 12 years old with active asthma (physician diagnosis and symptom or medication use in the past 12 months) were eligible for the study. At enrollment, research assistants placed Palmes tubes in the home to measure NO2 and recorded the
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presence of gas appliances. Mothers reported asthma symptoms in the two months prior to enrollment. To reduce confounding by socioeconomic status and housing characteristics, analyses were stratified by housing type (single family versus multi-family). Asthmatic children living in multi-family housing and exposed to gas stoves experienced increased symptoms of wheeze (OR ¼ 2.27, CI 1.15–4.47), shortness of breath (OR ¼ 2.38, CI 1.12–5.06) and chest tightness (OR ¼ 4.34, CI 1.76–10.69). There was no increase in symptoms associated with exposure to gas dryers, or among children in single-family housing. Exposure to measured NO2 concentrations confirmed the associations with gas stoves only among children in multi-family housing. The lack of an association of symptoms with exposure in single family homes may be due to the reduced exposure to NO2 resulting from newer appliances, or it might be due to less personal exposure due to larger homes. A case control study in Baltimore, MD, specifically looked at exposure to gas stoves among low-income children in the United States [22]. The investigators recruited 150 asthma cases and 150 controls to investigate factors associated with asthma development. All children lived in the inner city and high percentages were from low-income families (88% Medicaid) and were African American (91%). Asthma was not associated with either gas stove exposure or heating systems among these children. Because all subjects were low-income, differences between gas stove users and non-users cannot be attributed simply to poverty or substandard housing. The effects of ventilation have also been considered to explain the inconsistency in findings about gas stoves. As noted above, Mommers and colleagues [1] specifically analyzed gas stoves with a hood. However, many stoves have hoods that are not vented to the outside, further complicating analysis of the effects of gas cooking. Using birth cohort data from the Netherlands, Willers and colleagues [23] investigated gas cooking, controlling for ventilation. The ventilation variable included an assessment of the effectiveness of an extractor fan, the size of the kitchen, air supply to the kitchen, and use of other ventilation in the kitchen (eg, window fan or ceiling fan). Gas stove use was not statistically associated with asthma in this study (OR ¼ 1.50, CI 0.90-2.49). However, it was strongly correlated with poor ventilation (88% of gas users) and good ventilation was strongly associated with electric stove use (98% of electric users). Thus, information about ventilation did not provide additional information in the analysis of this study. Some studies have considered gender differences in the effects of gas stove use. In a nationally representative sample (NHANES III) of asthmatic children (8–16 years), Chapman and colleagues [24] compared the effects of gas stove use on lung function in boys and girls. Girls in homes where a gas stove was used for cooking had consistently lower lung function compared to homes with electric stoves. This association was limited to girls who did not use prescription medication for asthma.
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The ISAAC questionnaire administered in Munster, Germany (n ¼ 6,996) [10] also noted effects of gas cooking among girls, but not among boys. Gas cooking was positively associated with current wheeze (OR ¼ 1.52, CI 0.93– 2.47), but not with asthma (OR ¼ 0.77, CI 0.17–3.46). Some authors [10,19] have suggested that the increased risks for girls in these studies may be because girls are more likely than boys to help their mothers with cooking. However, a Swedish study also reported risks of gas stove exposure specifically in girls, although children in this study were less than 4 years old [25]; at this young age, it is unlikely that girls would be in the kitchen with their mothers more than boys. Children hospitalized for ‘‘wheezing bronchitis’’ (n ¼ 197) were compared to age matched controls (n ¼ 350) selected from population registers in the catchment area of the hospital. Among girls, exposure to a gas stove in the home was associated with wheezy bronchitis (RR ¼ 2.4, CI 1.0–5.9). Nitrogen dioxide exposure NO2 is a major pollutant produced by combustion. Some studies have assessed associations between asthma and indoor combustion by directly measuring NO2 concentrations in homes. The study by Belanger and colleagues [21] (described above) found that exposure to measured NO2 concentrations confirmed associations found with gas stoves. Children exposed to O20 ppb of NO2 in the home had increased days of wheeze (OR ¼ 1.33, 1.05–1.68) and chest tightness (OR ¼ 1.51, CI 1.18–1.91), but only among children in multi-family housing. NO2 concentrations in single family homes (mean [SD] ¼ 10.2 [12.3] ppb) were much lower than in multi-family homes (22.9 [17.0] ppb). In addition, single-family homes were larger (82% had six or more rooms), and personal exposure of children may have been much less than the measured concentration. Two studies [22,26] specifically looked at exposure to gas stoves and NO2 among low-income children in the United States. In the case control study conducted by Diette and colleagues [22] to investigate factors associated with asthma development, all children lived in the inner city and high percentages were from low-income families (88% Medicaid) and African American (91%). Measured concentrations of NO2 confirmed results described in the previous section suggesting no association between gas stove exposure and asthma development. For NO2, the medians [interquartile ranges] were 21.6[14–34] ppb and 20.9[14–31] ppb in homes of asthmatic children and controls, respectively. Fine particles % 2.5 micrometers in diameter (PM2.5) was also measured in the homes; no differences in median concentrations were found in the homes of asthmatics and nonasthmatics (median 28.7 [18–51] ug/m3 and 28.5 [17–50], respectively). Although concentrations did not vary between cases and controls, concentrations of NO2 and PM2.5 were high in both groups. Exposure to indoor combustion was also examined using data from the National Cooperative Inner City Asthma Study [26]. This study examined
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environmental factors contributing to increased asthma severity among asthmatic children. Results were reported by measured NO2 concentrations because more than 87% of participants used a gas stove. Children were often exposed to high NO2 concentrations (median ¼ 29.8 ppb), with 15.6% of children exposed in their homes to levels greater than 53ppb, the US EPA standard for outdoor air quality [27]. Gas stoves were the largest contributor to NO2 concentrations (median ¼ 31.7 ppb and 15.9 ppb for gas stove homes and electric stove homes, respectively). To analyze health outcomes, exposure above the 75 percentile of NO2 was compared to lower exposure and stratified by atopic status. Nonatopic children exposed to more than the 75 percentile of NO2 were at increased risk for more than 4 days of symptoms in a two-week period (OR ¼ 1.75, CI 1.10–2.78) and decreased peak flow (!80% expected) in the winter months (OR ¼ 1.46, 1.07–1.97). An advantage of these two studies is that all participants were from lowincome families, so differences between gas stove users and non-users, or children exposed to different NO2 concentrations, cannot be attributed simply to poverty or substandard housing. A disadvantage of the studies is that so many children were exposed to gas stoves and very high levels of NO2 that the comparison group has nearly as much exposure as the ‘‘exposed’’ group. In Australia [28], exposure to NO2 was measured both at school and at home for 174 asthmatic children. Relative risks were calculated per 10 ppb NO2. Exposure at school was associated with difficulty breathing during the day (RR ¼ 1.09, CI1.03–1.15), and at night (RR ¼ 1.11, CI 1.05–1.18); chest tightness at night (RR ¼ 1.12, CI 1.07–1.17); and difficulty breathing after exercise (RR ¼ 1.04, CI 1.01–1.09). Exposure at home was associated with difficulty breathing at night (RR ¼ 1.03, CI 1.01–1.05) and asthma attacks at night (RR ¼ 1.04, CI 1.00–1.07). Home exposure was also associated with decreased lung function (FEV1 ¼ 0.39% predicted per 10 ppb NO2, CI 0.76 to 0.02). In Japan [29], 842 school children participated in a study that measured NO2 concentrations in their homes and followed the children over three years to assess asthma, bronchitis and wheeze. The use of unvented heaters in the home was associated with higher NO2 concentrations, mean ¼ 34.4 ppb versus mean ¼ 18.4 ppb for homes with vented heaters. However, use of unvented heaters alone was not associated with any of the health outcomes. Exposure to a 10 ppb increase in NO2 was associated with asthma (OR ¼ 1.63, CI 1.06–2.54), bronchitis (OR ¼ 1.42 CI 1.06–1.90) and wheeze (OR ¼ 1.90 CI 1.30–2.83) among girls. Exposure to NO2 was not associated with any health outcome among boys.
Discussion This article did not find any studies that addressed the question of an association between indoor combustion and asthma incidence. To examine
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this question would require a cohort followed from birth. However, several studies considered increased asthma prevalence in association with combustion sources. Eight studies reported positive associations for asthma prevalence among children [9,11,12,14–16,25,29]; two studies reported negative findings [22,23]. Among adults, there was one positive [5] and one negative [6] association. A larger number of studies investigated increased symptoms, usually wheeze, or decreased lung function. Nine studies reported increased symptoms among children [1,3,9,12,16,17,20,21,28] and an additional four studies reported increased symptoms only in girls [10,24,25,29]. Two studies failed to find any association of asthma symptoms in children with combustion sources [8,23]. Among adults, indoor combustion was not associated with increased symptoms in three studies [6,7] and positively associated in one study, only with women [19]. Children appeared to be more susceptible to exposure to indoor combustion than adults; however, it is difficult to assess differences in susceptibility by age. Most studies specifically recruited children and only a limited number of studies of adult exposure was available. In three studies of adults exposed to woodstoves, only one was positive; and in three studies of adults exposed to gas cooking stoves, only one study had positive results, and only among women. Several studies investigating exposure to gas cooking stoves reported exposure associated with asthma in females, but not in males. This association could be explained among adult women, because women do more cooking in most families than men. However, this association was also reported among girls (even girls less than four years old). Differences between boys and girls may be related to exposure, or may indicate gender differences in susceptibility, for example hormonal differences. In general, exposure from indoor combustion for heating was more consistently associated with risk than exposure from cooking. This may reflect the higher exposure from heating devices that are used for many hours per day, rather than the shorter duration of exposure associated with cooking. Nonflued heating devices were more often associated with asthma prevalence or asthma symptoms than devices with flues. In particular, woodstoves that are always vented produced less risk. Removal of nonflued gas heaters in schools decreased symptoms in asthmatic children, even though some schools replaced these devices with flued gas heaters. Exposure from nonflued devices probably exceeds the exposure from flued devices, which might explain these findings. It appears that exposure to coal poses a special risk. All studies that reviewed burning coal in the home indicated increased asthma prevalence, and the three studies designed to measure increases in symptoms (eg, wheeze, phlegm, inhaler use) also noted increased symptoms in asthmatic children. Results were much less consistent for wood, where only one of the four studies indicated a positive association with increased asthma symptoms among adults. Nonflued gas heaters also posed a significant risk, and a randomized
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trial provides strong evidence that removing these heaters reduced asthma symptoms in children. Gas stove use is particularly common in central cities; in the United States, inner cities are associated with high rates of poverty and substandard housing. In rural areas, the use of secondary heating devices (kerosene heaters, unvented gas) may be a means to reduce heating costs among low-income families. Thus, it is possible that gas stoves and portable heating devices are markers for poverty and substandard housing, and this confounds any association with asthma. Two studies specifically analyzed children from low-income families living in inner city neighborhoods. Both studies measured exposure to nitrogen dioxide (one also measured PM2.5) and both documented very high exposures (exceeding the US Environmental Protection Agency [EPA] level for outdoor exposure in some cases). However, these studies found limited association with asthma (one found no association; in the other, associations were limited to subgroups). A limitation of these studies is that measured pollutant concentrations indicate there were no truly unexposed controls; even homes without gas stoves had high measured concentrations of NO2. Many of these homes were multifamily and children were probably exposed to pollutants from devices in the building, if not in their own apartments. An intervention study in the UK indicated a reduction in symptoms for children when sources in the home were removed and housing conditions improved. Overall, it appears that exposure to indoor combustion sources may increase the risk of asthma or asthma severity, particularly in children. Characteristics of the device (eg, frequency and intensity of use, type and age of appliance) and of the home (eg, size, ventilation) result in considerable variability in exposures, which may account for some of the inconsistent findings between studies.
References [1] Mommers M, Jongmans-Liedekerken AW, Derkx R, et al. Indoor environment and respiratory symptoms in children living in the Dutch-German borderland. Int J Hyg Environ Health 2005;208(5):373–81. [2] Hasselblad V, Eddy DM, Kotchmar DJ. Synthesis of environmental evidence: Nitrogen dioxide epidemiology studies. J Air Waste Manag Assoc 1992;42:662–71. [3] Pilotto LS, Nitschke M, Smith BJ, et al. Randomized controlled trial of unflued gas heater replacement on respiratory health of asthmatic schoolchildren. Int J Epidemiol 2004;33(1): 208–14. [4] Naeher LP, Brauer M, Lipsett M, et al. Woodsmoke health effects: a review. Inhal Toxicol 2007;19:67–106. [5] Thorn J, Brisman J, Toren K. Adult-onset asthma is associated with self-reported mold or environmental tobacco smoke exposures in the home. Allergy 2001;56(4):287–92. [6] Kilpelainen M, Koskenvuo M, Helenius H, et al. Wood stove heating, asthma and allergies. Respir Med 2001;95(11):911–6.
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[7] Eisner MD, Yelin EH, Katz PP, et al. Exposure to indoor combustion and adult asthma outcomes: environmental tobacco smoke, gas stoves, and woodsmoke. Thorax 2002;57(11): 973–8. [8] Noonan CW, Ward TJ. Environmental tobacco smoke, woodstove heating and risk of asthma symptoms. J Asthma 2007;44(9):735–8. [9] Bothwell JE, McManus L, Crawford VL, et al. Home heating and respiratory symptoms among children in Belfast, Northern Ireland. Arch Environ Health 2003;58(9):549–53. [10] Behrens T, Maziak W, Weiland SK, et al. Symptoms of asthma and the home environment. The ISAAC I and III cross-sectional surveys in Munster, Germany. Int Arch Allergy Immunol 2005;137(1):53–61. [11] Zheng T, Niu S, Lu B, et al. Childhood asthma in Beijing, China: a population-based casecontrol study. Am J Epidemiol 2002;156(10):977–83. [12] Qian Z, Zhang J, Korn LR, et al. Factor analysis of household factors: are they associated with respiratory conditions in Chinese children? Int J Epidemiol 2004;33(3):582–8. [13] Environmental Criteria and Assessment Office, Office of Research and Development. Air quality criteria for oxides of nitrogen. Research Triangle (NC): U.S. Environmental Protection Agency; 1993. [14] Ponsonby AL, Couper D, Dwyer T, et al. The relation between infant indoor environment and subsequent asthma. Epidemiology 2000;11(2):128–35. [15] Lanphear BP, Aligne CA, Auinger P, et al. Residential exposures associated with asthma in US children. Pediatrics 2001;107(3):505–11. [16] Phoa LL, Toelle BG, Ng K, et al. Effects of gas and other fume emitting heaters on the development of asthma during childhood. Thorax 2004;59(9):741–5. [17] Somerville M, Mackenzie I, Owen P, et al. Housing and health: does installing heating in their homes improve the health of children with asthma? Public Health 2000;114(6):434–9. [18] Eisner MD, Blanc PD. Gas stove use and respiratory health among adults with asthma in NHANES III. Occup Environ Med 2003;60(10):759–64. [19] Jarvis D, Chinn S, Luczynska C, et al. Association of respiratory symptoms and lung function in young adults with use of domestic gas appliances. Lancet 1996;347(8999):426–31. [20] Garrett MH, Hooper MA, Hooper BM, et al. Respiratory symptoms in children and indoor exposure to nitrogen dioxide and gas stoves. Am J Respir Crit Care Med 1998;158(3):891–5. [21] Belanger K, Gent JF, Triche EW, et al. Association of indoor nitrogen dioxide exposure with respiratory symptoms in children with asthma. Am J Respir Crit Care Med 2006;173(3): 297–303. [22] Diette GB, Hansel NN, Buckley TJ, et al. Home indoor pollutant exposures among innercity children with and without asthma. Environ Health Perspect 2007;115(11):1665–9. [23] Willers SM, Brunekreef B, Oldenwening M, et al. Gas cooking, kitchen ventilation, and asthma, allergic symptoms and sensitization in young children–the PIAMA study. Allergy 2006;61(5):563–8. [24] Chapman RS, Hadden WC, Perlin SA. Influences of asthma and household environment on lung function in children and adolescents: the third national health and nutrition examination survey. Am J Epidemiol 2003;158(2):175–89. [25] Pershagen G, Rylander E, Norberg S, et al. Air pollution involving nitrogen dioxide exposure and wheezing bronchitis in children. Int J Epidemiol 1995;24(6):1147–53. [26] Kattan M, Gergen PJ, Eggleston P, et al. Health effects of indoor nitrogen dioxide and passive smoking on urban asthmatic children. J Allergy Clin Immunol 2007;120(3):618–24. [27] U.S. Environmental Protection Agency. National Ambient Air Quality Standards [cited March 5, 2008]. Available at: http://www.epa.gov/air/criteria.html. Accessed February 6, 2008. [28] Nitschke M, Pilotto LS, Attewell RG, et al. A cohort study of indoor nitrogen dioxide and house dust mite exposure in asthmatic children. J Occup Environ Med 2006;48(5):462–9. [29] Shima M, Adachi M. Effect of outdoor and indoor nitrogen dioxide on respiratory symptoms in schoolchildren. Int J Epidemiol 2000;29(5):862–70.
Immunol Allergy Clin N Am 28 (2008) 521–537
Passive Smoking and Adult Asthma Mark D. Eisner, MD, MPH Division of Occupational and Environmental Medicine and Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California San Francisco, 505 Parnassus Avenue, M1097, San Francisco, CA 94143-0111, USA
Asthma is a common chronic health condition, affecting 5% of the United States adult population [1]. In most developed countries, the prevalence of asthma and its severity continues to increase. Understanding the factors contributing to asthma morbidity and mortality has important clinical and public health implications. Passive tobacco smoking results in exposure to a complex mixture of more than 4,000 chemical compounds, including known carcinogens [2]. Secondhand smoke (SHS) also contains potent respiratory irritants, such as sulfur dioxide, ammonia, formaldehyde, and acrolein. These chemicals irritate the upper and lower respiratory tract (Table 1) and may induce asthma through irritant or sensitizing mechanisms [3]. Because persons with established asthma have chronic airway disease, they may also be susceptible to adverse health effects from SHS exposure. This article evaluates the evidence that SHS exposure is a risk factor for new-onset asthma among adults and exacerbates pre-existing adult asthma, resulting in greater symptom burden and morbidity.
Prevalence of secondhand smoke exposure In the United States, there has been significant progress in reducing passive smoke exposure. During the period from 1988 to 2002, SHS exposure, as measured by serum cotinine, declined by 70% [4]. Nonetheless, nearly half of all Americans continue to have evidence of recent SHS exposure. Although they might be expected to avoid SHS, many United States adults with asthma actually experience significant exposure. In a cohort of adults with asthma living in Northern California, 29% reported regular SHS exposure [5]. Among adult health maintenance organization (HMO)
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Table 1 Common respiratory tract and sensory symptoms after secondhand smoke exposure Symptom class
Symptom
Sensory irritation symptoms/upper respiratory tract symptoms
Conjunctival injection or redness Conjunctival pruritis Tearing Rhinorrhea Nasal burning Nasal stuffiness Sore throat Cough Cough with phlegm production Wheezing Dyspnea (at rest) Dyspnea (with exertion)
Lower respiratory tract symptoms
members with asthma, 38% indicated regular exposure [6]. A populationbased study from Canada found that 42% of nonsmoking children and adults with asthma reported SHS exposure during the previous 24 hours, compared with 32% of the general population [7]. In the author’s study, using direct measurement of SHS exposure among adults with asthma, an even higher prevalence of exposure was found, ranging from 60% to 83% depending on the time frame and methodology [8]. In sum, it seems clear that adults with asthma continue to experience significant passive smoking exposure.
Secondhand smoke exposure and asthma induction in adults Extensive data support a causal association between SHS exposure and induction of asthma in children [3]. In a recent meta-analysis of 85 studies conducted by the California Environmental Protection Agency (EPA), passive smoking was associated with an increase in childhood asthma incidence of between 21% and 37% [2]. The literature was deemed to be sufficient to infer a causal relationship between passive smoking and childhood asthma induction. Until recently, however, the relationship between SHS exposure and adult-onset asthma has received less attention [9]. Fig. 1 shows a conceptual model of how SHS exposure may cause adult-onset asthma. Recent epidemiologic studies have evaluated the impact of SHS exposure on new-onset adult asthma. The Swiss Study on Air Pollution and Lung Diseases in Adults (SAPALDIA) focused on a random sample of adult never-smokers aged 18 to 60 years residing in Switzerland [10]. In a crosssectional analysis, investigators observed an association between selfreported SHS exposure during the previous 12 months and a greater risk of self-reported physician diagnosis of asthma (odds ratio or OR 1.39; 95% confidence interval or CI 1.04–1.86). Statistically controlling for age,
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SHS Birth
persistence
SHS ADULT ASTHMA
Childhood Asthma Onset
Asthma Exacerbation
SHS
Remission
SHS Birth
SHS Birth
“Asthma-like” Respiratory Symptoms
Fig. 1. Conceptual framework for how SHS exposure may lead to adult asthma induction or exacerbation.
gender, atopy, education, maternal and paternal smoking during childhood, and parental asthma history had no appreciable impact on this relationship. Furthermore, the investigators observed statistically significant exposureresponse trends for hours per day of SHS exposure, number of smokers, and years of exposure. A case-controlled study from semi-rural Sweden evaluated SHS exposure as a risk factor for asthma [11]. Asthma diagnosis was confirmed by a study lung specialist. SHS exposure at both home and work was assessed by written questionnaire, which was defined as exposure for at least 3 years before the age at asthma diagnosis (or comparable age for controls). Using this definition, workplace SHS exposure was associated with an increased risk of asthma (OR 1.5; 95% CI 0.8–2.5), but the confidence interval did not exclude no association. Exposure to SHS at home was not associated with the risk of asthma (OR 0.9; 95% CI 0.5–1.5). A population-based cross-sectional study aimed to elucidate environmental risk factors for asthma and allergic rhinitis among Swedish dairy farmers [12]. By postal questionnaire, asthma was defined as self-reported episodic respiratory symptoms, such as wheezing and dyspnea. SHS exposure was assessed for the current period (home and work) and during childhood. In this study, no measure of SHS exposure, past or present, was associated with the risk of asthma. In a previous article, the author examined cross-sectional data from 47,721 adult never-smoking Northern California Kaiser Permanente members who underwent multiphasic health check-ups between 1979 and 1985 [13]. Using a written questionnaire, current SHS exposure was ascertained
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for several locations: home, other small spaces (eg, office or car), and large indoor spaces (eg, restaurant). In each location, the survey assessed average duration of exposure. In both men and women, any SHS exposure was associated with a greater risk of self-reported physician-diagnosed asthma (OR 1.22; 95% CI 1.11–1.34), controlling for socioeconomic and demographic covariates. For weekly exposure duration, there was evidence of an exposure-response relation among women but not men. A population-based study of 8,008 adult never-smokers from Sweden examined the impact of childhood SHS exposure on current self-reported physician-diagnosed asthma during adulthood [14]. The prevalence of adult asthma was more common among subjects who indicated childhood SHS exposure (7.6%), compared with unexposed persons (5.8%) (P ¼ .035). Current self-reported ‘‘breathing difficulties from cigarette smoke’’ were also more common among subjects who indicated a history of childhood SHS exposure. In further analysis, the investigators stratified by family history of asthma. Although there was no clear impact of SHS among subjects without a family history of asthma, SHS exposure was associated with a greater risk of asthma among those with a positive family history (OR 1.82; 95% CI 1.28–2.58). These results could be consistent with higher rates of smoking cessation by asthmatic parents, reducing exposure of their children with asthma. The European Community Respiratory Health Survey investigators examined the respiratory health impacts of SHS exposure among 7,882 adult never-smokers aged 20 to 48 years [15]. Compared with no SHS exposure, any SHS exposure at home or work was not clearly associated with a greater risk of self-reported current asthma (OR 1.15; 95% CI 0.84–1.58). When each source of exposure was examined individually, workplace exposure was related to a higher risk of asthma (OR 1.90; 95% CI 1.25–2.88). There was no clear impact of home exposure (OR 1.14; 95% CI 0.68–1.90). These apparently discrepant results could be explained by the method of SHS exposure measurement. Home exposure was defined as living with at least one smoker, whereas workplace exposure ascertained regular smoking in the room where they worked. Because residence with a smoker may not always reflect domestic SHS exposure, use of this exposure measure could attenuate the effect estimate for home SHS exposure [16]. The investigators also found a similar pattern of results for several asthma-like symptoms, including wheeze, noctural chest tightness, and dyspnea. In these instances, workplace SHS exposure was related to a greater risk of respiratory symptoms, whereas home exposure had no apparent impact. Furthermore, both home and workplace SHS exposure were associated with greater bronchial hyper-responsiveness assessed by methacholine challenge. Because bronchial hyper-responsiveness is a cardinal feature of asthma, this result adds additional support to the observed link between SHS exposure and self-reported asthma. A Swedish population-based case-controlled study examined the impact of SHS exposure on adult-onset asthma (age O16 years) [17]. The
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investigators ascertained home exposure only, during or previous to the year of asthma diagnosis (and at a randomly selected time for control subjects). In this study, SHS exposure was associated with a greater risk of adult-onset asthma (OR 2.4; 95% CI 1.4–4.1). This increased risk was observed only among never-smokers and not among current or ex-smokers. When the results were stratified by sex, the association was stronger for males (OR 4.8; 95% CI 2–11.6) than for females (OR 1.5; 95% CI 0.8–3.1). Hu and colleagues [18] evaluated a cohort of 1,469 seventh grade students 7 years after a school-based smoking prevention program in southern California. At baseline, SHS exposure status was determined by parental reports of personal smoking. During young adulthood (7 years later), selfreported physician diagnosed asthma was ascertained by written questionnaire. Exposure to parental SHS at baseline was associated with an increased risk of subsequent asthma. Compared with no maternal smoking or light smoking at baseline (less than one-half pack per day), heavier maternal smoking was associated with an increased risk of self-reported asthma in young adulthood (OR 1.8; 95% CI 1.1–3.0). Similarly, heavy paternal smoking was related to a greater risk of asthma (OR 1.6; 95% CI 1.1–2.4). In addition, they observed an exposure-response relationship between number of parents smoking at baseline and the risk of asthma 7 years later. A longitudinal cohort study of 3,914 adult nonsmoking Seventh-Day Adventists living in California evaluated the relationship between SHS exposure and the incidence of self-reported physician diagnosed asthma during a 15-year period [19,20]. The investigators reported the 10-year [19] and 15-year cohort follow-up [20]. Duration of working with a smoker was associated with an increased risk of developing asthma (OR 1.5 per 10-year increment; 95% CI 1.2–1.8). At the 15-year follow-up, duration of working with a smoker was associated with an increased risk of incident asthma for women only (OR 1.21; 95% CI 1.04–1.39). In both analyses, there was no reported relationship between duration of residence with a smoker and risk of asthma. A recent population-based cross-sectional study from India examined the impact of home SHS exposure on self-reported asthma diagnosis on 62,109 never-smoking adults [21]. SHS exposure was associated with asthma after adjusting for age, gender, usual residence, exposure to biomass fuels, and atopy (OR 1.22; 95% CI 1.08–1.38). Respondents who reported both childhood SHS exposure and home exposure during adulthood had highest risk of having asthma (OR 1.69; 95% CI 1.38–2.07). A seminal population-based case-controlled study examined the relation between SHS exposure and new onset adult asthma among 239 asthma subjects and a 487 matched controls in Finland [22]. Lifetime passive smoke exposure was ascertained by questionnaire. Logistic regression analysis was used to control for age, gender, parental atopy or asthma, education, mold exposure, pets in the home, and other occupational exposures. The
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incidence of adult-onset asthma was significantly associated with total SHS exposure (combined home and workplace) during the preceding 12 months (OR 1.97; 95% CI 1.19–3.25) with evidence of an exposure response relationship (OR 1.33 per 10 cigarettes per day; 95% CI 1.02–1.75). After controlling for exposure at home, any exposure to SHS in the workplace was also associated with an increased risk of asthma (OR 2.16; 95% CI 1.26–3.72). There was also a substantive risk of asthma related to home SHS exposure (OR 4.77; 95% CI 1.29–17.7). When passive smoking was analyzed as cumulative lifetime exposure, the risk of asthma was also increased, especially from workplace and combined exposures. This study is important because it had excellent lifetime exposure estimation, was population based, and clearly ascertained adult onset asthma cases. There is no gold standard for defining asthma in epidemiologic research. Although self-reported asthma is commonly used in survey research, this definition may not detect all persons with asthma [23,24]. Respondents’ reports of respiratory symptoms, especially wheezing, may have a greater sensitivity for identifying adults with asthma [24]. Wheezing, in particular, correlates with the criterion of bronchial hyper-responsiveness (see Fig. 1) [25]. Earlier epidemiologic studies supported the relationship between SHS exposure and wheezing among adults [10,26–29]. Several more recent studies further support this relationship. In the SAPALDIA study, SHS exposure during the previous 12 months was associated with a greater risk of wheezing (OR 1.94; 95% CI 1.39–2.70), dyspnea on exertion (OR 1.45; 95% CI 1.2–1.79), and chronic bronchitis symptoms of cough or phlegm production (OR 1.65; 95% CI 1.17–2.16) [10]. As in the analysis focusing on asthma, controlling for demographic and socioeconomic covariates had minimal effect. For these symptom endpoints, investigators observed exposure-response trends for hours per day of exposure, number of smokers, and years of exposure. Using a case-crossover design, the author and colleagues studied the effects of California State Assembly Bill 13, which prohibited tobacco smoking in bars and taverns, on the respiratory health of bartenders [30]. Based on a random sample of all bars and taverns in San Francisco, the investigators interviewed and performed spirometry on 53 bartenders before and after the smoking ban. After prohibition of smoking, self-reported workplace SHS exposure sharply declined from a median of 28 to 2 hours per week. Of the 53 bartenders, 39 (74%) reported at least one respiratory symptom at baseline (including cough, dyspnea, and wheezing), while only 17 (32%) were still symptomatic at follow-up. Of the 39 bartenders reporting baseline symptoms, 23 subjects (59%) no longer indicated any respiratory symptoms after prohibition of smoking (P ! .001). In particular, 70% of the 17 bartenders reporting baseline wheezing noted resolution after workplace smoking prohibition. In conditional logistic regression analysis, a 5-hour reduction of workplace SHS exposure was associated with a lower risk of respiratory symptoms at follow-up (OR 0.7; 95% CI 0.5–0.9), after
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controlling for upper respiratory infections and reduced personal cigarette smoking. After prohibition of workplace smoking, the investigators also observed improvement in mean forced vital capacity (FVC) (0.189 L; 95% CI 0.082–0.296) and mean forced expiratory volume in the first second of expiration (FEV1) (0.039; 95% CI 0.030 to 0.107). Complete cessation of workplace SHS exposure was associated with an even greater pulmonary function improvement. More recently, Menzies and colleagues [31] reported the effects of a national smoking ban on bar workers in Scotland. Using a design similar to the author’s earlier study [30], these investigators documented markedly reduced SHS exposure after the smoking ban, based on both self-reported exposure and a biomarker of SHS exposure (serum cotinine). After the smoke-free legislation went into effect, bar workers experienced sustained reduction of sensory irritation symptoms and respiratory symptoms as well as improved pulmonary function. The study by Menzies and colleagues [31] confirms and amplifies previous research demonstrating reduced SHS exposure and decreased respiratory symptoms among restaurant and bar workers after smoke-free workplace mandates in the United States [30,32,33], Ireland [34–37], Norway [38], and New Zealand [39]. Taken together, there is compelling scientific evidence that smoke-free workplace legislation is rapidly effective in preventing asthma-like respiratory symptoms. The study by Menzies and colleagues [31] also provided valuable new information about bar workers with asthma. After the Scottish smoking ban went into effect, bar workers with asthma experienced an even larger improvement in pulmonary function than those without asthma. Moreover, the asthmatics had evidence of reduced airway inflammation (exhaled nitric oxide) and improved asthma-specific quality of life. Consequently, it appears that the benefits of smoke-free workplace legislation are even greater for persons with asthma. A population-based longitudinal cohort study from the United Kingdom followed children aged 6 to 8 years into adolescence (age 14–16 years) to examine factors associated with the development of respiratory symptoms [40]. In adolescence, SHS exposure was cross-sectionally associated with current wheeze (OR 1.48; 95% CI 1.17–1.88). Maternal smoking was related to a greater risk of parent-reported physician-diagnosed asthma (OR 1.50; 95% CI 1.14–1.98). There was no apparent impact of paternal smoking on current asthma. Among previously asymptomatic persons, paternal smoking was associated with new-onset wheeze during prospective followup (OR 1.55; 95% CI 1.03–2.32). Maternal smoking, however, was not associated with new-onset wheeze. New-onset asthma was not examined. Another population-based United Kingdom cohort study followed 18,559 children born during a single week in March 1958 through age 33 (31% complete follow-up) [41]. The study examined the association between household SHS exposure and the future incidence of wheezing.
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At both age 7 and 33 years, maternal smoking during pregnancy was associated with an increased risk of incident wheezing illness (OR 1.72; 95% CI 1.11–2.67 and OR 1.71; 95% CI 0.97–3, respectively). At age 33, maternal smoking at subject age 16 was associated with an increased incidence of wheezing (OR 1.19; 95% CI 0.86–1.65). SHS exposure both during pregnancy and age 16 was related to a greater risk of incident wheezing (OR 1.4; 95% CI 1.08–1.82). This study is limited by the low follow-up at age 33, which could have biased the results if SHS exposure was related to the probability of study participation. A population-based study of 2,195 Italian women examined the impact of exposure to self-reported history of home and workplace SHS exposure (ever- versus never-exposed) [42]. SHS exposure from both a husband and at work were significant risk factors for current dyspnea (OR 1.61; 95% CI 1.20–2.16), recent wheeze (OR 1.71; 95% CI 1.04–2.82), recent attacks of shortness of breath with wheeze (OR 1.85; 95% CI 1.05–3.26), and self-reported physician diagnosis of asthma diagnosis or respiratory symptoms (OR 1.50; 95% CI 1.09–2.08). The impact of SHS exposure on asthma diagnosis alone was not examined. Measurement of SHS exposure by self-report is potentially subject to bias, which limits many of the studies reviewed. The impact of exposure misclassification may be particularly problematic in cross-sectional studies. For example, adults with asthma might be more likely to remember and report SHS exposure, whereas asymptomatic persons might underreport SHS exposure. This bias would inflate the estimated risk associated with SHS exposure. In many studies examined, systematic misclassification of SHS exposure cannot be excluded. The prospective data, however, should be less affected by this potential bias. Moreover, studies that employed direct markers of SHS exposure, such as cotinine or personal nicotine exposure, would be free from this reporting bias. The consistency of study findings helps to support a causal relationship between SHS exposure and adult asthma induction. In samples drawn from different populations, ranging from clinical to population-based samples, and different countries around the world, investigators have observed the association between SHS exposure and new-onset asthma. The relationship between SHS exposure and asthma has been observed in a variety of study designs, including cross-sectional, case-controlled, and cohort studies. Exposure in different environments, such as home and work, has also been linked with asthma. The consistency of findings linking SHS exposure with different related respiratory health outcomes, including new-onset asthma and wheezing, supports a deleterious causal effect of SHS exposure on adult asthma. Because SHS contains potent respiratory irritants, exposure may adversely affect bronchial smooth muscle tone and airway inflammation [3]. Studies linking SHS exposure with a decrement in pulmonary function support the biologic plausibility of SHS-related asthma onset. Taken
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together, studies of adults support a small but significant deleterious effect of SHS on pulmonary function [26–28,30,43–54]. The studies reviewed also demonstrate coherence in the association between SHS exposure and asthma morbidity. SHS exposure has been associated with new-onset asthma, whether defined as self-reported physician diagnosed asthma or a clinical asthma diagnosis. Furthermore, SHS exposure is associated with related health outcomes, including other chronic airway diseases and respiratory symptoms, such as wheezing, cough, and dyspnea. The coherence of these findings among diverse respiratory outcomes supports a causal association. Secondhand smoke exposure and exacerbation of pre-existing adult asthma Because adults with asthma have chronic airway inflammation, they may be particularly susceptible to the effects of SHS exposure. Both the California EPA and United States EPA have affirmed a causal connection between passive smoke exposure and exacerbation of pre-existing asthma among children [2]. Adults with asthma commonly report SHS exposure as a trigger for asthma exacerbation [55,56]. However, the impact of SHS exposure on adults with asthma has received less research than in children. Recent epidemiologic studies support a link between SHS exposure and adult asthma exacerbation. In a cross-sectional study, investigators examined the impact of self-reported SHS exposure on 200 never-smoking adults with asthma attending a university-based chest clinic in India [57]. Compared with unexposed patients, adult asthmatics reporting SHS exposure indicated greater reliance on daily bronchodilators (66% versus 56%, P!.01) and intermittent corticosteroid use (56% versus 42%, P!.01). Although there was no relationship with hospitalization, SHS-exposed subjects had a higher mean number of emergency department visits for asthma during the previous year (0.82 visits per person versus 0.6 visits per person, P!.01) and more work absence (3.6 weeks per person versus 3 weeks per person, P!.01). SHS exposure was also associated with worse pulmonary function, including lower FEV1 (68.7% versus 80.8% of predicted), FEV1/ FVC (63.5% versus 78.4%), and forced expiratory flow (FEF25%–75%) (54.3% versus 75.7%). In the Swedish component of the European Community Respiratory Health Survey, Blanc and colleagues [58] examined the cross-sectional impact of self-reported workplace SHS exposure among 2,065 adults (aged 20–44 years). Regular workplace SHS exposure was associated with a greater risk of respiratory-related work disability (prevalence ratio 1.8; 95% CI 1.1– 3.1), defined as self-reported change in job or leaving work because of affected breathing. Moreover, workplace SHS exposure was related to a greater risk of work-associated symptomatic asthma, defined as selfreported asthma, airway hyper-responsiveness, and work-related chest tightness or wheezing (prevalence ratio 1.7; 95% CI 0.9–3.3). Because this study
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focused on workplace factors, home and other sources of SHS exposure were not examined. In a prospective panel study of 164 adult nonsmokers with asthma, Ostro and colleagues [59] examined the impact of SHS exposure on asthma status during a 3-month period. Subjects completed daily diaries, including SHS exposure (home and work) and respiratory symptoms. During longitudinal follow-up, SHS exposure was associated with subsequent greater risks of cough (1.21; 95% CI 1.01–1.46), dyspnea (OR 1.85; 95% CI 1.57–2.18), nocturnal asthma symptoms (OR 1.24; 95% CI 1–1.53), and restricted activity (OR 2.08; 95% CI 1.63–2.64). In this longitudinal panel study, the close temporal link between SHS exposure and outcome supports a causal relationship between exposure and asthma exacerbation. In an analysis of 43,732 adults completing the Health Promotion and Disease Prevention supplement of the 1991 National Health Interview Survey, the cross-sectional association between self-reported SHS exposure at home or work and the risk of ‘‘chronic respiratory disease exacerbation’’ was examined [60]. This study outcome was defined as activity limitation or a physician visit because of a chronic respiratory disease: asthma, chronic bronchitis, emphysema, or chronic sinusitis. Among never-smokers, SHS exposure was associated with an increased risk of chronic respiratory disease exacerbation (OR 1.44; 95% CI 1.07–1.95). Although the population-based sampling and careful control of confounding are study strengths, the relationship between SHS exposure and asthma alone cannot be clearly elucidated from the published study. Using data from the Third National Health and Nutrition Examination Survey, the author examined the relationship between serum cotinine and pulmonary function among 440 nonsmoking adults with asthma (corresponding to a population of 4.9 million asthmatics) [53]. There was no apparent impact of SHS exposure, as measured by serum cotinine level and pulmonary function among men. In the female stratum, higher levels of SHS exposure were associated with greater impairment of FEV1, FVC, and FEV1/FVC ratio. In particular, the highest cotinine tertile was related to a mean FEV1 decrement of 261 mL (95% CI 492 to 30). The impact of SHS exposure appeared to be greater among adults with asthma when compared with nonsmoking members of the general population. The SAPALDIA study focused on a random sample of adult neversmokers aged 18 to 60 years residing in Switzerland. A report from the SAPALDIA investigators found similar effects of self-reported SHS exposure on pulmonary function among 3,534 never-smoking adults with asthma [61]. SHS exposure at work was related to a substantive decrement of FEV1 (4.8%), FVC (1.7%), and forced expiratory flows at mid-lung volumes (FEF25%–75%, 12.4%). The impact of SHS exposure on FEV1 and FEF25%–75% was greater among women than men (8.7% versus 0.5% and 20.8% versus 1.4%, respectively). There was evidence of linear exposureresponse trend for daily exposure duration and numbers of years of exposure.
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In a cross-sectional study, Jindal and colleagues [62] recruited 50 women with asthma from a university hospital chest clinic in India. SHS exposure at home and work was assessed by questionnaire. Compared with women who indicated no SHS exposure, subjects indicating any SHS exposure had similar FEV1 (78% predicted versus 79%) and FEV1/FVC ratio (94% versus 86%) (P¼ not significant in both cases). The SHS-exposed women had greater bronchial hyperresponsiveness, as indicated by lower PD20 (median 1.70 versus 6.1 units; P!.01). SHS exposure was also associated with greater asthma medication use. The proportion who indicated ‘‘continuous’’ bronchodilator use was higher among exposed women (39% versus 26%; P!.05), although the precise definition of this term was not provided. Taken together with the European Community Respiratory Health Survey results described earlier, SHS exposure is related to greater bronchial hyperresponsiveness among adults with asthma. A cohort study of 619 adult HMO members with asthma evaluated the association between SHS exposure and health outcomes [6]. The prevalence of self-reported regular SHS exposure was 38% and a small proportion of subjects (11%) indicated current personal cigarette smoking. In crosssectional analysis of baseline data, regular SHS exposure was associated with worse asthma-specific quality of life and generic health status (SF-36 physical functioning and general health domains). During longitudinal follow-up, SHS exposure was associated with a greater incidence of hospital-based episodes of asthma care (28 events versus 10 events per 100 person-years). After controlling for sociodemographic covariates, SHS exposure was with a greater risk of hospital-based care (risk ratio 2.34; 95% CI 1.8–3.1). To study the impact of SHS exposure on adults with asthma, the author and colleagues used data from an ongoing prospective cohort study of adults with asthma recruited from a random sample of allergy, pulmonary, and family practice physicians practicing in Northern California [16]. Of the overall cohort, the investigators recruited 50 subjects to wear a personal nicotine badge monitor for 1 week. At the conclusion of the monitoring period, respiratory symptoms and medication use were ascertained. Compared with subjects with no measurable nicotine levels for the past 7 days, lower level (0 mg/m3–0.05 mg/m3) and higher level exposure (O0.05 mg/m3) were associated with a greater risk of respiratory symptoms at follow-up (OR 1.9; 95% CI 0.4–8.8 and OR 6.8; 95% CI 1.4–32.3). Lower- and higher-level SHS exposures were also related to an increased risk of extra bronchodilator use after exposure (OR 2.2 and 8.1). For both outcomes, there was evidence of a linear exposure-response relationship. In the larger prospective cohort study of 349 adults with asthma, the author and colleagues examined the impact of self-reported SHS exposure on subsequent health outcomes [63]. SHS exposure at baseline interview was associated with impaired health status at longitudinal follow-up. Compared with respondents with no baseline self-reported exposure to SHS,
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higher level exposure (O7 hours per week) was associated with worse severity of asthma scores at follow-up, controlling for baseline asthma severity, age, sex, race, income, and educational attainment (mean score increment 1.5 points; 95% CI 0.4–2.6). Higher-level baseline exposure to SHS was also related to poorer physical health status (mean decrement 4.9 points; 95% CI 8.4 to 1.3) and asthma specific quality of life (mean increase 4.4 points; 95% CI 0.2 to 9) at longitudinal follow up. Higher-level baseline SHS exposure was associated with a greater risk of emergency department visits (OR 3.4; 95% CI 1.1–10.3) and hospital admissions for asthma at prospective follow up (OR 12.2; 95% CI 1.5–102). Taken together with the direct exposure measurement results from this cohort, these studies support the adverse impact of passive smoking on adult asthma status. In another prospective cohort study of adult nonsmokers recently admitted to hospital for asthma, the impact of SHS exposure on asthma health outcomes was examined [8]. Recent SHS exposure during the previous 7 days was directly measured using a personal nicotine badge (n ¼ 189) and exposure during the previous 3 months was estimated using hair nicotine and cotinine levels (n ¼ 138). Asthma severity and health status were ascertained during telephone interviews, and subsequent admission to hospital for asthma was determined from computerized use databases. The highest level of recent SHS exposure, as measured by the personal nicotine badge, was related to greater asthma severity (mean score increment for highest tertile of nicotine level 1.56 points; 95% CI 0.18–2.95), controlling for sociodemographic covariates and previous smoking history. Moreover, the second and third tertiles of hair nicotine exposure during the previous month were associated with a greater baseline prospective risk of hospital admission for asthma (hazard ratio or HR 3.73; 95% CI 1.04–13.30 and HR 3.61; 95% CI 1–12.9, respectively). A prospective cohort study from Canada followed children and adults with asthma for the development of acute exacerbation [64]. The main goal was to evaluate the impact of viral upper respiratory infections on the risk of asthma exacerbation. More than half of the subjects were aged 13 years or greater (58%), ranging up to age 55 years. Within the cohort, a nested case-controlled study was performed, with cases of acute asthma exacerbation compared with controls without exacerbation. Cases with asthma exacerbation were defined by increasing asthma symptoms refractory to usual medications for more than 48 hours or urgent health care use for asthma: hospitalization, emergency department visit, or urgent physician visit. Cases (with acute asthma exacerbation) were more likely to have indicated SHS exposure during the previous year (39%) than controls without exacerbation (17%) (P!.03) (Tarlo SM, personal communication, 2002) [64]. Although the investigators ascertained exposures to colds, dust, and other factors during the week preceding the exacerbation, SHS exposure was not reported for this period.
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Taken together, the current evidence suggests that SHS exposure can cause asthma exacerbation among adults. Although there are fewer studies than in children, the data consistently link SHS exposure with poorer asthma status among adults with the condition. Based on the available literature, adults with asthma should avoid SHS exposure. Examination of the Bradford Hill criteria supports a causal association between SHS exposure and exacerbation of adult asthma. Several studies demonstrated an exposure-response relationship between SHS exposure exacerbation of adult asthma [16,53,61,63] The temporal relationship between SHS exposure and the development of asthma or asthma-like symptoms was clearly delineated in most studies, especially the longitudinal cohort studies. Biologic plausibility is supported by the fact that SHS includes potent respiratory irritants and immunogens; exposure has been linked to greater bronchial hyper-responsiveness [15,62]. The consistency of study findings also supports a causal relationship between SHS exposure and asthma morbidity. In samples drawn from different populations, ranging from clinical to population-based samples, SHS has been consistently linked with poorer asthma status. The relationship between SHS exposure and asthma has also been observed in a variety of study designs, including cross-sectional, case-controlled, and cohort studies. The studies reviewed also demonstrate coherence in the association between SHS exposure and exacerbation of adult asthma. SHS exposure has been associated with an adverse impact on a variety of asthma outcomes, including diverse endpoints, such as respiratory symptoms, pulmonary function, and hospitalization for asthma. Taken together, the evidence is consistent with a causal effect of SHS on adult asthma exacerbation. Summary The long-term health consequences of SHS exposure have been established over the past two decades. Consistent epidemiologic evidence links SHS exposure with serious chronic health effects, including lung cancer and cardiovascular disease [3,65,66]. In the present article, the evidence suggests a causal relationship between SHS exposure and new-onset asthma and asthma exacerbation among adults. Despite the growing knowledge of SHS-related health effects, smoking is still permitted in many public locations and workplaces [67,68]. Because asthma is a visible condition among the general public, the evidence linking SHS exposure with adverse asthma health outcomes should provide policymakers with additional impetus for regulating public smoking and creating smoke-free public environments. References [1] Mannino DM, Homa DM, Pertowski CA, et al. Surveillance for asthmadUnited States, 1960–95. MMWR CDC Surveill Summ 1998;47(1):1–27.
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[2] California Environmental Protection Agency. Health effects assessment for environmental tobacco smoke. Sacremento (CA): Office of Environmental Health Hazard Assessment; 2005. [3] California Environmental Protection Agency. Health effects of exposure to environmental tobacco smoke. Sacramento (CA): Office of Environmental Health Hazard Assessment; 1997. [4] Pirkle JL, Bernert JT, Caudill SP, et al. Trends in the exposure of nonsmokers in the US population to secondhand smoke: 1988–2002. Environ Health Perspect 2006;114(6): 853–8. [5] Eisner MD, Yelin EH, Henke J, et al. Environmental tobacco smoke and adult asthma. The impact of changing exposure status on health outcomes. Am J Respir Crit Care Med 1998; 158(1):170–5. [6] Sippel JM, Pedula KL, Vollmer WM, et al. Associations of smoking with hospital-based care and quality of life in patients with obstructive airway disease. Chest 1999;115(3):691–6. [7] Leech JA, Wilby K, McMullen E. Environmental tobacco smoke exposure patterns: a subanalysis of the Canadian Human Time-Activity Pattern Survey. Can J Public Health 1999; 90(4):244–9. [8] Eisner MD, Klein J, Hammond SK, et al. Directly measured second hand smoke exposure and asthma health outcomes. Thorax 2005;60(10):814–21. [9] Coultas DB. Health effects of passive smoking. 8. Passive smoking and risk of adult asthma and COPD: an update. Thorax 1998;53(5):381–7. [10] Leuenberger P, Schwartz J, Ackermann-Liebrich U, et al. Passive smoking exposure in adults and chronic respiratory symptoms (SAPALDIA Study). Swiss Study on Air Pollution and Lung Diseases in Adults, SAPALDIA Team [see comments]. Am J Respir Crit Care Med 1994;150(5 Pt 1):1222–8. [11] Flodin U, Jeonsson P, Ziegler J, et al. An epidemiologic study of bronchial asthma and smoking. Epidemiology 1995;6(5):503–5. [12] Kronqvist M, Johansson E, Pershagen G, et al. Risk factors associated with asthma and rhinoconjunctivitis among Swedish farmers. Allergy 1999;54(11):1142–9. [13] Iribarren C, Friedman GD, Klatsky AL, et al. Exposure to environmental tobacco smoke: association with personal characteristics and self reported health conditions. J Epidemiol Community Health 2001;55(10):721–8. [14] Larson ML, Frisk M, Hallstrom J, et al. Environmental tobacco smoke exposure during childhood is associated with increased prevalence of asthma in adults. Chest 2001;120:711–7. [15] Janson C, Chinn S, Jarvis D, et al. Effect of passive smoking on respiratory symptoms, bronchial responsiveness, lung function, and total serum IgE in the European Community Respiratory Health Survey: a cross-sectional study. Lancet 2001;358(9299):2103–9. [16] Eisner MD, Katz PP, Yelin EH, et al. Measurement of environmental tobacco smoke exposure among adults with asthma. Environ Health Perspect 2001;109(8):809–14. [17] Thorn J, Brisman J, Toren K. Adult-onset asthma is associated with self-reported mold or environmental tobacco smoke exposures in the home. Allergy 2001;56(4):287–92. [18] Hu FB, Persky V, Flay BR, et al. An epidemiological study of asthma prevalence and related factors among young adults. J Asthma 1997;34(1):67–76. [19] Greer JR, Abbey DE, Burchette RJ. Asthma related to occupational and ambient air pollutants in nonsmokers. J Occup Med 1993;35(9):909–15. [20] McDonnell WF, Abbey DE, Nishino N, et al. Long-term ambient ozone concentration and the incidence of asthma in nonsmoking adults: the AHSMOG Study. Environ Res 1999; 80(2 Pt 1):110–21. [21] Gupta D, Aggarwal AN, Chaudhry K, et al. Household environmental tobacco smoke exposure, respiratory symptoms and asthma in non-smoker adults: a multicentric population study from India. Indian J Chest Dis Allied Sci 2006;48(1):31–6. [22] Jaakkola MS, Piipari R, Jaakkola N, et al. Environmental tobacco smoke and adult-onset asthma: a population-based incident case-control study. Am J Public Health 2003;93(12): 2055–60.
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[23] McWhorter WP, Polis MA, Kaslow RA. Occurrence, predictors, and consequences of adult asthma in NHANESI and follow-up survey. Am Rev Respir Dis 1989;139(3): 721–4. [24] Toraen K, Brisman J, Jearvholm B. Asthma and asthma-like symptoms in adults assessed by questionnaires. A literature review [see comments]. Chest 1993;104(2):600–8. [25] Burney PG, Laitinen LA, Perdrizet S, et al. Validity and repeatability of the IUATLD (1984) bronchial symptoms questionnaire: an international comparison. Eur Respir J 1989;2(10): 940–5. [26] Ng TP, Hui KP, Tan WC. Respiratory symptoms and lung function effects of domestic exposure to tobacco smoke and cooking by gas in non-smoking women in Singapore. J Epidemiol Community Health 1993;47(6):454–8. [27] Kauffmann F, Dockery DW, Speizer FE, et al. Respiratory symptoms and lung function in relation to passive smoking: a comparative study of American and French women. Int J Epidemiol 1989;18(2):334–44. [28] Comstock GW, Meyer MB, Helsing KJ, et al. Respiratory effects on household exposures to tobacco smoke and gas cooking. Am Rev Respir Dis 1981;124(2):143–8. [29] Jaakkola MS, Jaakkola JJ, Becklake MR, et al. Effect of passive smoking on the development of respiratory symptoms in young adults: an 8-year longitudinal study. J Clin Epidemiol 1996;49(5):581–6. [30] Eisner MD, Smith AK, Blanc PD. Bartenders’ respiratory health after establishment of smoke-free bars and taverns [see comments]. JAMA 1998;280(22):1909–14. [31] Menzies D, Nair A, Williamson PA, et al. The impact of a legislative ban on smoking in public places on the quality of health, pulmonary function and inflammation of bar-workers in Scotland. JAMA 2006;296(14):1742–8. [32] Farrelly MC, Nonnemaker JM, Chou R, et al. Changes in hospitality workers’ exposure to secondhand smoke following the implementation of New York’s smoke-free law. Tob Control 2005;14(4):236–41. [33] Eisner MD. Banning smoking in public places: time to clear the air. JAMA 2006;296(14): 1778–9. [34] Allwright S, Paul G, Greiner B, et al. Legislation for smoke-free workplaces and health of bar workers in Ireland: before and after study. BMJ 2005;331(7525):1117. [35] Fong GT, Hyland A, Borland R, et al. Reductions in tobacco smoke pollution and increases in support for smoke-free public places following the implementation of comprehensive smoke-free workplace legislation in the Republic of Ireland: findings from the ITC Ireland/UK Survey. Tob Control 2006;15(Suppl 3):iii51–8. [36] McCaffrey M, Goodman PG, Kelleher K, et al. Smoking, occupancy and staffing levels in a selection of Dublin pubs pre and post a national smoking ban, lessons for all. Ir J Med Sci 2006;175(2):37–40. [37] Goodman P, Agnew M, McCaffrey M, et al. Effects of the Irish smoking ban on respiratory health of bar workers and air quality in Dublin pubs. Am J Respir Crit Care Med 2007; 175(8):840–5. [38] Eagan TM, Hetland J, Aaro LE. Decline in respiratory symptoms in service workers five months after a public smoking ban. Tob Control 2006;15(3):242–6. [39] Bates MN, Fawcett J, Dickson S, et al. Exposure of hospitality workers to environmental tobacco smoke. Tob Control 2002;11(2):125–9. [40] Withers NJ, Low L, Holgate ST, et al. The natural history of respiratory symptoms in a cohort of adolescents [see comments]. Am J Respir Crit Care Med 1998;158(2): 352–7. [41] Strachan DP, Butland BK, Anderson HR. Incidence and prognosis of asthma and wheezing illness from early childhood to age 33 in a national British cohort [see comments]. BMJ 1996; 312(7040):1195–9. [42] Simoni M, Baldacci S, Puntoni R, et al. Respiratory symptoms/diseases and environmental tobacco smoke (ETS) in never smoker Italian women. Respir Med 2007;101(3):531–8.
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[43] Hole DJ, Gillis CR, Chopra C, et al. Passive smoking and cardiorespiratory health in a general population in the west of Scotland [see comments]. BMJ 1989;299(6696):423–7. [44] Masi MA, Hanley JA, Ernst P, et al. Environmental exposure to tobacco smoke and lung function in young adults. Am Rev Respir Dis 1988;138(2):296–9. [45] O’Connor GT, Weiss ST, Tager IB, et al. The effect of passive smoking on pulmonary function and nonspecific bronchial responsiveness in a population-based sample of children and young adults [published erratum appears in Am Rev Respir Dis 1987 Aug;136(2):532]. Am Rev Respir Dis 1987;135(4):800–4. [46] Xu X, Li B. Exposure-response relationship between passive smoking and adult pulmonary function. Am J Respir Crit Care Med 1995;151(1):41–6. [47] Schilling RS, Letai AD, Hui SL, et al. Lung function, respiratory disease, and smoking in families. Am J Epidemiol 1977;106(4):274–83. [48] Brunekreef B, Fischer P, Remijn B, et al. Indoor air pollution and its effect on pulmonary function of adult non-smoking women: III. Passive smoking and pulmonary function. Int J Epidemiol 1985;14(2):227–30. [49] Abbey DE, Burchette RJ, Knutsen SF, et al. Long-term particulate and other air pollutants and lung function in nonsmokers. Am J Respir Crit Care Med 1998;158(1):289–98. [50] Carey IM, Cook DG, Strachan DP. The effects of environmental tobacco smoke exposure on lung function in a longitudinal study of British adults. Epidemiology 1999;10(3): 319–26. [51] Jaakkola MS, Jaakkola JJ, Becklake MR, et al. Passive smoking and evolution of lung function in young adults. An 8-year longitudinal study. J Clin Epidemiol 1995;48(3): 317–27. [52] Dimich-Ward H, Lawason J, Chan-Yeung M. Work shift changes in lung function in bar workers exposed to environmental tobacco smoke. Am J Respir Crit Care Med 1998;157: A505. [53] Eisner MD. Environmental tobacco smoke exposure and pulmonary function among adults in NHANES III: impact on the general population and adults with current asthma. Environ Health Perspect 2002;110(8):765–70. [54] Eisner MD, Wang Y, Haight TJ, et al. Secondhand smoke exposure, pulmonary function, and cardiovascular mortality. Ann Epidemiol 2007;17(5):364–73. [55] Dales RE, Kerr PE, Schweitzer I, et al. Asthma management preceding an emergency department visit. Arch Intern Med 1992;152(10):2041–4. [56] Abramson MJ, Kutin JJ, Rosier MJ, et al. Morbidity, medication and trigger factors in a community sample of adults with asthma. Med J Aust 1995;162(2):78–81. [57] Jindal SK, Gupta D, Singh A. Indices of morbidity and control of asthma in adult patients exposed to environmental tobacco smoke [see comments]. Chest 1994;106(3):746–9. [58] Blanc PD, Ellbjar S, Janson C, et al. Asthma-related work disability in Sweden. Am J Respir Crit Care Med 1999;160(6):2028–33. [59] Ostro BD, Lipsett MJ, Mann JK, et al. Indoor air pollution and asthma. Results from a panel study [see comments]. Am J Respir Crit Care Med 1994;149(6):1400–6. [60] Mannino DM, Siegel M, Rose D, et al. Environmental tobacco smoke exposure in the home and worksite and health effects in adults: results from the 1991 National Health Interview Survey. Tob Control 1997;6(4):296–305. [61] Kunzli N, Schwartz J, Stutz EZ, et al. Association of environmental tobacco smoke at work and forced expiratory lung function among never smoking asthmatics and non-asthmatics. The SAPALDIA-Team. Swiss Study on Air Pollution and Lung Disease in Adults. Soz Praventivmed 2000;45(5):208–17. [62] Jindal SK, Jha LK, Gupta D. Bronchial hyper-responsiveness of women with asthma exposed to environmental tobacco smoke. Indian J Chest Dis Allied Sci 1999;41(2):75–82. [63] Eisner MD, Yelin EH, Katz PP, et al. Exposure to indoor combustion and adult asthma outcomes: environmental tobacco smoke, gas stoves, and woodsmoke. Thorax 2002; 57(11):973–8.
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[64] Tarlo SM, Broder I, Corey P, et al. A case-control study of the role of cold symptoms and other historical triggering factors in asthma exacerbations. Can Respir J 2000;7(1):42–8. [65] Hackshaw AK, Law MR, Wald NJ. The accumulated evidence on lung cancer and environmental tobacco smoke [see comments]. BMJ 1997;315(7114):980–8. [66] Kawachi I, Colditz GA, Speizer FE, et al. A prospective study of passive smoking and coronary heart disease [see comments]. Circulation 1997;95(10):2374–9. [67] Emmons KM, Marcus BH, Abrams DB, et al. Use of a 24-hour recall diary to assess exposure to environmental tobacco smoke. Arch Environ Health 1996;51(2):146–9. [68] Gerlach KK, Shopland DR, Hartman AM, et al. Workplace smoking policies in the United States: results from a national survey of more than 100,000 workers [see comments]. Tob Control 1997;6(3):199–206.
Immunol Allergy Clin N Am 28 (2008) 539–561
The Impact of Respiratory Viral Infection on Wheezing Illnesses and Asthma Exacerbations Kecia N. Carroll, MD, MPHa, Tina V. Hartert, MD, MPHb,c,* a
Division of General Pediatrics, Department of Pediatrics, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, AA 0220 Medical Center North, Nashville, TN 37232-2504, USA b Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Centre for Health Services Research, 6107 MCE, Nashville, TN 37232-8300, USA c Institute for Medicine and Public Health, 2525 West End Avenue, 6th Floor, Nashville, TN 37203, USA
The etiology and morbidity associated with asthma are thought to stem from both genetic factors and potentially modifiable environmental factors, such as viral infections [1–7]. Although it is unclear whether respiratory viral infections cause asthma, observational studies have demonstrated a high rate of asthma in children with a history of severe viral lower respiratory tract infections (LRTIs) during infancy, and viruses are associated with the majority of asthma exacerbations among both children and adults. This article discusses the pathogens associated with virus-induced wheezing illnesses during infancy and early childhood, the association of bronchiolitis during infancy with an increased risk of childhood asthma, and the association of respiratory viruses with asthma exacerbations in older children and adults.
* Corresponding author. Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Centre for Health Services Research, 6107 MCE, Nashville, TN 37232-8300. E-mail address:
[email protected] (T.V. Hartert). 0889-8561/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.iac.2008.03.001 immunology.theclinics.com
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Respiratory viral-induced wheezing illnesses in young children Overview Viral bronchiolitis is a LRTI typically associated with cough, tachypnea, retractions, and diffuse wheezing and rales [8,9]. Bronchiolitis is a leading cause of hospitalizations in the first year of life, accounting for an estimated 120,000 infant hospitalizations annually [10]. In infants, the etiologic agents of bronchiolitis and other viral respiratory infections associated with wheezing include respiratory syncytial virus (RSV), rhinovirus, influenza, parainfluenza (PIV), adenovirus, and more recently identified viruses, such as human metapneumovirus (hMPV) and human boca virus (hBoV) [11–14]. RSV causes epidemics of bronchiolitis and typically circulates in temperate climates during November to April with peaks in the winter months [11,15,16]. In tropical climates, peaks are related to temperature and level of rainfall [17]. RSV infects the majority of children during their first year of life and essentially all children show evidence of RSV infection by age 3 years [18]. The initial RSV infection is typically the most severe, causing lower respiratory tract disease, such as bronchiolitis, in 20% to 30% of infants [11,18,19]. Other viruses such as rhinovirus, PIV, and adenovirus circulate nearly year-round with seasonal peaks of illness [10,11,19,20]. Although RSV has long been identified as the major cause of infant bronchiolitis, the use of molecular techniques, such as polymerase chain reaction (PCR) assays, has allowed for more sensitive detection of rhinovirus and other viruses in respiratory infections [21,22]. Rhinovirus, which circulates year-round with major peaks during the autumn and spring, is a leading cause of upper respiratory tract infections, and most children show evidence of having had a rhinovirus infection by age 2 years [23–27]. Although, rhinovirus historically was thought to be limited to the upper respiratory tract, investigations have demonstrated that rhinovirus can infect the lower airways, is associated with infant bronchiolitis, and becomes a more dominant pathogen in wheezing illness as children get older [13,28–30]. Viral pathogens associated with bronchiolitis and wheezing illnesses in young children Observational studies have described the viral etiology of bronchiolitis and wheezing illnesses in infants and very young children (Table 1) [11–14,19,20,31–39]. The first descriptive studies of the viral etiology of bronchiolitis in the 1960s through the 1980s primarily used such detection methods as cell culture, antigen detection, and serologic testing. Kim and colleagues [11] studied the epidemiology of RSV infection in infants and young children admitted to a children’s hospital in Washington, D.C., from 1960 to the mid-70s and found that 40% of children with bronchiolitis had evidence of infection with RSV. In a Norwegian study from 1972 to 1979, the investigators used immunofluorescence and cell culture to
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investigate the epidemiology of respiratory viruses in young children admitted to the hospital with respiratory illness [31]. Of the 979 infants diagnosed with a respiratory virus infection, RSV accounted for 58% of all diagnosed infections, and 87% of RSV infections were associated with lower respiratory tract illness. The study also described the typical distribution of known viruses at the time, including the winter epidemics of RSV, influenza in the late winter and spring, and the seasonal distribution of rhinovirus with peaks in the autumn and spring [31]. Using multiple virus detection methods, including PCR, Jartti and colleagues [34] investigated the etiology of wheezing illness in 293 hospitalized children in Finland from September 2000 through May 31, 2002. Of the 76 infants studied, RSV (54%) was the most common virus detected, followed by picornavirus (42%) and hMPV (11%). Calvo and colleagues [36] studied consecutive respiratory admissions of 382 children less than 2 years of age to a single hospital in Spain from September 2003 to July 2005. Nasopharyngeal samples were obtained from 340 children and virus was isolated in 244 (71.7%) of the subjects. Of these, RSV accounted for 41.5%, rhinovirus 34.8%, adenovirus 8.3%, influenza 6.5%, and hMPV 5.9%. In children in whom rhinovirus was detected, recurrent wheezing and bronchiolitis were the leading diagnoses. Birth cohorts Cohorts of children recruited at birth have allowed longitudinal followup of children, including those with less severe disease who did not require hospitalization. In the Tucson Children’s Respiratory Study, a birth cohort of 1179 infants enrolled May 1980 to January 1985, Wright and colleagues [37] described the epidemiology of LRTIs during infancy. Overall, 80% of infants were followed through the first year of life. In total, 348 children contributed 460 LRTIs evaluated by physicians, with 292 respiratory cultures obtained at the initial illness. The cumulative incidence rate of lower respiratory tract illnesses in the first year of life was 32.9 per 100 children. One percent of infants were hospitalized for their illness. Immunofluorescence and viral culture were employed to detect infection by RSV; PIV types 1, 2 and 3; influenza A and B; adenovirus; enterovirus; cytomegalovirus; and rhinovirus. An infectious agent was identified by viral culture in 193 of 292 (66%) available samples obtained from infants with lower respiratory tract illness. RSV accounted for 65% of the 183 first bronchiolitis diagnoses [37]. Other viruses detected in infants with bronchiolitis diagnoses included PIV types 1, 2, and 3 (14%); influenza A and B (4%); and adenovirus (2%). An Australian cohort of 263 infants with at least one parent with doctordiagnosed atopy, recruited infants from July 1996 to July 1999 and followed them through the first year of life [38]. Nasopharyngeal aspirates and detailed information were collected prospectively during acute respiratory illnesses and PCR was used to identify viral respiratory pathogens. Acute respiratory illnesses associated with wheeze or ‘‘rattly chest’’ were classified
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Table 1 Studies of the epidemiology of viral-associated wheezing illnesses in infancy and early childhood Study period
Study population
Glezen et al [32]
12/1963–6/1969
855 episodes of bronchiolitis in children attending pediatric group practice
Carlsen et al [31]
11/1972–12/1979
Wright et al [37]
Birth cohort enrolled 5/1980–1/1985
Virus detection techniques
Viruses detected
Results
Throat swab for viral culture
RSV, PIV types 1–3, influenza A and B, adenovirus, enterovirus, rhinovirus
979 infants with hospital admission for respiratory infection
Nasopharyngeal swab for viral culture, immunofluorescence, and/or complement fixation
RSV, PIV types 1–3, influenza A and B, adenovirus, rhinovirus
1179 infants followed through first year of life; 80% with LRTIs
Nasopharyngeal and throat swab specimens for viral culture and/or immunofluorescence
RSV, PIV types 1–3, influenza A and B, adenovirus, enterovirus, cytomegalovirus, rhinovirus
Virus detected in 25% of bronchiolitis episodes: RSV (8.8%), PIV types 1–3 (8.3%), influenza A and B (1.8%), adenovirus (1.8%), enterovirus (0.35%), and rhinovirus (1.8%) RSV (58%), influenza (7.1%), PIV types 1–3 (6.3% viral culture, 4.9% serology), adenovirus (12.5% viral culture, 4.2% serology) Viruses detected in first bronchiolitis diagnoses included RSV (65%), PIV types 1–3 (14%), influenza A and B (4%), adenovirus (2%), enterovirus (7%)
CARROLL & HARTERT
Investigators
1/1993–4/1994
70 children presenting to emergency department with wheezing and 59 nonwheezing controls
Nasal washes for viral culture, enzyme immunoassay, and/or PCR
RSV, PIV types 1–3, influenza A and B, adenovirus, coronavirus, rhinovirus
Heymann et al [45]
4/2000–3/2001
133 children admitted with wheezing and 133 nonwheezing controls
Nasal washes for viral culture, enzyme immunoassay, and/or PCR
Jartti et al [34]
9/1/2000–5/ 31/2002
76 infants, 2933 mo–16 y hospitalized with wheezing
Nasopharyngeal aspirate for viral culture, immunofluorescence, enzyme immunoassay, and/or PCR
Williams et al [12]
1976–2001
Nasal wash specimens for PCR
Kusel et al [38]
Birth cohort enrolled 7/1996–7/ 1999 and followed through first year of life.
248 of 341 specimens from lower respiratory tract illnesses with no known cause from children birth to 5 years 263 infants (with a parent with atopy) during acute respiratory infections
RSV, PIV types 1–3, influenza A and B, adenovirus, coronavirus, rhinovirus RSV, PIV types 1–3, influenza A and B, adenovirus, enteroviruses, coronavirus, hMPV, rhinovirus HMPV
Nasopharyngeal aspirates for PCR
RSV, PIV types 1–3, influenza A and B, adenovirus, coronaviruses, hMPV, rhinovirus, and other picornaviruses
Viruses detected in 84% of wheezing children !3 y versus 55% controls; 61% of wheezing children O3 y versus 21% controls Viruses detected in O80% of children
In children 3–11 mo: RSV (54%), respiratory picornaviruses (42%), hMPV (11%) HMPV detected in 20% of samples from previously negative lower respiratory tract illnesses Rhinovirus detected in 45.3% of ‘‘wheezy’’ LRTIs; RSV in 16.8%
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Rakes et al [30]
(continued on next page) 543
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Table 1 (continued ) Study period
Study population
Kesebir et al [14]
1/2004–12/2004
Miller et al [13]
10/2000–9/2001
425 respiratory specimens from children !2 y submitted to clinical virology laboratory direct fluorescent antibody–negative for RSV, PIV, influenza A and B, and adenovirus during clinical visits/ admissions; 96 nasal wash specimens asymptomatic children 592 children !5 y hospitalized with respiratory symptoms or fever
Calvo et al [36]
9/2003–7/2005
340 of 382 children !2 years admitted for ‘‘respiratory tract infection’’
Virus detection techniques
Viruses detected
Results
Respiratory specimens for PCR
HBoV
HBoV detected in 5.2% of 425 respiratory specimens and 10% of hBoV-positive specimens associated with wheezing; no HBoV detected in asymptomatic controls
Nasopharyngeal and throat specimens for viral culture, immunofluorescence, and/or PCR
RSV, PIV types 1–3, influenza A and B, hMPV, picornavirus (rhinovirus and enterovirus)
Nasopharyngeal aspirate for viral culture, immunofluorescence, and/or PCR
RSV; PIV types 1–3; influenza A, B, and C; adenovirus; coronaviruses; enteroviruses; rhinovirus; hMPV
Virus detected in 61% of samples: rhinovirus (26%), RSV (20%), influenza (3%), PIV (7%), hMPV (3%), enterovirus (2%) 25% of hospitalized children !2 y rhinovirus-positive. Of positive viruses: RSV (41.5%), rhinovirus (34.8%), adenovirus (8.3%), influenza (6.5%), hMPV (5.9%)
CARROLL & HARTERT
Investigators
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as LRTIs. Of the 329 LRTIs, 28.9% were associated with wheeze. Rhinovirus was isolated in 45% of ‘‘wheezy’’ LRTIs, and RSV in 16.8%. Newly identified respiratory viruses The role of newly identified viruses, such as hMPV and hBoV, in infant wheezing illnesses is still being defined [12,14,40–42]. Williams and colleagues [12,43] investigated the role of hMPV in LRTIs in children enrolled at birth and followed to age 5 years in a vaccine clinic. HMPV, first identified in 2001, was detected in 20% of 248 available samples obtained from children with lower respiratory tract illness in which no respiratory pathogen was previously detected. HMPV therefore accounted for 12% of lower respiratory tract illnesses in this cohort of otherwise healthy young children [12,43]. Kesebir and colleagues [14,44] used available respiratory specimens submitted to a hospital-based clinical virology laboratory (January to December 2004) to investigate the prevalence of hBoV, first identified in 2005. HBoV was detected in 5% of the study samples obtained from children less than 2 years of age and negative for other viruses, although testing for rhinovirus was not performed. Wheezing illness was associated with approximately 50% of the hBoV-associated cases [14]. Allander and colleagues [42] found hBoV as the sole virus isolated in approximately 5% (12 of 259) of respiratory samples from children under 3 years of age who were hospitalized with acute wheezing. In general, the use of sensitive molecular techniques has confirmed the major role of RSV in infant bronchiolitis, broadened the role of viruses that were previously difficult to detect by culture, and allowed for the identification of new respiratory viruses. Furthermore, studies using PCR have demonstrated that while RSV appears to be the virus most commonly associated with wheezing in infants, rhinovirus plays a more prominent role after the age of 2 to 3 years [30,45]. The increasing importance of rhinovirus in wheezing illnesses in older children Epidemiologic studies in infants and children have highlighted the importance of RSV-associated wheezing in infants and rhinovirus-associated wheezing in older children [30,45,46]. Rakes and colleagues [30] conducted a cross-sectional study of 70 children who presented to the emergency department with wheezing between January 1993 and April 1994, and compared them with 59 controls who presented to the emergency department with nonrespiratory complaints over the same period. Respiratory viruses were isolated in over 82% of the wheezing children less than 2 years of age. RSV was the most common virus detected in children less than 2 years of age (68%) and was not detected in any control subjects. However, in the children less than 2 years of age, similar proportions of nasal aspirates from those with wheezing and controls were positive for rhinovirus (41%). In the children older than 2 years, viruses were detected in 83% of wheezing
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children. Rhinovirus was detected by PCR in 71% of the wheezing older children compared with 36% of the nonwheezing controls. RSV was detected in 6% of the wheezing children who were 2 years or older. In addition, the investigators found that 48% of the wheezing children who were 2 years or older had a positive test for rhinovirus and a measured marker of atopy compared with only 5% of the respective control group. In a similar 1-year study (2000–2001), 133 children (2 months to 18 years) admitted to the hospital for wheezing were compared with 133 age-matched controls admitted without wheezing [45]. In the younger children, virus was detected in 84% of the wheezing children compared with 54% of the respective controls. Consistent with other studies, RSV was the predominant virus in the younger children during the winter. However, rhinovirus was detected more frequently in young children hospitalized for wheezing from April through November. Among children older than 3 years, a respiratory virus was significantly more likely to be detected in children admitted for wheezing, than children without wheezing. Rhinovirus detection was significantly associated with wheezing. In addition, wheezing was strongly associated with atopy, as measured by total IgE and skin testing, in the children older than 3 years. These studies highlight the different pathogens associated with wheezing illnesses by age and the association of rhinovirus and atopy with wheezing in children beyond infancy.
The association of viral-associated wheezing illnesses during infancy and subsequent childhood asthma Overview The association between bronchiolitis during infancy and the development of asthma has been an area of interest for decades [4,47–74]. Most, but not all, previous studies have primarily included case infants who were hospitalized with bronchiolitis during infancy. Therefore, studies examining wheezing only after hospitalization for bronchiolitis during infancy may not reflect the outcomes of the large majority of infants with bronchiolitis who have only outpatient visits, emergency department visits, or no health care visit at all [75]. Although several early studies focused solely on RSV bronchiolitis or were conducted before routine testing for rhinovirus was available, more recent studies have used PCR to investigate the association of non-RSV bronchiolitis and subsequent wheezing [62,66,69,70,74,76,77]. Therefore, the diverse group of research investigations in this area includes case infants in whom the specific viral agents of bronchiolitis were not determined, case infants with only RSV bronchiolitis, and case infants with either RSV or non-RSV bronchiolitis. Overall, there is convincing evidence from several cohorts that RSV and rhinovirus bronchiolitis during infancy are risk factors or markers for subsequent wheezing within the first decade of life [47,55,65–67,69–71,74].
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Hospitalization for bronchiolitis during infancy and the association with recurrent wheezing and asthma during childhood Respiratory syncytial virus bronchiolitis Because RSV is known to be a major cause of bronchiolitis during infancy, several early cohorts included case infants who were hospitalized with RSV bronchiolitis during infancy [65,70,71,78]. Sigurs and colleagues [70,71] studied the relationship between RSV hospitalization during infancy and asthma in a small cohort of Swedish children. This prospective study included 47 children hospitalized with RSV bronchiolitis during infancy and 93 matched controls. The investigators defined the study outcomes as ‘‘asthma’’ (three or more episodes of bronchial obstruction verified by a physician), ‘‘recurrent wheezing’’ (three or more episodes of bronchial obstruction not physician verified), and ‘‘any wheezing’’ (asthma, recurrent wheezing, or one or two episodes of wheezing). At age 7.5 years, approximately one third of children with a history of severe RSV bronchiolitis were diagnosed with asthma and these children were significantly more likely to have a diagnosis of asthma than their nonhospitalized controls [70]. Though the cohort was small, the evidence from this study points to the likelihood of increased risk of asthma through age 13 among children who have a history of severe RSV bronchiolitis during infancy [71]. Respiratory syncytial virus bronchiolitis and non–respiratory syncytial virus bronchiolitis Historical data also demonstrate the increased risk of wheezing or asthma after non-RSV bronchiolitis and emerging data suggest that children with a history of LRTI with viruses other than RSV may have an even greater risk of subsequent wheezing. As early as the 1960s, in a study of hospitalized children less than 5 years of age, Simon and Jordan [79] speculated that children with non-RSV bronchiolitis had a predisposition to develop asthma. Murray and colleagues [68] conducted an investigation of 73 children with either RSV or non-RSV bronchiolitis hospitalization during infancy and a retrospectively recruited nonhospitalized control group. The investigators found that the children hospitalized for bronchiolitis during infancy were more likely than controls to have wheezing (42.5% versus 15.0%) at 5.5 years [68]. In addition, wheezing by parent report (34% versus 13%) and use of bronchodilators (33% versus 3%) at 9 to 10 years after the initial bronchiolitis episode were more common in children with a history of a bronchiolitis hospitalization [47]. Fjaerli and colleagues [67] found that a group of 57 children hospitalized with bronchiolitis during infancy, whether RSV-positive or RSV-negative, were more likely to be under a doctor’s care for asthma at age 7, compared with a retrospectively recruited, nonhospitalized control group of 64 children. Piippo-Savolainen and colleagues [80] also found that children hospitalized for bronchiolitis in the first 2 years of life were more likely to have asthma in young adulthood. In a subset of participants,
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Piippo-Savolainen and colleagues [63] found that adults with a history of non-RSV bronchiolitis during the first 2 years of life were at greater risk of developing asthma than were comparable adults with a history of RSV bronchiolitis. In a cohort of 81 children, Kotaniemi-Syrja¨nen and colleagues [66] investigated the relationship of non-RSV bronchiolitis during the first 2 years of life and the subsequent risk of asthma around age 7 years. They found that a rhinovirus-positive hospitalization for wheezing during the first 2 years of life was associated with a fourfold increased risk of asthma around age 7 years, compared with nonrhinovirus hospitalizations. Finally, GarciaGarcia and colleagues [62] found an increased risk of early childhood asthma in children previously hospitalized with hMPV (23 children) or RSV (32 children) bronchiolitis compared with a control group hospitalized with gastroenteritis (38 children). Overall, this data suggests that viral LRTI with viruses other than RSV are associated with as high or even higher risk of childhood asthma then RSV-associated LRTI. Birth cohorts A limited number of longitudinal investigations of viral infections during infancy and subsequent wheezing have followed infants from birth, with the goal of prospectively identifying and investigating the spectrum of acute respiratory illnesses during infancy and early childhood on the risk of developing asthma [69,74,81]. These studies have allowed for the investigation of the association of viral LRTI that did not require hospitalization with subsequent wheezing. In the cohort of children enrolled at birth in the Tucson Children’s Respiratory Study, Stein and colleagues [4,69] found that children with a history of RSV LRTI in the first 3 years of life were 3.2 times more likely to have parental report of infrequent wheeze (one to three episodes of wheezing in past year) and 4.3 times more likely to have frequent wheeze (more than three episodes of wheezing in the past year) at 6 years, compared with infants with no LRTIs in the first 3 years of life. However, the association of RSV LRTI during infancy and infrequent and frequent wheeze decreased with age and neither was significant at age 13 years. At age 13 years, 517 of the 888 children (58%) followed for the first 3 years of life were included. The investigators suggested that, although RSV LRTI during early childhood was a risk factor for recurrent wheezing, it was not a risk factor for atopic asthma. Lemanske and colleagues [74] found that a rhinovirus wheezing episode during infancy was the strongest predictor of persistent wheezing in preschool years among children enrolled in the Childhood Origins of Asthma Study (COAST). The COAST cohort is different from the Tucson cohort in that it includes only children with an increased risk of developing asthma [2]. All of the children in the cohort have at least one parent with respiratory allergies or physician-diagnosed asthma. The investigators found that children with at least one moderate to severe rhinovirus-associated wheezing illness during infancy had a 6.6-fold greater chance of subsequent wheezing
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in the third year of life and those with RSV had a threefold greater chance of wheezing in the third year of life [74]. In the combined moderate-severe illness group without wheezing, there was an increased risk for wheezing in the third year of life (odds ratio 3.9; 95% CI 1.1–15). This study is the first to show that, particularly in genetically susceptible hosts, even moderate to severe viral infections during infancy that are not associated with wheezing or hospitalization are associated with an increased risk of subsequent wheezing [74]. In another birth cohort of infants at high risk for asthma development, Kusel and colleagues [81] found that children with a history of ‘‘wheezy’’ LRTI infections with rhinovirus or RSV during infancy were at increased risk of having wheezing at age 5 years. Respiratory viral infections and acute asthma exacerbations Overview A number of epidemiologic approaches have been employed to study the relationship between viral infections and asthma exacerbations (Table 2) [82–90]. These approaches include comparing the prevalence of respiratory viruses detected in asthma patients with and without acute exacerbations, and comparing virus detection in patients with asthma to that in patients without asthma in community, emergency department, or hospital settings. In general, many studies before the use of sensitive molecular techniques detected lower rates of viral infection during acute asthma exacerbations [83,87,88,91–93]. More recently, the use of PCR has resulted in increased detection of respiratory viruses in patients with asthma exacerbations [94]. Asthma exacerbations in children Viruses are important triggers of asthma exacerbations in children and have been detected in up to 80% to 85% of exacerbations in children in studies using PCR for viral detection (see Table 2) [30,45,83,88,94–96]. Johnston and colleagues [94] investigated the association of viral infections and asthma exacerbations in a 13-month longitudinal study of 108 9- to 11year-old English children with reported wheeze or persistent cough. Families recorded twice-daily peak flows and daily respiratory symptoms. Lower respiratory symptoms were defined and recorded as cough (day or night), wheeze (day or night), difficulty breathing or shortness of breath, or not fit to go to school because of chest problems. Viruses were detected in approximately 80% of reported episodes of LRTIs with associated decreases in peak flow measurements. Picornaviruses, which include rhinovirus and enteroviruses, accounted for two thirds of the positive samples. As a comparison, the investigators tested respiratory aspirates for picornavirus from the group of 65 children who provided a respiratory sample when they were asymptomatic. The investigators found that 12% of these samples were positive. In another investigation, Johnston and colleagues [97] found strong
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Table 2 Studies of virus detection associated with acute asthma exacerbations in children and adults Study period
Study population
Viral detection techniques
Viruses detected
Results
McIntosh et al [83]
Longitudinal follow-up 10/1967–5/1968 (group 1) or 10/1968–4/1969 (group 2) Longitudinal follow-up 10/1971–5/1972
32 children with history of ‘‘severe recurrent reversible obstructive airways disease’’ hospitalized during observation period 16 children with R4 ‘‘attacks of asthma’’ in previous year
Nasopharyngeal and throat swabs for viral and bacterial culture and/or serology
RSV, PIV types 1–3, influenza A and B, adenovirus, and coronavirus
33% (group 1) and 51% (group 2) of wheezing episodes associated with proven respiratory infection
PIV, influenza A and B, adenovirus, enterovirus, rhinovirus
42 of 61 episodes of asthma associated with a symptomatic respiratory infection
Minor et al [88]
Longitudinal follow-up 10/1971–5/1972
16 children with asthma and 15 siblings without asthma
Daily record of symptoms, twice-weekly examinations with nasopharyngeal viral and mycoplasma samples, monthly bacterial Nasopharyngeal and throat swabs twice weekly for viral detection, monthly bacterial, quarterly blood samples
RSV, PIV, influenza A and B, adenovirus, enterovirus, rhinovirus
Mitchell et al [87]
Enrolled Jan–March 1975 and follow-up for 1 year
16 children with pre-enrollment history of R3 ‘‘wheezing attacks’’ in previous year
Nasopharyngeal and throat swabs for viral culture at respiratory illness and every 6 wk.
RSV, PIV, Coxsackie, adenovirus, enterovirus, and rhinovirus
Carlsen et al [82]
1/1981–1/1983
169 children R2 y (256 exacerbations) with asthma seen in study hospital
Nasopharyngeal specimens for immunofluorescence and viral culture and/or serology
RSV, PIV types 1–3, influenza A and B, adenovirus, rhinovirus
54 versus 35 episodes of viral infections asthma versus nonasthma. Children with asthma with more symptomatic rhinovirus infections 91 of 127 captured episodes of wheezing: 14% virus isolation rate; rare virus isolation during asymptomatic testing Virus detected in 29% of asthma exacerbations (rhinovirus detected in 12.9% of all exacerbations)
Minor et al [84]
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Investigators
Nicholson et al [89]
Johnston et al [94]
Longitudinal follow-up recruited 10/1990–8/1992 Longitudinal follow-up 4/1989–5/1990
Cross-sectional recruited 9/1990–3/1991
Teichtahl et al [104]
Recruited 8/1993–7/1994
Atmar et al [105]
Longitudinal follow-up of 29 adults 12/1991–5/1994
Corne et al [110]
Longitudinal 9–12/1993
Longitudinal follow-up of 108 children with reported wheeze and/or cough 33 adults with asthma presenting to emergency department with 35 asthma exacerbations 79 hospitalized adults with asthma and 54 hospitalized nonasthmatic adult controls (54) 29 adults with asthma
76 subjects with asthma and their cohabitating partners without asthma
RSV, PIV types 1–3, influenza A and B, adenovirus, RV
Virus detected in 44% of asthma exacerbations with available respiratory specimens Virus detected in 81% of reported LRTIs
Nasopharyngeal and throat swabs for viral culture, serology, and rhinovirus PCR Nasal aspirates for viral culture, immunofluorescence, serology, and/or PCR and internal probe hybridization Nasal swab for viral culture, immunofluorescence, and/or serology
RSV, PIV types 1–3, influenza A and B, enterovirus, coronavirus, adenovirus, rhinovirus RSV, PIV types 1–3, influenza A and B, adenovirus, rhinovirus
Nasopharyngeal aspirate for viral culture, and/or serology
RSV, PIV, influenza A and B, adenovirus, coronavirus, rhinovirus
Viruses detected in 37% of adults with asthma versus 9% controls
Nasopharyngeal samples for virus culture and PCR; serology
Picornavirus, coronavirus, influenza A and B, PIV types 1–3, RSV, adenovirus Rhinovirus
Viruses detected in 44% of asthma exacerbations
Nasal aspirates for PCR
No viruses detected by study techniques
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Rhinovirus detected in lower respiratory tract in 43% first infections asthma group versus 17% controls
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138 adults with asthma
Table 2 (continued ) Study population
Viral detection techniques
Viruses detected
Results
Tan et al [107]
Acute and quiescent (4–6 wk) viral detection
Viral detection in 52% of acute episodes and 7% of quiescent
Recruited 10/1998–6/1999
Tracheal aspirates near fatal asthma; induced sputum in patients with acute asthma or chronic obstructive pulmonary disease for PCR Nasal secretions for PCR, immunofluorescent assay, and/or serology
Picornavirus, RSV, PIV, influenza A and B, adenovirus
Thumerelle et al [99]
Johnston et al [96]
Recruited 9/10–9/30 2001
RSV, PIV types 1–3, influenza A and B, adenovirus, coronavirus, picornavirus (rhinovirus and enterovirus) RSV, PIV types 1–3, adenovirus, influenza A and B, coronavirus, picornavirus (rhinovirus)
Viruses detected in 38% of children with exacerbations versus 3.7% children without exacerbation Viruses detected in 62% cases versus 41% controls
Williams et al [108]
12/1999–12/2003 acute and quiescent (3 mo) viral detection 12/1999–12/2003 acute and quiescent (3 mo) viral detection Recruited 3/2003–2/2004
17 patients with near-fatal asthma; 29 acute asthma; 14 with chronic obstructive pulmonary disease 82 children with active asthma admitted with exacerbation versus 27 asymptomatic children with asthma Children with asthma presenting either to emergency department (57 cases) or community recruits (157 controls) 101 adults hospitalized with asthma
Nasal wash specimens for PCR
HMPV
101 adults hospitalized with asthma
Nasal wash specimens for PCR
Rhinovirus
Children with persistent asthma with asthma exacerbation (65 cases) and well-controlled asthma (77 controls)
Nasopharyngeal and throat swabs for PCR
RSV, PIV types 1–3, influenza A and B, adenovirus, hMPV, picornaviruses (rhinovirus and enteroviruses)
HMPV detected in 6.9% of acute hospitalizations and in 1.3% at follow-up Rhinovirus detected in 21% acute hospitalization and in 1.3% at follow-up Viruses detected in 63.1% of cases versus 23.4% of controls
Vernarske et al [109]
Khetsuriani et al [98]
Spontaneous or nasal wash samples for PCR
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Investigators
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correlations between the rates of upper respiratory tract infections, divided in half-monthly segments, and rates of pediatric and adult hospital admissions for asthma as determined by International Classification of Diseases, Ninth Revision codes. These studies demonstrate the high prevalence of respiratory viruses in children with asthma and the correlation of peaks in respiratory infections with asthma hospitalizations. The New Vaccine Surveillance Network is a population-based surveillance investigation of hospitalized pediatric patients ages birth to 5 years from two United States counties [13]. Based on the 592 children enrolled October 2000 through September 2001, children with a history of wheezing or asthma had significantly higher estimated rates of rhinovirus-associated hospitalizations (25.3 of 1000 children) than those without a history of wheezing or asthma (3.1 of 1000 children) (P!.001). Prevalence of virus detection in children with and without asthma exacerbations Other investigations have examined the relationship between respiratory virus infection and asthma exacerbations by comparing virus detection in asthma patients with and without an acute exacerbation [98,99]. Thumerelle and colleagues [99] conducted a regional study of 82 French children (October 1, 1998, through June 30, 1999), aged 2 to 16 years. In children with asthma, the investigators found higher rates of virus detection among those hospitalized with an exacerbation compared with those without an exacerbation in the prior 3 weeks. Khetsuriani and colleagues [98] studied children aged 2 to 17 years with persistent asthma. Sixty-five children with acute asthma exacerbations and 77 children with well-controlled asthma were enrolled. One or more viruses were detected in 63% of the patients with asthma exacerbations and in 23.4% of the patients with well-controlled asthma. Rhinovirus was detected among 60% of case patients and 18% of controls. Symptomatic respiratory infections positive for at least one virus were associated with asthma exacerbations, while asymptomatic infections were not. The September epidemic of asthma Observational studies have also been used to investigate the association of respiratory viruses with asthma morbidity. An increase in asthma hospitalizations during early autumn has been noted in several countries, and respiratory viruses, in particular rhinovirus, have been speculated as causative agents [24,90,100–102]. Johnston and colleagues [96] investigated the etiology of the ‘‘September epidemic of asthma exacerbations’’ in a case group of 57 Canadian children with asthma who presented to the emergency department during the last 3 weeks of September compared with a group of 157 controls with asthma recruited from the community. Although the control group did not have an emergency department visit, a majority reported asthma symptoms, including continuous or repeated breathing trouble,
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waking at night, and activity limitations. Viruses were detected in a significantly larger proportion of the children presenting to the emergency department than children who did not present to the emergency department (62% versus 41%). Cases were also less likely than controls to have been prescribed an inhaled corticosteroid. In a separate study, Johnston and colleagues [103] used a mathematical model to investigate the relationship between peak asthma hospitalizations in Canada and the return to school. The investigators found that over the 13 study years, the average timing of the peak of asthma hospitalizations in school-age children occurred 17.7 days following the return to school, with later peaks for preschool children and adults. The investigators concluded that school-age children were the likely source of the etiologic agent resulting in the yearly peak in asthma hospitalizations, with a plausible hypothesis being transmission of such infectious agents as rhinovirus. Asthma exacerbations in adults Respiratory virus detection in adults with asthma Viruses are important triggers of asthma exacerbations in adults, and studies using PCR have detected viruses in approximately 40% to 50% of exacerbations (see Table 2) [89,91,104–106]. A study by Teichtahl and colleagues [104] included adults admitted for asthma exacerbations and matched controls admitted for elective surgery, August 1993 to July 1994. Seventy-nine patients with asthma and 54 controls were included. Overall, 37% of the adults admitted with asthma had a virus detected compared with 9% of the control group. Atmar and colleagues [105] conducted a longitudinal study of 29 adults with asthma recruited from pulmonary clinics and a cross-sectional study of a convenience sample of 148 adults who presented to the emergency department with an asthma exacerbation. Viruses were detected using virus-specific PCR. The investigators found that, in the longitudinal study, 44% of asthma exacerbation were associated with a respiratory tract viral infection. In the cross-sectional emergency department study, 55% were associated with a viral infection. Rhinovirus, coronavirus, influenza, and PIV were the most common viruses detected. Prevalence of virus detection in adults with asthma during exacerbations and quiescence Several studies have performed viral detection both during asthma exacerbations and subsequent follow-up. Using PCR, Tan and colleagues [107] investigated the prevalence of viral respiratory infections in 17 adults with near-fatal asthma requiring ventilatory support, 29 adults hospitalized with an asthma exacerbation, and 14 hospitalized with chronic obstructive pulmonary disease. Samples for viral detection were taken during the acute asthma exacerbation and follow-up samples were obtained 4 to 6 weeks after hospital discharge. During the acute exacerbation, 52% of the overall samples were
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positive, including 59% of the near-fatal asthma and 41% of the acute exacerbations. In the near-fatal asthma group, 47% of the viruses detected were picornavirus and 24% were adenovirus. Viral detection was positive in 7% of the 29 specimens collected 4 to 6 weeks after hospital admission [107]. Other studies have used molecular diagnostic techniques to investigate the role of more recently discovered viruses in the pathogenesis of asthma exacerbations. Williams and colleagues [108] determined the prevalence of hMPV in a cohort of 101 adults at initial enrollment during an asthma hospitalization (1999–2003) and at follow-up 3 months later. HMPV was detected in 6.9% of subjects at admission compared with 1.3% in followup. Furthermore, none of the subjects positive for hMPV at admission were positive at follow-up [108]. Another study involving this cohort of patients described the prevalence of rhinovirus in patients during an acute asthma exacerbation and 3-month follow-up [109]. Over the 4-year study period, 21% of the cohort was rhinovirus-positive by PCR during the asthma exacerbation. Seventy-six of the 101 participants completed the 3-month follow-up. At follow-up, only 1.3% (1 patient) were positive and none of the subjects who were rhinovirus-positive during the preceding asthma exacerbation were positive at follow-up. Subjects who were rhinovirus-positive were more likely to smoke cigarettes and be nonusers of inhaled corticosteroids compared with rhinovirus-negative subjects, similar to the findings of lower use of inhaled corticosteroids among children seen in the hospital during the September asthma epidemic associated with rhinovirus [96,109]. Rhinovirus clinical lower respiratory tract infections in adults with and without asthma Corne and colleagues [110] conducted a longitudinal investigation of rhinovirus infection by following 76 subjects with asthma and their cohabitating partners without asthma over a 3-month period (September through December 1993). Subjects maintained diaries of severity of upper and lower respiratory tract symptoms and nasal aspirates were obtained from subjects every 2 weeks. Overall, there were no differences in rhinovirus positivity between the subjects with and without asthma. However, the investigators found that participants with asthma had more frequent clinical LRTIs associated with rhinovirus than did controls (43% versus 17%, respectively). In addition, the group of patients with asthma had significantly higher severity scores (median 1 versus 0) and longer duration of illness (median 2.5 days versus 0 days) [110]. Summary Epidemiologic investigations have provided valuable insight into the role of respiratory viruses in wheezing illnesses in children and adults. Viruses are the most important cause of LRTIs in infancy and early childhood, and LRTIs with respiratory viral pathogens have been identified as
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significant risk factors for the development of early childhood asthma. RSV is an important pathogen in wheezing illnesses during infancy and appears to become less commonly associated with wheezing illnesses in older children. The newly appreciated role of non-RSV LRTI and the strong association of rhinovirus illness with a marked increased risk of future wheezing among children born to a parent with asthma suggest a differential ‘‘asthmagenicity’’ of respiratory viruses in asthma pathogenesis. Although it is unclear whether respiratory viruses induce asthma development, children with severe infections during infancy are at increased risk of subsequent wheezing, and large longitudinal studies will, it is hoped, help answer this critical question. Knowing whether respiratory viruses cause asthma presents the hope for a new strategy for asthma prevention. In addition, viruses, implicated in the vast majority of significant disease exacerbations, are important triggers of asthma exacerbations in children and adults, and respiratory viral illness prevention would likely decrease the significant morbidity related to this common chronic disease. References [1] Gern JE, Rosenthal LA, Sorkness RL, et al. Effects of viral respiratory infections on lung development and childhood asthma. J Allergy Clin Immunol 2005;115(4):668–74. [2] Lemanske RF Jr. The childhood origins of asthma (COAST) study. Pediatr Allergy Immunol 2002;13(Suppl 15):38–43. [3] Chan-Yeung M, Ferguson A, Watson W, et al. The Canadian Childhood Asthma Primary Prevention Study: outcomes at 7 years of age. J Allergy Clin Immunol 2005;116(1):49–55. [4] Martinez FD, Wright AL, Taussig LM, et al. Asthma and wheezing in the first six years of life. The Group Health Medical Associates. N Engl J Med 1995;332(3):133–8. [5] Arshad SH. Primary prevention of asthma and allergy. J Allergy Clin Immunol 2005; 116(1):3–14. [6] Jaakkola JJ, Gissler M. Maternal smoking in pregnancy, fetal development, and childhood asthma. Am J Public Health 2004;94(1):136–40. [7] Mannino DM, Homa DM, Akinbami LJ, et al. Surveillance for asthmadUnited States, 1980–1999. MMWR Surveill Summ 2002;51(1):1–13. [8] Kafetzis DA, Astra H, Tsolia M, et al. Otitis and respiratory distress episodes following a respiratory syncytial virus infection. Clin Microbiol Infect 2003;9(10):1006–10. [9] Smyth RL, Openshaw PJ. Bronchiolitis. Lancet 2006;368(9532):312–22. [10] Shay DK, Holman RC, Newman RD, et al. Bronchiolitis-associated hospitalizations among US children, 1980–1996. JAMA 1999;282(15):1440–6. [11] Kim HW, Arrobio JO, Brandt CD, et al. Epidemiology of respiratory syncytial virus infection in Washington, D.C. I. Importance of the virus in different respiratory tract disease syndromes and temporal distribution of infection. Am J Epidemiol 1973;98(3):216–25. [12] Williams JV, Harris PA, Tollefson SJ, et al. Human metapneumovirus and lower respiratory tract disease in otherwise healthy infants and children. N Engl J Med 2004;350(5): 443–50. [13] Miller EK, Lu X, Erdman DD, et al. Rhinovirus-associated hospitalizations in young children. J Infect Dis 2007;195:773–81. [14] Kesebir D, Vazquez M, Weibel C, et al. Human bocavirus infection in young children in the United States: molecular epidemiological profile and clinical characteristics of a newly emerging respiratory virus. J Infect Dis 2006;194(9):1276–82.
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[15] Centers for Disease Control and Prevention (CDC). Respiratory syncytial virus activityd United States, 2003–2004. MMWR Morb Mortal Wkly Rep 2004;53(49):1159–60. [16] Yusuf S, Piedimonte G, Auais A, et al. The relationship of meteorological conditions to the epidemic activity of respiratory syncytial virus. Epidemiol Infect 2007;135(7):1077–90. [17] Stensballe LG, Devasundaram JK, Simoes EA. Respiratory syncytial virus epidemics: the ups and downs of a seasonal virus. Pediatr Infect Dis J 2003;22(2 Suppl):S21–32. [18] Glezen WP, Taber LH, Frank AL, et al. Risk of primary infection and reinfection with respiratory syncytial virus. Am J Dis Child 1986;140(6):543–6. [19] Denny FW, Collier AM, Henderson FW, et al. The epidemiology of bronchiolitis. Pediatr Res 1977;11(3 Pt 2):234–6. [20] Glezen WP. Pathogenesis of bronchiolitisdepidemiologic considerations. Pediatr Res 1977;11(3 Pt 2):239–43. [21] Weinberg GA, Erdman DD, Edwards KM, et al. Superiority of reverse-transcription polymerase chain reaction to conventional viral culture in the diagnosis of acute respiratory tract infections in children. J Infect Dis 2004;189(4):706–10. [22] Jennings LC, Anderson TP, Werno AM, et al. Viral etiology of acute respiratory tract infections in children presenting to hospital: role of polymerase chain reaction and demonstration of multiple infections. Pediatr Infect Dis J 2004;23(11):1003–7. [23] Arruda E, Pitkaranta A, Witek TJ Jr, et al. Frequency and natural history of rhinovirus infections in adults during autumn. J Clin Microbiol 1997;35(11):2864–8. [24] Gwaltney JM Jr. The Jeremiah Metzger Lecture. Climatology and the common cold. Trans Am Clin Climatol Assoc 1985;96:159–75. [25] Makela MJ, Puhakka T, Ruuskanen O, et al. Viruses and bacteria in the etiology of the common cold. J Clin Microbiol 1998;36(2):539–42. [26] Blomqvist S, Roivainen M, Puhakka T, et al. Virological and serological analysis of rhinovirus infections during the first two years of life in a cohort of children. J Med Virol 2002; 66(2):263–8. [27] Gwaltney JM Jr, Hendley JO, Simon G, et al. Rhinovirus infections in an industrial population. I. The occurrence of illness. N Engl J Med 1966;275(23):1261–8. [28] Gern JE, Galagan DM, Jarjour NN, et al. Detection of rhinovirus RNA in lower airway cells during experimentally induced infection. Am J Respir Crit Care Med 1997;155(3): 1159–61. [29] Papadopoulos NG, Bates PJ, Bardin PG, et al. Rhinoviruses infect the lower airways. J Infect Dis 2000;181(6):1875–84. [30] Rakes GP, Arruda E, Ingram JM, et al. Rhinovirus and respiratory syncytial virus in wheezing children requiring emergency care. IgE and eosinophil analyses. Am J Respir Crit Care Med 1999;159(3):785–90. [31] Carlsen KH, Orstavik I, Halvorsen K. Viral infections of the respiratory tract in hospitalized children. A study from Oslo during a 90 months’ period. Acta Paediatr Scand 1983; 72(1):53–8. [32] Glezen WP, Loda FA, Clyde WA Jr, et al. Epidemiologic patterns of acute lower respiratory disease of children in a pediatric group practice. J Pediatr 1971;78(3):397–406. [33] Henderson FW, Clyde WA Jr, Collier AM, et al. The etiologic and epidemiologic spectrum of bronchiolitis in pediatric practice. J Pediatr 1979;95(2):183–90. [34] Jartti T, Lehtinen P, Vuorinen T, et al. Respiratory picornaviruses and respiratory syncytial virus as causative agents of acute expiratory wheezing in children. Emerg Infect Dis 2004; 10(6):1095–101. [35] Boyce TG, Mellen BG, Mitchel EF Jr, et al. Rates of hospitalization for respiratory syncytial virus infection among children in Medicaid. J Pediatr 2000;137(6):865–70. [36] Calvo C, Garcia-Garcia ML, Blanco C, et al. Role of rhinovirus in hospitalized infants with respiratory tract infections in Spain. Pediatr Infect Dis J 2007;26(10):904–8. [37] Wright AL, Taussig LM, Ray CG, et al. The Tucson Children’s Respiratory Study. II. Lower respiratory tract illness in the first year of life. Am J Epidemiol 1989;129(6):1232–46.
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[38] Kusel MM, de Klerk NH, Holt PG, et al. Role of respiratory viruses in acute upper and lower respiratory tract illness in the first year of life: a birth cohort study. Pediatr Infect Dis J 2006;25(8):680–6. [39] Korppi M, Kotaniemi-Syrjanen A, Waris M, et al. Rhinovirus-associated wheezing in infancy: comparison with respiratory syncytial virus bronchiolitis. Pediatr Infect Dis J 2004;23(11):995–9. [40] do Carmo DM, Bordignon J, Duarte dos Santos CN, et al. Acute respiratory infection by human metapneumovirus in children in southern Brazil. J Clin Virol 2007;39(1):59–62. [41] Esper F, Martinello RA, Boucher D, et al. A 1-year experience with human metapneumovirus in children aged. J Infect Dis 2004;189(8):1388–96. [42] Allander T, Jartti T, Gupta S, et al. Human bocavirus and acute wheezing in children. Clin Infect Dis 2007;44(7):904–10. [43] van den Hoogen BG, de Jong JC, Groen J, et al. A newly discovered human pneumovirus isolated from young children with respiratory tract disease. Nat Med 2001;7(6):719–24. [44] Allander T, Tammi MT, Eriksson M, et al. Cloning of a human parvovirus by molecular screening of respiratory tract samples. Proc Natl Acad Sci U S A 2005;102(36):12891–6. [45] Heymann PW, Carper HT, Murphy DD, et al. Viral infections in relation to age, atopy, and season of admission among children hospitalized for wheezing. J Allergy Clin Immunol 2004;114(2):239–47. [46] Lazzaro T, Hogg G, Barnett P. Respiratory syncytial virus infection and recurrent wheeze/ asthma in children under five years: an epidemiological survey. J Paediatr Child Health 2007;43(1–2):29–33. [47] Noble V, Murray M, Webb MS, et al. Respiratory status and allergy nine to 10 years after acute bronchiolitis. Arch Dis Child 1997;76(4):315–9. [48] Rooney JC, Williams HE. The relationship between proved viral bronchiolitis and subsequent wheezing. J Pediatr 1971;79(5):744–7. [49] Sims DG, Gardner PS, Weightman D, et al. Atopy does not predispose to RSV bronchiolitis or postbronchiolitic wheezing. Br Med J (Clin Res Ed) 1981;282(6282):2086–8. [50] Pullan CR, Hey EN. Wheezing, asthma, and pulmonary dysfunction 10 years after infection with respiratory syncytial virus in infancy. Br Med J (Clin Res Ed) 1982;284(6330): 1665–9. [51] Wittig H, Glaser J. The relationship between bronchiolitis and childhood asthma; a followup study of 100 cases of bronchiolitis. J Allergy 1959;30(1):19–23. [52] Gomez R, Colas C, Sebastian A, et al. Respiratory repercussions in adults with a history of infantile bronchiolitis. Ann Allergy Asthma Immunol 2004;93(5):447–51. [53] Larouch V, Rivard G, Deschesnes F, et al. Asthma and airway hyper-responsiveness in adults who required hospital admission for bronchiolitis in early childhood. Respir Med 2000;94(3):288–94. [54] Duiverman EJ, Neijens HJ, van SR, et al. Lung function and bronchial responsiveness in children who had infantile bronchiolitis. Pediatr Pulmonol 1987;3(1):38–44. [55] Korppi M, Piippo-Savolainen E, Korhonen K, et al. Respiratory morbidity 20 years after RSV infection in infancy. Pediatr Pulmonol 2004;38(2):155–60. [56] Gurwitz D, Mindorff C, Levison H. Increased incidence of bronchial reactivity in children with a history of bronchiolitis. J Pediatr 1981;98(4):551–5. [57] McConnochie KM, Roghmann KJ. Bronchiolitis as a possible cause of wheezing in childhood: new evidence. Pediatrics 1984;74(1):1–10. [58] Wennergren G, Amark M, Amark K, et al. Wheezing bronchitis reinvestigated at the age of 10 years. Acta Paediatr 1997;86(4):351–5. [59] Schauer U, Hoffjan S, Bittscheidt J, et al. RSV bronchiolitis and risk of wheeze and allergic sensitisation in the first year of life. Eur Respir J 2002;20(5):1277–83. [60] Kotaniemi-Syrjanen A, Laatikainen A, Waris M, et al. Respiratory syncytial virus infection in children hospitalized for wheezing: virus-specific studies from infancy to preschool years. Acta Paediatr 2005;94(2):159–65.
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[61] Hyvarinen M, Piippo-Savolainen E, Korhonen K, et al. Teenage asthma after severe infantile bronchiolitis or pneumonia. Acta Paediatr 2005;94(10):1378–83. [62] Garcia-Garcia ML, Calvo C, Casas I, et al. Human metapneumovirus bronchiolitis in infancy is an important risk factor for asthma at age 5. Pediatr Pulmonol 2007;42(5): 458–64. [63] Piippo-Savolainen E, Korppi M, Korhonen K, et al. Adult asthma after non-respiratory syncytial virus bronchiolitis in infancy: subgroup analysis of the 20-year prospective follow-up study. Pediatr Int 2007;49(2):190–5. [64] Elphick HE, Ritson S, Rigby AS, et al. Phenotype of acute respiratory syncytial virus induced lower respiratory tract illness in infancy and subsequent morbidity. Acta Paediatr 2007;96(2):307–9. [65] Henderson J, Hilliard TN, Sherriff A, et al. Hospitalization for RSV bronchiolitis before 12 months of age and subsequent asthma, atopy and wheeze: A longitudinal birth cohort study. Pediatr Allergy Immunol 2005;16(5):386–92. [66] Kotaniemi-Syrjanen A, Vainionpaa R, Reijonen TM, et al. Rhinovirus-induced wheezing in infancydthe first sign of childhood asthma? J Allergy Clin Immunol 2003;111(1): 66–71. [67] Fjaerli HO, Farstad T, Rod G, et al. Acute bronchiolitis in infancy as risk factor for wheezing and reduced pulmonary function by seven years in Akershus County, Norway. BMC Pediatr 2005;5(1):31. [68] Murray M, Webb MS, O’Callaghan C, et al. Respiratory status and allergy after bronchiolitis. Arch Dis Child 1992;67(4):482–7. [69] Stein RT, Sherrill D, Morgan WJ, et al. Respiratory syncytial virus in early life and risk of wheeze and allergy by age 13 years. Lancet 1999;354(9178):541–5. [70] Sigurs N, Bjarnason R, Sigurbergsson F, et al. Respiratory syncytial virus bronchiolitis in infancy is an important risk factor for asthma and allergy at age 7. Am J Respir Crit Care Med 2000;161(5):1501–7. [71] Sigurs N, Gustafsson PM, Bjarnason R, et al. Severe respiratory syncytial virus bronchiolitis in infancy and asthma and allergy at age 13. Am J Respir Crit Care Med 2005;171(2): 137–41. [72] Wennergren G, Kristjansson S. Relationship between respiratory syncytial virus bronchiolitis and future obstructive airway diseases. Eur Respir J 2001;18(6):1044–58. [73] Reijonen TM, Kotaniemi-Syrjanen A, Korhonen K, et al. Predictors of asthma three years after hospital admission for wheezing in infancy. Pediatrics 2000;106(6):1406–12. [74] Lemanske RF Jr, Jackson DJ, Gangnon RE, et al. Rhinovirus illnesses during infancy predict subsequent childhood wheezing. J Allergy Clin Immunol 2005;116(3):571–7. [75] Carroll K, Gebratsadik T, Griffin M, et al. The increasing burden and risk factors for bronchiolitis-related medical visits in infants enrolled in a state healthcare insurance plan. Pediatrics 2008, in press. [76] Williams JV, Tollefson SJ, Heymann PW, et al. Human metapneumovirus infection in children hospitalized for wheezing. J Allergy Clin Immunol 2005;115(6):1311–2. [77] Bradley JP, Bacharier LB, Bonfiglio J, et al. Severity of respiratory syncytial virus bronchiolitis is affected by cigarette smoke exposure and atopy. Pediatrics 2005;115(1):e7–14. [78] Hall CB, Hall WJ, Gala CL, et al. Long-term prospective study in children after respiratory syncytial virus infection. J Pediatr 1984;105(3):358–64. [79] Simon G, Jordan WS Jr. Infectious and allergic aspects of bronchiolitis. J Pediatr 1967; 70(4):533–8. [80] Piippo-Savolainen E, Remes S, Kannisto S, et al. Asthma and lung function 20 years after wheezing in infancy: results from a prospective follow-up study. Arch Pediatr Adolesc Med 2004;158(11):1070–6. [81] Kusel MM, de Klerk NH, Kebadze T, et al. Early-life respiratory viral infections, atopic sensitization, and risk of subsequent development of persistent asthma. J Allergy Clin Immunol 2007;119(5):1105–10.
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[82] Carlsen KH, Orstavik I, Leegaard J, et al. Respiratory virus infections and aeroallergens in acute bronchial asthma. Arch Dis Child 1984;59(4):310–5. [83] McIntosh K, Ellis EF, Hoffman LS, et al. The association of viral and bacterial respiratory infections with exacerbations of wheezing in young asthmatic children. J Pediatr 1973; 82(4):578–90. [84] Minor TE, Dick EC, DeMeo AN, et al. Viruses as precipitants of asthmatic attacks in children. JAMA 1974;227(3):292–8. [85] Cherry JD, Diddams JA, Dick EC. Rhinovirus infections in hospitalized children. Provocative bacterial interrelationships. Arch Environ Health 1967;14(3):390–6. [86] Pattemore PK, Johnston SL, Bardin PG. Viruses as precipitants of asthma symptoms. I. Epidemiology. Clin Exp Allergy 1992;22(3):325–36. [87] Mitchell I, Inglis JM, Simpson H. Viral infection as a precipitant of wheeze in children. Combined home and hospital study. Arch Dis Child 1978;53(2):106–11. [88] Minor TE, Baker JW, Dick EC, et al. Greater frequency of viral respiratory infections in asthmatic children as compared with their nonasthmatic siblings. J Pediatr 1974;85(4): 472–7. [89] Nicholson KG, Kent J, Ireland DC. Respiratory viruses and exacerbations of asthma in adults. BMJ 1993;307(6910):982–6. [90] Dales RE, Schweitzer I, Toogood JH, et al. Respiratory infections and the autumn increase in asthma morbidity. Eur Respir J 1996;9(1):72–7. [91] Sokhandan M, McFadden ER Jr, Huang YT, et al. The contribution of respiratory viruses to severe exacerbations of asthma in adults. Chest 1995;107(6):1570–4. [92] Tarlo S, Broder I, Spence L. A prospective study of respiratory infection in adult asthmatics and their normal spouses. Clin Allergy 1979;9(3):293–301. [93] Tarlo SM, Broder I, Corey P, et al. A case-control study of the role of cold symptoms and other historical triggering factors in asthma exacerbations. Can Respir J 2000;7(1): 42–8. [94] Johnston SL, Pattemore PK, Sanderson G, et al. Community study of role of viral infections in exacerbations of asthma in 9-11 year old children. BMJ 1995;310(6989):1225–9. [95] Asher MI, Keil U, Anderson HR, et al. International Study of Asthma and Allergies in Childhood (ISAAC): rationale and methods. Eur Respir J 1995;8(3):483–91. [96] Johnston NW, Johnston SL, Duncan JM, et al. The September epidemic of asthma exacerbations in children: a search for etiology. J Allergy Clin Immunol 2005;115(1):132–8. [97] Johnston SL, Pattemore PK, Sanderson G, et al. The relationship between upper respiratory infections and hospital admissions for asthma: a time-trend analysis. Am J Respir Crit Care Med 1996;154(3 Pt 1):654–60. [98] Khetsuriani N, Kazerouni NN, Erdman DD, et al. Prevalence of viral respiratory tract infections in children with asthma. J Allergy Clin Immunol 2007;119(2):314–21. [99] Thumerelle C, Deschildre A, Bouquillon C, et al. Role of viruses and atypical bacteria in exacerbations of asthma in hospitalized children: a prospective study in the Nord-Pas de Calais region (France). Pediatr Pulmonol 2003;35(2):75–82. [100] Salvaggio J, Hasselblad V, Seabury J, et al. New Orleans asthma. II. Relationship of climatologic and seasonal factors to outbreaks. J Allergy 1970;45(5):257–65. [101] Weiss KB. Seasonal trends in US asthma hospitalizations and mortality. JAMA 1990; 263(17):2323–8. [102] Khot A, Evans N, Lenney W. Seasonal trends in childhood asthma in south east England. Br Med J (Clin Res Ed) 1983;287(6401):1257–8. [103] Johnston NW, Johnston SL, Norman GR, et al. The September epidemic of asthma hospitalization: school children as disease vectors. J Allergy Clin Immunol 2006;117(3):557–62. [104] Teichtahl H, Buckmaster N, Pertnikovs E. The incidence of respiratory tract infection in adults requiring hospitalization for asthma. Chest 1997;112(3):591–6. [105] Atmar RL, Guy E, Guntupalli KK, et al. Respiratory tract viral infections in inner-city asthmatic adults. Arch Intern Med 1998;158(22):2453–9.
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[106] Afghani B, Ngo T, Leu SY, et al. The effect of an interventional program on adherence to the American Academy of Pediatrics guidelines for palivizumab prophylaxis. Pediatr Infect Dis J 2006;25(11):1019–24. [107] Tan WC, Xiang X, Qiu D, et al. Epidemiology of respiratory viruses in patients hospitalized with near-fatal asthma, acute exacerbations of asthma, or chronic obstructive pulmonary disease. Am J Med 2003;115(4):272–7. [108] Williams JV, Crowe JE Jr, Enriquez R, et al. Human metapneumovirus infection plays an etiologic role in acute asthma exacerbations requiring hospitalization in adults. J Infect Dis 2005;192(7):1149–53. [109] Venarske DL, Busse WW, Griffin MR, et al. The relationship of rhinovirus-associated asthma hospitalizations with inhaled corticosteroids and smoking. J Infect Dis 2006; 193(11):1536–43. [110] Corne JM, Marshall C, Smith S, et al. Frequency, severity, and duration of rhinovirus infections in asthmatic and non-asthmatic individuals: a longitudinal cohort study. Lancet 2002;359(9309):831–4.
Immunol Allergy Clin N Am 28 (2008) 563–576
Occupational Exposures and Adult Asthma Susan M. Tarlo, MB, BS University of Toronto and University Health Network, Toronto Western Hospital, EW7-449, Asthma Center, 399 Bathurst Street, Toronto, Ontario M5T 2S8, Canada
Relationships between asthma and occupation Adult asthma can relate to occupational exposures in several potential ways. First, adult asthma, especially if not well controlled, can reduce the ability of adults to perform their jobs effectively and lead to time off work [1–3]. Time may be lost from work if there is an exacerbation of asthma or if asthma is poorly controlled, even if it is not the result of work exposures. As an example, a manual worker with asthma who develops a respiratory viral infection with an associated exacerbation of asthma may not be able to exercise normally at that time, even for several weeks. An outdoor worker with asthma who has run out of or has not been appropriately prescribed inhaled asthma medications (in particular inhaled steroids) [3] may not be able to function well in cold or hot and humid weather. Second, asthma can be caused by occupational exposures, termed occupational asthma (OA), or can be exacerbated or aggravated by occupational exposures, termed work-exacerbated asthma (WEA) or work-aggravated asthma. Although OA has been recognized and investigated for many years, exacerbation or aggravation of asthma from occupational exposures (although not a new phenomenon), in contrast, is a relatively new focus of research studies. This is considered a separate entity from OA because the job has not caused the new onset of asthma and the implications for workers’ compensation are different from those of OAdin many jurisdictions it is not compensable despite the fact that significant morbidity and socioeconomic impact can result from OA and from WEA [4–6]. OA and WEA can be included under the term, work-related asthma, yet even recently, most clinical guides have addressed only the subgroup with OA [7,8]. This article covers some aspects of epidemiologic studies of OA and reviews aspects of WEA to illustrate what has been learned from these studies. E-mail address:
[email protected] 0889-8561/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.iac.2008.03.002 immunology.theclinics.com
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This is not a comprehensive or systematic review of all published epidemiologic studies in this area. Studies of the effects of common asthma on the ability to work, on time missed from work, or job changes due to asthma are not reviewed in this article. Occupational asthma OA is reported as the most common chronic occupational lung disease in industrialized regions, especially with the decline in prevalence of pneumoconioses [9,10]. It has been defined as asthma resulting from causes and conditions attributable to a specific work exposure and not to causes outside the workplace. This is a clinical definition and assumes that clinical diagnostic tests are able to establish the probability of an occupational causation for asthma. In epidemiologic studies, the definition often is by necessity different from the clinical definition [11], usually based on (a) questionnaire findings with positive responses to questions about improvement of asthma symptoms away from work (weekends or holidays) as compared with working days; (b) a history of asthma symptoms or doctor-diagnosed asthma, starting during a working period; and (c) an exposure history consistent with a high-level irritant exposure (irritant-induced asthma or reactive airways dysfunction syndrome) or a history of exposure at work to an agent capable of causing respiratory sensitization and asthma. Such self-reported symptoms are relatively sensitive for a diagnosis of OA [12] among a population in a tertiary referral occupational lung clinic, and a positive exposure history is expected to add to the sensitivity, particularly for OA induced by a high molecular weight occupational allergen. Nevertheless, the specificity of self-reported features is low in comparison to a clinical gold standard of specific challenge tests. A history of wheezing worse at work and associated nasal and eye symptoms but absence of loss of voice is reported as having the best historical positive predictive value in a model derived from these factors (positive predictive value 74%) for OA induced by high molecular weight allergens [13] but no historical factors were reliable for predicting OA caused by low molecular weight allergens (to distinguish OA from WEA or other diagnoses) in that study. Even within tertiary referral clinics, a proportion of patients referred for assessment of suspected work-related asthma does not have asthma but has other causes of work-related symptoms, such as vocal cord dysfunction, upper airway cough syndrome, or gastroesophageal reflux. In one tertiary referral clinic, 31% of those referred for assessment of possible OA had no objective evidence of asthma although still working with the implicated occupational exposure [14]. In addition, the first onset of asthma during a working period, despite being a typical characteristic of patients who have OA, is not specific, because the proportion of all adult asthma attributable to occupation is estimated at 5% to 19%, median 9% [15], implying that a majority of adult asthma begins coincidental to work exposures.
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Therefore, considerations in epidemiologic studies assessing OA include (1) How confident is the diagnosis of asthma and has there been an additional objective measure to confirm asthma in addition to questionnaire responses? and (2) Can OA be distinguished from WEA? Although many epidemiologic studies use validated asthma questions [16,17], fewer include an objective measure to add to the certainty of diagnosis [17]. The addition of a methacholine challenge has been used in a subset in some population-based studies, such as the Canadian six-community study [18] and an international population study relating risks for new-onset asthma to occupation [19]. In the Canadian asthma study [18], a case definition of OA was derived from (1) exposure in a high-risk occupation and industry at the time of onset of asthma (considered probable OA) and (2) exposure to a substance that may cause OA but not being in a high-risk job at the time of onset of asthma (considered possible OA). The investigators also estimated the population-attributable risk for high-risk jobs and exposures. They reported a high prevalence of possible and probable occupational asthma, 36%, and a population-attributable risk for adult asthma in high-risk jobs and exposures of 18%. The international study [19] showed significant excess asthma risk from exposure to agents known to cause OA, especially among those who had asthma defined by symptoms and a positive methacholine response (ie, those who had objectively confirmed asthma [relative risk (RR) 2.4; 95% CI, 1.3–4]), illustrating the value of a more definite asthma diagnosis when possible in such studies. Risks also increased after reported inhalation accidents, consistent with irritant-induced asthma (RR 3.3; 95%, CI 1–11). In population epidemiologic studies, it is difficult to distinguish OA from WEA with certainty. Perhaps for that reason, some other population epidemiologic studies have reported ‘‘the occupational contribution to the burden of asthma’’ [20] rather than ‘‘occupational asthma.’’ Other epidemiologic studies have focused on specific groups of workers who had relatively uniform exposure. For example, some studies have assessed workers exposed to high molecular weight allergens (such as workers in bakeries [21], workers in animal care facilities [22], enzymeexposed workers [23], and snow crab workers [24]); those exposed to low molecular weight sensitizers (such as spray painters [exposed to diisocyanates] [25], red cedar workers [26], and workers exposed to complex platinum salts [27]), and others who have exposure to agents known to be respiratory sensitizers capable of causing OA. These studies have clarified the prevalence of OA related to various sensitizers and helped identify host and environmental risk factors, including atopy, smoking for some agents, and degree of exposure. Outcomes also have been determined in some studies. Some publications report incidence of sensitization and OAdfor example, a series of prospective studies of apprentices in Quebec in pastry-making, animal care work, and dental assistants (with latex glove use) [28–30]. The effects of intervention, including primary, secondary,
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and tertiary preventive measures, also have been assessed in various occupational settings [8,31,32]. Not all workers who have OA have a clearly identified workplace sensitizer, however, and in many workers there may be mixtures of potential sensitizers and irritant agents. Even in the examples described previously, animal care workers may wear powdered latex gloves and may have exposure to other dusts or endotoxin [33], which can be associated with symptoms; dental workers may be exposed to acrylic compounds; and autobody workers may use paints or other compounds with sensitizers besides diisocyanates, such as epoxy compounds or amines. Studies of workforces, such as hospital workers, have shown the potential for development of physician-diagnosed asthma from several causes in a single workplace. Many were assessed in a study by Delclos and colleagues [34], including medical instrument cleaning (odds ratio [OR] 2.22; 95% CI, 1.34–3.67), general cleaning (OR 2.02; 95% CI, 1.20–3.40), use of powdered latex gloves (only between 1992 and 2000) (OR 2.17; 95% CI, 1.27–3.73), and exposure to aerosolized medications (OR 1.72; 95% CI, 1.05–2.83). That study also used a second outcome measure, bronchial hyper-responsiveness–related symptoms, also based on symptoms alone, which had some different associations and may have included symptoms from mucous membrane irritation. The associations were with general cleaning (OR 1.63; 95% CI, 1.21–2.19), aerosolized medication administration (OR 1.40; 95% CI, 1.06–1.84), use of adhesives on patients (OR 1.65; 95% CI, 1.22–2.24), and exposure to a chemical spill (OR 2.02; 95% CI, 1.28–3.21). Studies such as this have shown the ability to assess temporal changes in the relationship of asthma to various sensitizers, in particular natural rubber latex in this study. Other studies, which have examined changes in sensitization and asthma from natural rubber latex in relation to changes in the use of powdered latex gloves, similarly showed significant declines as gloves have been changed to low-protein, low-powdered latex gloves or nonlatex gloves [35,36]. Cleaners are another group of workers who have a mixed exposure to potential respiratory sensitizers and irritants at work. They became a population of interest after initial population studies indicated increased confirmed asthma among cleaners in Spain and other European countries [37,38]. A series of epidemiologic studies have focused on cleaners and have shown some unexpected results [39–43]. Zock and colleagues [41] have shown that domestic cleaners are more likely to have asthma than other professional cleaners but, although they were more likely to be sensitized to dust mites (28%) than other professional cleaners (3%), they had a similar rate of dust mite sensitization as a control group of office workers. In addition, rather than showing an association of asthma with a recognized allergen (dust mites), asthma among domestic cleaners was associated mainly with kitchen cleaning and furniture polishing. In contrast, cleaners who were not domestic cleaners did not show an increased risk for asthma,
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suggesting a specific relationship with domestic cleaning. In a case-control study, which included personal exposure measurements of chlorine and ammonia in a subset, domestic cleaners who had asthma had greater exposure to chlorine (more frequent use of bleach) than those who did not [40], and a subsequent panel study of domestic cleaners who had recent respiratory symptoms (asthma or chronic bronchitis) [39] showed symptoms associated mainly with bleach, degreasing sprays, and air fresheners. It may be expected that high-level accidental exposures, such as to mixtures of bleach and ammonia, might induce OA on an irritant basis (reactive airways dysfunction syndrome) and this might account for some of the increased asthma among domestic cleaners. It remains unclear at present whether or not chronic moderate concentrations of irritant agents can induce new onset of asthma or whether or not such exposures may cause the new onset or recurrence of symptoms in workers who have underlying airway hyperresponsiveness, which otherwise would be asymptomatic. Assessment of serial peak flow recordings in the panel study [39] showed that only a minority of symptomatic workers had peak flow changes suggestive of work-related asthma despite the associations with symptoms, suggesting that some of the work-attributed symptoms may have been based on mucous membrane irritation rather than asthmatic responses from this exposure. These studies illustrate the difficulty in drawing diagnostic conclusions from epidemiologic occupational studies of asthma when a specific occupational sensitizer has not been identified. Among epidemiologic studies of workers, unless spirometry and methacholine tests are performed, it may be difficult to distinguish asthma from chronic bronchitis, and, without further diagnostic tests, may also be hard to differentiate between OA and WEA. Even when a specific sensitizer is present in the workplace, such as for laboratory animal workers, the concurrent presence of other agents, such as endotoxin and dust, can cause diagnostic confusion unless additional immunologic tests are included to determine whether or not there is sensitization to the known workplace allergens (for example laboratory animals) [33]. Other epidemiologic studies focusing on the course and outcome of OA may give insight into the natural history of asthma [44]. Several workplace sensitizers that cause asthma may not be encountered commonly outside the work environment; therefore, the effects of complete avoidance of exposure can be studied more easily than those of common environmental allergens, such as dust mite and cat allergens. Follow-up studies of workers who have sensitizer-induced OA have reported improvement in asthma symptoms, medication needs, and airway responsiveness to methacholine in a subset after removal from exposure to the relevant work sensitizer. Outcome, as reported in some studies, is better in patients who had initial milder asthma at the time of removal from exposure and a shorter duration of asthma at the time of removal [45,46]. Duration of follow-up and the reported results are not uniform between studies, however, and one systematic review concludes
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that the studies were not sufficiently uniform for formal analyses although plotting of results suggested improvement from removal as compared with reduced or continuing exposure [47]. Another systematic review [48] showed a wide range of follow-up in published studies, but pooled estimates indicated a 32% symptomatic recovery rate with best outcome among younger subjects and those who had shorter duration of exposure. Nonspecific airway hyper-responsiveness persisted in 73% and this figure was higher among those sensitized to a high molecular weight occupational agent. The authors concluded, ‘‘The available data on the prognosis of OA are insufficiently consistent to allow confident advice to be given to patients with the disease’’ [48]. They recommend, ‘‘Clinicians and epidemiologists with an interest in this disease should consider a collaborative and carefully standardized study of the prognosis of occupational asthma’’ [48]. Ideally there would be more uniform follow-up of workers who have OA to better determine prognostic factors and allow identification of those workers who have OA who are likely to improve with complete future avoidance of a work sensitizer versus reduced exposure. There are significant socioeconomic impacts resulting from work changes due to OA [4,49,50] and it is important to identify if there are patients who have sensitizer-induced OA who may be managed with markedly reduced but not complete avoidance strategies, as is suggested for health care workers who have OA from natural rubber latex [51]. In an occupational setting, as indicated by Nicholson [52], it is unlikely to be feasible to perform randomized, double-blind, control studies for interventions, including removal or reduced exposure for workers who have OA. Similarly it often is difficult to assess the effects of individual components of primary and secondary preventive measures in an occupational setting because they usually are not performed in isolation as single intervention methods [31]. As an example, the removal of high-protein powdered latex gloves from a health care setting (a primary preventive measure) was accompanied by a medical surveillance program, including worker education and a questionnaire, skin testing for natural rubber latex (secondary prevention), and transfer of symptomatic sensitized workers away from areas where they might have direct contact with natural latex products (tertiary prevention) [36]. In addition, the effects of a medical surveillance program may differ in a ‘‘real life’’ work application as compared with effects during a research study, as illustrated in bakeries in the United Kingdom [21]. Nevertheless, it is hoped that high-quality epidemiologic studies can be developed to answer many of these questions remaining in OA. Work-exacerbated asthma There is no uniform definition of WEA (termed, in some studies, workaggravated asthma) [6,53–56]. WEA is a term used to describe worsening of pre-existing asthma at work or the worsening of asthma at work when
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asthma begins during a work period but is not believed to be caused by work (ie, it is considered to start coincidentally to work but then is exacerbated by work exposures). There is a wide range of severity and duration of exacerbations of asthma in epidemiologic studies of WEA. At one extreme, several have included exacerbations that are transient (often based on symptomatic worsening without any objective documentation) [55], and, at the other extreme, studies have included only prolonged symptomatic worsening that has presented with a clinical history similar to that of OA and has been diagnosed by the absence of a specific inhalation challenge response to a workplace sensitizer [4,56]. The source of cases also has influenced the severity; cases based on surveys of working asthmatics in a primary care setting [57] not surprisingly have reported exacerbations that are generally milder, of shorter duration, and less well documented than those from surveys of an occupational pulmonary tertiary referral clinic setting [4,56]. A few studies have included cases from workers’ compensation in a jurisdiction where WEA can receive compensation. These have included a mixture of cases initiated by primary care physicians, emergency physicians, occupational health care workers, and pulmonologists. A majority of compensated WEA cases have not been seen by a specialist but claims have been initiated from primary care and emergency visits, and the individuals have had transient worsening of symptoms attributed to a work exposure, often with few or no missed days from work [54,55]. The exposures that cause an exacerbation of asthma at work often are different from the causes of OA. Sensitizer-induced OA by definition is asthma caused by a specific work sensitizer, which may be a high molecular weight allergen (such as enzymes, animal, plant, or fungal allergens) associated with development of specific IgE antibodies or may be a chemical sensitizer, such as diisocyanates, epoxy compounds, or plicatic acid, for which the exact mechanism of sensitization may be unclear [58]. In contrast, the causative agent for WEA often is not a sensitizer but one or more asthma triggers, such as smoke, fumes, sprays, dusts, cold air, extremes of humidity, and frequently some combination of these [54,59]. Such agents are expected to trigger bronchoconstriction in subjects who have asthma to a varying extent depending at least in part on the degree of exposure, the severity and control of asthma at the time of exposure, and other potential factors. Additional agents that may be expected to exacerbate asthma at work include endotoxin [60] (for which there may be additional individual susceptibility in the response) [61,62]; common allergens, such as domestic animal or dust mite exposure in asthmatic domestic cleaners who are allergic to these [43]; and outdoor pollen or fungal exposures in outdoor workers on a seasonal basis. As discussed previously, Zock and colleagues [43] have shown that Spanish domestic cleaners are more likely allergic to dust mites than other professional cleaners despite relating their symptoms mainly to chemical cleaning agents, so it is difficult to determine whether or not those
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sensitized domestic cleaners who have asthma should be classified as having WEA from a common allergen or from nonspecific irritant chemicals or true OA. Individuals who have increased work exposure to small children (teachers and daycare workers) or those in crowded settings may be expected to be at increased risk for respiratory viral infections likely leading to exacerbation of asthma. Potentially emotional stress at work also might contribute to an exacerbation of asthma symptoms. It also can be expected that there may be a combination of factors leading to an exacerbation, for example an asthmatic teacher who has a cold and who is asked to supervise children in outdoor activities on a cold day or a factory worker who has asthma and is exposed to dusts, fumes, and sprays at work on a day when the ventilation is malfunctioning. Nevertheless, there is currently little information in published studies as to the background/baseline severity or level of control of asthma in those who have transient WEA and the exact exposure conditions that trigger the exacerbation. It is expected that asthmatic workers who have more severe asthma (associated with greater airway inflammation and greater airway hyper-responsiveness) are more likely to have an exacerbation of asthma at work under particular exposure conditions than asthmatics who have milder asthma. The use of asthma medications, however, also may modulate the response to work exposures that otherwise may exacerbate asthmadanalogous to the prevention of bronchoconstriction from methacholine or cold/dry air or exercise challenge by pretreatment with bronchodilators [63] and to a lesser extent by pretreatment with inhaled steroids [64]. Lack of asthma control, as a result of insufficient environmental or pharmacologic management, or a recent respiratory viral infection might be expected to lead to greater susceptibility to exacerbation from asthma triggers in the workplace in the same way that it may increase the airway response to bronchoconstrictor agents, such as methacholine in the laboratory setting [63], but this has not been adequately assessed in epidemiologic studies of WEA to date. Most epidemiologic studies on WEA have been based on questionnaire or self-reported responses [53,57,59]. As an example, Henneberger and colleagues [65] reported baseline findings from a longitudinal study of more than 500 working asthmatics enrolled in a single health maintenance organization. A telephone questionnaire was used to determine a work-related symptom score based on asthma symptoms, medications, and triggers. Their definition of WEA for their study was self-report of work-related worsening symptoms (symptom improvement on weekends and periods off work), increased medication needs on working versus nonworking days, and identification of exposures at work that seemed to trigger asthma symptoms. A probability rating was determined from these and from determination by an expert panel that there was a likely asthmagenic agent at work. A scoring system was developed for the probability of an exacerbating exposure using separate probability ratings for sensitizers and irritant agents and
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including rating of frequency and intensity of likely exposure. Using these criteria, they identified 61% of working men and 41% of working women as having exposure to potential sensitizers or irritants at work. They identified 23% of the working asthmatics as having moderate or strong evidence of WEA using their work-related symptom score and exposure score. These workers more likely were men (45% versus 27%) and had more days in which they were bothered by asthma in the week before the interview. Among the approximately 200 who were employed when their asthma started, 10% believed that it began as a result of work, which if correct is considered OA (a percentage similar to the estimates of the burden of asthma due to occupational exposures) [15,20]. This article [65] illustrates the high prevalence of potential exacerbating factors at work for adults who have asthma, and others also have identified a high frequency of symptomatic worsening at work among asthmatics [66]. Another perspective can be gained from review of workers’ compensation claims for WEA. Although such claims are not eligible for compensation in many jurisdictions, they can be compensated in Ontario, Canada, as ‘‘work aggravated asthma,’’ a separate category from ‘‘occupational asthma.’’ An older review of compensated asthma claims in Ontario from 1984 to 1988 [54] showed that a similar number of claims was accepted for workaggravated asthma (used with the same meaning as WEA) as for OA during that period. A more recent review has shown these accepted claims to greatly exceed OA [67], with more than 80% from work-aggravated asthma/WEA. A study including comparison of clinical investigations in WEA and OA has shown that in contrast to the investigations usually available for OA to confirm the work relationship, in the majority of workaggravated asthma/WEA claims there is little objective confirmation of the diagnosisdmost were seen for a transient exacerbation of asthma by a primary care physician or an emergency physician [55]. In contrast to claims for irritant-induced OA (including reactive airways dysfunction syndrome) most claims for work-aggravated asthma/WEA were for a short period of time off work [68]. An illustration of this is the identification of a large transient spike in asthma exacerbation claims from workers in schools associated with a strike of maintenance workers and assumed increased dust and indoor air pollution at that time [10]. These findings are consistent with a recent report [69] that identified cases of work-related asthma from the educational services industry as reported to four states in the Sentinel Event Notification System for Occupational Risks (SENSOR). Nine percent of all work-related asthma cases reported were from this industrial sector, of which approximately one third were classified in their system as work-aggravated asthma rather than new-onset asthma. Most cases were teachers and teachers’ aides and the most common self-implicated exposures for those who had WEA were to ‘‘mold,’’ ‘‘dust,’’ and ‘‘indoor air pollutants.’’ The amount of time missed from work and the duration of the asthma ‘‘aggravation,’’ however, were not reported.
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A proportion of individuals who have WEA may have more prolonged or consistent exacerbation of asthma at work such that the clinical history may be similar to OA with frequent worsening of symptoms on working days and improvement on weekends or holidays. These may fall into the category of more ‘‘definite’’ WEA in the study by Henneberger and colleagues [65]. This subgroup also may be the subjects more likely to be referred for investigation of possible work-related asthma to a specialist and to undergo more objective investigations to exclude OA from a sensitizer: objective confirmation of a diagnosis of asthma, serial peak expiratory flow monitoring, methacholine challenge at the end of a work week and after a period off work, immunologic tests to assess a possible IgE antibody response to a work agent, and in some centers induced sputum and consideration of specific chamber challenge testing. There are few studies that have reported findings from such a group who have undergone detailed investigation [4,6,56,70], and (as indicated previously), these are likely to represent a subgroup that has more prolonged and severe work-related symptoms. A specific chamber challenge test generally is undertaken only if OA is a possibility in the differential diagnosis and if there is a work exposure agent that might be a sensitizer. In these circumstances a patient who has a negative specific challenge but work-related asthma symptoms is regarded as having WEA. When defined in this way, serial peak expiratory flow recordings were reported to show similar patterns as in those who had OA, and the diagnosis of WEA versus OA could not be distinguished by visual inspection or by using the computerized Occupational Asthma Expert System (OASYS) [71], although the mean diurnal variability was statistically less among those who had WEA than in those who had OA [56]. Similarly, improvement in airway responsiveness to methacholine while away from work exposures compared with results during working weeks is reported as showing similar changes among those who had WEA as among those who had OA (with the diagnosis again defined by specific challenge responses) [72]. An increase in sputum eosinophils during a work period was more likely to occur among those who had OA in this study although there was overlap between groups [72]. A difficulty in using this definition of WEA to identify different characteristics of those who have OA versus WEA is the possibility that the gold standard of specific challenge may be falsely negative if the correct exposure agent is not selected or if the duration or concentration of exposure is not sufficient to induce a true response and, conversely, could be falsely positive if the exposure is irritant [73,74]. To date there are no reported studies assessing management of WEA or preventive measures. It may be expected that good pharmacologic control of asthma and limitation of exposure to asthma triggers at work may reduce morbidity and the socioeconomic impact of WEA but documentation of this is needed.
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Summary There is significant current interest not only in OA but also in the potential of work exposures to exacerbate/aggravate adult asthma. The range of potential triggers for OA and WEA is wide. OA can result in persisting asthma even after removal from exposure to the work agent and for WEA the exacerbation could range from very transient worsening of symptoms to persistent daily worsening at work. OA and WEA can have significant socioeconomic impacts. Underlying host factors, such as asthma severity and medication use, and compliance likely are contributing factors to WEA. It is hoped that epidemiologic studies in the future will help clarify these common conditions. OA is a challenge to definitively identify in epidemiologic studies. Nevertheless, case definitions for epidemiologic studies have been developed and there is a need for greater use of such tools to better identify the prevalence and causes of OA worldwide and prognostic factors and results of preventive measures.
References [1] Milgrom H. Unfulfilled expectations in asthma. Allergy Asthma Proc 2007;28(2):111–3. [2] Sullivan SD, Rasouliyan L, Russo PA, et al. Extent, patterns, and burden of uncontrolled disease in severe or difficult-to-treat asthma. Allergy 2007;62(2):126–33. [3] Peters J, Pickvance S, Wilford J, et al. Predictors of delayed return to work or job loss with respiratory ill-health: a systematic review. J Occup Rehabil 2007;17(2):317–26. [4] Vandenplas O, Toren K, Blanc PD. Health and socioeconomic impact of work-related asthma. Eur Respir J 2003;22(4):689–97. [5] Larbanois A, Jamart J, Delwiche JP, et al. Socioeconomic outcome of subjects experiencing asthma symptoms at work. Eur Respir J 2002;19(6):1107–13. [6] Pelissier S, Chaboillez S, Teolis L, et al. Outcome of subjects diagnosed with occupational asthma and work-aggravated asthma after removal from exposure. J Occup Environ Med 2006;48(7):656–9. [7] Newman Taylor AJ, Cullinan P, Burge PS, et al. BOHRF guidelines for occupational asthma. Thorax 2005;60(5):364–6. [8] Nicholson PJ, Cullinan P, Taylor AJ, et al. Evidence based guidelines for the prevention, identification, and management of occupational asthma. Occup Environ Med 2005;62(5): 290–9. [9] Lagier F, Cartier A, Malo JL. [Medico-legal statistics on occupational asthmna in Quebec between 1986 and 1988]. Rev Mal Respir 1990;7(4):337–41 [in French]. [10] Tarlo SM, Liss GM. Occupational respiratory disease in Canada. Life Life and Breath, Respiratory Disease in Canada 2007 . Available at: http://www.phac-aspc.gc.ca. [11] Tarlo SM, Malo JL. An ATS/ERS report: 100 key questions and needs in occupational asthma. Eur Respir J 2006;27(3):607–14. [12] Malo JL, Ghezzo H, L’Archeveque J, et al. Is the clinical history a satisfactory means of diagnosing occupational asthma? Am Rev Respir Dis 1991;143(3):528–32. [13] Vandenplas O, Ghezzo H, Munoz X, et al. What are the questionnaire items most useful in identifying subjects with occupational asthma? Eur Respir J 2005;26(6):1056–63. [14] Tarlo SM, Broder I. Outcome of assessments for occupational asthma. Chest 1991;100(2): 329–35.
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[15] Blanc PD, Toren K. How much adult asthma can be attributed to occupational factors? Am J Med 1999;107(6):580–7. [16] Venables KM, Farrer N, Sharp L, et al. Respiratory symptoms questionnaire for asthma epidemiology: validity and reproducibility. Thorax 1993;48(3):214–9. [17] Pekkanen J, Sunyer J, Anto JM, et al. Operational definitions of asthma in studies on its aetiology. Eur Respir J 2005;26(1):28–35. [18] Johnson AR, Dimich-Ward HD, Manfreda J, et al. Occupational asthma in adults in six Canadian communities. Am J Respir Crit Care Med 2000;162(6):2058–62. [19] Kogevinas M, Zock JP, Jarvis D, et al. Exposure to substances in the workplace and newonset asthma: an international prospective population-based study (ECRHS-II). Lancet 2007;370(9584):336–41. [20] Balmes J, Becklake M, Blanc P, et al. American Thoracic Society statement: occupational contribution to the burden of airway disease. Am J Respir Crit Care Med 2003;167(5): 787–97. [21] Brant A, Nightingale S, Berriman J, et al. Supermarket baker’s asthma: how accurate is routine health surveillance? Occup Environ Med 2005;62(6):395–9. [22] Matsui EC, Diette GB, Krop EJ, et al. Mouse allergen-specific immunoglobulin G and immunoglobulin G4 and allergic symptoms in immunoglobulin E-sensitized laboratory animal workers. Clin Exp Allergy 2005;35(10):1347–53. [23] Brant A, Zekveld C, Welch J, et al. The prognosis of occupational asthma due to detergent enzymes: clinical, immunological and employment outcomes. Clin Exp Allergy 2006;36(4): 483–8. [24] Howse D, Gautrin D, Neis B, et al. Gender and snow crab occupational asthma in Newfoundland and Labrador, Canada. Environ Res 2006;101(2):163–74. [25] Pronk A, Preller L, Raulf-Heimsoth M, et al. Respiratory symptoms, sensitization, and exposure response relationships in spray painters exposed to isocyanates. Am J Respir Crit Care Med 2007;176(11):1090–7. [26] Marabini A, Dimich-Ward H, Kwan SY, et al. Clinical and socioeconomic features of subjects with red cedar asthma. A follow-up study. Chest 1993;104(3):821–4. [27] Merget R, Schultze-Werninghaus G, Muthorst T, et al. Asthma due to the complex salts of platinumda cross-sectional survey of workers in a platinum refinery. Clin Allergy 1988; 18(6):569–80. [28] Gautrin D, Ghezzo H, Infante-Rivard C, et al. Incidence and host determinants of work-related rhinoconjunctivitis in apprentice pastry-makers. Allergy 2002;57(10): 913–8. [29] Gautrin D, Infante-Rivard C, Ghezzo H, et al. Incidence and host determinants of probable occupational asthma in apprentices exposed to laboratory animals. Am J Respir Crit Care Med 2001;163(4):899–904. [30] Archambault S, Malo JL, Infante-Rivard C, et al. Incidence of sensitization, symptoms, and probable occupational rhinoconjunctivitis and asthma in apprentices starting exposure to latex. J Allergy Clin Immunol 2001;107(5):921–3. [31] Cullinan P, Tarlo S, Nemery B. The prevention of occupational asthma. Eur Respir J 2003; 22(5):853–60. [32] Tarlo SM, Liss GM. Prevention of occupational asthmadpractical implications for occupational physicians. Occup Med (Lond) 2005;55(8):588–94. [33] Pacheco KA, McCammon C, Liu AH, et al. Airborne endotoxin predicts symptoms in nonmouse-sensitized technicians and research scientists exposed to laboratory mice. Am J Respir Crit Care Med 2003;167(7):983–90. [34] Delclos GL, Gimeno D, Arif AA, et al. Occupational risk factors and asthma among health care professionals. Am J Respir Crit Care Med 2007;175(7):667–75. [35] Allmers H, Schmengler J, Skudlik C. Primary prevention of natural rubber latex allergy in the German health care system through education and intervention. J Allergy Clin Immunol 2002;110(2):318–23.
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[36] Tarlo SM, Easty A, Eubanks K, et al. Outcomes of a natural rubber latex control program in an Ontario teaching hospital. J Allergy Clin Immunol 2001;108(4):628–33. [37] Kogevinas M, Anto JM, Soriano JB, et al. The risk of asthma attributable to occupational exposures. A population-based study in Spain. Spanish group of the European asthma study. Am J Respir Crit Care Med 1996;154(1):137–43. [38] Kogevinas M, Anto JM, Sunyer J, et al. Occupational asthma in Europe and other industrialised areas: a population-based study. European community respiratory health survey study group. Lancet 1999;353(9166):1750–4. [39] Medina-Ramon M, Zock JP, Kogevinas M, et al. Short-term respiratory effects of cleaning exposures in female domestic cleaners. Eur Respir J 2006;27(6):1196–203. [40] Medina-Ramon M, Zock JP, Kogevinas M, et al. Asthma, chronic bronchitis, and exposure to irritant agents in occupational domestic cleaning: a nested case-control study. Occup Environ Med 2005;62(9):598–606. [41] Medina-Ramon M, Zock JP, Kogevinas M, et al. Asthma symptoms in women employed in domestic cleaning: a community based study. Thorax 2003;58(11):950–4. [42] Zock JP, Kogevinas M, Sunyer J, et al. Asthma characteristics in cleaning workers, workers in other risk jobs and office workers. Eur Respir J 2002;20(3):679–85. [43] Zock JP, Kogevinas M, Sunyer J, et al. Asthma risk, cleaning activities and use of specific cleaning products among Spanish indoor cleaners. Scand J Work Environ Health 2001; 27(1):76–81. [44] Tarlo SM. Occupational asthma: a valid model for adult asthma? Curr Opin Allergy Clin Immunol 2003;3(2):91–4. [45] Tarlo SM, Banks D, Liss G, et al. Outcome determinants for isocyanate induced occupational asthma among compensation claimants. Occup Environ Med 1997;54(10):756–61. [46] Perfetti L, Cartier A, Ghezzo H, et al. Follow-up of occupational asthma after removal from or diminution of exposure to the responsible agent: relevance of the length of the interval from cessation of exposure. Chest 1998;114(2):398–403. [47] Beach J, Rowe BH, Blitz S, et al. Diagnosis and management of work-related asthma. Evid Rep Technol Assess (Summ) 2005;(129):1–8. [48] Rachiotis G, Savani R, Brant A, et al. Outcome of occupational asthma after cessation of exposure: a systematic review. Thorax 2007;62(2):147–52. [49] Ameille J, Descatha A. Outcome of occupational asthma. Curr Opin Allergy Clin Immunol 2005;5(2):125–8. [50] Moscato G, Dellabianca A, Perfetti L, et al. Occupational asthma: a longitudinal study on the clinical and socioeconomic outcome after diagnosis. Chest 1999;115(1):249–56. [51] Vandenplas O, Jamart J, Delwiche JP, et al. Occupational asthma caused by natural rubber latex: outcome according to cessation or reduction of exposure. J Allergy Clin Immunol 2002;109(1):125–30. [52] Nicholson PJ. How to undertake a systematic review in an occupational setting. Occup Environ Med 2007;64(5):353–8, 303. [53] Saarinen K, Karjalainen A, Martikainen R, et al. Prevalence of work-aggravated symptoms in clinically established asthma. Eur Respir J 2003;22(2):305–9. [54] Tarlo SM, Liss G, Corey P, et al. A workers’ compensation claim population for occupational asthma. Comparison of subgroups. Chest 1995;107(3):634–41. [55] Santos MS, Jung H, Peyrovi J, et al. Occupational asthma and work-exacerbated asthma: factors associated with time to diagnostic steps. Chest 2007;131(6):1768–75. [56] Chiry S, Cartier A, Malo JL, et al. Comparison of peak expiratory flow variability between workers with work-exacerbated asthma and occupational asthma. Chest 2007;132(2):483–8. [57] Henneberger PK, Deprez RD, Asdigian N, et al. Workplace exacerbation of asthma symptoms: findings from a population-based study in Maine. Arch Environ Health 2003; 58(12):781–8. [58] Mapp CE, Boschetto P, Maestrelli P, et al. Occupational asthma. Am J Respir Crit Care Med 2005;172(3):280–305.
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[59] Goe SK, Henneberger PK, Reilly MJ, et al. A descriptive study of work aggravated asthma. Occup Environ Med 2004;61(6):512–7. [60] Rylander R, Michel O. Organic dust induced inflammationdrole of atopy and TLR-4 and CD14 gene polymorphisms. Am J Ind Med 2005;48(4):302–7. [61] LeVan TD, Von Essen S, Romberger DJ, et al. Polymorphisms in the CD14 gene associated with pulmonary function in farmers. Am J Respir Crit Care Med 2005;171(7):773–9. [62] Kline JN, Cowden JD, Hunninghake GW, et al. Variable airway responsiveness to inhaled lipopolysaccharide. Am J Respir Crit Care Med 1999;160(1):297–303. [63] Crapo RO, Casaburi R, Coates AL, et al. Guidelines for methacholine and exercise challenge testing-1999. This official statement of the American thoracic society was adopted by the ATS board of directors, July 1999. Am J Respir Crit Care Med 2000;161(1):309–29. [64] Currie GP, Fowler SJ, Lipworth BJ. Dose response of inhaled corticosteroids on bronchial hyperresponsiveness: a meta-analysis. Ann Allergy Asthma Immunol 2003;90(2):194–8. [65] Henneberger PK, Derk SJ, Sama SR, et al. The frequency of workplace exacerbation among health maintenance organisation members with asthma. Occup Environ Med 2006;63(8): 551–7. [66] Tarlo SM, Leung K, Broder I, et al. Asthmatic subjects symptomatically worse at work: prevalence and characterization among a general asthma clinic population. Chest 2000; 118(5):1309–14. [67] Buyantseva LV, Liss GM, Luce CE, et al. Work-aggravated asthma and occupational asthma in Ontario: relative frequency and exposures. Proceedings of the American Thoracic Society 2007;4:A804. [68] Chatkin JM, Tarlo SM, Liss G, et al. The outcome of asthma related to workplace irritant exposures: a comparison of irritant-induced asthma and irritant aggravation of asthma. Chest 1999;116(6):1780–5. [69] Mazurek JM, Filios M, Willis R, et al. Work-related asthma in the educational services industry: California, Massachusetts, Michigan, and New Jersey, 1993–2000. Am J Ind Med 2008;51(1):47–59. [70] Lemiere C, Forget A, Dufour MH, et al. Characteristics and medical resource use of asthmatic subjects with and without work-related asthma. J Allergy Clin Immunol 2007; 120(6):1354–9. [71] Baldwin DR, Gannon P, Bright P, et al. Interpretation of occupational peak flow records: level of agreement between expert clinicians and Oasys-2. Thorax 2002;57(10):860–4. [72] Girard F, Chaboillez S, Cartier A, et al. An effective strategy for diagnosing occupational asthma: use of induced sputum. Am J Respir Crit Care Med 2004;170(8):845–50. [73] Tarlo SM. Laboratory challenge testing for occupational asthma. J Allergy Clin Immunol 2003;111(4):692–4. [74] Williams PB. Critical analysis of studies concerning reports of respiratory sensitization to certain wood dusts. Allergy Asthma Proc 2005;26(4):262–7.
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Traffic, Outdoor Air Pollution, and Asthma Fernando Holguin, MD, MPH Emory University School of Medicine, Division of Pulmonary, Allergy, and Critical Care, Clinical Research Center, Davis Fisher Building, Room 2331, 550 Peachtree Street NE, Atlanta, GA 30308, USA
It is well known that outdoor air pollution can affect the health of patients with asthma. Epidemiologic studies have shown that increased levels of outdoor pollutants are associated with acute and chronic changes in lung function, increased risk for asthma exacerbations, increased risk for work or school absenteeism, and need for rescue bronchodilators. Fortunately, we have also learned that reducing ambient levels of air pollutants can decrease acute health care use for asthma and therefore improve the quality of life of these patients [1]. The epidemiology of asthma and outdoor air pollution has shown that respiratory health effects can vary in relation to different emission sources, types of pollutants, underlying nutritional status, medication use, and genetic polymorphisms. Using sophisticated exposure assessment methods in conjunction with clinical tests and biomarkers that provide mechanistic information, the study of outdoor epidemiology and asthma has evolved into a complex multidisciplinary field. This article presents an overview of the mechanisms by which outdoor air pollution and traffic-related emissions lead to changes in respiratory health and lung function in subjects with asthma.
The outdoor air pollution mix Polluted outdoor air contains a complex mixture of particle and gasphase pollutants. Most epidemiologic studies on asthma and air pollution have focused on understanding the health effects of criteria air pollutants, which are routinely monitored by the Environmental Protection Agency and include ozone, nitrogen dioxide, sulfur dioxide, lead, carbon monoxide,
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and particulate matter (PM) [2,3]. PM is further subdivided into coarse particulate matter or PM10 (PM with an aerodynamic diameter %10 mm), fine particulate matter or PM2.5 (PM with an aerodynamic diameter %2.5 mm), and ultrafine or PM1.0 (PM with an aerodynamic diameter %1.0 mm) [4]. The criteria pollutants are derived from different emissions sources. For example, nitrogen dioxide and ground-level ozone (which results from the effect of ultraviolet light on nitrogen dioxide) are primarily derived from vehicle exhaust, whereas sulfur dioxide derives from combustion of sulfurcontaining fuels (eg, coal burning plants). Coarse particulate matter is primarily derived from dispersed ground or fugitive dust; fine and ultrafine particulate matter comes primarily from vehicular exhaust [5]. Coarse and fine particulates differ not only in their size and physical properties, but also in their chemical composition. PM10 is largely composed of geological materials, in contrast to PM2.5 and PM1.0, which have larger fractions of elemental and organic carbon [6]. These PM variations in chemical composition are associated with different toxicity profiles and can be used as tracers of vehicular emissions. For example, elemental carbon can be used for tracking traffic-related emissions [7]. The first challenge in studying the impact of air pollution on asthma status is to accurately quantify exposure. Determining that a patient with asthma may be more or less susceptible to different pollutants is easy, but trying to understand the pollution mixture actually inhaled is practically impossible. Exposure to different pollution mixtures can vary by location, proximity to roads, time of day, seasonality, and other factors. Epidemiologic research on outdoor air pollution employs different methodologies to overcome many of these limitations. This may include relating health outcomes to emission sources as the main exposure of interest (eg, proximity to roads, traffic density estimates, road densities) and use of personal air pollution monitors in smaller, better-characterized panel studies. An in-depth review of epidemiologic and exposure assessment methods used in outdoor air pollution is beyond the scope of this article. However, there are many different ways of associating air pollution exposure with respiratory health outcomes and this methodological variation is often the source inconsistent results across studies.
Outdoor air pollution and mechanisms of injury pertinent to asthma Airway inflammation Outdoor air pollutants are known to exacerbate asthma by causing inflammation in the airways [8,9]. Even short-term exposures to vehicular traffic emissions (PM2.5, PM1.0, elemental carbon, and nitrogen dioxide) in subjects with asthma are associated with evidence of neutrophilic inflammation and reduced airway pH [7]. Evidence that outdoor air pollution leads to airway inflammation in asthma is also supported by studies using exhaled
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nitric oxide as a biomarker. In a panel of 19 children with asthma in Seattle, a same-day increase of 10 mm/m3 of PM2.5 was associated with increased in exhaled nitric oxide of 4.3 ppb [95% CI 1.4–7.29] [10]. Exposure to ambient elemental carbon has also been associated with increased exhaled nitric oxide, suggesting that vehicular emissions may lead to increased airway inflammation [11]. Allergy sensitization Outdoor air pollution may increase the risk for asthma by mechanisms that involve increased allergic sensitization. Exposure to diesel exhaust particles (DEP) before an allergen challenge has been shown to increase Th-2 cytokine levels, when compared with allergen exposure alone. Furthermore, DEP exposure favors lymphocyte-B cell differentiation and IgE production [12,13]. Short-term ambient exposure to PM2.5 has also been associated with increased allergic inflammation by increasing the proportion of eosinophils in the nasal lavage of asthmatic children but not in healthy controls [14]. However, large-scale epidemiologic studies, such as the European Community Respiratory Health study, did not demonstrate an association between variations of annual average regional PM2.5 and sulfur levels and allergic sensitization [15]. In contrast, the Study on Air Pollution and Lung Diseases in Adults (SAPALDIA) found significant associations between allergic sensitization to pollen and living near streets with higher vehicular traffic [16]. Whether or not air pollution induces allergic sensitization is debatable and inconsistencies across studies may be the result of methodological differences [17]. Clinical and physiologic lung changes associated with outdoor air pollution Acute changes in lung volumes Subjects with asthma are far more susceptible than healthy subjects to the effects of outdoor air pollution. Most studies have found that increased concentrations of outdoor air pollution can be associated with acute reductions in forced vital capacity (FVC) and forced exhaled lung volume in one second (FEV1) among persons with asthma. The magnitude and lag between exposure and change in lung function varies considerably according to the exposure assessment (type of pollutants being measured) and study design. Outdoor PM10 and PM2.5 have been associated with acute reductions in FEV1 and FVC. These reductions in lung volumes are observed either within the same day, a few hours after exposure, or days after exposure (lag response) [7,18]. Sulfur dioxide is oxidized in the atmosphere to sulfuric acid with resulting acid aerosol and acid rain production. Acid aerosols are associated with significant reductions in FEV1 and FVC. Sulfur dioxide can acutely induce bronchoconstriction in subjects with asthma [19,20]. Moreover, ozone is
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a strong oxidizing agent well known to reversibly reduce FEV1 and FVC, promote bronchial hyperresponsiveness, increase airway resistance, and reduce peak expiratory flows [21,22]. Compared to subjects without chronic airway obstruction, subjects with asthma exhibit larger reductions in FEV1 in association with exposure to ambient nitrogen dioxide [23]. In controlled exposure chamber studies, however, investigators have failed to show FEV1 reductions in asthmatics exposed to nitrogen dioxide [24]. Discrepancies between chamber exposure and epidemiologic studies are not uncommon and may derive from the fact that, in an epidemiologic study, what we attribute to be the exposure of interest functions as a tracer or surrogate for other pollutants or a complex mixture of pollutants, such as a mixture of nitrogen dioxide, PM2.5, and other vehicular traffic–related emissions. Chronic lung-volume changes Understanding the chronic respiratory health effects of outdoor air pollutants is more complex. It requires either a longitudinal approach in large study populations with repeated measures of lung function and air pollution exposure over time, or an ecological approach in which lung function values are compared in populations across a gradient of outdoor air pollution levels. The Children’s Health Study is a large cohort study that enrolled children from 12 communities with varying air pollution exposure profiles across California. Results from this cohort show that children from ages 10 to 18 years exposed to higher air pollutant concentrations have reduced lung growth. Deficits in lung function were associated with nitrogen dioxide, acid vapor, and PM2.5, but not with ozone [25]. Importantly, air pollution– related lung-growth deficits occurred in children with and without asthma. In a dynamic cohort from Mexico City that included 3120 healthy children 8 years of age at baseline and followed for 3 years, exposure to ozone, PM10, and nitrogen dioxide were associated with significant deficits in lung growth [26]. Results from these studies suggest that air pollution–related deficits in lung growth prevents many children from achieving their peak lung volume. Chronic exposure to outdoor air pollutants is also associated with increased rate of lung-volume decline over time. Results from the SAPALDIA show that long-term exposure to pollutants (nitrogen dioxide, PM10, and sulfur dioxide) is associated with increased decline in FEV1 and FVC. For FVC, an increment of 10 mg/m3 in PM10 was associated with a 3.4% change in FVC [27]. The good news is that lung function can improve once exposure to air pollution is reduced, even after long-term exposure. In the same study, 9651 adults (18 to 60 years of age and assessed in 1991 and 2002), experienced an overall reduction in their outdoor PM10 exposure. The net effect of a decline of 10 mg of PM10 per cubic meter over an 11-year period was to reduce the annual rate of decline in FEV1 by 9% and of FEF25–75 by 16% [28]. In the California Children’s Study, participants who moved to
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communities with lower PM10 showed increased lung growth, whereas moving to higher PM10 environments was associated with reduced lung growth. These associations were predominantly observed in children who had been living in their new communities for at least 3 years [29]. Outdoor air pollution and asthma health status Many epidemiologic studies have shown that increased outdoor air pollutant levels are a significant morbidity risk for subjects with asthma. Increased outdoor exposure to air pollution has been associated with increased severity of respiratory symptoms, increased risk for asthma exacerbations requiring emergency department evaluation or hospitalization, and more frequent urgent medical visits and use of asthma medications [2,4,30]. Also, higher levels of air pollution are associated with increased school and work absenteeism resulting in a large economic cost to society [31,32]. Clearly not every subject with asthma experiences adverse respiratory outcomes when exposed to higher levels of outdoor air pollutants. Several factors have been shown to either increase susceptibility or confer resistance to air pollution. The interaction between environment and genetic polymorphisms is an area of intense research and some recent studies are worth reviewing. In asthmatics, the presence of GSTM1 (glutathione s-transferase null polymorphism) and GSTP1 (val/val genotype) has been associated with increased to susceptibility to ambient ozone exposure [33,34]. The GSTM1 polymorphism, which is present in approximately 40% of the general population, has been associated with increased levels of nasal biomarkers of inflammation and reduced peak expiratory flows in asthmatic children in association with ozone [33]. Both GSTM1 and GSTP1 polymorphisms are also associated with increased dyspnea in children with asthma exposed to ozone [33]. The presence of GSTM1 also increases the risk for systemic inflammation in association with traffic-related particles (black carbon and concentration of particles) [35]. Children who are GSTM1 homozygous and most susceptible to outdoor air pollution benefit the most from antioxidant supplementation. Romieu and colleagues [34] showed that, compared with placebo, children receiving antioxidant supplementation did not exhibit ozone-related reductions in lung volumes. Antioxidant supplementation was most effective in protecting children who were GSTM1 null homozygous. Not all genetic polymorphisms have been associated with increased susceptibility. Among 3699 children participating in the children’s health study in California, those who were homozygous for the tumor necrosis factor a (TNF-a) 308G polymorphism (range from 71% non-Hispanic whites to 87% in Asians) had a reduced risk for lifetime asthma prevalence and wheezing, compared with those carrying one allele. Furthermore, homozygous children living in lower-ozone communities were protected from
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wheezing in relation to ozone exposure, particularly in those with the GSTM1 polymorphism [36]. It is thought that the homozygous TNFa 308G polymorphism may protect from ozone exposure by reducing the inflammatory response to oxidative stress [36]. Air pollution as a risk factor for asthma incidence Outdoor air pollution not only exacerbates asthma, but is also a risk factor for developing new-onset asthma. For example, increased asthma incidence has been described in children playing outdoor sports exposed to higher ozone levels. In this study, children who played three or more outdoor sports in communities with high ozone concentrations during the summer had a relative risk of developing asthma of 3.3 [95% CI 1.9–5.8], compared with children playing no sports. Also, the risk for asthma prevalence increases proportionately with increased vehicular emission exposures, suggesting that chronic exposure to these pollutants may increase the risk of developing asthma [37,38]. In a large study of 6000 children from six French cities, the 3-year averaged concentration of ozone, PM10, sulfur dioxide, and nitrogen dioxide were associated with increased odds of developing allergic rhinitis, atopy (positive skin test), and lifetime asthma [39]. A matched case control study by Zmirou and colleagues evaluated the risk for incident asthma (recent medical diagnosis within the preceding 2 years) in children of ages between 4 and 14 years and exposure to traffic density. Exposure to traffic density was calculated retrospectively and divided into an overall cumulative life exposure and an early life exposure (birth to 3 years). Early life exposure to traffic density, but not the cumulative measure, was associated with increased odds for asthma incidence [40]. Results from these studies suggest that outdoor air pollutants may play a role in increasing the risk for developing asthma and atopy, particularly early in life. Reducing the health burden associated with outdoor air pollution Relocating to cities with less air pollution can reduce the risk for some of the chronic lung effects and improve respiratory health. However, this option is probably not feasible or practical for most patients with asthma. Health care providers should advise their patients with asthma to follow their local air pollution forecasts to avoid outdoor exposure as much as possible during alerts. This means cutting out exercise during peak air pollution hours [41]. This advice is useful for reducing ozone exposure in subjects who live or work in air-conditioned environments. Outdoor avoidance may not provide the same degree of protection from fine and ultrafine particles, which have higher filtration coefficients and can achieve relatively high concentrations indoors. Whether treatment with inhaled corticosteroids or other antiasthma medications can provide relief from air pollution is unclear. In a panel of 19 children with asthma, exposure to ambient PM2.5 was associated with increased
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exhaled nitric oxide. This association was not observed in children taking inhaled corticosteroids (change in exhaled nitric oxide per 10 mg/m3 increase in PM2.5 in children with inhaled corticosteroids: 6.3 [95% CI 2.6–10]; change in exhaled nitric oxide per 10 mg/m3 increase in PM2.5 in children not on inhaled corticosteroids: –0.77 [95% CI -4.6, 3]) [42]. In the California Children’s Health Study, ambient ozone exposure was associated with increased prevalence of medication use and wheezing among asthmatic children, particularly in those who spent more time outdoors [43]. However, the prevalence of medication use in this study was a proxy for increased susceptibility to the exposure and no data was provided to determine whether use of inhaled corticosteroids modified the association with outdoor air pollutants. Rundell and colleagues showed that one dose of montelukast prevented bronchoconstriction in young males exercising during exposure to high PM concentrations [44]. This suggests that particulate air pollution could induce lung function deficits via leukotriene inflammatory pathways. Two other small exposure studies have shown that long-acting theophylline and salmeterol may prevent sulfur dioxide–mediated bronchoconstriction [45,46]. These results clearly need to be replicated in a larger study population. The use of antioxidant supplementation has been shown to reduce the impact of outdoor air pollution on respiratory symptoms and decline in lung volumes [34]. However, these results stem from small panel studies and do not provide the level of evidence needed to make broader clinical or public health recommendations to use antioxidants as a secondary prevention strategy.
Traffic and asthma Asthma and traffic-related emissions Evidence that there is considerable spatial variability in the concentration of traffic-related pollutants has sparked interest in assessing the health effects associated with vehicular emissions. Several studies have found that exposure to traffic-related emissions are associated with higher rates of adverse respiratory health outcomes in comparison with background air pollution exposure [47–51]. This phenomenon may be explained by the pollutant mix properties near vehicular emission sources, including larger concentration of fine and ultrafine particles [52] and higher concentrations of carbon monoxide and nitrogen dioxide levels [53]. Although there is no clear consensus on what constitutes exposure to vehicular-related emissions, most studies have found that the rate of adverse respiratory health effects appears to increase proportionately in relation to road-proximity [38] and with increasing traffic density [54]. Proximity to major traffic roads and high traffic density has been associated with higher rates of wheezing [50], atopy [55,56], respiratory symptoms, and health care use in children [57–59]. In a cohort of 200 children aged 6 to 12 years (half of them with asthma), the author and colleagues determined the associations between road
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densities (defined as total kilometers of roads within a defined area) near schools and homes and exposure to outdoor air pollution (nitrogen dioxide, elemental carbon, and PM2.5). These exposures were then related to changes in lung volumes and exhaled nitric oxide. This study found that road density (a proxy measure for vehicular traffic) within the 50- and 100-m buffers (radius around a geographically designated area), particularly at home, was associated with reduced FEV1 and FVC and increased exhaled nitric oxide only in children with asthma [60]. Because road density and related traffic volumes remain constant or change slowly, road density constitutes a persistent traffic exposure. In contrast, no significant associations with the ambient levels of measured pollutants (a longitudinal exposure) were observed. One possibility to explain this finding is the potential for exposure misclassification. For example, the study’s pollutant exposure assessment may not accurately represent exposure during a critical time window that would be associated with changes in exhaled nitric oxide or lung volumes. Alternatively, cumulative long-term exposure may be more relevant than shorterterm peak exposures to pulmonary function in this cohort. The effect of exposure to traffic-related emissions on respiratory health, above and beyond the background air pollution, remains controversial. Other studies have not shown significant associations [61–63]. Discrepancies among studies can be partly explained by different exposure measures, including subjective quantification of traffic density, direct measurement of traffic counts, and exposure defined at different proximity levels to roads with greater traffic densities. Also, an important source of bias when evaluating the effects of vehicular emissions is socioeconomic status position (SEP). Lower SEP has been associated with road proximity and with increased vulnerability to the effects of air pollutants [64]. Disentangling the extent of bias attributed to SEP in traffic studies can be quite difficult, as the SEP definition among studies was highly variable. Additionally, other unmeasured factors, such as noise and related stress, can be important sources of bias [65,66]. Summary There is growing evidence that exposure to traffic-related emissions is different than that of background air pollutants in terms of the composition of the pollution mix and the health risks. However, given the broad differences in methodology and exposure assessment, it is difficult to reach a consensus on what constitutes an exposure to ‘‘traffic- or vehicle-related emission.’’ This limitation leaves many important questions unanswered and hampers the capacity of research to translate results into community environmental improvements aimed at reducing health risks. For example, there is no consensus regarding exposure thresholds. That is, at what distance from roads or traffic emission sources would the exposure to vehicular emissions be diminished to safe levels? Should we advise patients with asthma to avoid prolonged exposure in close proximity to roads. If so, how much time
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constitutes prolonged exposure? What distance is far enough away? What volume of traffic is tolerable? Should an asthmatic be advised not to reside or attend school or work based on the potential for nearby traffic exposure? The answers to these questions could have clinical implications for the caring of patients with asthma and for public health policies, urban planning and development, and other areas of society. References [1] Friedman MS, Powell KE, Hutwagner L, et al. Impact of changes in transportation and commuting behaviors during the 1996 Summer Olympic Games in Atlanta on air quality and childhood asthma. JAMA 2001;285(7):897–905. [2] Koren HS. Associations between criteria air pollutants and asthma. Environ Health Perspect 1995;103(Suppl 6):235–42. [3] Environmental Protection Agency. Criteria air pollutants 2008. Available at: www.epa.gov. Accessed 2008. [4] Kappos AD, Bruckmann P, Eikmann T, et al. Health effects of particles in ambient air. Int J Hyg Environ Health 2004;207(4):399–407. [5] Harrison R. Measurements of concentrations of air pollutants. In: Holgate S, Samet J, Hillel K, et al, editors. Air pollution and health. London: Academic Press; 1999. p. 63–81. [6] Hetland RB, Cassee FR, Lag M, et al. Cytokine release from alveolar macrophages exposed to ambient particulate matter: heterogeneity in relation to size, city and season. Part Fibre Toxicol 2005;2:4. [7] McCreanor J, Cullinan P, Nieuwenhuijsen MJ, et al. Respiratory effects of exposure to diesel traffic in persons with asthma. N Engl J Med 2007;357(23):2348–58. [8] Peden DB, Boehlecke B, Horstman D, et al. Prolonged acute exposure to 0.16 ppm ozone induces eosinophilic airway inflammation in asthmatic subjects with allergies. J Allergy Clin Immunol 1997;100(6 Pt 1):802–8. [9] Aris RM, Christian D, Hearne PQ, et al. Ozone-induced airway inflammation in human subjects as determined by airway lavage and biopsy. Am Rev Respir Dis 1993;148(5):1363–72. [10] Koenig JQ, Jansen K, Mar TF, et al. Measurement of offline exhaled nitric oxide in a study of community exposure to air pollution. Environ Health Perspect 2003;111(13):1625–9. [11] Delfino RJ, Staimer N, Gillen D, et al. Personal and ambient air pollution is associated with increased exhaled nitric oxide in children with asthma. Environ Health Perspect 2006; 114(11):1736–43. [12] Diaz-Sanchez D. The role of diesel exhaust particles and their associated polyaromatic hydrocarbons in the induction of allergic airway disease. Allergy 1997;52(38 Suppl):52–6. [13] Diaz-Sanchez D, Tsien A, Fleming J, et al. Combined diesel exhaust particulate and ragweed allergen challenge markedly enhances human in vivo nasal ragweed-specific IgE and skews cytokine production to a T helper cell 2-type pattern. J Immunol 1997;158(5):2406–13. [14] Nikasinovic L, Just J, Sahraoui F, et al. Nasal inflammation and personal exposure to fine particles PM2.5 in asthmatic children. J Allergy Clin Immunol 2006;117(6):1382–8. [15] Bedada GB, Heinrich J, Gotschi T, et al. Urban background particulate matter and allergic sensitization in adults of ECRHS II. Int J Hyg Environ Health 2007;210(6):691–700. [16] Wyler C, Braun-Fahrlander C, Kunzli N, et al. Exposure to motor vehicle traffic and allergic sensitization. The Swiss Study on Air Pollution and Lung Diseases in Adults (SAPALDIA) Team. Epidemiology 2000;11(4):450–6. [17] Polosa R, Salvi S, Di Maria GU. Allergic susceptibility associated with diesel exhaust particle exposure: clear as mud. Arch Environ Health 2002;57(3):188–93. [18] Delfino RJ, Quintana PJ, Floro J, et al. Association of FEV1 in asthmatic children with personal and microenvironmental exposure to airborne particulate matter. Environ Health Perspect 2004;112(8):932–41.
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[19] Raizenne M, Neas LM, Damokosh AI, et al. Health effects of acid aerosols on North American children: pulmonary function. Environ Health Perspect 1996;104(5):506–14. [20] Balmes JR, Fine JM, Sheppard D. Symptomatic bronchoconstriction after short-term inhalation of sulfur dioxide. Am Rev Respir Dis 1987;136(5):1117–21. [21] Kreit JW, Gross KB, Moore TB, et al. Ozone-induced changes in pulmonary function and bronchial responsiveness in asthmatics. J Appl Physiol 1989;66(1):217–22. [22] Higgins BG, Francis HC, Yates CJ, et al. Effects of air pollution on symptoms and peak expiratory flow measurements in subjects with obstructive airways disease. Thorax 1995; 50(2):149–55. [23] Lagorio S, Forastiere F, Pistelli R, et al. Air pollution and lung function among susceptible adult subjects: a panel study. Environ Health 2006;5:11. [24] Morrow PE, Utell MJ. Responses of susceptible subpopulations to nitrogen dioxide. Res Rep Health Eff Inst 1989;23:1–45. [25] Gauderman WJ, Vora H, McConnell R, et al. Effect of exposure to traffic on lung development from 10 to 18 years of age: a cohort study. Lancet 2007;369(9561):571–7. [26] Rojas-Martinez R, Perez-Padilla R, Olaiz-Fernandez G, et al. Lung function growth in children with long-term exposure to air pollutants in Mexico City. Am J Respir Crit Care Med 2007;176(4):377–84. [27] Ackermann-Liebrich U, Leuenberger P, Schwartz J, et al. Lung function and long term exposure to air pollutants in Switzerland. Study on Air Pollution and Lung Diseases in Adults (SAPALDIA) Team. Am J Respir Crit Care Med 1997;155(1):122–9. [28] Downs SH, Schindler C, Liu LJ, et al. Reduced exposure to PM10 and attenuated agerelated decline in lung function. N Engl J Med 2007;357(23):2338–47. [29] Avol EL, Gauderman WJ, Tan SM, et al. Respiratory effects of relocating to areas of differing air pollution levels. Am J Respir Crit Care Med 2001;164(11):2067–72. [30] von Klot S, Wolke G, Tuch T, et al. Increased asthma medication use in association with ambient fine and ultrafine particles. Eur Respir J 2002;20(3):691–702. [31] Gilliland FD, Berhane K, Rappaport EB, et al. The effects of ambient air pollution on school absenteeism due to respiratory illnesses. Epidemiology 2001;12(1):43–54. [32] Pope CA III, Bates DV, Raizenne ME. Health effects of particulate air pollution: time for reassessment? Environ Health Perspect 1995;103(5):472–80. [33] Romieu I, Ramirez-Aguilar M, Sienra-Monge JJ, et al. GSTM1 and GSTP1 and respiratory health in asthmatic children exposed to ozone. Eur Respir J 2006. [34] Romieu I, Sienra-Monge JJ, Ramirez-Aguilar M, et al. Genetic polymorphism of GSTM1 and antioxidant supplementation influence lung function in relation to ozone exposure in asthmatic children in Mexico City. Thorax 2004;59(1):8–10. [35] Zeka A, Sullivan JR, Vokonas PS, et al. Inflammatory markers and particulate air pollution: characterizing the pathway to disease. Int J Epidemiol 2006;35(5):1347–54. [36] Li YF, Gauderman WJ, Avol E, et al. Associations of tumor necrosis factor G-308A with childhood asthma and wheezing. Am J Respir Crit Care Med 2006;173(9):970–6. [37] McConnell R, Berhane K, Gilliland F, et al. Asthma in exercising children exposed to ozone: a cohort study. Lancet 2002;359(9304):386–91. [38] McConnell R, Berhane K, Yao L, et al. Traffic, susceptibility, and childhood asthma. Environ Health Perspect 2006;114(5):766–72. [39] Penard-Morand C, Charpin D, Raherison C, et al. Long-term exposure to background air pollution related to respiratory and allergic health in schoolchildren. Clin Exp Allergy 2005;35(10):1279–87. [40] Zmirou D, Gauvin S, Pin I, et al. Traffic related air pollution and incidence of childhood asthma: results of the Vesta case-control study. J Epidemiol Community Health 2004;58(1):18–23. [41] Shofer S, Chen TM, Gokhale J, et al. Outdoor air pollution: counseling and exposure risk reduction. Am J Med Sci 2007;333(4):257–60. [42] Mar TF, Jansen K, Shepherd K, et al. Exhaled nitric oxide in children with asthma and shortterm PM2.5 exposure in Seattle. Environ Health Perspect 2005;113(12):1791–4.
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[43] Millstein J, Gilliland F, Berhane K, et al. Effects of ambient air pollutants on asthma medication use and wheezing among fourth-grade school children from 12 Southern California communities enrolled in The Children’s Health Study. Arch Environ Health 2004;59(10): 505–14. [44] Rundell KW, Spiering BA, Baumann JM, et al. Bronchoconstriction provoked by exercise in a high-particulate-matter environment is attenuated by montelukast. Inhal Toxicol 2005; 17(2):99–105. [45] Gong H Jr, Linn WS, Shamoo DA, et al. Effect of inhaled salmeterol on sulfur dioxide– induced bronchoconstriction in asthmatic subjects. Chest 1996;110(5):1229–35. [46] Koenig JQ, Dumler K, Rebolledo V, et al. Theophylline mitigates the bronchoconstrictor effects of sulfur dioxide in subjects with asthma. J Allergy Clin Immunol 1992;89(4):789–94. [47] Meng YY, Rull RP, Wilhelm M, et al. Living near heavy traffic increases asthma severity. Policy Brief (UCLA Cent Health Policy Res) 2006;1–5. [48] Lwebuga-Mukasa JS, Oyana T, Thenappan A, et al. Association between traffic volume and health care use for asthma among residents at a U.S.-Canadian border crossing point. J Asthma 2004;41(3):289–304. [49] Lin S, Munsie JP, Hwang SA, et al. Childhood asthma hospitalization and residential exposure to state route traffic. Environ Res 2002;88(2):73–81. [50] Venn AJ, Lewis SA, Cooper M, et al. Living near a main road and the risk of wheezing illness in children. Am J Respir Crit Care Med 2001;164(12):2177–80. [51] Ciccone G, Forastiere F, Agabiti N, et al. Road traffic and adverse respiratory effects in children. SIDRIA Collaborative Group. Occup Environ Med 1998;55(11):771–8. [52] Reponen T, Grinshpun SA, Trakumas S, et al. Concentration gradient patterns of aerosol particles near interstate highways in the Greater Cincinnati airshed. J Environ Monit 2003;5(4):557–62. [53] Sahsuvaroglu T, Arain A, Kanaroglou P, et al. A land use regression model for predicting ambient concentrations of nitrogen dioxide in Hamilton, Ontario, Canada. J Air Waste Manag Assoc 2006;56(8):1059–69. [54] English P, Neutra R, Scalf R, et al. Examining associations between childhood asthma and traffic flow using a geographic information system. Environ Health Perspect 1999;107(9): 761–7. [55] Nicolai T, Carr D, Weiland SK, et al. Urban traffic and pollutant exposure related to respiratory outcomes and atopy in a large sample of children. Eur Respir J 2003;21(6): 956–63. [56] Kramer U, Koch T, Ranft U, et al. Traffic-related air pollution is associated with atopy in children living in urban areas. Epidemiology 2000;11(1):64–70. [57] Morgenstern V, Zutavern A, Cyrys J, et al. Respiratory health and individual estimated exposure to traffic-related air pollutants in a cohort of young children. Occup Environ Med 2007;64(1):8–16. [58] Smargiassi A, Berrada K, Fortier I, et al. Traffic intensity, dwelling value, and hospital admissions for respiratory disease among the elderly in Montreal (Canada): a case-control analysis. J Epidemiol Community Health 2006;60(6):507–12. [59] Kim JJ, Smorodinsky S, Lipsett M, et al. Traffic-related air pollution near busy roads: the East Bay Children’s Respiratory Health Study. Am J Respir Crit Care Med 2004;170(5): 520–6. [60] Holguin F, Flores S, Ross Z, et al. Traffic-related exposures, airway function, inflammation, and respiratory symptoms in children. Am J Respir Crit Care Med 2007;176(12):1236–42. [61] Venn A, Lewis S, Cooper M, et al. Local road traffic activity and the prevalence, severity, and persistence of wheeze in school children: combined cross sectional and longitudinal study. Occup Environ Med 2000;57(3):152–8. [62] Wilkinson P, Elliott P, Grundy C, et al. Case-control study of hospital admission with asthma in children aged 5–14 years: relation with road traffic in north west London. Thorax 1999;54(12):1070–4.
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[63] Lewis SA, Antoniak M, Venn AJ, et al. Secondhand smoke, dietary fruit intake, road traffic exposures, and the prevalence of asthma: a cross-sectional study in young children. Am J Epidemiol 2005;161(5):406–11. [64] O’neill MS, Jerrett M, Kawachi I, et al. Health, wealth, and air pollution: advancing theory and methods. Environ Health Perspect 2003;111(16):1861–70. [65] Ising H, Lange-Asschenfeldt H, Lieber GF, et al. Respiratory and dermatological diseases in children with long-term exposure to road traffic immissions. Noise Health 2003;5(19): 41–50. [66] Ising H, Lange-Asschenfeldt H, Moriske HJ, et al. Low frequency noise and stress: bronchitis and cortisol in children exposed chronically to traffic noise and exhaust fumes. Noise Health 2004;6(23):21–8.
Immunol Allergy Clin N Am 28 (2008) 589–602
Obesity and Asthma E. Rand Sutherland, MD, MPH National Jewish Medical and Research Center and University of Colorado, 1400 Jackson Street, J220, Denver, CO 80206, USA
Over the last two decades, the convergence of secular trends indicating increases in the prevalence of obesity and asthma has led to a hypothesis that these two disorders might be related. Data from the 1999–2002 National Health and Nutrition Examination Survey (NHANES) indicate that 65% of U.S. adults greater than 20 years of age are overweight or obese [1], a 10% increase when compared with the 1988 through 1994 period [2]. Although asthma affects a smaller proportion of the U.S. population than does obesity and recent data suggest asthma prevalence may not be increasing as rapidly as in the past, the age-adjusted asthma prevalence of 7.9% reported based on 2005 National Health Interview Survey data [3] is more than twice that reported in 1984–1986 National Ambulatory Medical Care Survey data [4]. Although the mechanisms underlying a putative relationship between obesity and asthma have not been fully described, a relatively mature body of literature suggests that obesity increases the risk of incident asthma [5]. Obesity may also skew prevalent asthma toward a more difficult-to-control phenotype [6] and alter response to therapy [7,8]. Despite these emerging data, much remains to be elucidated [9], leading some to question whether the two disorders are related [10]. This review addresses studies that could be interpreted as supporting the hypothesis that obesity leads to asthma. We evaluate animal studies that provide biological underpinnings to an association between the two disorders and clinical and epidemiologic studies that suggest that the relationship between these two disorders is clinically important. Obesity and asthma incidence and prevalence Cross-sectional and case-control studies in children and adults have demonstrated an increased prevalence of asthma in obese individuals [11–19]. Support: NIH HL090982. E-mail address:
[email protected] 0889-8561/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.iac.2008.03.003 immunology.theclinics.com
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Representative of these studies is the study by Sin and colleagues [18], who used data from 16,692 participants (age R17 years) in the Third National Health and Nutrition Evaluation Survey (NHANES III). The investigators categorized body mass index (BMI, defined as kg/m2) into quintiles and evaluated the relationship between BMI quintile and self-reported asthma, degree of airflow limitation, and rescue bronchodilator use. In their analysis, individuals in the highest BMI quintile had the greatest odds of self-reported asthma (odds ratio [OR], 1.50; 95% confidence interval [CI], 1.24–1.81). There was a trend for increasing odds of asthma as BMI increased (P ¼ .001 for the trend), with similar findings of increased rescue bronchodilator use as BMI increased. These clinical outcomes were not associated with a similar trend toward increasing airflow limitation as BMI increased. Beckett and colleagues [11] used data from 4547 participants in the Coronary Artery Risk Development in Young Adults study of 18- to 30-year-old subjects. In this analysis, there was no association between increasing baseline BMI quintile and baseline asthma prevalence (P ¼ .74 for difference between quintiles), but elevated BMI at baseline was associated with an increased subsequent risk of developing asthma, with a hazard rate ratio of 1.6 (95% CI, 1.12–2.30) in the highest BMI quintile compared with the reference quintile. Many of these cross-sectional and case-control studies benefit from the ability to evaluate large numbers of subjects and have provided important insights into the epidemiology of the two disorders. A potential limitation of studies of thousands of subjects is a limited capacity to carefully phenotype participants with regard to the exposure and outcome variables, and many of these studies relied on self-reported weight and height to determine BMI or self-reported asthma diagnosis to ascertain cases of asthma, raising the possibility of inaccuracies or biases related to reporting. This limitation does not apply to all epidemiologic studies of the obesity–asthma relationship, however, and in studies that used measured rather than self-reported height and weight to define BMI [11,14,17] there was a significant association between elevated BMI and asthma. Perhaps more limiting with regard to the generalizability of many of these studies is the use of a self-reported physician’s diagnosis of asthma rather than formal physiologic evaluation to determine cases, particularly because respiratory symptoms classified as asthma could be dyspnea due to obesity-related physiologic impairment [20,21]. Prospective studies have often included more rigorous definitions of asthma in their study populations [22–28] and as a group introduce the additional benefit of being able to assess whether pre-existing obesity is associated with a subsequent increase in asthma risk. Most have shown a steady dose–response relationship with an elevation in incident asthma as BMI increases, and most demonstrate the effect to be stronger in women than in men. Many of these longitudinal studies control for diet and physical activity, strengthening the conclusion that it is obesity,
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and not a lack of exercise or a dietary factor, that is associated with asthma. For example, Camargo and colleagues [22] performed a prospective analysis of the relationship between BMI and asthma in a study of 85,911 women followed for 4 years. In their multivariate model, the relative risk of incident asthma increased as BMI across six categories, with relative risks ranging from 0.9 (lowest BMI group) to 2.7 (highest BMI group; P value for trend !.001). This study differed from some other prospective studies in its enrollment of women only and in the use of self-reported height and weight, but other prospective studies by Ford [24] and Nystad and colleagues [27], which included men and women and used a definition of BMI that was based on measured weight and height, found associations between elevated BMI and incident asthma of similar strength. Some of these prospective studies have suggested that the relationship between obesity and asthma is stronger in women, leading to the hypothesis that this effect may be modified by estrogen or another sex-based biologic difference. However, the difference in the point estimates of effect between men and women is usually small, and some studies have shown conflicting results. For example, in Chen and colleagues’ [23] 2002 Canadian National Population Health Survey study, the incidence of asthma was associated with the degree of baseline adiposity in women but not in men, but two other prospective studies [25,29] demonstrated that the association between obesity and asthma was similar in men and women. In children, Castro-Rodrı´ guez and colleagues [30] showed that although there was no association between BMI and asthma at age 6, the development of overweight or obesity between age 6 and 11 was associated with a sevenfold increased risk of new asthma symptoms, and the effect was strongest among girls beginning puberty before age 11. Finally, in adult postmenopausal women, exogenous estrogen in the form of hormone replacement therapy has been associated with an increased risk of asthma [31], and a recent study showed that the association between BMI and asthma severity was stronger in women with early menarche than in women without early menarche [32]. Although potential mechanisms underlying an association between sex hormones and asthma are being explored [33–36], the importance of these models in the obesity–asthma relationship in humans remains to be determined. The majority of prospective studies have reported that obesity is a risk factor for the development of a new diagnosis of asthma, with risk or odds ratios of between 1.1 and 3.0 comparing the highest with lowest BMI categories, with the suggestion of a stronger effect in women. When this heterogeneity of effect was examined in a meta-analysis of studies investigating overweight and obesity as a risk factor for incident asthma, the authors concluded that, overall, overweight and obesity increased the odds of incident asthma in a dose-dependent manner and that the strength of this relationship was similar in men and women. Random-effects meta-analysis
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of data from seven studies (n ¼ 333,102) indicated that, compared with normal weight, overweight and obesity were associated with an increased odds of incident asthma (OR, 1.51; 95% CI, 1.27–1.80). A dose–response effect of elevated BMI on asthma risk was observed; the OR for incident asthma comparing normal weight versus overweight (BMI 25–29.9) was 1.38 (95% CI, 1.17–1.62) versus 1.92 (95% CI, 1.43–2.59) comparing normal weight with obesity (BMI R 30), with P ! .0001 for the trend. A similar increase in the odds of incident asthma due to overweight and obesity was observed in men (OR, 1.46; 95% CI, 1.05–2.02) and women (OR, 1.68; 95% CI, 1.45–1.94) [5]. Some studies call the strength of obesity as an asthma risk. For example, in the community-based cohort study of Hasler and colleagues [37], which followed 591 adults between the ages of 20 and 40, asthma was significantly associated with obesity cross sectionally (OR, 3.9; 95% CI, 1.2–12.2), but a multivariate analysis revealed that obesity was not a risk factor for subsequent asthma; rather, asthma was a risk factor for subsequent obesity. The pediatric literature also suggests a relationship between body mass and asthma risk with regard to asthma and atopy, a principal asthma risk factor in children. For example, in a prospective study of 9828 children age 6 to 14 who were followed for a median of 5 years, Gold and colleagues [38] reported that for girls, higher BMI at entry and a greater increase in BMI over the study were associated with a higher risk of asthma, with a 2.2 times greater risk of asthma in the highest versus lowest BMI quintile in girls. In boys and girls enrolled in the study, greater increases in BMI over the course of the study were associated with an elevated risk of asthma. A report from the Children’s Health Study echoed the dose-dependence of increased BMI and asthma risk, with overweight (BMI 25–29.9) and obesity (BMI R 30) increasing the risk of incident asthma (OR, 1.52; 95% CI, 1.14–2.03 and OR, 1.60; 95% CI, 1.08–2.36, respectively), with obese boys having an increased risk of asthma compared with girls [39]. As in adults, not all studies of children show a significant association between obesity and asthma. Chinn and Rona [40] reported that in a group of British school children, the annualized odds of developing asthma was 1.09 95% CI, 1.07– 1.11) for boys and girls, a number that did not change significantly when adjusting for BMI. The relationship between obesity and atopy in children seems to be less robust than the relationship between obesity and asthma, as evidenced by data from pediatric participants in NHANES III. In unadjusted analyses, the prevalence of asthma and atopy increased with increasing BMI, but after adjusting for confounding factors, only the relationship between BMI and asthma remained significant (OR, 1.77; 95% CI, 1.44–2.19) [41]. In a study from Hancox and colleagues [42], elevated BMI was modestly but significantly (OR, 1.14; 95% CI, 1.10–1.30) associated with positive skin tests and elevated IgE; this relationship was not seen in boys.
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Obesity and asthma severity Compared with large-scale epidemiologic studies, there have been fewer reports of the effect of elevated body mass on biomarkers of asthma impairment and risk in well-characterized study populations. Although studies have suggested that health status is impaired in obese individuals with asthma [43], it is not clear if this due to increased airway inflammation, altered pulmonary physiology, or other variables that could influence health status. In children, a report from the Childhood Asthma Management Program suggested that there was no statistically significant relationship between BMI and many markers of asthma control, including school absenteeism, emergency department care, requirement for corticosteroids, or hospitalizations. BMI did not seem to affect eosinophil counts or IgE concentrations, and although there was a weak inverse relationship between BMI and bronchodilator reversibility (b ¼ 0.003; P ¼ .02), there was no impact of BMI on airway hyperresponsiveness (AHR) to methacholine [44]. The generalizability of these data is somewhat limited by the observation that most participants were pre-pubertal and that the median BMI was 17.09. A recent study by Santamaria and colleagues [45] evaluated a population more obese (50 children with a BMIO95th percentile) than that in CAMP, and although there was a high prevalence of atopy (58%) in the study population, significant differences were not found between lean and obese participants with regard to exhaled nitric oxide (FeNO) concentrations (a biomarker of airway inflammation) independent of and adjusted for the diagnosis of atopy or asthma. There are conflicting data about whether obesity makes prevalent asthma severe. The observation that obesity is associated with a more severe asthma phenotype has been supported in part by data from the TENOR study of patients who have severe asthma, in which the mean BMI in adults with severe asthma was 30.4 kg/m2 [6]. However, a recent report from the Severe Asthma Research Program investigators [46] indicated that obesity was not more prevalent in severe [47] than in moderate asthma, raising some uncertainty about the importance of obesity as a modifier of asthma severity. This clinical controversy has perhaps been further underscored by recent studies that fail to demonstrate a robust relationship between obesity and biomarkers of airway inflammation in adults who have asthma. In an evaluation of lung function and spirometry in 297 patients who had asthma across the BMI spectrum, there was an inverse relationship between BMI and FeNO in unadjusted analyses (rS ¼ 0.307; P ! .001) and in analyses adjusted for age, forced expiratory volume in 1 second (FEV1), sex, concurrent atopy, and inhaled corticosteroid use [48]. McLachlan and colleagues [49] reported similar findings in a population-based cohort of approximately 1000 individuals, demonstrating that although adiposity (reflected in percentage of body fat) was associated with asthma and airflow limitation in women, there was no meaningful association between FeNO or adiposity
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in women or men. Todd and colleagues [50] used induced sputum cell counts as an alternative means of assessing airway inflammation in 727 obese subjects with and without asthma. Although sputum eosinophil counts were higher overall in subjects who had asthma, there was no significant correlation between BMI and sputum eosinophils in participants who had asthma or in the study population as a whole. Although these data are not conclusive, in aggregate they seem to suggest that biomarkers of airway inflammation do not necessarily increase as body mass increases in subjects who have asthma. Obesity and pulmonary physiology Obesity has well-described effects on lung function, with physiologic studies suggesting that obesity has important mechanical effects that can lead to symptoms of dyspnea without causing the pathophysiologic changes commonly observed in asthma. Alterations in airflows, respiratory system compliance, lung volumes, peripheral airway diameter, and AHR have been described in obesity. Obesity causes airflow limitation, with reduction of FEV1 and forced vital capacity (FVC) [51]. Unlike asthma, these reductions in airflow are typically symmetric and result in a preserved FEV1/FVC ratio [18]. Some authors have shown that the FEV1/FVC ratio is increased in obesity, consistent with a restrictive physiology [51]. Reductions in absolute airflows are accompanied by a reduction in respiratory system compliance due to a combination of excess soft tissue weight compressing the thoracic cage, fatty infiltration of the chest wall, and increased pulmonary blood volume [52–55]. These alterations of pulmonary physiology lead obese individuals to breathe shallowly near their closing volume [56], which may be one cause of the observed subjective increase in dyspnea [18]. Lung volumes, particularly the expiratory reserve volume and functional residual capacity (FRC) [51,57], are also reduced in obesity. The reductions in lung volumes observed in obese individuals are associated with a reduction in peripheral airway diameter [58], a phenomenon that over time perturbs smooth muscle function, potentially increasing airway obstruction and AHR [59]. The available clinical data on obesity and AHR are conflicting. In the European Community Respiratory Health Survey, AHR increased with increasing BMI in men but not in women [60], and in a case-control study from participants in the Normative Aging Study, high initial BMI was associated with the development of AHR to methacholine (OR, 10; 95% CI, 2.6–37.9) when subjects in the highest BMI quintile were compared with those in the middle BMI quintile. There was also a linear relationship between increasing BMI over the study period and the subsequent development of AHR [61]. In contrast, Schachter and colleagues [62] showed that in a group of 1971 adults, BMI was associated with a diagnosis of asthma and symptoms of
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dyspnea and wheeze but was not associated with airflow obstruction or AHR. Another study from this group showed that elevated BMI was a risk factor for wheeze and cough but not AHR or the diagnosis of asthma in a study population of almost 6000 children [63]. Therefore, although obesity leads to a number of physiologic perturbations that could cause respiratory symptoms, physiologic studies do not uniformly support the conclusion that obesity leads to increases in AHR. Medical weight loss studies in patients who have asthma have demonstrated that weight loss can lead to improvements in clinical and physiologic parameters. In an observational study of 14 obese patients who had asthma before and after an 8-week very-low-calorie diet, weight loss reduced diurnal peak flow variability, increased FRC, and improved measures of airflow limitation [64]. In a similarly designed, 6-month medical weight loss study of 58 obese women (24 of whom had asthma), weight loss improved lung function as measured by FEV1 and FVC but did not affect methacholine responsiveness [65]. In a study of two groups of 19 patients who had obesity and asthma, the group randomized to supervised medical weight loss demonstrated improved lung function, asthma symptoms, and health status when compared with control subjects [66]. In a more substantial clinical weightloss setting, studies of patients undergoing surgical weight-loss operations have demonstrated substantial improvements in physiologic parameters such as expiratory reserve volume and FRC, along with improvements in total lung capacity, residual volume [67], and respiratory muscle function [68].
Systemic and airway inflammation in obesity In a subset of obese individuals, obesity is associated with a systemic proinflammatory state [69], which has been implicated in a number of the metabolic and cardiovascular complications of obesity. Whether this environment can lead to the development of airway inflammation and asthma in humans is not known, but a number of observations suggest that obesity might affect the lung by modulating airway inflammation. Much of the literature focusing on the relationship between obesity, airway inflammation, and asthma has focused on the role of leptin. Leptin, the product of the Ob gene, is a central mediator of inflammation in obesity and has been shown to regulate T-cell proliferation and activation, to recruit and activate monocytes and macrophages, and to promote angiogenesis [70]. Leptin is also important for normal lung development, serving as a critical mediator of the differentiation of lipofibroblasts to normal fibroblasts and of pulmonary surfactant phospholipid synthesis [71]. Exogenous leptin has been shown to modulate allergic airway responses in mice, independent of obesity. Shore and colleagues [72] sensitized and challenged lean BALB/cJ mice with ovalbumin and infused saline or leptin subcutaneously. Leptin infusion led to increased serum leptin levels and was
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associated with an enhancement of AHR and an increase in serum IgE after inhaled ovalbumin challenge, responses not observed in animals challenged with inhaled phosphate-buffered saline. There was no effect of leptin administration on bronchoalveolar lavage (BAL) fluid cell counts or lung tissue cytokine mRNA expression. Endogenous leptin levels can be increased by overfeeding wild-type lean mice, leading to obesity and enhancing the airway inflammatory response. Overfed mice that were sensitized and challenged with ovalbumin had higher antigen-induced T-cell responses, increased mitogen-induced splenocyte interferon-g production, and increased numbers of tracheal mast cells compared with lean control mice, although ovalbumin-specific immunoglobulin levels were reduced in obese mice versus lean control mice [73]. These studies suggest that leptin seems to have an important immunomodulatory role that is relevant to airway function and immune response, independent of body mass. The relationship between obesity and enhanced airway inflammation cannot be attributed solely to leptin because the obese leptin-deficient ob/ob mouse demonstrates enhanced airway immune response. In a study of airway response to ozone, Shore and colleagues [74] exposed lean wild-type C57BL/6J mice and obese ob/ob mice to ozone, after which AHR and airway inflammation were evaluated. Exposed ob/ob mice had enhanced AHR when compared with lean control mice, and although BAL levels of eotaxin (an eosinophil chemoattractant) were increased, a predominantly Th1 inflammatory phenotypic response was observed in the ob/ob mouse, with elevated BAL levels of interleukin (IL)-6 and the neutrophil chemoattractants MIP-2 and KC. In this study, a subset of lean and obese mice was given intraperitoneal injections of leptin before and directly after ozone exposure, and although leptin administration did not further enhance inflammatory responses in the ob/ob mice, leptin significantly increased BAL levels of IL-6 and KC in lean control mice. This suggests that the mechanisms by which exogenous leptin alters airway immune response might vary between obese and lean animals, depending on factors such as endogenous leptin concentrations, receptor number or affinity, or other concurrent modifications of inflammatory pathways. A recent set of experiments from Johnston and colleagues [75] evaluated AHR and other relevant biomarkers of airway inflammation after ovalbumin sensitization and challenge in wild-type (lean) mice, ob/ob mice, and db/db mice (deficient in the leptin receptor but with normal leptin concentrations). Innate AHR was increased in ob/ob mice when compared with wildtype mice, and ovalbumin sensitization and challenge further enhanced AHR in ob/ob mice and induced a nearly twofold greater increase in serum IgE in ob/ob mice than that observed in wild-type mice. Although AHR and serum IgE were increased in the obese mice when compared with lean wildtype control mice, commensurate increases in eosinophil counts and Th2 cytokine expression were not observed; in fact, lower levels of these biomarkers were seen in the obese mice. The authors concluded that although
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allergic sensitization increased pulmonary resistance and serum IgE, these alterations could not be attributed to the induction of a Th2 inflammatory profile in the airway. Obesity as a modifier of therapeutic response in asthma In obesity, systemic inflammation [69] may not only increase asthma risk but may also interfere with response to controller therapies, particularly inhaled corticosteroids. Many of the cytokines and other mediators found to be elevated in obesity-related systemic inflammation (eg, leptin, tumor necrosis factor [TNF]-a, IL-6, and C-reactive protein) have been reported to mediate the development of glucocorticoid (GC) resistance in asthma [76]. Emerging clinical data suggest that there is the potential for an interrelationship between obesity-related systemic inflammation and glucocorticoid resistance because TNF-a and IL-6 have been reported to be up-regulated in lung macrophages from patients who had glucocorticoid-resistant asthma [77], suggesting that the cytokine environment described in obesity may modify therapeutic response to GCs. In this regard, two recent reports [7,8] indicate that overweight and obese patients who have asthma may not respond as well as their lean counterparts to inhaled GCs, the most effective asthma controller therapy [78,79]. Peters-Golden and colleagues [8], in a post hoc analysis of clinical trials randomizing subjects to beclomethasone, montelukast, or placebo, reported that clinical response to beclomethasone (as reflected by asthma control days, a composite of rescue b-agonist use, nighttime awakenings, and concurrent asthma exacerbation) was reduced as BMI increased, a trend not observed with montelukast. Significant differences with regard to lung function (measured as FEV1) and rescue b-agonist use were not demonstrated, and in all BMI strata there was a numerically greater response to beclomethasone than to montelukast versus placebo, although these differences did not achieve statistical significance in overweight and obese participants. A separate post hoc analysis by Boulet and Franssen [7] also demonstrated a reduction in asthma control achieved in response to fluticasone as BMI increased; their pooled analysis of 1242 patients who had asthma allocated to fluticasone (100 mg twice daily) or fluticasone/salmeterol (100 mg/50 mg twice daily) suggested that, with both forms of asthma controller therapy, obese patients who had asthma were less likely to achieve asthma control than were those who were not obese. The elevations in TNF-a observed in obesity may be relevant to the treatment of obese patients who have asthma. A recent clinical trial demonstrated that increased expression of membrane-bound TNF-a, TNF-a receptor 1, and TNF-a–converting enzyme in peripheral blood mononuclear cells from patients who had severe asthma were associated with GC insensitivity [47]. This study also suggested a beneficial effect of soluble TNF-a receptor etanercept in these patients, as shown by improvements in AHR, FEV1, and
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asthma-related quality of life [80], raising the possibility that controller agents other than corticosteroids may be effective in obese patients who have asthma in whom systemic inflammation and GC insensitivity are shown to be important factors.
Summary Although emerging data are beginning to shed light on the nature of the obesity–asthma relationship, much work remains to be done. Longitudinal epidemiologic investigations suggest that there is an association between the two disorders, with obesity increasing an individual’s risk of developing asthma. In studies of carefully phenotyped prevalent asthma, the impact of BMI on asthma status seems to be modest. Careful phenotyping studies in matched cohorts of subjects with and without asthma and obesity are needed to describe how airway physiologic and inflammatory phenotypes are modified by obesity. Although animal models have the potential to expand our understanding, a continued emphasis on well-characterized animal models with regard to the interaction of obesity, environmental exposures (eg, allergen, infection), genetics, host factors (eg, sex hormones), and airway inflammation is needed to guide further hypothesis development and testing in humans. Clinical investigators should conduct studies to identify the most appropriate interventions and outcomes with which to optimize care for this important subset of patients who have asthma.
References [1] Hedley AA, Ogden CL, Johnson CL, et al. Prevalence of overweight and obesity among US children, adolescents, and adults, 1999–2002. JAMA 2004;291:2847–50. [2] Flegal KM, Carroll MD, Kuczmarski RJ, et al. Overweight and obesity in the United States: prevalence and trends, 1960–1994. Int J Obes Relat Metab Disord 1998;22:39–47. [3] Schiller JS, Martinez M, Barnes P. Early release of selected estimates based on data from the January–June 2005 National Health Interview Survey. National Center for Health Statistics; 2005. Available at: http://www.cdc.gov/nchs/nhis.htm. Accessed May 19, 2008. [4] Mannino DM, Homa DM, Pertowski CA, et al. Surveillance for asthma–United States, 1960–1995. MMWR CDC Surveill Summ 1998;47:1–27. [5] Beuther DA, Sutherland ER. Overweight, obesity, and incident asthma: a meta-analysis of prospective epidemiologic studies. Am J Respir Crit Care Med 2007;175:661–6. [6] Dolan CM, Fraher KE, Bleecker ER, et al. Design and baseline characteristics of the epidemiology and natural history of asthma: Outcomes and Treatment Regimens (TENOR) study: a large cohort of patients with severe or difficult-to-treat asthma. Ann Allergy Asthma Immunol 2004;92:32–9. [7] Boulet LP, Franssen E. Influence of obesity on response to fluticasone with or without salmeterol in moderate asthma. Respir Med 2007;101:2240–7. [8] Peters-Golden M, Swern A, Bird SS, et al. Influence of body mass index on the response to asthma controller agents. Eur Respir J 2006;27:495–503. [9] Weiss ST, Shore S. Obesity and asthma: directions for research. Am J Respir Crit Care Med 2004;169:963–8.
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[10] Wilson MM, Irwin RS. The association of asthma and obesity: is it real or a matter of definition, Presbyterian minister’s salaries, and earlobe creases? Arch Intern Med 1999;159: 2513–4. [11] Beckett WS, Jacobs DR Jr, Yu X, et al. Asthma is associated with weight gain in females but not males, independent of physical activity. Am J Respir Crit Care Med 2001;164:2045–50. [12] Cassol VE, Rizzato TM, Teche SP, et al. Obesity and its relationship with asthma prevalence and severity in adolescents from southern Brazil. J Asthma 2006;43:57–60. [13] Chen Y, Dales R, Krewski D, et al. Increased effects of smoking and obesity on asthma among female Canadians: the National Population Health Survey, 1994–1995. Am J Epidemiol 1999;150:255–62. [14] Guerra S, Sherrill DL, Bobadilla A, et al. The relation of body mass index to asthma, chronic bronchitis, and emphysema. Chest 2002;122:1256–63. [15] Luder E, Ehrlich RI, Lou WY, et al. Body mass index and the risk of asthma in adults. Respir Med 2004;98:29–37. [16] Ronmark E, Andersson C, Nystrom L, et al. Obesity increases the risk of incident asthma among adults. Eur Respir J 2005;25:282–8. [17] Shaheen SO, Sterne JA, Montgomery SM, et al. Birth weight, body mass index and asthma in young adults. Thorax 1999;54:396–402. [18] Sin DD, Jones RL, Man SF. Obesity is a risk factor for dyspnea but not for airflow obstruction. Arch Intern Med 2002;162:1477–81. [19] Young SY, Gunzenhauser JD, Malone KE, et al. Body mass index and asthma in the military population of the northwestern United States. Arch Intern Med 2001;161:1605–11. [20] Beuther DA, Sutherland ER. Obesity and pulmonary function testing. J Allergy Clin Immunol 2005;115:1100–1. [21] Beuther DA, Weiss ST, Sutherland ER. Obesity and asthma. Am J Respir Crit Care Med 2006;174:112–9. [22] Camargo CA Jr, Weiss ST, Zhang S, et al. Prospective study of body mass index, weight change, and risk of adult-onset asthma in women. Arch Intern Med 1999;159:2582–8. [23] Chen Y, Dales R, Tang M, et al. Obesity may increase the incidence of asthma in women but not in men: longitudinal observations from the Canadian National Population Health Surveys. Am J Epidemiol 2002;155:191–7. [24] Ford ES, Mannino DM, Redd SC, et al. Body mass index and asthma incidence among USA adults. Eur Respir J 2004;24:740–4. [25] Gunnbjornsdottir MI, Omenaas E, Gislason T, et al. Obesity and nocturnal gastro-oesophageal reflux are related to onset of asthma and respiratory symptoms. Eur Respir J 2004;24: 116–21. [26] Huovinen E, Kaprio J, Laitinen LA, et al. Incidence and prevalence of asthma among adult Finnish men and women of the Finnish Twin Cohort from 1975 to 1990, and their relation to hay fever and chronic bronchitis. Chest 1999;115:928–36. [27] Nystad W, Meyer HE, Nafstad P, et al. Body mass index in relation to adult asthma among 135,000 Norwegian men and women. Am J Epidemiol 2004;160:969–76. [28] Romieu I, Avenel V, Leynaert B, et al. Body mass index, change in body silhouette, and risk of asthma in the E3N cohort study. Am J Epidemiol 2003;158:165–74. [29] Huovinen E, Kaprio J, Koskenvuo M. Factors associated to lifestyle and risk of adult onset asthma. Respir Med 2003;97:273–80. [30] Castro-Rodriguez JA, Holberg CJ, Morgan WJ, et al. Increased incidence of asthmalike symptoms in girls who become overweight or obese during the school years. Am J Respir Crit Care Med 2001;163:1344–9. [31] Troisi RJ, Speizer FE, Willett WC, et al. Menopause, postmenopausal estrogen preparations, and the risk of adult-onset asthma: A prospective cohort study. Am J Respir Crit Care Med 1995;152:1183–8. [32] Varraso R, Siroux V, Maccario J, et al. Asthma severity is associated with body mass index and early menarche in women. Am J Respir Crit Care Med 2005;171:334–9.
600
SUTHERLAND
[33] Hamano N, Terada N, Maesako K, et al. Effect of female hormones on the production of IL-4 and IL-13 from peripheral blood mononuclear cells. Acta Otolaryngol Suppl 1998; 537:27–31. [34] Hamano N, Terada N, Maesako K, et al. Effect of sex hormones on eosinophilic inflammation in nasal mucosa. Allergy Asthma Proc 1998;19:263–9. [35] Hellings PW, Vandekerckhove P, Claeys R, et al. Progesterone increases airway eosinophilia and hyper-responsiveness in a murine model of allergic asthma. Clin Exp Allergy 2003;33: 1457–63. [36] Salem ML, Matsuzaki G, Kishihara K, et al. beta-estradiol suppresses T cell-mediated delayed-type hypersensitivity through suppression of antigen-presenting cell function and Th1 induction. Int Arch Allergy Immunol 2000;121:161–9. [37] Hasler G, Gergen PJ, Ajdacic V, et al. Asthma and body weight change: a 20-year prospective community study of young adults. Int J Obes (Lond) 2006;30:1111–8. [38] Gold DR, Damokosh AI, Dockery DW, et al. Body-mass index as a predictor of incident asthma in a prospective cohort of children. Pediatr Pulmonol 2003;36:514–21. [39] Gilliland FD, Berhane K, Islam T, et al. Obesity and the risk of newly diagnosed asthma in school-age children. Am J Epidemiol 2003;158:406–15. [40] Chinn S, Rona RJ. Can the increase in body mass index explain the rising trend in asthma in children? Thorax 2001;56:845–50. [41] von Mutius E, Schwartz J, Neas LM, et al. Relation of body mass index to asthma and atopy in children: the National Health and Nutrition Examination Study III. Thorax 2001;56: 835–8. [42] Hancox RJ, Milne BJ, Poulton R, et al. Sex differences in the relation between body mass index and asthma and atopy in a birth cohort. Am J Respir Crit Care Med 2005;171:440–5. [43] Vortmann M, Eisner MD. BMI and health status among adults with asthma. Obesity (Silver Spring, MD) 2008;16:146–52. [44] Tantisira KG, Litonjua AA, Weiss ST, et al. Association of body mass with pulmonary function in the Childhood Asthma Management Program (CAMP). Thorax 2003;58: 1036–41. [45] Santamaria F, Montella S, De Stefano S, et al. Asthma, atopy, and airway inflammation in obese children. J Allergy Clin Immunol 2007;120:965–7. [46] Wenzel SE, Busse WW. Severe asthma: lessons from the Severe Asthma Research Program. J Allergy Clin Immunol 2007;119:14–21. [47] Proceedings of the ATS workshop on refractory asthma: current understanding, recommendations, and unanswered questions. Am J Respir Crit Care Med 2000;162:2341–51. [48] Barros R, Moreira A, Fonseca J, et al. Obesity and airway inflammation in asthma. J Allergy Clin Immunol 2006;117:1501–2. [49] McLachlan CR, Poulton R, Car G, et al. Adiposity, asthma, and airway inflammation. J Allergy Clin Immunol 2007;119:634–9. [50] Todd DC, Armstrong S, D’Silva L, et al. Effect of obesity on airway inflammation: a crosssectional analysis of body mass index and sputum cell counts. Clin Exp Allergy 2007;37: 1049–54. [51] Biring MS, Lewis MI, Liu JT, et al. Pulmonary physiologic changes of morbid obesity. Am J Med Sci 1999;318:293–7. [52] Barrera F, Hillyer P, Ascanio G, et al. The distribution of ventilation, diffusion, and blood flow in obese patients with normal and abnormal blood gases. Am Rev Respir Dis 1973;108: 819–30. [53] Fadell EJ, Richman AD, Ward WW, et al. Fatty infiltration of respiratory muscles in the Pick-wickian syndrome. N Engl J Med 1962;266:861–3. [54] Naimark A, Cherniack RM. Compliance of the respiratory system and its components in health and obesity. J Appl Physiol 1960;15:377–82. [55] Zerah F, Harf A, Perlemuter L, et al. Effects of obesity on respiratory resistance. Chest 1993; 103:1470–6.
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[56] Hedenstierna G, Santesson J, Norlander O. Airway closure and distribution of inspired gas in the extremely obese, breathing spontaneously and during anaesthesia with intermittent positive pressure ventilation. Acta Anaesthesiol Scand 1976;20:334–42. [57] Bedell GN, Wilson WR, Seebohm PM. Pulmonary function in obese persons. J Clin Invest 1958;37:1049–60. [58] Rubinstein I, Zamel N, DuBarry L, et al. Airflow limitation in morbidly obese, nonsmoking men. Ann Intern Med 1990;112:828–32. [59] Fredberg JJ, Inouye DS, Mijailovich SM, et al. Perturbed equilibrium of myosin binding in airway smooth muscle and its implications in bronchospasm. Am J Respir Crit Care Med 1999;159:959–67. [60] Chinn S, Jarvis D, Burney P. Relation of bronchial responsiveness to body mass index in the ECRHS. European Community Respiratory Health Survey. Thorax 2002;57:1028–33. [61] Litonjua AA, Sparrow D, Celedon JC, et al. Association of body mass index with the development of methacholine airway hyperresponsiveness in men: the Normative Aging Study. Thorax 2002;57:581–5. [62] Schachter LM, Salome CM, Peat JK, et al. Obesity is a risk for asthma and wheeze but not airway hyperresponsiveness. Thorax 2001;56:4–8. [63] Schachter LM, Peat JK, Salome CM. Asthma and atopy in overweight children. Thorax 2003;58:1031–5. [64] Hakala K, Stenius-Aarniala B, Sovijarvi A. Effects of weight loss on peak flow variability, airways obstruction, and lung volumes in obese patients with asthma. Chest 2000;118: 1315–21. [65] Aaron SD, Fergusson D, Dent R, et al. Effect of weight reduction on respiratory function and airway reactivity in obese women. Chest 2004;125:2046–52. [66] Stenius-Aarniala B, Poussa T, Kvarnstrom J, et al. Immediate and long term effects of weight reduction in obese people with asthma: randomised controlled study. BMJ 2000; 320:827–32. [67] Thomas PS, Cowen ER, Hulands G, et al. Respiratory function in the morbidly obese before and after weight loss. Thorax 1989;44:382–6. [68] Weiner P, Waizman J, Weiner M, et al. Influence of excessive weight loss after gastroplasty for morbid obesity on respiratory muscle performance. Thorax 1998;53:39–42. [69] Fantuzzi G. Adipose tissue, adipokines, and inflammation. J Allergy Clin Immunol 2005; 115:911–9. [70] Sierra-Honigmann MR, Nath AK, Murakami C, et al. Biological action of leptin as an angiogenic factor. Science 1998;281:1683–6. [71] Torday JS, Sun H, Wang L, et al. Leptin mediates the parathyroid hormone-related protein paracrine stimulation of fetal lung maturation. Am J Physiol Lung Cell Mol Physiol 2002; 282:L405–10. [72] Shore SA, Schwartzman IN, Mellema MS, et al. Effect of leptin on allergic airway responses in mice. J Allergy Clin Immunol 2005;115:103–9. [73] Bantel H, Schmitz ML, Raible A, et al. Critical role of NF-kappaB and stress-activated protein kinases in steroid unresponsiveness. FASEB J 2002;16:1832–4. [74] Shore SA, Rivera-Sanchez YM, Schwartzman IN, et al. Responses to ozone are increased in obese mice. J Appl Physiol 2003;95:938–45. [75] Johnston RA, Zhu M, Rivera-Sanchez YM, et al. Allergic airway responses in obese mice. Am J Respir Crit Care Med 2007;176:650–8. [76] Webster JC, Oakley RH, Jewell CM, et al. Proinflammatory cytokines regulate human glucocorticoid receptor gene expression and lead to the accumulation of the dominant negative beta isoform: a mechanism for the generation of glucocorticoid resistance. Proc Natl Acad Sci U S A 2001;98:6865–70. [77] Hauk PJ, Goleva E, Liu AH, et al. Corticosteroid resistant asthma is associated with classical activation of airway macrophages and exposure to lipopolysaccharide [abstract #749]. J Allergy Clin Immunol 2006;117:S194.
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[78] National Heart, Lung, and Blood Institute; National Asthma Education and Prevention Program. Expert Panel Report 3: guidelines for the diagnosis and management of asthma. Bethesda (MD): National Heart, Lung, and Blood Institute; 2007. [79] Global Initiative for Asthma. 2006 Global strategy for asthma management and prevention. Available at: http://www.ginasthma.org. Accessed December 5, 2007. [80] Berry MA, Hargadon B, Shelley M, et al. Evidence of a role of tumor necrosis factor alpha in refractory asthma. N Engl J Med 2006;354:697–708.
Immunol Allergy Clin N Am 28 (2008) 603–629
Dietary Factors and the Development of Asthma Augusto A. Litonjua, MD, MPH Channing Laboratory and Pulmonary and Critical Care Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115, USA
Asthma and related allergic diseases are substantial public health problems worldwide [1,2]. Data from the United States Centers for Disease Control indicate that the self-reported prevalence of asthma in the United States increased 73.9% from1980 to 1996 [1]. In 2002, estimates from the National Health Interview Survey revealed that 72 people per 1000, or 20 million people, have asthma in the United States [3]. Worldwide, it is clear that more affluent westernized countries and countries making the transition to a westernized lifestyle have higher prevalence of asthma compared with less developed countries [2]. Although recent findings suggest that the prevalence of asthma may have reached a ‘‘plateau’’ in most industrialized countries [4–8], there are no clear reasons for the increase in prevalence of asthma and allergies in these developed countries. It is likely that a changing environment and the behaviors associated with a ‘‘westernized’’ lifestyle are contributing to the problem. It is postulated, for example, that, because of improvements in hygiene and control of infectious disease, decreased exposure to infectious agents in early childhood may predispose to the development of asthma and allergies [9]. Thus, some studies have shown that exposure to markers associated with such infectious agents as endotoxin [10], farm animals [11], and pets [12] may decrease the risk of these disorders. Other factors associated with a western lifestyle and implicated in the development of these conditions include obesity [13] and exposure to allergens [14]. Another aspect of this lifestyle is the change in diet that has occurred. This article briefly discusses this change, describes how diet is evaluated in epidemiologic studies, and summarizes existing data relating
Dr. Litonjua is funded by grants R01AI056230, R01AG027014, and R21HL089842 from the National Institutes of Health. E-mail address:
[email protected] 0889-8561/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.iac.2008.03.005 immunology.theclinics.com
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diet with asthma. There have been a number of comprehensive reviews of this topic [15–17]. This article updates these with recent studies, where available. Additionally, in the past 5 years, new information has surfaced regarding the association of early-life diet and nutrition on subsequent asthma [18,19]. This article reviews these studies, with an emphasis on effects of maternal diet in pregnancy.
Dietary changes in westernized countries In 1994, Seaton and colleagues highlighted changes in the United Kingdom diet that had preceded and paralleled the increase in asthma and atopic disease [19,20]. They observed that there had been a decrease in vegetable consumption, particularly of potatoes and green vegetables, and suggested that a westernized diet, increasingly deficient in antioxidants, had increased population susceptibility with consequent large increases in the prevalence of asthma and allergy. In the United States, recent analyses have shown that fruit and vegetable consumption remains low [21,22] despite public health efforts to improve overall diet quality [23]. It is postulated that decreased dietary antioxidant intake leads to reduced antioxidant defenses in the lung, leading to increased oxidative stress with increased susceptibility to airway inflammation and asthma [24]. Aside from antioxidants, intake of fats, particularly the changing composition of polyunsaturated fatty acids (PUFAs) in western diets, has been implicated in asthma. In 1997, Black and Sharpe [25] reviewed the changes in dietary intake of fats as a result of public health efforts to reduce the incidence of coronary heart disease, and suggested that the changing composition of PUFAs played a role in the increase in asthma and allergies. In westernized countries, including the United States, the reduction in intake of saturated fat was accompanied by an increase in consumption of n6 PUFAs, particularly linoleic acid and arachidonic acid, through increased use of margarine and vegetable oils (instead of butter and lard) [26,27]. In addition, there has also been a decrease in consumption of oily fish, a rich source of n3 PUFAs, such as eicosapentaenoic acid and docosahexaenoic acid. Thus, the hypothesis is that the increased ratio of n6:n3 PUFAs in westernized diet may have contributed to the increased asthma incidence.
The assessment of diet in epidemiologic studies Several methods are used to assess dietary exposures in epidemiologic studies (Table 1) [28]. The most commonly used methods include 24-hour recall interviews [29], diet records [29], food-frequency questionnaires [30,31], and measurements of nutrient biomarkers [32]. Trained interviewers administer 24-hour recall interviews and ask subjects to report everything they had to eat or drink in the past 24-hour period [29]. This method
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Table 1 Methods for assessment of diet and nutrition in epidemiologic studies Method
Pro(s) and con(s)
24-hour recall
Pro: relatively precise (recent memory); relatively low participant burden Con: may not reflect long-term diet; requires well-trained interviewers; nutrient analysis may be laborious Pro: precise record of intake over several days; recall error and bias are reduced because of prospective nature Con: requires high level of subject literacy and motivation; may not capture long-term diet Pro: applicable to large cohorts; assesses long-term diet; ease of administration allows for repeat measurements to capture changes in diet over time; provides information on large numbers of foods; relatively cheap to analyze and calculate nutrients Con: population-specific; food list needs to be validated in a particular population to ensure that main foods are captured Pro: precise measure of short-term status, depending on nutrient and nutrient half-life; may be the only reliable measurement of nutrient exposure Con: invasive; requires collection of biological sample (blood, hair, nail)
Diet record
Food-frequency questionnaire
Biomarker
depends on the short-term memory of the subject. The interview may be conducted over the telephone or in person, and it is important to have skilled interviewers to probe for additional foods and to do so in a neutral manner so as not to influence the subjects’ responses. With properly trained interviewers, high-quality dietary information can be collected. However, the use of such interviewers is expensive and impractical for large-scale epidemiologic studies. Interactive, computer-based 24-hour recall software programs are being developed to circumvent these limitations [33]. The food-record or food-diary method is similar to the 24-hour recall method, except that subjects record actual food and drink intake prospectively on 1 or more days [29]. Food records are quantified by asking the subject to either weigh the foods or determine volume using common household measuring tools. Assistance may be provided by the use of photographs. This prospective record minimizes reliance on memory and does not require trained interviewers. However, this method requires a reasonably high level of subject literacy and motivation, and requires some level of training in recording complete and accurate food intake. Furthermore, food records done on consecutive days may be correlated and may introduce bias in the measurement. Both the 24-hour recall and the food-record methods may not capture seasonal variation of diet or may not reflect usual long-term diets.
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These limitations may be reduced by performing these measurements on multiple days over several months of the year. Food-frequency questionnaires are the most frequently used method for many epidemiologic studies [30,31]. They consist of a list of foods and beverages that represent the major contributors to the diet of the population being studied and a frequency response to report how often each food is consumed. Food-frequency questionnaires should be validated for a particular population or ethnicity because lists of foods and beverages may be specific to a particular group (eg, young children usually eat a more limited variety of foods compared with adults; recent immigrants tend to seek out foods native to their country of origin). Food-frequency questionnaires are easily administered in person or mailed to subjects. They provide information on usual intake of a large number of foods, food groups, and supplements; are substantially less expensive than other methods of dietary assessment; and can be administered repeatedly over several years to capture diet changes over time. From responses to the questionnaire, individual nutrient intake can be calculated based on the known nutrient content of foods. Alternatively, analyses based on usual intake of foods taken directly from the responses to the questionnaires (ie, frequency of intake of fruits and vegetables) can also be performed. Biochemical markers of dietary intake are also commonly used in epidemiologic studies [32]. In many cases, these biomarkers are used to validate information obtained from food-frequency questionnaires. However, they are also used to indicate the status of the individual with regard to the nutrient of interest. In the case of some nutrients, biochemical indicators are the only reliable markers of nutrient status. For example, because selenium content of soil varies from area to area, the selenium content of similar foods obtained from different places can vary up to 100-fold. While these biomarkers can be considered as unbiased indicators of nutrient intake, many issues must be considered before using them for analyses of diet– disease associations. Biomarkers must accurately reflect nutrient intake, but this is not always the case, as genetic variation, lifestyle factors, and intake of other nutrients, among many other considerations [32], may affect the level of the nutrient of interest. Additionally, knowledge of the halflife of the biomarker is necessary for interpretation of findings (ie, shortterm versus long-term exposure). Evidence for the association between diet and asthma Many studies have examined the association between various nutrients or foods and asthma and asthma-related phenotypes, such as lung function, airway responsiveness, and symptoms. Most of these studies have been cross-sectional in design with a few prospective studies, and have been conducted in adults or in older children. Tables 2 and 3 summarize selected studies that have investigated dietary factors in relation to lung function,
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asthma, and asthma-related symptoms. Studies that had large numbers of subjects were included, with emphasis on more recent findings, when available. Comprehensive tabular summaries are available in other recent reviews [16,17]. Antioxidants Oxidative stress plays a central role in asthma pathogenesis [24] and dietary antioxidants improve oxidant defenses [34] against free radicals. Antioxidants, namely vitamin C, vitamin E, carotenoids, and flavonoids, have been the most widely studied nutrients with regard to asthma and allergies, either as individual nutrients or in analyses assessing fruit and vegetable intake. Vitamin C is found in vegetables (red and green peppers, broccoli, tomatoes, potatoes, and spinach), fruits (oranges, tangerines, strawberries, cantaloupes), and fruit juices [35]. Vitamin E is also found in fruits (apples and mangos), vegetables, vegetable oils, meat, poultry, nuts, and eggs [36]. The most abundant carotenoids in the North American diet are beta-carotene, alpha-carotene, gamma-carotene, lycopene, beta-cryptoxanthin, and lutein-zeaxanthin. Food sources of carotenoids include carrots, sweet potatoes, spinach, kale, collard greens, and tomatoes [37]. Flavonoids, a large family of compounds synthesized by plants, have a wide range of biologic activities, including antioxidant activities, participation in cell signaling pathways, and activities related to decreasing inflammation [38]. Flavonoids are found in fruits, vegetables, teas, soybeans, and legumes. In general, observational studies have shown a protective effect of these antioxidants on atopy and either lung-function asthma diagnosis or wheeze (see Tables 2 and 3). However, results across studies have differed, with some studies showing effects with one antioxidant and others showing effects with another. Most of these studies were cross-sectional and the few longitudinal studies [39–41] have also shown some protective effects of dietary antioxidants on asthma or lung-function decline. Several intervention studies with antioxidants have also been conducted. A randomized placebo-controlled trial of vitamin C and magnesium supplementation for 16 weeks in 300 asthmatics on inhaled corticosteroids did not show any benefit on lung function, methacholine airway responsiveness, peak flows, or symptom scores [42]. A second study from the same group showed that supplementation with vitamin C but not magnesium had modest steroidsparing effects in 92 asthmatics [43]. In a randomized placebo-controlled trial of vitamin E supplementation for 6 weeks in 72 asthma patients, no evidence of clinical benefit was found [44]. Several small trials have shown protective effects of vitamin C [45,46], beta-carotene [47], and lycopene [48] on either exercise-induced bronchoconstriction or exercise-induced lung-function decrements. Antioxidants given together may work better than individual supplementation, and there is evidence to suggest that antioxidants protect against
Cohort or country
Dietary assessment method
Antioxidant vitamins, carotenoids, and minerals NHANES I, United States Schwartz & Weiss [125]
2526 adults; cross-sectional
Food-frequency questionnaires and 24-hour recall
Chuwers et al [126]
CARET, United States
816 adult men with asbestos exposure; cross-sectional
Food-frequency questionnaires; serum b-carotene and retinol
Hu & Cassano [127]
NHANES III, United States
18,162 adults; cross-sectional
Hu et al [128]
69 counties in rural China
3085 adults; cross-sectional
24-hour recall; serum vitamins C and E, b-carotene and selenium 3-day weighed records; plasma vitamin C from pooled samples
Britton et al [129]
Nottingham, United Kingdom
2633 adults; cross-sectional
Food-frequency questionnaires
Association Positive association between dietary vitamin C intake and FEV1; no association between vitamin C–rich vegetables and lung function Positive association between serum b-carotene and both FEV1 and FVC; weak positive association between serum retinol and both FEV1 and FVC; no association between intakes of these nutrients from food-frequency questionnaires and lung function Positive associations between dietary and serum antioxidants and FEV1 Positive associations between dietary vitamin C and both FEV1 and FVC; pooled plasma vitamin C levels were positively associated with county mean FEV1 Positive associations between vitamin C and vitamin E and both FEV1 and FVC; intakes of vitamin C and E were correlated and there was no effect of vitamin E independent of vitamin C
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Population and study design
Investigators
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Table 2 Selected epidemiologic studies relating dietary factors with lung function or airway hyperresponsiveness
Southampton, United Kingdom
178 elderly men and women; cross-sectional
Food-frequency questionnaires
Butland et al [131]
Wales, United Kingdom
2512 men; cross-sectional
Food-frequency questionnaires
Ness et al [132]
East Anglia, United Kingdom
835 men and 1025 women; cross-sectional
Plasma vitamin C
Grievink et al [133]
MORGEN Study, Netherlands
6555 adults; cross-sectional
Food-frequency questionnaires
Tabak et al [134]
Finland, Italy, and Netherlands
Middle-aged men from Finland (n ¼ 1248), Italy (n ¼ 1386), and Netherlands (n ¼ 691); cross-sectional
Diet history
Carey et al [39]
Health and Lifestyle Survey, United Kingdom
2171 British adults; longitudinal (7-y follow-up)
Food-frequency questionnaires
Britton et al [79]
Nottingham, United Kingdom
2415 adults
Food-frequency questionnaires
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Positive associations between vitamin E and both FEV1 and FVC; no association for vitamin C and lung function In multivariable models, positive association between vitamin E and FEV1; no associations between intakes of vitamin C, magnesium, and b-carotene with FEV1; Positive association between intake of apples and FEV1 Positive associations between plasma vitamin C and both FEV1 and FVC in men only Positive associations between dietary vitamin C and b-carotene and both FEV1 and FVC; no associations for dietary vitamin E and lung function; vitamin E associated with productive cough; b-carotene associated with wheeze Positive associations between vitamin C and b-carotene and both FEV1 and FVC; positive association between vitamin E and FEV1 in Finnish men only Subjects who decreased fruit consumption had greatest FEV1 decline over 7 years Subjects with higher magnesium intake had decreased airway responsiveness
DIETARY FACTORS AND THE DEVELOPMENT OF ASTHMA
Dow et al [130]
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Table 2 (continued ) Cohort or country
Population and study design
Dietary assessment method
McKeever et al [41]
Nottingham, United Kingdom
2633 subjects; cross-sectional and longitudinal (follow-up on 1346 subjects after 9 y)
Food-frequency questionnaires
Cook et al [135] Vitamin D Black & Scragg [61] Minerals Burney et al [64]
England and Wales
2650 children; cross-sectional
Plasma vitamin C
NHANES III, United States
14,091 adults aged R 20 y
Serum 25(OH)D
Positive associations for 25(OH)D levels and both FEV1 and FVC
Hampshire, United Kingdom
138 men; cross-sectional
24-hour urinary sodium excretion
Pistelli et al [66]
Latium region, Italy
2593 subjects aged 9–16 y; cross-sectional
Dietary questionnaire; urinary sodium and potassium levels
Devereux et al [65]
Northern England
234 male shipyard workers exposed to welding fumes; 121 male rural and 111 male urban dwellers; cross-sectional
24-hour urinary sodium excretion
Increased odds for having PD20 %8 mmol in subjects with greater sodium excretion Positive association with table-salt use and symptoms but not with airway responsiveness; higher urinary potassium but not urinary sodium was associated with airway responsiveness in boys Increased odds for methacholine airways responsiveness with greater sodium excretion among male urban dwellers only
Investigators
Association
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Positive cross-sectional associations between vitamin C and magnesium intakes and FEV1; higher vitamin C intake was associated with slower FEV1 decline; no associations between vitamin A or vitamin E and lung function No association of vitamin C levels with lung function
Normative Aging Study, United States
273 middle-aged to older men; cross-sectional
24-hour urinary sodium and potassium excretion
Gilliland et al [80]
Children’s Health Study, United States
2566 children aged 11–19 y; cross-sectional
Food-frequency questionnaires
Fatty acids McKeever et al [88]
MORGEN-EPIC Study, Netherlands
13,820 adults; cross-sectional
Food-frequency questionnaires
Schwartz & Weiss [84]
NHANES I, United States
2526 adults; cross-sectional
24-hour diet recall
Sharp et al [85]
Honolulu Heart Program, Hawaii, United States
6346 men; cross-sectional
Food-frequency questionnaires
Butland et al [131]
Wales, United Kingdom
2512 men; cross-sectional
Food-frequency questionnaires
Positive relationship between potassium excretion and methacholine airway responsiveness; no association of sodium excretion and airway responsiveness Children with lower magnesium and potassium intakes had lower lung function indices; no effect of sodium intake No association between n-3 fatty acids and FEV1; inverse association between some n-6 fatty acids and FEV1 Small but significant effect of fish intake on FEV1; effect was stronger in nonsmokers; did not distinguish effects of different types of fish Interaction between fish intake and smoking; lower decrements of FEV1 due to smoking among high fish intake No effect of fish intake on lung function
DIETARY FACTORS AND THE DEVELOPMENT OF ASTHMA
Sparrow et al [67]
Abbreviations: 25(OH)D, 25-hydroxyvitamin D; CARET, Carotene and Retinol Efficacy Trial; EPIC, European Prospective Investigation into Cancer and Nutrition Study; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; MORGEN, Monitoring Project on Risk Factors for Chronic Diseases; NHANES, National Health and Nutrition Examination Survey; PD20, dose required to cause a 20% fall in FEV1.
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Table 3 Selected epidemiologic studies relating dietary factors with asthma, asthma-related symptoms, and atopy Investigators
Cohort or country
Population and study design
Dietary assessment method Association
Troisi et al [40]
Nurses Health Study, United States
77,866 nurses; longitudinal
Food-frequency questionnaires
Shaheen et al [138]
Greenwich, South London, United Kingdom
607 cases, 864 controls (adults) Food-frequency questionnaires
Garcia et al [139] Greenwich, South London, United Kingdom
607 cases, 864 controls (adults) Food-frequency questionnaires
Serum vitamin C inversely associated with wheezing and diagnosed bronchitis Higher vitamin E intake was inversely associated with total IgE concentrations and was associated with decreased odds for atopy In adults, a-carotene, b-cryptoxantine, and vitamin E were inversely associated with atopy, but lycopene was positively associated with atopy; vitamin A increased the risk of atopy in children Positive association between vitamin C supplement users and the risk for asthma; dietary vitamin E inversely associated with asthma; b-carotene weakly protective for asthma Consumption of apples was inversely associated with asthma; selenium intake inversely associated with asthma; no association between intakes of vitamins C and E and asthma No association between intake of three major classes of flavonoids and asthma
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Antioxidant vitamins, flavonoids, and minerals Schwartz NHANES II, 9074 adults; cross-sectional 24-hour diet recall & Weiss [136] United States Food-frequency Fogarty Nottingham, 2633 subjects with allergy questionnaires et al [137] United Kingdom skin test results and 2498 subjects with total IgE; cross-sectional McKeever et al NHANES III, 5858 adults and 4428 children Serum levels of United States several nutrients
Greenwich, South London, United Kingdom
2560 children aged 5–10 y; cross-sectional
Food-frequency questionnaires
Chatzi et al [141]
Menorca, Spain
460 children aged 6.5 y: cross-sectional
Food-frequency questionnaires
Chatzi et al [142]
Crete, Greece
690 children aged 7–18 y; cross-sectional
Food-frequency questionnaires
Montreal, Canada
187 cases and 145 controls aged 5–13 y
Food-frequency questionnaires
No association of usual salt intake with asthma or exercise-induced bronchospasm; positive association with methacholine airway hyperresponsiveness
12,345 adults RHINE; Norway, Iceland, Denmark, Estonia, and Sweden
Food-frequency questionnaires
ISAAC-2, Netherlands 598 children aged 8–13 y; cross-sectional
Food-frequency questionnaires
Low current fish intake was associated with greater odds of asthma and wheeze; for intake of cod oil, there was a U-shaped association with asthma Fish intake was inversely associated with current asthma and with atopic asthma with bronchial hyperresponsiveness; intake of whole grains was inversely associated with atopic asthma with bronchial hyperresponsiveness
Sodium Demissie et al [143]
Fatty acids Laerum et al [86]
Tabak et al [87]
Consumption of apple juice and bananas was negatively associated with wheeze but not asthma; fresh apple consumption was not associated with asthma or symptoms Vegetable intake was inversely associated with current wheeze and atopic wheeze; fish intake was inversely associated with atopy Intake of local fruits and tomatoes was inversely associated with wheeze and allergic rhinitis but not atopy; adherence to the Mediterranean diet was inversely associated with allergic rhinitis
DIETARY FACTORS AND THE DEVELOPMENT OF ASTHMA
Okoko et al [140]
Abbreviations: ISAAC, International Study of Asthma and Allergies in Childhood; NHANES, National Health and Nutrition Examination Survey; RHINE, Respiratory Health in Northern Europe.
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exposure to outdoor air pollution, particularly ozone exposure. In a randomized, double-blind crossover study of 47 street workers in Mexico City, supplementation of vitamin C, vitamin E, and beta-carotene protected against ozone-induced decrements in lung function [49]. A study from the same group showed that supplementation with vitamin C and vitamin E attenuated the effects of ambient ozone exposure on lung function indices in Mexican children [50]. In a randomized, double-blind crossover study, 17 adult asthmatics were supplemented with both vitamin C and vitamin E, then exposed to ozone during moderate exercise, after which bronchial provocation testing with sulfur dioxide was performed [51]. Antioxidant supplementation protected against ozone-induced bronchial hyperresponsiveness. Overall, observational studies have shown protective effects of antioxidants on asthma-related phenotypes, but large trials of antioxidant supplementation have not shown any benefit for asthma symptoms or control. McKeever and Britton [16] have discussed issues related to these discrepancies between observation studies and intervention trials. Some of these issues relate to accuracy of measurements of the dietary intakes in observational studies, confounding by other exposures linked with diet, and lack of effectiveness of single-nutrient supplements if other nutrients are important or if foods are more important than the individual nutrient. It is also possible, as the smaller intervention trials show, that antioxidant effects may be seen in only particular subsets of asthmatics (eg, exerciseinduced asthmatics) or in response to specific exposures (eg, ozone exposures). Alternatively, because the intervention trials have been conducted in adults or children who have asthma, they do not address the issue of primary prevention of asthma. Early-life programming leading to predisposition to adult diseases is a growing area of research [52]. It is possible that the effects of dietdincluding all nutrientsdon asthma may occur much earlier in life than researchers have assumed [18]. Studies of diet in early life and related efftects on asthma incidence are reviewed later in this article. Vitamin D Vitamin D is both a nutrient and a hormone. However, unlike usual nutrients, vitamin D does not naturally occur in foods that humans eat, except in oily fish and fish liver oil, egg yolk, and offal [53]. Therefore, most of the vitamin D that we ingest comes from fortified foods (In the United States, milk; some milk products, such as yogurt and margarine; and breakfast cereals are fortified with vitamin D [54,55].) and from supplements. The Institute of Medicine [54] currently recommends intakes of 200 IU/d from birth through age 50 years, 400 IU/d for those aged 51 to 70 years, and 600 IU/d for those over 70 years. However, there is now widespread consensus that these recommendations are woefully
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inadequate for overall health [56]. From an evolutionary standpoint, humans do not require vitamin D in the food supply because it is effectively produced in the skin on exposure to sunlight in the UV-B range. Because people in westernized countries now spend most of their time indoors, it has been postulated that vitamin D deficiency may explain a large portion of the asthma epidemic [57]. Vitamin D may reverse steroid-resistance in asthmatics through induction of IL-10–secreting T-regulatory cells [58], and vitamin D has been shown to regulate expression of many genes in bronchial smooth muscle cells, including genes previously implicated in asthma predisposition and pathogenesis [59]. Two recent analyses have related vitamin D with lung function. The first, published in abstract form, involved 2112 adolescents from 12 cities in the United States and Canada [60] and found that vitamin D intake was inversely associated with lung function. The second study was a cross-sectional analysis of 14,901 adults from the National Health and Nutrition Examination Survey [61]. Circulating serum vitamin D levels (25-hydroxyvitamin D3) were measured from stored samples and subjects with higher vitamin D levels had higher values of forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC). There are no trials of vitamin D supplementation in subjects with asthma. Minerals Sodium In 1987, Burney [62,63] highlighted an association between regional table-salt sales and asthma mortality, and subsequent studies have shown a positive relationship between salt intake and the presence of airway hyperresponsiveness [64,65]. However, this finding has not been universal [66,67]. Thus, it remains unclear whether salt is directly associated with asthma or is merely a marker for a diet that increases the risk for asthma. A recent study suggests that dietary salt loading enhances airway inflammation [68]. A Cochrane Database review of six randomized controlled trials did not find any significant effect of dietary salt restriction on asthma treatment or management [69]. No longitudinal studies have addressed the association between salt intake and development of asthma. Selenium Selenium is a trace mineral involved in antioxidant defenses as a coenzyme of glutathione peroxidase, which recycles glutathione. Plant foods are the major dietary sources of selenium in most countries [70]. Assessment of selenium intake is difficult because the selenium content of the same type of foods varies widely depending on where the food is obtained, owing to the variability in selenium content of soil [32]. Several case-control studies have documented lower selenium blood levels in asthmatic subjects compared with nonasthmatics [71–73]. In a small trial of 12 adult
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asthmatics, selenium supplementation for 14 weeks showed improvement in clinical parameters but not in objective markers of asthma [74]. A recent larger trial of 197 adult asthmatics, most of whom were on inhaled steroids, did not show any clinical benefit of selenium supplementation over 24 weeks [75]. Magnesium Magnesium is a cation with modulatory effects on smooth muscle cell contractility [76], such that hypomagnesemia induces contraction (bronchoconstriction) while hypermagnesemia induces relaxation (bronchodilatation). This potential bronchodilatory property of magnesium has led to its use in emergency department care of acute asthma exacerbations [77]. Green vegetables, such as spinach, are good dietary sources of magnesium [78]. Cross-sectionally, evidence suggests that higher magnesium intakes are associated with decreased airway hyperreponsiveness and symptoms in adults [79] and decreased lung function in children [80]. Clinical trials of supplementation with magnesium (given with vitamin C) did not show any clinical benefit on lung function, symptoms, or on ability to decrease steroid dose in asthmatics [42,43]. Polyunsaturated fatty acids While there is some evidence relating diets rich in saturated fats from milk and dairy products with a reduced risk for asthma in preschool children [81] and young adults [82], most studies have investigated intakes of n3 and n6 PUFAs. The anti-inflammatory role of n3 PUFAs and the proinflammatory role of n6 PUFAs are well documented [83]. Briefly, n6 PUFAs (arachidonic acid and linoleic acid) give rise to the eicosanoid family of mediators (prostaglandins, thromboxanes, leukotrienes, and related metabolites), which have proinflammatory actions and regulate the production of inflammatory cytokines, while n3 PUFAs (eicosapentaenoic acid and docosahexaenoic acid) decrease the production of arachidonic acid–derived eicosanoids and inflammatory cytokines (tumor necrosis factor, IL-6), and decrease the expression of adhesion molecules involved in inflammation. Several large cross-sectional studies have found positive associations between fish intake and lung function [84,85], and inverse associations between fish intake and asthma [86,87]. However, Butland and colleagues did not find any effect of fish intake on lung function in 2512 men. McKeever and colleagues [88] found no association between n3 PUFA intake and lung function, although there were inverse associations between some n6 PUFAs and FEV1. Other recent studies have likewise not found associations between measured n3 PUFAs and asthma [89,90]. Several small trials of fish oil supplementation have shown mixed results [91–94]. Results of trials of fish oil supplementation in the prenatal and early-life period are presented below.
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Prenatal diet and nutrition There is growing recognition that prenatal and early-life exposures, including exposures related to diet and nutrition, may have a role in the development of many adult diseases [52]. Research into the developmental origins of health and disease has focused mainly on obesity, the metabolic syndrome, and cardiovascular disorders, but asthma and other respiratory disorders are also affected by early exposures [95,96]. Despite the difficulty in diagnosing asthma in very young children, the available epidemiologic evidence suggests that about half of all cases of childhood asthma are diagnosed by age 3 years and 80% of all asthma cases are diagnosed by age 6 [97,98]. Thus, it is clear that early-life factors play a role in the inception of the disease. However, identifying the causative early-life factors remains challenging. Smoking in pregnancy, through its effects on lung development in utero, is the only definite prenatal risk factor for asthma that has been identified to date [99]. In the past few years, several studies have been published that have investigated the effects of maternal diet in pregnancy on immune outcomes and wheezing illnesses in young children (Table 4). It has been hypothesized that specific nutrients may exert their effect at the critical time period when the fetal immune system and lung development is occurring [18,57,100]. Devereux and colleagues [101] studied the T helper cell proliferative responses of cord blood mononuclear cells from a sample of 223 neonates from Aberdeen, Scotland, and found that higher maternal intakes of vitamin E were associated with lower cord blood mononuclear proliferative responses to timothy grass and house dust mite, compared with mothers whose intakes were in the lowest tertile of vitamin E. Follow-up of these children in the larger cohort of over 1000 children has found that higher maternal vitamin E intakes were associated with decreased risks for wheezing and asthma in the children at 2 and 5 years of age [102,103]. Maternal vitamin E (both intake during pregnancy and plasma level of a-tocopherol at delivery) was also inversely associated with levels of exhaled nitric oxide (a marker of airway inflammation) and positively associated with postbronchodilator FEV1 in a subset of the 5-year-old children. Additionally, maternal zinc intake was also associated with decreased risks for several asthma-related phenotypes at 5 years. While maternal vitamin C was associated with increased risks for wheezing phenotypes at 2 years, this association disappeared when the children turned 5 years old. In a cohort from Boston, Massachusetts, Litonjua and colleagues [104] similarly found that higher maternal antioxidant intakes (vitamin E and zinc) were also associated with decreased risks of any wheeze and persistent wheeze in 1290 2-year-old children. A subsequent study from the Scottish cohort reported that mothers who consumed more apples and fish in pregnancy had children who were less likely to wheeze [105]. A study of 631 children from Ireland also showed
Investigators
Cohort and country
Antioxidant vitamins and minerals SEATON, Martindale et al [102] Aberdeen, Scotland Devereux SEATON, et al [103] Aberdeen, Scotland
Shaheen et al [107]
Devereux et al [108]
Vitamin D Devereux et al [112]
Project Viva, Boston, Massachusetts, United States ALSPAC, United Kingdom
SEATON, Aberdeen, Scotland, United Kingdom
SEATON, Aberdeen, Scotland, United Kingdom
1374 2-y-old children
Dietary assessment method Food-frequency questionnaire
1253 5-y-old children; Food frequency questionnaire; 478 5-y-old children with lung function maternal measures a-tocopherol levels in pregnancy 1290 children Food-frequency questionnaire
2044 children for wheezing analyses; 2173 children for eczema analyses 1282 2-y-old children and 1167 5-y-old children
1253 5-y-old children
Cord blood levels of trace elements and minerals
Maternal and cord blood plasma selenium and erythrocyte glutathione peroxidase Food-frequency questionnaire
Association Maternal vitamin E intakes were negatively associated with wheeze in the absence of a cold; maternal vitamin C intakes were positively associated with ever wheeze Maternal intakes of vitamin E and zinc were negatively associated with wheeze and asthma in 5-y-old children; maternal plasma a-tocopherol levels were positively associated with FEV1 in the 5-y-old children Maternal intakes of vitamin E and zinc were negatively associated with any wheeze and recurrent wheeze in 2-y-old children Cord blood selenium was negatively associated with persistent wheeze up to 42 months of age; cord blood iron was negatively associated with late-onset wheeze (wheeze occurring at 30–42 mo but not before 6 mo) and eczema at 18–30 mo Maternal and cord blood plasma selenium were inversely associated with wheezing in 2-y-old children; however, maternal and cord blood selenium levels were not associated with asthma or wheeze at 5 y; no associations between erythrocyte glutathione peroxidase and wheezing were found Maternal intakes of vitamin D were negatively associated with ever wheeze, wheeze in the past year, and persistent wheeze in 5-y-old children
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Litonjua et al [104]
Population
618
Table 4 Studies of the association between maternal diet and nutrient status in pregnancy and immune markers, asthma, and asthma-related outcomes in childhood
Camargo et al [111]
1194 children
440 infants for eczema; Maternal 25(OH)D level 178 for asthma
Maternal 25(OH)D levels were positively associated with eczema and asthma, although only univariate associations were presented
Fatty acids Yu et al [118]
Linko¨ping, Sweden
Galli et al [119]
Rome, Italy
68 infants (33 babies Cord blood levels of fatty acids born to allergic mothers and 35 babies born to nonallergic mothers) followed to 6 y 57 infants Cord blood and infant levels of fatty acids
Newson et al [120]
ALSPAC, United Kingdom
Significant correlations between various n-6 fatty acids and between n-3 and n-6 fatty acids were found in cord blood of children who did not develop allergic disease (allergic dermatitis or asthma) by 6 y of age; these correlations were not found in cord blood of children who developed allergic disease by 6 y of age Lower AA and dihomo-gamma-linolenic acid in cord blood among infants who developed atopy (10 eczema and 3 asthma) in the first year of life Cord blood ratio of AA:EPA was positively associated with eczema (at 18–30 mo), ratio of LA:ALA was positively associated with late-onset wheeze (wheeze occurring at 30–42 mo but not before 6 mo), and ratio of ALA:n3 was negatively associated with late-onset wheeze; however, after adjustment for multiple testing, these associations were no longer significant; no associations between maternal red cell fatty acids and infant outcomes
Gale et al [114]
Wheezing analyses: 1191 and 2764 infants for cord and maternal analyses, respectively; eczema analyses: 1238 and 2945 infants for cord blood and maternal analyses, respectively
Food-frequency questionnaire
Maternal and cord blood red cell fatty acid measurements
Maternal intakes of vitamin D were negatively associated with recurrent wheeze; no association with eczema
DIETARY FACTORS AND THE DEVELOPMENT OF ASTHMA
Project Viva, Boston, Massachusetts, United States Southampton, United Kingdom
(continued on next page) 619
620
Table 4 (continued ) Investigators Dunstan et al [124]
Fitzsimon et al
Population
Dietary assessment method
Association
Fish Oil Supplementation Trial, Perth, Australia
Clinical trial of fish oil 83 pregnant supplementation women (40 with in 83 atopic pregnant fish oil women supplementation and 43 with olive oil supplementation) and their 1-y-old children
Reductions in positive skin tests to allergens, although not statistically significant; nonsignificant reduction in risks for recurrent wheeze and asthma
SEATON, Aberdeen, Scotland, United Kingdom Ireland
1253 children
Food-frequency questionnaire
Maternal intakes of apples were negatively associated with wheeze and asthma; maternal intakes of fish were negatively associated with eczema
631 3-y-old children
Food-frequency questionnaires
Maternal intakes of fruits and vegetables were inversely associated with asthma; maternal fat intake increased the risk for asthma
LITONJUA
Foods Willers et al [105]
Cohort and country
Abbreviations: 25(OH)D, 25-hydroxyvitamin D; AA, arachidonic acid; ALA, a-linolenic acid; ALSPAC, Avon Longitudinal Study of Pregnancy and Childhood; EPA, eicosapentaenoic acid, SEATON, Study of Eczema and Asthma To Observe the Effects of Nutrition.
DIETARY FACTORS AND THE DEVELOPMENT OF ASTHMA
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that higher fruit and vegetable intake in pregnancy decreased the risk for asthma by age 3 [106], although it is unclear whether the food-frequency questionnaire was administered to the mothers during pregnancy or at recruitment when the children were 3 years old. That study also found that higher added fats (from butter, margarine, and other spreads; salad dressings; and mayonnaise) in maternal diet in pregnancy increased the risk for asthma in the 3-year-old children. The United Kingdom Avon Longitudinal Study of Pregnancy and Childhood cohort study reported low umbilical cord selenium concentrations to be associated with an increased likelihood of persistent wheeze in 2044 children in the first 42 months of life [107]. The Scottish group also found an inverse relationship between maternal and cord blood plasma selenium and wheeze phenotypes in 2-year-old children, but this relationship disappeared when the children turned 5 years old [108]. There are no published intervention studies of prenatal antioxidant supplementation and asthma in children. Vitamin D is both a nutrient and a hormone, and it is important for immune regulation [109]. Deficiency in vitamin D is widespread and has been postulated to contribute to the rise in asthma [110]. Two birth cohorts have assessed maternal vitamin D intake in pregnancy and wheezing symptoms in 3- to 5-year-old children. In the Boston cohort of 1194 3-year-old children, children born to mothers who had intakes of vitamin D in the highest quartile had significantly decreased risks of recurrent wheezing (odds ratio 0.39; 95% CI 0.25–0.62) compared with children born to mothers in the lowest quartile of vitamin D intake [111]. In the Aberdeen [112] cohort, similar findings were obtained in 1212 children. Children born to mothers with vitamin D intakes in the highest quintile had significantly decreased risks for persistent wheeze (odds ratio 0.33; 95% CI 0.11–0.98) compared with children born to mothers with vitamin D intakes in the lowest quintile. Two other studies have suggested that vitamin D intake increases the risk for asthma. In the Northern Finland Birth Cohort, data on vitamin D supplementation in the first year of life and subsequent asthma and atopy outcomes at 31 years of age were obtained on 7648 subjects [113]. The risk for atopy (odds ratio 1.33; 95% CI 1.07–1.64) and allergic rhinitis (odds ratio 1.33; 95% CI 1.12–1.58) at age 31 years was higher in subjects who had received regular vitamin D supplementation in the first year compared with other subjects. However, there was no assessment of maternal vitamin D intake and no assessment of vitamin D intake in the intervening period between the first year of life and age 31 years. A second study measured circulating vitamin D levels in pregnant women and reported that higher circulating vitamin D levels in pregnant women were associated with increased risks for eczema at 9 months and asthma at 9 years [114]. However, results were reported only in univariate models without adjustment for potential confounders, and there was significant loss to followup in the cohort, especially at 9 years. Thus, the question of whether vitamin D is a protective or a risk factor for asthma in children remains unresolved.
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Future studies will need to account for factors that affect vitamin D levels, such as use of sunscreen, time spent outdoors in the sun, season of the year, and skin color. There are no published intervention studies of vitamin D supplementation in pregnancy. A few studies have related childhood asthma and atopic disease to maternal dietary intake of foods rich in n3-fatty acids (eg, fish intake), but these studies were limited by retrospective recall of diet in pregnancy (eg, mothers were asked to recall diet 5–20 years previously) [115,116]. Several studies have measured cord blood levels of PUFAs and related these to immune responses in cord blood mononuclear cells. Gold and colleagues [117] investigated cord blood PUFA levels in 192 cord blood samples and found that increased cord plasma eicosapentaenoic acid (n-3) and arachidonic acid (n-6) were both associated with decreased proliferative and IFN-g responses, in addition to increased IL-13 responses. Several observational studies of cord blood PUFAs and atopic disease development in childhood have been conducted with variable results [118–120]. More importantly, there have been two intervention studies using fatty acids to prevent asthma or allergies. The first was conducted in the Childhood Asthma Prevention Study [121–123]. In 616 children at risk for atopic disease, the dietary intervention was 500 mg daily of n-3 PUFA–rich fish oil, in addition to n-3–rich oils and spreads for the family, compared with the controls, who received placebo and n-6–rich oils and spreads for the family. This study found a reduction in wheeze symptoms at 18 months [122] but minimal, if any, beneficial effect on asthma or atopic disease at 3 years [121]. The associations were null at 5 years [123]. However, this study applied the intervention postpartum. Dunstan and colleagues [124] supplemented the diets of 40 pregnant atopic women with n-3 PUFA–rich fish oil from 20 weeks’ gestation, and 43 control women received olive oil. Fish oil supplementation was associated with a general reduction in cord blood mononuclear cell cytokine responses (IL-5, IL-10, IL-13, and IFN-g). In addition, maternal supplementation with fish oil was associated with borderline significant reduction in atopic sensitization to egg in 1-year-old children. No further follow-up studies on these children have been published. Summary Changes in diet predating the increases in asthma and allergy that have occurred in westernized countries are postulated to be among the reasons for the asthma epidemic. Many observational studies in adults and children have implicated deficiencies in specific nutrients as potential causes of the asthma and allergy epidemic. However, these have not been borne out in large intervention trials of supplementation with specific nutrients in asthmatics. Smaller trials, specifically with antioxidant supplementation, suggest that the effects may be limited to subsets of asthmatics (eg, exercise-induced
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asthmatics) or as modifiers of the effects of pollutants (eg, ozone). Alternatively, because asthma and allergies have their beginnings in early life, it is likely that nutrients may exert their effects in utero and in very early life, when the immune system and the lungs are not yet fully developed. Several observational studies have shown effects of maternal diet in pregnancy, and two intervention trials on n3 PUFA supplementation have been conducted. More studies are needed to further clarify the effects of diet in early life on the inception of asthma and allergies.
References [1] Mannino DM, Homa DM, Akinbami LJ, et al. Surveillance for asthmadUnited States, 1980–1999. MMWR Surveill Summ 2002;51(1):1–13. [2] Masoli M, Fabian D, Holt S, et al. Global Iniative for Asthma (GINA) Program. The global burden of asthma: executive summary of the GINA Dissemination Committee report. Allergy 2004;59(5):469–78. [3] CDC. Asthma prevalence, health care use, and mortality, 2002. Hyattsville (MD): US Department of Health and Human Services, CDC, National Center for Health Statistics; 2004. [4] Ronchetti R, Villa MP, Barreto M, et al. Is the increase in childhood asthma coming to an end? Findings from three surveys of schoolchildren in Rome, Italy. Eur Respir J 2001;17(5): 881–6. [5] Braun-Fahrlander C, Gassner M, Grize L, et al. No further increase in asthma, hay fever and atopic sensitisation in adolescents living in Switzerland. Eur Respir J 2004;23(3): 407–13. [6] Beasley R, Crane J, Lai CK, et al. Prevalence and etiology of asthma. J Allergy Clin Immunol 2000;105(2 Pt 2):S466–72. [7] Asher MI, Montefort S, Bjorksten B, et al. Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC phases one and three repeat multicountry cross-sectional surveys. Lancet 2006;368(9537):733–43. [8] Pearce N, Ait-Khaled N, Beasley R, et al. Worldwide trends in the prevalence of asthma symptoms: phase III of the International Study of Asthma and Allergies in Childhood (ISAAC). Thorax 2007;62(9):757–65. [9] Strachan DP. Hay fever, hygiene, and household size. BMJ 1989;299(6710):1259–60. [10] Park JH, Gold DR, Spiegelman DL, et al. House dust endotoxin and wheeze in the first year of life. Am J Respir Crit Care Med 2001;163(2):322–8. [11] Braun-Fahrlander C, Gassner M, Grize L, et al. Prevalence of hay fever and allergic sensitization in farmer’s children and their peers living in the same rural community. SCARPOL team. Swiss study on childhood allergy and respiratory symptoms with respect to air pollution. Clin Exp Allergy 1999;29(1):28–34. [12] Remes ST, Castro-Rodriguez JA, Holberg CJ, et al. Dog exposure in infancy decreases the subsequent risk of frequent wheeze but not of atopy. J Allergy Clin Immunol 2001;108(4): 509–15. [13] Tantisira KG, Weiss ST. Complex interactions in complex traits: obesity and asthma. Thorax 2001;56(Suppl 2):ii64–73. [14] Gold DR, Burge H, Carey V, et al. Predictors of repeated wheeze in the first year of life: the relative roles of cockroach, birth weight, acute lower respiratory illness, and maternal smoking. Am J Respir Crit Care Med 1999;160(1):227–36. [15] Fogarty A, Britton J. The role of diet in the aetiology of asthma. Clin Exp Allergy 2000; 30(5):615–27. [16] McKeever TM, Britton J. Diet and asthma. Am J Respir Crit Care Med 2004;170(7):725–9.
624
LITONJUA
[17] Romieu I, Trenga C. Diet and obstructive lung diseases. Epidemiol Rev 2001;23(2): 268–87. [18] Devereux G. Early life events in asthma–diet. Pediatr Pulmonol 2007;42(8):663–73. [19] Devereux G, Seaton A. Diet as a risk factor for atopy and asthma. J Allergy Clin Immunol 2005;115(6):1109–17. [20] Seaton A, Godden DJ, Brown KM. Increase in asthma: a more toxic environment or a more susceptible population? Thorax 1994;49:171–4. [21] Casagrande SS, Wang Y, Anderson C, et al. Have Americans increased their fruit and vegetable intake? The trends between 1988 and 2002. Am J Prev Med 2007;32(4):257–63. [22] Centers for Disease Control and Prevention. Fruit and vegetable consumption among adultsdUnited States, 2005. MMWR Morb Mortal Wkly Rep. 2007;56(10):213–7. [23] Heimendinger J, Van Duyn MA, Chapelsky D, et al. The national 5 a day for better health program: a large-scale nutrition intervention. J Public Health Manag Pract 1996;2(2): 27–35. [24] Riedl MA, Nel AE. Importance of oxidative stress in the pathogenesis and treatment of asthma. Curr Opin Allergy Clin Immunol 2008;8(1):49–56. [25] Black PN, Sharpe S. Dietary fat and asthma: is there a connection? Eur Respir J 1997;10: 6–12. [26] Raper NR, Marston RM. Levels and sources of fat in the US food supply. In: Ip C, editor. Dietary Fat and Cancer. New York: Alan R. Liss; 1986. p. 127–52. [27] Roberts DC. Dietary factors in the fall in coronary heart disease mortality. Prostaglandins Leukot Essent Fatty Acids 1991;44(2):97–101. [28] Willett W. Nutritional Epidemiology. 2nd edition. New York: Oxford University Press; 1998. [29] Buzzard M. 24-Hour dietary recall and food record methods. In: Willett W, editor. Nutritional epidemiology. 2nd edition. New York: Oxford University Press; 1998. p. 50–73. [30] Willett W. Food frequency methods. In: Willett W, editor. Nutritional epidemiology. 2nd edition. New York: Oxford University Press; 1998. p. 74–100. [31] Willett W, Lenart E. Reproducibility and validity of food-frequency questionnaires. In: Willett W, editor. Nutritional epidemiology. 2nd edition. New York: Oxford University Press; 1998. p. 101–47. [32] Hunter DJ. Biochemical indicators of dietary intake. In: Willett W, editor. Nutritional epidemiology. 2nd edition. New York: Oxford University Press; 1998. p. 174–243. [33] Subar AF, Thompson FE, Potischman N, et al. Formative research of a quick list for an automated self-administered 24-hour dietary recall. J Am Diet Assoc 2007;107(6):1002–7. [34] Lesgards JF, Durand P, Lassarre M, et al. Assessment of lifestyle effects on the overall antioxidant capacity of healthy subjects. Environ Health Perspect 2002;110(5):479–86. [35] Ohio State University. Vitamin C. Available at: http://ohioline.osu.edu/hyg-fact/5000/ 5552.html/. Accessed February 14, 2008. [36] Available at: http://ohioline.osu.edu/hyg-fact/5000/5554.html/. Accessed February 14, 2008. [37] National Institutes of Health. Dietary supplement fact sheet: Vitamin A and carotenoids. Available at: http://dietary-supplements.info.nih.gov/factsheets/vitamina.asp/. Accessed February 12, 2008. [38] Linus Pauling Institute. Flavonoids. Available at: http://lpi.oregonstate.edu/infocenter/ phytochemicals/flavonoids/. Accessed February 14, 2008. [39] Carey IM, Strachan DP, Cook DG. Effects of changes in fresh fruit consumption on ventilatory function in healthy British adults. Am J Respir Crit Care Med 1998;158:728–33. [40] Troisi RJ, Willett WC, Weiss ST, et al. A prospective study of diet and adult-onset asthma. Am J Respir Crit Care Med 1995;151:1401–8. [41] McKeever TM, Scrivener S, Broadfield E, et al. Prospective study of diet and decline in lung function in a general population. Am J Respir Crit Care Med 2002;165(9):1299–303.
DIETARY FACTORS AND THE DEVELOPMENT OF ASTHMA
625
[42] Fogarty A, Lewis SA, Scrivener SL, et al. Oral magnesium and vitamin C supplements in asthma: a parallel group randomized placebo-controlled trial. Clin Exp Allergy 2003; 33(10):1355–9. [43] Fogarty A, Lewis SA, Scrivener SL, et al. Corticosteroid sparing effects of vitamin C and magnesium in asthma: a randomised trial. Respir Med 2006;100(1):174–9. [44] Pearson PJ, Lewis SA, Britton J, et al. Vitamin E supplements in asthma: a parallel group randomised placebo controlled trial. Thorax 2004;59(8):652–6. [45] Cohen HA, Neuman I, Nahum H. Blocking effect of vitamin C in exercise-induced asthma. Arch Pediatr Adolesc Med 1997;151(4):367–70. [46] Tecklenburg SL, Mickleborough TD, Fly AD, et al. Ascorbic acid supplementation attenuates exercise-induced bronchoconstriction in patients with asthma. Respir Med 2007; 101(8):1770–8. [47] Neuman I, Nahum H, Ben-Amotz A. Prevention of exercise-induced asthma by a natural isomer mixture of beta-carotene. Ann Allergy Asthma Immunol 1999;82(6):549–53. [48] Neuman I, Nahum H, Ben-Amotz A. Reduction of exercise-induced asthma oxidative stress by lycopene, a natural antioxidant. Allergy 2000;55(12):1184–9. [49] Romieu I, Meneses F, Ramirez M, et al. Antioxidant supplementation and respiratory functions among workers exposed to high levels of ozone. Am J Respir Crit Care Med 1998;158(1):226–32. [50] Romieu I, Sienra-Monge JJ, Ramirez-Aguilar M, et al. Antioxidant supplementation and lung functions among children with asthma exposed to high levels of air pollutants. Am J Respir Crit Care Med 2002;166(5):703–9. [51] Trenga CA, Koenig JQ, Williams PV. Dietary antioxidants and ozone-induced bronchial hyperresponsiveness in adults with asthma. Arch Environ Health 2001;56(3):242–9. [52] Gillman MW. Developmental origins of health and disease. N Engl J Med 2005;353(17): 1848–50. [53] Lamberg-Allardt C. Vitamin D in foods and as supplements. Prog Biophys Mol Biol 2006; 92(1):33–8. [54] Food and Nutrition Board. Institute of Medicine. Dietary reference intakes for calcium, phosphorus, magnesium, vitamin D, and fluoride. Washington, DC: National Academy Press; 1997. [55] Calvo MS, Whiting SJ, Barton CN. Vitamin D fortification in the United States and Canada: current status and data needs. Am J Clin Nutr 2004;80(Suppl 6):1710S–6S. [56] Vieth R, Bischoff-Ferrari H, Boucher BJ, et al. The urgent need to recommend an intake of vitamin D that is effective. Am J Clin Nutr 2007;85(3):649–50. [57] Litonjua AA, Weiss ST. Is vitamin D deficiency to blame for the asthma epidemic? J Allergy Clin Immunol 2007;120(5):1031–5. [58] Xystrakis E, Kusumakar S, Boswell S, et al. Reversing the defective induction of IL-10–secreting regulatory T cells in glucocorticoid-resistant asthma patients. J Clin Invest 2006;116(1):146–55. [59] Bosse Y, Maghni K, Hudson TJ. 1alpha, 25-dihydroxy-vitamin D3 stimulation of bronchial smooth muscle cells induces autocrine, contractility, and remodeling processes. Physiol Genomics 2007;29(2):161–8. [60] Burns JS, Dockery DW, Speizer FE. Low levels of dietary vitamin D intake and pulmonary function in adolescents. Proc Am Thorac Soc 2006;3:A526. [61] Black PN, Scragg R. Relationship between serum 25-hydroxyvitamin D and pulmonary function in the third National Health and Nutrition Examination Survey. Chest 2005; 128(6):3792–8. [62] Burney P. A diet rich in sodium may potentiate asthma. Epidemiologic evidence for a new hypothesis. Chest 1987;91(Suppl 6):143S–8S. [63] Burney P. The causes of asthmadDoes salt potentiate bronchial reactiviey? Discussion paper. J R Soc Med 1987;80:364–7.
626
LITONJUA
[64] Burney PG, Britton JR, Chinn S, et al. Response to inhaled histamine and 24 hour sodium excretion. Br Med J (Clin Res Ed) 1986;292(6534):1483–6. [65] Devereux G, Beach JR, Bromly C, et al. Effect of dietary sodium on airways responsiveness and its importance in the epidemiology of asthma: an evaluation in three areas of northern England. Thorax 1995;50(9):941–7. [66] Pistelli R, Forastiere F, Corbo GM, et al. Respiratory symptoms and bronchial responsiveness are related to dietary salt intake and urinary potassium excretion in male children. Eur Respir J 1993;6(4):517–22. [67] Sparrow D, O’Connor GT, Rosner B, et al. Methacholine airway responsiveness and 24-hour urine excretion of sodium and potassium. The Normative Aging Study. Am Rev Respir Dis 1991;144(3 Pt 1):722–5. [68] Mickleborough TD, Lindley MR, Ray S. Dietary salt, airway inflammation, and diffusion capacity in exercise-induced asthma. Med Sci Sports Exerc 2005;37(6):904–14. [69] Ram FS, Ardern KD. Dietary salt reduction or exclusion for allergic asthma. Cochrane Database Syst Rev 2004;(3):CD000436. [70] National Institutes of Health. Dietary supplement fact sheet: selenium. Available at: http:// dietary-supplements.info.nih.gov/factsheets/selenium.asp/. Accessed February 14, 2008. [71] Stone J, Hinks LJ, Beasley R, et al. Reduced selenium status of patients with asthma. Clin Sci (Lond) 1989;77(5):495–500. [72] Flatt A, Pearce N, Thomson CD, et al. Reduced selenium in asthmatic subjects in New Zealand. Thorax 1990;45(2):95–9. [73] Kadrabova J, Mad’aric A, Kovacikova Z, et al. Selenium status is decreased in patients with intrinsic asthma. Biol Trace Elem Res 1996;52(3):241–8. [74] Hasselmark L, Malmgren R, Zetterstrom O, et al. Selenium supplementation in intrinsic asthma. Allergy 1993;48(1):30–6. [75] Shaheen SO, Newson RB, Rayman MP, et al. Randomised, double blind, placebocontrolled trial of selenium supplementation in adult asthma. Thorax 2007;62(6):483–90. [76] Dominguez LJ, Barbagallo M, Di Lorenzo G, et al. Bronchial reactivity and intracellular magnesium: a possible mechanism for the bronchodilating effects of magnesium in asthma. Clin Sci (Lond) 1998;95(2):137–42. [77] Rowe BH, Camargo CA Jr. The role of magnesium sulfate in the acute and chronic management of asthma. Curr Opin Pulm Med 2008;14(1):70–6. [78] National Institutes of Health. Magnesium. Available at: http://dietary-supplements.info. nih.gov/factsheets/magnesium.asp/. Accessed February 14, 2008. [79] Britton J, Pavord I, Richards K, et al. Dietary magnesium, lung function, wheezing, and airway hyperreactivity in a random adult population sample. Lancet 1994;344(8919): 357–62. [80] Gilliland FD, Berhane KT, Li YF, et al. Dietary magnesium, potassium, sodium, and children’s lung function. Am J Epidemiol 2002;155(2):125–31. [81] Wijga AH, Smit HA, Kerkhof M, et al. Association of consumption of products containing milk fat with reduced asthma risk in pre-school children: the PIAMA birth cohort study. Thorax 2003;58(7):567–72. [82] Woods RK, Walters EH, Raven JM, et al. Food and nutrient intakes and asthma risk in young adults. Am J Clin Nutr 2003;78(3):414–21. [83] Calder PC. Polyunsaturated fatty acids and inflammation. Prostaglandins Leukot Essent Fatty Acids 2006;75(3):197–202. [84] Schwartz J, Weiss ST. The relationship of dietary fish intake to level of pulmonary function in the first National Health and Nutrition Survey (NHANES I). Eur Respir J 1994;7(10): 1821–4. [85] Sharp DS, Rodriguez BL, Shahar E, et al. Fish consumption may limit the damage of smoking on the lung. Am J Respir Crit Care Med 1994;150(4):983–7. [86] Laerum BN, Wentzel-Larsen T, Gulsvik A, et al. Relationship of fish and cod oil intake with adult asthma. Clin Exp Allergy 2007;37(11):1616–23.
DIETARY FACTORS AND THE DEVELOPMENT OF ASTHMA
627
[87] Tabak C, Wijga AH, de Meer G, et al. Diet and asthma in Dutch school children (ISAAC-2). Thorax 2006;61(12):1048–53. [88] McKeever TM, Lewis SA, Cassano PA, et al. The relation between dietary intake of individual fatty acids, FEV1 and respiratory disease in Dutch adults. Thorax 2008;63(3): 208–14. [89] Bolte G, Kompauer I, Fobker M, et al. Fatty acids in serum cholesteryl esters in relation to asthma and lung function in children. Clin Exp Allergy 2006;36(3):293–302. [90] Woods RK, Raven JM, Walters EH, et al. Fatty acid levels and risk of asthma in young adults. Thorax 2004;59(2):105–10. [91] Nagakura T, Matsuda S, Shichijyo K, et al. Dietary supplementation with fish oil rich in omega-3 polyunsaturated fatty acids in children with bronchial asthma. Eur Respir J 2000;16(5):861–5. [92] Moreira A, Moreira P, Delgado L, et al. Pilot study of the effects of n-3 polyunsaturated fatty acids on exhaled nitric oxide in patients with stable asthma. J Investig Allergol Clin Immunol 2007;17(5):309–13. [93] Mickleborough TD, Lindley MR, Ionescu AA, et al. Protective effect of fish oil supplementation on exercise-induced bronchoconstriction in asthma. Chest 2006;129(1):39–49. [94] Mickleborough TD, Murray RL, Ionescu AA, et al. Fish oil supplementation reduces severity of exercise-induced bronchoconstriction in elite athletes. Am J Respir Crit Care Med 2003;168(10):1181–9. [95] Hanrahan JP, Tager IB, Segal MR, et al. The effect of maternal smoking during pregnancy on early infant lung function. Am Rev Respir Dis 1992;145:1129–35. [96] Maritz GS, Morley CJ, Harding R. Early developmental origins of impaired lung structure and function. Early Hum Dev 2005;81(9):763–71. [97] Sherman CB, Tosteson TD, Tager IB, et al. Early childhood predictors of asthma. Am J Epidemiol 1990;132(1):83–95. [98] Yunginger JW, Reed CE, O’Connell EJ, et al. A community-based study of the epidemiology of asthma. Incidence rates, 1964–1983. Am Rev Respir Dis 1992;146(4):888–94. [99] Ng SP, Zelikoff JT. Smoking during pregnancy: subsequent effects on offspring immune competence and disease vulnerability in later life. Reprod Toxicol 2007;23(3):428–37. [100] Devereux G. The increase in the prevalence of asthma and allergy: food for thought. Nat Rev Immunol 2006;6(11):869–74. [101] Devereux G, Barker RN, Seaton A. Antenatal determinants of neonatal responses to allergens. Clin Exp Allergy 2002;32:43–50. [102] Martindale S, McNeill G, Devereux G, et al. Antioxidant intake in pregnancy in relation to wheeze and eczema in the first two years of life. Am J Respir Crit Care Med 2005;171(2): 121–8. [103] Devereux G, Turner SW, Craig LC, et al. Low maternal vitamin E intake during pregnancy is associated with asthma in 5-year-old children. Am J Respir Crit Care Med 2006;174(5): 499–507. [104] Litonjua AA, Rifas-Shiman SL, Ly NP, et al. Maternal antioxidant intake in pregnancy and wheezing illnesses at 2 years of age. Am J Clin Nutr 2006;84:903–11. [105] Willers SM, Devereux G, Craig LC, et al. Maternal food consumption during pregnancy and asthma, respiratory and atopic symptoms in 5-year-old children. Thorax 2007;62(9): 772–8. [106] Fitzsimon N, Fallon U, O’Mahony D, et al. Mothers’ dietary patterns during pregnancy and risk of asthma symptoms in children at 3 years. Ir Med J 2007;100(Suppl 8):27–32. [107] Shaheen SO, Newson RB, Henderson AJ, et al. Umbilical cord trace elements and minerals and risk of early childhood wheezing and eczema. Eur Respir J 2004;24(2):292–7. [108] Devereux G, McNeill G, Newman G, et al. Early childhood wheezing symptoms in relation to plasma selenium in pregnant mothers and neonates. Clin Exp Allergy 2007;37(7):1000–8. [109] Cantorna MT, Zhu Y, Froicu M, et al. Vitamin D status, 1,25-dihydroxyvitamin D3, and the immune system. Am J Clin Nutr 2004;80(Suppl 6):1717S–20S.
628
LITONJUA
[110] Litonjua AA, Weiss ST. Is vitamin D deficiency to blame for the asthma epidemic? J Allergy Clin Immunol 2007;120(5):1031–5. [111] Camargo CA Jr, Rifas-Shiman SL, Litonjua AA, et al. Maternal intake of vitamin D during pregnancy and risk of recurrent wheeze in children at age 3 years. Am J Clin Nutr 2007;85: 788–95. [112] Devereux G, Litonjua AA, Turner S, et al. Maternal vitamin D intake during pregnancy and early childhood wheezing. Am J Clin Nutr 2007;85:853–9. [113] Hypponen E, Sovio U, Wjst M, et al. Infant vitamin D supplementation and allergic conditions in adulthood: northern Finland birth cohort 1966. Ann N Y Acad Sci 2004; 1037:84–95. [114] Gale CR, Robinson SM, Harvey NC, et al. Maternal vitamin D status during pregnancy and child outcomes. Eur J Clin Nutr 2008;62(1):68–77. [115] Salam MT, Li YF, Langholz B, et al. Maternal fish consumption during pregnancy and risk of early childhood asthma. J Asthma 2005;42(6):513–8. [116] Calvani M, Alessandri C, Sopo SM, et al. Consumption of fish, butter and margarine during pregnancy and development of allergic sensitizations in the offspring: role of maternal atopy. Pediatr Allergy Immunol 2006;17(2):94–102. [117] Gold DR, Willwerth BM, Tantisira KG, et al. Associations of cord blood fatty acids with lymphocyte proliferation, IL-13, and IFN-gamma. J Allergy Clin Immunol 2006;117(4): 931–8. [118] Yu G, Kjellman NI, Bjorksten B. Phospholipid fatty acids in cord blood: family history and development of allergy. Acta Paediatr 1996;85(6):679–83. [119] Galli E, Picardo M, Chini L, et al. Analysis of polyunsaturated fatty acids in newborn sera: a screening tool for atopic disease? Br J Dermatol 1994;130(6):752–6. [120] Newson RB, Shaheen SO, Henderson AJ, et al. Umbilical cord and maternal blood red cell fatty acids and early childhood wheezing and eczema. J Allergy Clin Immunol 2004;114(3): 531–7. [121] Peat JK, Mihrshahi S, Kemp AS, et al. Three-year outcomes of dietary fatty acid modification and house dust mite reduction in the childhood asthma prevention study. J Allergy Clin Immunol 2004;114(4):807–13. [122] Mihrshahi S, Peat JK, Marks GB, et al. Eighteen-month outcomes of house dust mite avoidance and dietary fatty acid modification in the Childhood Asthma Prevention Study (CAPS). J Allergy Clin Immunol 2003;111(1):162–8. [123] Almqvist C, Garden F, Xuan W, et al. Omega-3 and omega-6 fatty acid exposure from early life does not affect atopy and asthma at age 5 years. J Allergy Clin Immunol 2007;119(6): 1438–44. [124] Dunstan JA, Mori TA, Barden A, et al. Fish oil supplementation in pregnancy modifies neonatal allergen-specific immune responses and clinical outcomes in infants at high risk of atopy: a randomized, controlled trial. J Allergy Clin Immunol 2003;112(6):1178–84. [125] Schwartz J, Weiss ST. Relationship between dietary vitamin C intake and pulmonary function in the first National Health and Nutrition Examination Survey (NHANES I). Am J Clin Nutr 1994;59:110–4. [126] Chuwers P, Barnhart S, Blanc P, et al. The protective effect of beta-carotene and retinol on ventilatory function in an asbestos-exposed cohort. Am J Respir Crit Care Med 1997; 155(3):1066–71. [127] Hu G, Cassano PA. Antioxidant nutrients and pulmonary function: the third National Health and Nutrition Examination Survey (NHANES III). Am J Epidemiol 2000; 151(10):975–81. [128] Hu G, Zhang X, Chen J, et al. Dietary vitamin C intake and lung function in rural China. Am J Epidemiol 1998;148(6):594–9. [129] Britton JR, Pavord ID, Richards KA, et al. Dietary antioxidant vitamin intake and lung function in the general population. Am J Respir Crit Care Med 1995;151:1292–3.
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[130] Dow L, Tracey M, Villar A, et al. Does dietary intake of vitamins C and E influence lung function in older people? Am J Respir Crit Care Med 1996;154:1401–4. [131] Butland BK, Fehily AM, Elwood PC. Diet, lung function, and lung function decline in a cohort of 2512 middle aged men. Thorax 2000;55:102–8. [132] Ness AR, Khaw KT, Bingham S, et al. Vitamin C status and respiratory function. Eur J Clin Nutr 1996;50:573–9. [133] Grievink L, Smit HA, Ocke MC, et al. Dietary intake of antioxidant (pro)-vitamins, respiratory symptoms, and pulmonary function: the MORGEN study. Thorax 1998;53: 166–71. [134] Tabak C, Smit HA, Rasanen L, et al. Dietary factors and pulmonary function: a cross sectional study in middle aged men from three European countries. Thorax 1999;54:1021–6. [135] Cook DG, Carey IM, Whincup PH, et al. Effect of fresh fruit consumption on lung function and wheeze in children. Thorax 1997;52:628–33. [136] Schwartz J, Weiss ST. Dietary factors and their relation to respiratory symptoms. The second National Health and Nutrition Examination Survey. Am J Epidemiol 1990;132: 67–76. [137] Fogarty A, Lewis S, Weiss ST, et al. Dietary vitamin E, IgE concentrations, and atopy. Lancet 2000;356:1573–4. [138] Shaheen SO, Sterne JAC, Thompson RL, et al. Dietary antioxidants and asthma in adults. Population-based case-control study. Am J Respir Crit Care Med 2001;164:1823–8. [139] Garcia V, Arts IC, Sterne JA, et al. Dietary intake of flavonoids and asthma in adults. Eur Respir J 2005;26(3):449–52. [140] Okoko BJ, Burney PG, Newson RB, et al. Childhood asthma and fruit consumption. Eur Respir J 2007;29(6):1161–8. [141] Chatzi L, Torrent M, Romieu I, et al. Diet, wheeze, and atopy in school children in Menorca, Spain. Pediatr Allergy Immunol 2007;18(6):480–5. [142] Chatzi L, Apostolaki G, Bibakis I, et al. Protective effect of fruits, vegetables and the Mediterranean diet on asthma and allergies among children in Crete. Thorax 2007;62(8): 677–83. [143] Demissie K, Ernst P, Gray Donald K, et al. Usual dietary salt intake and asthma in children: a case-control study. Thorax 1996;51(1):59–63.
Immunol Allergy Clin N Am 28 (2008) 631–647
Living on a Farm: Impact on Asthma Induction and Clinical Course Erika von Mutius, MD, MSca,*, Katja Radon, PhD, MScb a
University Children’s Hospital, Lindwurmstr 4, D 80337 Munich, Germany Unit for Occupational and Environmental Epidemiology & Net Teaching, Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, Clinical Centre of the Ludwig-Maximilians-University Munich, Ziemssenstr. 1, D-80336 Munich, Germany b
As with many other chronic conditions, asthma, atopic dermatitis, and hay fever are likely to be determined by multiple factors, some of which constitute intrinsic host characteristics such as gender, race, genetic predisposition, and atopy, and some of which consist of extrinsic, environmental influences. These various factors are likely to interact on many different levels. In addition, the developmental aspects of a maturing and growing organism from infancy through the toddler years to childhood, adolescence and adulthood have to be considered as the natural history of allergic conditions varies. Therefore, complex time-dependent interactions between genetic determinants and environmental exposures are likely to exist, which should be kept in mind when investigating potential determinants of asthma and allergies in diverse populations. In general, reported rates of asthma, hay fever, and atopic dermatitis are higher in affluent, Western countries than in developing countries. The worldwide prevalence of allergic diseases was assessed in the 1990s by the large scale International Study of Asthma and Allergy in Childhood (ISAAC Phase I) [1]. Between 20-fold and 60-fold differences were found between centers. In the more recent Phase II of ISAAC, which included objective measures of asthma and allergies, a wide variation in the prevalence of atopic sensitization across study centers was seen confirming the previous questionnaire-based observations [2]. Interestingly, a strong correlation of the association between wheeze and atopic sensitization with the gross national income of the respective countries was found [2]. Likewise, large geographic differences existed in the prevalence of respiratory symptoms, * Corresponding author. E-mail address:
[email protected] (E. von Mutius). 0889-8561/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.iac.2008.03.010 immunology.theclinics.com
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asthma, bronchial responsiveness and atopic sensitization with high prevalence in English speaking countries and low prevalences in the Mediterranean region and Eastern Europe according to the European Community Respiratory Health Survey (ECRHS) studying adults aged 20–44 years [3]. The geographic pattern emerging from questionnaire findings was consistent with the distribution of atopy and airway hyperresponsiveness; the data support the conclusion that the geographic variation in asthma is real and not attributable to methodological factors such as the questionnaire phrasing, the skin testing technique, or the type of assay for the measurement of specific IgE. Thereby, the validity of ISAAC and ECRHS study instruments has clearly been demonstrated. Within the global perspective, some comparisons seem particularly informative. Studies of populations with comparable ethnic backgrounds but with striking differences in environmental exposures may be especially revealing. In the past, the East German–West German comparisons showed that high levels of domestic and industrial air pollution were not related to increased asthma and allergy risk in East Germany [4]. More recently, studies in China among children living in Hong Kong and in mainland China, namely in Beijing and Urumqui, have yielded interesting results [5]. The children of Beijing reported significantly more asthma symptoms than those living in Urumqui, but children of Hong Kong had the highest prevalence of asthma and other allergic symptoms of all. Urumqui, Beijing, and Hong Kong represent communities at increasing stages of affluence and westernization, and the findings from these three cities can be interpreted as a reflection of a worldwide trend for increasing prevalence of asthma and allergies as westernization intensifies. In many countries of the developing world, westernization goes along with urbanization and thus with a loss of rural living conditions. Recent studies performed in Mongolia, which is in transition from having rural, farming communities to being an industrial society, allow the investigation of such factors. The prevalence of allergic rhinoconjunctivitis and allergic sensitization was 9.3% and 13.6% in Mongolian villages, 12.9% and 25.3% in rural towns, and 18.4% and 31.0% in Ulaanbaatar city, respectively. Migration from villages to towns and to the large city of Ulaanbaatar influenced prevalence estimates. The risks of allergic rhinoconjunctivitis (adjusted odds ratio [aOR] ¼ 0.43, 95% CI: 0.19–0.98) and allergic sensitization (aOR 0.26, 95% CI: 0.13–0.55) were lowest in subjects living in a village since birth and intermediate in subjects who had relocated from a village to a town (aOR for rhinoconjunctivitis 0.68, 95% CI: 0.36–1.27; aOR for sensitization 0.62, 95% CI: 0.35–1.12) compared with subjects living in a town since birth. The farming environment A somewhat similar approach has attracted attention in Europe and other affluent countries in recent years. Several studies have been performed
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in rural areas in Europe, namely in Switzerland [6–8], Germany [7–9], Austria [7,8,10], France [11], Sweden [8,12,13], Denmark [14,15], Finland [16–18] and Britain [19]; the studies contrast the prevalence of asthma and allergic diseases in children and adults living on farms as compared with subjects also living in rural areas but not on farms. Almost all studies reported a decreased prevalence of hay fever and allergic rhinoconjunctivitis among farm children compared with non-farm children; studies that included objective measures of specific IgE antibodies (by skin prick tests or serum measurements) demonstrated the most significant results [20]. Findings relating to asthma and wheeze are somewhat less consistent. According to a large survey including over 10,000 schoolchildren in Germany [9], children of farmers had a lower prevalence of asthma (Odds ratio [OR] ¼ 0.65, 95% CI: 0.39–1.09]) and wheeze (OR ¼ 0.55, 95% CI: 0.36–0.86), yet other surveys in Switzerland [6], France [11] and Finland [16] did not find significant differences between groups. Only three studies included measures of airway hyperresponsiveness and one of these studies used exposure to wood and coal heating as a proxy for farming [14,21,22]. In the Danish and German studies, the prevalence of airway hyperresponsiveness was significantly reduced among farm children compared with nonfarm children [14,21]. A Canadian survey confirmed these findings [23]. To the authors’ knowledge, no study has shown an increased prevalence of airway hyperresponsiveness among children raised on farms. Looking at adult farming populations, similar figures have been observed. In the European farmers’ study, the prevalence of allergic rhinitis was 14.0% (95% CI: 12.7–15.3%) in 20–44 year old animal farmers as compared with 20.7% (95% CI: 19.9–21.5%) among the participants of the European Community Respiratory Health Survey [24]. Likewise, the prevalence of asthma was significantly lower among animal farmers compared with the general population (1.3; 0.9–1.7 % versus 3.2; 2.9–3.5%, respectively). For asthma, these findings have been confirmed in Norway, the Netherlands, Denmark and Canada (British Columbia) [15,25–27]. Only the Norwegian study could not confirm a protective association between working on a farm and allergic rhinitis [25]. The studies referenced above were based on a cross-sectional design. Only two studies have used a prospective, longitudinal approach. In Canada, over 13,000 asthma-free children aged 0–11 years were surveyed and the incidence of physician-diagnosed asthma was determined prospectively two years later [28]. The two-year cumulative incidence of asthma was 2.3%, 5.3% and 5.7% among children living in farming, rural non-farming, and non-rural environments, respectively. From the multivariate analysis with adjustment for confounders, children from a farming environment had a reduced risk of asthma compared with children from rural non-farming environment with OR of 0.22 (95% CI: 0.07–0.74) and 0.39 (95% CI: 0.24–0.65) for children with and without parental history of asthma, respectively. In Austria, 1150 elementary school children (mean age of 7.8 years) were
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recruited from nine different areas in 1994 and followed for three years [29]. Adjusting for potential confounders, parental farming was inversely related to the prevalence and new occurrence of skin prick test positivity (no farming 12.2%, part-time farming 6%, full-time farming 2.2% incidence; OR farming versus non-farming 0.34, 95% CI: 0.12–0.98). Furthermore, children living in a farming environment were more likely to lose their positive allergy skin prick test during follow-up (no farming 14.6%, part-time farming 50%, full-time farming 60% loss of sensitization; OR farming versus non-farming 8.06; 95% CI: 2.05–31.75). To date, no cohort study following subjects with and without farm contact from childhood to adulthood exists.
Sources of protective exposures in farming environments Farming practices vary between farms and between countries; this diversity may contribute to the heterogeneity of farm effects on asthma across studies and countries (Fig. 1). Some investigators have attempted to identify individual exposures in farm surroundings contributing to the reduction in risk of asthma and allergic diseases. Initial observations from Germany and Switzerland showed that children from full-time farmers had lower risk of atopic disease than children of part-time farmers [6,9] suggesting a doseresponse effect. Two recent studies conducted outside of Europe [30,31]
Fig. 1. Farming practices in different regions of the world.
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seem to suggest that an important component of the farm environment is livestock exposure because no protective effect of farming was observed among children living in a primarily crop farming region in Australia. This conclusion is supported by the findings of European studies where exposure to livestock was identified as an important contributor to the protective farm effect [7,9,16,19]. Interestingly, in the Austrian study, children who did not live on a farm but who had regular contact with farm animals also had a lower prevalence of allergic sensitization (13.5 % versus 34.8%) [10]. Another source of protection has been identified in a number of studies: the consumption of unpasteurized milk [7,19,31]. As with livestock exposure, this effect was not restricted to children living on a farm, but was also seen among non-farm populations consuming unpasteurized milk [19]. A recent, more in-depth analysis of the multicenter PARSIFAL study of rural areas in Europe has also shown significant inverse relations of a diagnosis of asthma with keeping pigs in addition to dairy farming (aOR ¼ 0.57; 95% CI: 0.38–0.86) and the use of silage as fodder for the animals (aOR ¼ 0.55; 95% CI: 0.31–0.98) [32]. European studies among adult farmers also gave some evidence that the protective effect of farming on atopic diseases might be more pronounced among animal farmers, with the strongest effect among pig and cattle farmers [26,33,34]. However, recent studies outside of Europe were less consistent [27,35,36]. While Douwes and colleagues [35] in New Zealand found all farmers – independent of whether they had livestock contact or not – to be protected from asthma; only those working with dairy had a significantly reduced risk for allergic rhinitis as compared with those without farm contact (Fig. 2). In Canada, living on a farm had an overall protective effect on asthma and allergic rhinitis. Taking intensity of livestock contact into account did not make a difference with respect to prevalence of asthma or allergic rhinitis [27]. Likewise, US farm women who worked with animals had the same prevalence of atopic and non-atopic asthma as those not working with animals [36]. Therefore, differences in farming practices as well as the size of farming operations have to be taken into account when studying the effect of different types of farming exposure on allergies and asthma.
Timing of farming exposures There is increasing evidence to suggest that the effect of a given exposure strongly depends on the timing of this exposure. At least throughout infancy, childhood, and adolescence, the human organism is in a constant process of development and maturation. It is conceivable that these predefined processes display windows of accessibility and vulnerability toward extrinsic influences at certain stages of development. Moreover, prenatal factors may play a significant role either through mechanisms acting in utero or as epigenetic modulation of subsequent developmental trajectories. In the
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A Asthma
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Fig. 2. Current or childhood exposure to farming environments and (A) asthma prevalence, (B) prevalence of allergic rhinitis, and (C) prevalence of allergic sensitization (prick or specific IgE) during adulthood [15,25–27,35,38,40,41]. Adjusted ORs with 95% CIs as provided in the articles. Definition of symptoms may differ across studies.
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C Allergic sensitization
adjusted OR (95% CI) 2.0
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Fig. 2 (continued )
PARSIFAL Study, the risk of atopic sensitization was not only influenced by a child’s exposure to the farming environment, but it was also strongly determined by maternal exposure to stables during pregnancy (aOR ¼ 0.58; 95% CI: 0.39–0.86) [37]. Studies on allergic rhinitis among adults A number of studies have addressed the association between childhood contact to farming environments and the prevalence of asthma and allergies during adulthood (see Fig. 2) [15,26,38–41]. All of the studies found an inverse association between being raised on a farm and the prevalence of allergic sensitization to common allergens, as well as allergic rhinitis, during adulthood. To further analyze the relevance of timing of exposure, several studies have assessed the potential interaction between childhood and adulthood exposure to farming environments and the prevalence of allergies and asthma during adulthood (Fig. 3) [15,26,27,35,36,38,39]. Across these studies, the protective effect of farming environments on respiratory allergies was largest when farm contact started during childhood and was sustained until adulthood. Several of these studies indicated modification of effects by farm contact during childhood. That is to say, the protective effect of farm contact during childhood and adulthood on respiratory allergy might be more than additive. In these studies, childhood exposure was defined in various ways from living on a farm during the first year of life to living on a farm any time
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A
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Fig. 3. Combined effect of current and childhood exposure to farming environments and (A) asthma prevalence (B) prevalence of allergic sensitiziation/rhinitis during adulthood [26,27,35,36,39,41]. Adjusted ORs with 95% CIs as provided in the articles. Definition of symptoms may differ across studies. No/No, neither farm contact during childhood nor recent farm contact; No/Yes, no farm contact during childhood, recent farm contact; Yes/No, farm contact during childhood, no recent farm contact; Yes/Yes, farm contact during childhood and recent farm contact.
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before the age of 18 years. One study tried to disentangle the relevance of different time periods of farming exposure during childhood and the effect on self-reported allergic rhinitis in adult life [42]. Overall, it was shown that the protective effect of regular visits to animal dwellings on respiratory allergy was largest when these visits started during the first 6 years of life. However, because the authors had to rely on self-reported onset of exposure, misclassification of exposure might have affected the results. For those people who started farm contact later than when they were 6 yrs old, only a weak protective effect on allergic rhinitis or sensitization was seen. Therefore, infant exposure seems to be of uppermost importance in the life course of allergic sensitization [43,44]. Assuming that farm contact during childhood is also a proxy for prenatal and infant exposure provides additional evidence for the importance of prenatal factors on the development of asthma and allergies. One recent study among 137 university employees, of whom 36% were working with laboratory animals, indicated that those with farm contact during infancy were protected from sensitization to occupational allergens later in life [45]. Likewise, among rural adults living in an agricultural area of Germany, occupational exposure to high molecular weight agents could not be shown to increase the risk of allergic sensitization. In contrast, such exposure was shown to be inversely related to allergic sensitization to common allergens [46]. One might wonder why those who stopped their contact to farming environments do not encounter the same protection as those with continuous farm contact. It might be an indication of a healthy worker bias, meaning that those with symptoms leave the farming environment [39,47,48]. Although this might partly explain the effect, the strengths of the relationship and the consistency of the association across studies cannot be explained by a self-selection into farming alone [35]. Another issue that has been discussed is that farmers tend to underreport symptoms [39]. However, as the findings are not only evident for self-reported symptoms but also for objective markers of disease (ie, allergic sensitization assessed by skin prick test or specific IgE), the underreporting of symptoms is an implausible explanation (see Fig. 3). It is more likely that the underlying cause of the observed interaction is a complex interplay between prenatal factors, early childhood exposures, and events encountered over the life course. It was argued that the high prevalence of asthma and atopy among US inner-city populations with lower standards of hygiene contradicts the ‘‘hygiene hypothesis’’ [49,50]. Because several studies have indicated that obesity is not only associated with asthma but also with allergic rhinitis (for review, see Ref. [51]), the high prevalence of obesity in inner-city populations might help to understand these paradoxical observations. To test this hypothesis, data from 1861 adults living in a rural area of Lower Saxony (Germany) have been analyzed. Results indicated that obesity might diminish or even cancel out the protective effect of childhood farm contact later in life [52].
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Further analyses suggested that the underlying association between adipokines and sensitization might be more pronounced in subjects with childhood farm contact [53]. Studies on asthma among adults With respect to the association between farm contact and asthma, the findings across studies have been less clear-cut (see Fig. 3A). Interpreting the inconsistencies, one has to bear in mind that less than half of adult asthma is characterized by an eosinophilic response [54,55]. In many cases, asthma is associated with a neutrophilic inflammation, a condition for which the term ‘‘asthma-like syndrome’’ has been coined. Although there is good evidence that farming also protects from atopic asthma, farming exposures, especially long-term exposure to endotoxin, constitute a risk factor for non-atopic asthma [35,38,42,56–59].
Microbial exposures If livestock and other farming exposures are associated with a decreased prevalence of asthma and atopy, then underlying exposures should be investigated next. Children exposed to livestock may be exposed to more allergens, bacteria, viruses and fungi than children without exposure to livestock. Yet, only few out of the many microbial exposures have been measured in farming environments so far. Bacterial substances, such as endotoxin from gram negative species and muramic acid, a component of peptidoglycan from the cell wall of all types of bacteria, have been found to be more abundant in mattress dust from farm children than non-farm children [60]. Likewise, extracellular polysaccharide (EPS) from Penicillium and Aspergillus spp. is more prevalent in farming households than non-farm households [60]. In the ALEX study, a multicenter study conducted in rural areas of Austria, Switzerland and Germany, endotoxin levels in dust samples from the children’s mattresses were inversely related to the occurrence of hay fever, atopic asthma, and atopic sensitization [61]. However, nonatopic wheeze was not significantly associated with endotoxin levels. In turn, independently of endotoxin concentrations, increasing mattress dust muramic acid levels were associated with a lower frequency of wheezing and asthma among rural school children in the ALEX study [62]. The inverse association found in the ALEX study between endotoxin and atopic wheeze was confirmed in the larger multicenter PARSIFAL survey performed in Sweden, the Netherlands, Germany, Austria, and Switzerland [63]. When restricting the PARSIFAL analyses to similar groups of children as in the ALEX study, farm and farm-reference children in Germany, Austria, and Switzerland, a decreased risk (aOR ¼ 0.56, 95 %CI: 0.35–0.90) was
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observed. After adjustment for glucans and EPS, the effect of endotoxin was, however, no longer significant. Since exposures to endotoxin, EPS, and glucans were moderately, but significantly, correlated, a firm conclusion about the degree to which specific agents contributed to the observed effect is precluded. Moreover, these microbial agents might be markers of a much broader spectrum of microbial agents. Muramic acid was not measured in the PARSIFAL study. In this study, all measured microbial compounds (ie, endotoxin, glucans, and EPS) did not explain the protective ‘farming effect’ which suggests that other, yet unknown, microbial exposures confer the protection seen in the farming environments. The results do, however, also suggest that mold components might modulate immune responses and thereby protect against allergic diseases, as was previously suggested for endotoxin [60]. This conclusion is in line with a study on the effects of endotoxin and fungal spores on atopy and asthma in adult farmers, in which fungal spores, rather than endotoxin, were inversely related to atopic wheeze [58]. Another study, among Dutch adult farmers, designed a job exposure matrix (JEM) to assign individual occupational exposure to endotoxins [64]. Using this JEM, endotoxin exposure was inversely related to self-reported symptoms of allergic rhinitis among the farmers. However, the prevalence of asthma symptoms increased with exposure. As no data on atopy were available, the authors could not stratify for atopic and non-atopic asthma. Furthermore, no data on fungal exposure were available. This study basically confirms an earlier case-control study among Dutch pig farmers [59]. While higher endotoxin levels were associated with a reduced odds ratio for sensitization to common allergens (0.03; 95% CI: 0.0–0.34), farmers with higher levels of endotoxin exposure were more likely to show airway hyperresponsiveness and to have reduced lung function. These studies give further evidence that farming exposure might not only be beneficial for the respiratory system. While protecting from respiratory allergies and atopic asthma, such exposure seems to pose a risk for non-atopic asthma in adulthood [24,38,57– 59,64]. In the context of the hygiene hypothesis, some studies have indicated that foodborne and orofecal infections such as Helicobacter pylori, Toxoplasma gondii, and hepatitis A virus might as well protect from respiratory allergy [65–67]. Therefore, one explanation for the protective effect of the farming environment might be that exposure to microbial agents in the farm environment is a proxy for such infections. A study analyzing the association between farm animal contact, serologic markers of foodborne and orofecally transmitted infections, and atopy provided evidence that these mechanisms act independently [68]. It was shown that early contact with animal dwellings increases the likelihood of Toxoplasma gondii seropositivity. However, early contact to farm animals was still the strongest predictor of atopy (OR 0.49, 95% CI: 0.26–0.96).
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Mechanisms of protection in farming environments Few studies have investigated the immune responses in children raised on farms and compared those responses to immune responses in children raised in rural but non-farming environments. Since farming is associated with elevated exposure to microbes and/or microbial components, the Swiss arm of the ALEX study investigated whether growing up on a farm affects the expression of receptors for microbial compounds. Pathogen-associated molecular patterns (PAMPs), which are evolutionarily highly conserved structural components of microbes, are recognized by similarly conserved receptors of host innate immune systems, the pattern recognition receptors (PRRs). Examples of PAMPs are the bacterial compounds cited above, lipopolysaccharide (LPS, endotoxin), and muramic acid, a component of peptidoglycan, which is part of the cell wall of most bacteria. Examples of human PRRs are the human Toll-like receptors (TLRs) and CD14. To date, ten functional TLRs have been described in humans. By engaging TLRs, which belong to a first-line defense of innate immunity [69], signals required for initiating and modulating the adaptive immune response are also being generated [70]. In the context of the development of asthma and allergies, TLR4 (as receptor for LPS) and TLR2, which recognizes peptidoglycan of gram-positive bacteria, have received the most attention. Peripheral blood leukocytes from children of the ALEX population living on a farm were found to display increased expression of the genes for CD14, TLR2, and TLR4 [71] as compared with non-farm children. The impact of farming on the expression of innate immunity genes was then further examined by the Swiss research team in 125 children of farmers and 127 children of non-farmers from the PARSIFAL study [37]. RNA was extracted from EDTA-treated blood, and expression of all TLRs and CD14 was determined by quantitative PCR (TaqMan). The results confirmed the initial observation suggesting that environmental exposures, in particular exposure to microbial components, affect the expression of genes encoding microbial ligand receptors [71]. A number of individual farm characteristics were related to the up-regulation of distinct TLR genes [32]. The Swiss research team then assessed whether changes in gene expression correlated with prenatal or postnatal exposure to farm factors. After adjusting for age, sex, family history of atopy, parental education, environmental tobacco smoke, maternal smoking during pregnancy, number of older siblings, contact with pets ever, study center, and current farm exposures, maternal exposure to stables during pregnancy (ie, prenatal exposure of the child) significantly correlated with an increase in the expression of TLR2 (geometric means ratio and 95% CI: 1.44 [1.04–1.98]), TLR4 (1.40 [1.07–1.83]) and CD14 (1.66 [1.18–2.33]) [37]. Interestingly, a dose response relation was seen. Expression of TLR2, TLR4 and CD14 increased with the number of different farm animal species the mother had contact with during
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her pregnancy. Overall, these findings support the idea that prenatal environmental exposures affect the allergy and asthma risk of a child. These findings also suggest a role for innate immunity in response to these environmental exposures. With respect to sensitization to common aeroallergens, the underlying mechanisms may be even more complex. In the ALEX study, allergendependent switching patterns were reconstructed in vivo to identify the levels at which farm exposure acts to protect against atopy by assessing serum IgG1 to IgG4 and IgE levels to grass, cat, and mite allergens [72]. Farm exposure had complex allergen-specific effects on IgG1, IgG4, and IgE levels. Exposure protected against grass-specific responses at every step along the IgG1/IgG4/IgE switching pathway. Protection from cat responses was concentrated at the IgG1 level. For all allergens, failure to express IgG1 was associated with low prevalence of IgG4 or IgE responses. These findings suggest that the protective effects of farm exposure on atopic sensitization are allergen and switch stage specific. No counterbalancing, protective effect of IgG4 production as proposed in the context of urban cat exposure [73] has been seen in these farming environments. The genetic background of children raised on farms and elsewhere in rural areas interacts with the environmental exposures. Polymorphisms in the genes for TLR4, TLR2 and NOD2 have furthermore been shown to interact with the farm environment, modulating the asthma and allergy protective effect [74]. Recently, a significant interaction between genetic variation in CD14/-1721 and farm milk consumption was found. Adjusted odds ratios for the association between farm milk and asthma varied between the genotypes: AA, 0.18 (95% CI, 0.07–0.47); AG, 0.47 (95% CI, 0.26–0.86); and GG, 0.98 (95% CI, 0.46–2.08). Similar patterns were observed for symptoms of allergic rhinoconjunctivitis and pollen sensitization. CD14/-1721 also modified the association between farm milk and CD14 gene expression. Taken together, these findings suggest that the protective effect of various farm exposures is modified by an individual’s genetic makeup. This is supported by two recent studies among adults. In these studies, the potential gene-environment interaction between the genes for CD14 has been assessed [11,75]. Both studies point toward an interaction between different positions in the promoter region of CD14 (-159T, -651T and -260T) and the prevalence of atopy in adult farmers [75] and the general population with childhood farm contact [11]. In conclusion, there is convincing evidence that a childhood spent on farms confers protection from respiratory allergies with a sustained effect into adulthood, particularly with continued exposure. The nature of individual protective exposures in the environments has not been elucidated. Studies so far suggest that, at least in childhood, contact with farm animals, their fodder, and their products (such as milk consumed directly from the farm) contribute to the ‘‘farm effect’’. The underlying mechanisms are still ill defined, but they are likely to involve a number of steps in innate and adaptive
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immunity. An individual’s genetic background modifies the effects of the environmental exposures. References [1] Worlwide variations in the prevalence of asthma symptoms: the International Study of Asthma and Allergies in Childhood (ISAAC). Eur Respir J 1998;12:315–35. [2] Weinmayr G, Weiland SK, Bjo¨rkste´n B, et al. Atopic sensitization and the international variation of asthma symptom prevalence in children. Am J Respir Crit Care Med 2007;176(6): 565–74. [3] Janson C, Anto J, Burney P, et al. The European Community Respiratory Health Survey: what are the main results so far? Eur Respir J 2001;18:598–611. [4] von Mutius E, Martinez FD, Fritzsch C, et al. Prevalence of asthma and atopy in two areas of West and East Germany. Am J Respir Crit Care Med 1994;149(2 Pt 1):358–64. [5] Zhao T, Wang A, Chen Y, et al. Prevalence of childhood asthma, allergic rhinitis and eczema in Urumqui and Beijing. J Paediatr Child Health 2000;36:128–33. [6] Braun-Fahrlander C, Gassner M, Grize L, et al. Prevalence of hay fever and allergic sensitization in farmer’s children and their peers living in the same rural community. SCARPOL team. Swiss Study on Childhood Allergy and Respiratory Symptoms with Respect to Air Pollution. Clin Exp Allergy 2002;57(12):1094–6. [7] Riedler J, Braun-Fahrlaender C, Eder W, et al. Early life exposure to farming environment is essential for protection against the development of asthma and allergy: a cross-sectional survey. Lancet 2001;358:1129–33. [8] Alfven T, Braun-Fahrlaender C, Brunekreef B, et al. Allergic diseases and atopic sensitization in children related to farming and anthroposophic lifestyle–the PARSIFAL study. Allergy 2006;61(4):414–21. [9] Von Ehrenstein OS, von Mutius E, Illi S, et al. Reduced risk of hay fever and asthma among children of farmers. Clin Exp Allergy 2000;30:187–93. [10] Riedler J, Eder W, Oberfeld G, et al. Austrian children living on a farm have less hay fever, asthma and allergic sensitization. Clin Exp Allergy 2000;30(2):194–200. [11] Leynaert B, Guilloud-Bataille M, Soussan D, et al. Association between farm exposure and atopy, according to the CD14 C-159T polymorphism. J Allergy Clin Immunol 2006;118(3): 658–65. [12] Braback L, Hjern A, Rasmussen F. Trends in asthma, allergic rhinitis and eczema among Swedish conscripts from farming and non-farming environments. A nationwide study over three decades. Clin Exp Allergy 2004;34(1):38–43. [13] Klintberg B, Berglund N, Lilja G, et al. Fewer allergic respiratory disorders among farmers’ children in a closed birth cohort from Sweden. Eur Respir J 2001;17(6):1151–7. [14] Omland O, Sigsgaard T, Hjort C, et al. Lung status in young Danish rurals: the effect of farming exposure on asthma-like symptoms and lung function. Eur Respir J 1999;13(1): 31–7. [15] Portengen L, Sigsgaard T, Omland O, et al. Low prevalence of atopy in young Danish farmers and farming students born and raised on a farm. Clin Exp Allergy 2002;32(2): 247–53. [16] Remes ST, Iivanainen K, Koskela H, et al. Which factors explain the lower prevalence of atopy amongst farmers’ children? Clin Exp Allergy 2003;33(4):427–34. [17] Kilpelainen M, Terho EO, Helenius H, et al. Farm environment in childhood prevents the development of allergies. Clin Exp Allergy 2000;30(2):201–8. [18] Kilpelainen M, Terho EO, Helenius H, et al. Childhood farm environment and asthma and sensitization in young adulthood. Allergy 2002;57(12):1130–5. [19] Perkin MR, Strachan DP. Which aspects of the farming lifestyle explain the inverse association with childhood allergy? J Allergy Clin Immunol 2006;117(6):1374–81.
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[20] Naleway AL. Asthma and atopy in rural children: is farming protective? Clin Med Res 2004; 2(1):5–12. [21] von Mutius E, Illi S, Nicolai T, et al. Relation of indoor heating with asthma, allergic sensitisation, and bronchial responsiveness: survey of children in south Bavaria. BMJ 1996; 312(7044):1448–50. [22] Kilpelainen M, Koskenvuo M, Helenius H, et al. Wood stove heating, asthma and allergies. Respir Med 2001;95(11):911–6. [23] Ernst P, Cormier Y. Relative scarcity of asthma and atopy among rural adolescents raised on a farm. Am J Respir Crit Care Med 2000;161(5):1563–6. [24] Radon K, Danuser B, Iversen M, et al. Respiratory symptoms in European animal farmers. Eur Respir J 2001;17(4):747–54. [25] Eduard W, Omenaas E, Bakke PS, et al. Atopic and non-atopic asthma in a farming and a general population. Am J Ind Med 2004;46(4):396–9. [26] Smit LA, Zuurbier M, Doekes G, et al. Hay fever and asthma symptoms in conventional and organic farmers in The Netherlands. Occup Environ Med 2007;64(2):101–7. [27] Dimich-Ward H, Chow Y, Chung J, et al. Contact with livestock–a protective effect against allergies and asthma? Clin Exp Allergy 2006;36(9):1122–9. [28] Midodzi WK, Rowe BH, Majaesic CM, et al. Reduced risk of physician-diagnosed asthma among children dwelling in a farming environment. Respirology 2007;12(5):692–9. [29] Horak F Jr, Studnicka M, Gartner C, et al. Parental farming protects children against atopy: longitudinal evidence involving skin prick tests. Clin Exp Allergy 2002;32(8):1155–9. [30] Downs SH, Marks GB, Mitakakis TZ, et al. Having lived on a farm and protection against allergic diseases in Australia. Clin Exp Allergy 2001;31(4):570–5. [31] Wickens K, Lane JM, Fitzharris P, et al. Farm residence and exposures and the risk of allergic diseases in New Zealand children. Allergy 2002;57(12):1171–9. [32] Ege MJ, Frei R, Bieli C, et al. Not all farming environments protect against the development of asthma and wheeze in children. J Allergy Clin Immunol 2007;119(5):1140–7. [33] Monso E, Schenker M, Radon K, et al. Region-related risk factors for respiratory symptoms in European and Californian farmers. Eur Respir J 2003;21(2):323–31. [34] Monso E, Magarolas R, Radon K, et al. Respiratory symptoms of obstructive lung disease in European crop farmers. Am J Respir Crit Care Med 2000;162(4 Pt 1):1246–50. [35] Douwes J, Travier N, Huang K, et al. Lifelong farm exposure may strongly reduce the risk of asthma in adults. Allergy 2007;62(10):1158–65. [36] Hoppin JA, Umbach DM, London SJ, et al. Pesticides and atopic and nonatopic asthma among farm women in the Agricultural Health Study. Am J Respir Crit Care Med 2008; 177(1):11–8. [37] Ege MJ, Bieli C, Frei R, et al. Prenatal farm exposure is related to the expression of receptors of the innate immunity and to atopic sensitization in school-age children. J Allergy Clin Immunol 2006;117(4):817–23. [38] Schulze A, van Strien RT, Praml G, et al. Characterisation of asthma among adults with and without childhood farm contact. Eur Respir J 2007;29(6):1169–73. [39] Radon K, Schulze A, Nowak D. Inverse association between farm animal contact and respiratory allergies in adulthood: protection, underreporting or selection? Allergy 2006;61(4): 443–6. [40] Leynaert B, Neukirch C, Jarvis D, et al. Does living on a farm during childhood protect against asthma, allergic rhinitis, and atopy in adulthood? Am J Respir Crit Care Med 2001;164(10 Pt 1):1829–34. [41] Koskela HO, Happonen KK, Remes ST, et al. Effect of farming environment on sensitisation to allergens continues after childhood. Occup Environ Med 2005;62(9):607–11. [42] Radon K, Ehrenstein V, Praml G, et al. Childhood visits to animal buildings and atopic diseases in adulthood: an age-dependent relationship. Am J Ind Med 2004;46(4):349–56. [43] von Mutius E, Le Souef PN. Early gene-environment interactions: can they inform primary preventive strategies for asthma? Semin Respir Crit Care Med 2007;28(3):255–63.
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[44] Chan-Yeung M, Hegele RG, Dimich-Ward H, et al. Early environmental determinants of asthma risk in a high-risk birth cohort. Pediatr Allergy Immunol 2008, in press. [45] Dorevitch S, Tharenos L, Demirtas H, et al. Inverse association between rural environment in infancy and sensitization to rodents in adulthood. Ann Allergy Asthma Immunol 2007; 98(5):440–6. [46] Janßen C. Berufsbedingtes Asthma und Allergien im la¨ndlichen Niedersachsen. In: Institute and outpatient clinic for occupational, social and environmental medicine. Munich (Germany): Ludwig-Maximilians-University; 2007. p. 1–81. [47] Eisen EA. Healthy worker effect in morbidity studies. Med Lav 1995;86(2):125–38. [48] Le Moual N, Kauffmann F, Eisen EA, et al. The healthy worker effect in asthma: work may cause asthma, but asthma may also influence work. Am J Respir Crit Care Med 2008;177(1): 4–10. [49] Perzanowski MS, Miller RL, Thorne PS. Endotoxin in inner-city homes: associations with wheeze and eczema in early childhood. J Allergy Clin Immunol 2006;117(5):1082–9. [50] Platts-Mills TA, Erwin E, Heymann P, et al. Is the hygiene hypothesis still a viable explanation for the increased prevalence of asthma? Allergy 2005;60(Suppl 79):25–31. [51] Hersoug LG, Linneberg A. The link between the epidemics of obesity and allergic diseases: does obesity induce decreased immune tolerance? Allergy 2007;62(10):1205–13. [52] Radon K, Schulze A. Adult obesity, farm childhood, and their effect on allergic sensitization. J Allergy Clin Immunol 2006;118(6):1279–83. [53] Radon, K, Schulze A, Schierl R, et al. Serum leptin and adiponectin levels and their association with allergic sensitization. Allergy, in press. [54] Douwes J, Gibson P, Pekkanen J, et al. Non-eosinophilic asthma: importance and possible mechanisms. Thorax 2002;57(7):643–8. [55] Sunyer J, Jarvis D, Pekkanen J, et al. Geographic variations in the effect of atopy on asthma in the European Community Respiratory Health Study. J Allergy Clin Immunol 2004; 114(5):1033–9. [56] Radon K, Monso E, Weber C, et al. Prevalence and risk factors for airway diseases in farmers–summary of results of the European Farmers’ Project. Ann Agric Environ Med 2002;9(2):207–13. [57] Radon K. The two sides of the ‘‘endotoxin coin’’. Occup Environ Med 2006;63(1):73–8, 10. [58] Eduard W, Douwes J, Omenaas E, et al. Do farming exposures cause or prevent asthma? Results from a study of adult Norwegian farmers. Thorax 2004;59(5):381–6. [59] Portengen L, Preller L, Tielen M, et al. Endotoxin exposure and atopic sensitization in adult pig farmers. J Allergy Clin Immunol 2005;115(4):797–802. [60] Schram D, Doekes G, Boeve M, et al. Bacterial and fungal components in house dust of farm children, Rudolf Steiner school children and reference children–the PARSIFAL Study. Allergy 2005;60(5):611–8. [61] Braun-Fahrlander C, Riedler J, Herz U, et al. Environmental exposure to endotoxin and its relation to asthma in school-age children. N Engl J Med 2002;347:869–77. [62] van Strien RT, Engel R, Holst O, et al. Microbial exposure of rural school children, as assessed by levels of N-acetyl-muramic acid in mattress dust, and its association with respiratory health. J Allergy Clin Immunol 2004;113(5):860–7. [63] Schram D, Doekes G, Douwes J, et al. Bacterial and fungal agents in house dust of farm children: the PARSIFAL study. Allergy 2005;35(5):611–8. [64] Smit LA, Heederik D, Doekes G, et al. Exposure-response analysis of allergy and respiratory symptoms in endotoxin exposed adults. Eur Respir J 2008. [65] Janson C, Asbjornsdottir H, Birgisdottir A, et al. The effect of infectious burden on the prevalence of atopy and respiratory allergies in Iceland, Estonia, and Sweden. J Allergy Clin Immunol 2007;120(3):673–9. [66] Matricardi PM, Rosmini F, Riondino S, et al. Exposure to foodborne and orofecal microbes versus airborne viruses in relation to atopy and allergic asthma: epidemiological study. BMJ 2000;320(7232):412–7.
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[67] Leonardi S, Miraglia del Giudice M, La Rosa M, et al. Atopic disease, immune system, and the environment. Allergy Asthma Proc 2007;28(4):410–7. [68] Radon K, Windstetter D, Eckart J, et al. Farming exposure in childhood, exposure to markers of infections and the development of atopy in rural subjects. Clin Exp Allergy 2004;34(8):1178–83. [69] Brightbill HD, Modlin RL. Toll-like receptors: molecular mechanisms of the mammalian immune response. Immunology 2000;101(1):1–10. [70] Takeda K, Akira S. Toll-like receptors in innate immunity. Int Immunol 2005;17(1):1–14. [71] Lauener RP, Birchler T, Adamski J, et al. Expression of CD14 and Toll-like receptor 2 in farmers’ and non-farmers’ children. Lancet 2002;360(9331):465–6. [72] Stern DA, Riedler J, Nowak D, et al. Exposure to a farming environment has allergen-specific protective effects on T(H)2-dependent isotype switching in response to common inhalants. J Allergy Clin Immunol 2006. [73] Erwin EA, Wickens K, Custis NJ, et al. Cat and dust mite sensitivity and tolerance in relation to wheezing among children raised with high exposure to both allergens. J Allergy Clin Immunol 2005;115(1):74–9. [74] Eder W, Klimecki W, Yu L, et al. Toll-like receptor 2 as a major gene for asthma in children of European farmers. J Allergy Clin Immunol 2004;113:482–8. [75] Smit LA, Bongers SI, Ruven HJ, et al. Atopy and new-onset asthma in young Danish farmers and CD14, TLR2, and TLR4 genetic polymorphisms: a nested case-control study. Clin Exp Allergy 2007;37(11):1602–8.
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Does the Social Environment Contribute to Asthma? Edith Chen, PhD*, Hannah M.C. Schreier, BA Department of Psychology, University of British Columbia, 2136 West Mall, Vancouver, British Columbia V6T 1Z4, Canada
The impact of the social environment on asthma has recently begun to receive increasing attention. This article reviews the current literature to investigate the impact of the social environment at three levelsdthe neighborhood level, the peer level, and the family leveldand to explore pathways through which the social environment ‘‘gets under the skin’’ to impact asthma onset and morbidity. Research to date suggests that adverse social conditions at the neighborhood and family levels impact asthma morbidity through direct effects on physiologic systems as well as by altering health behaviors. The impact on asthma of social networks, such as friendships, is less clear and will need to be investigated further. Future research will need to take into account the impact of the social environment to develop more comprehensive models of asthma pathogenesis.
Does the social environment contribute to asthma? Asthma is widely recognized as a complex disease with multiple contributing factors. These include environmental exposures, viral infections, and genetics, the roles of which have been well established [1–4]. However, in contrast to the above factors, the role of social factors in asthma has been less well-established. Clinical anecdotes have long existed describing patients whose asthma appeared to be exacerbated by social circumstances, such as a significant stressful life event. However, empirical evidence supporting this claim has only appeared more recently. This article provides an overview of studies that have addressed the role of the social environment in asthma, This work was supported by the Canadian Institutes of Health Research and the Michael Smith Foundation for Health Research. * Corresponding author. E-mail address:
[email protected] (E. Chen). 0889-8561/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.iac.2008.03.007 immunology.theclinics.com
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and discusses the biological mechanisms by which social factors might influence the course of asthma. What is the social environment? The social environment includes the connections a person has to a larger social community. This could include interpersonal or close relationships with others, the daily social contacts an individual has with others, as well as an individual’s social position within a larger community. We argue that in considering the role of the social environment in asthma, it is important to acknowledge social factors at multiple levels. For example, the most proximal level of social environment is a person’s family. For many, family members are those with whom interactions take place daily and those with whom individuals have had their longest relationships. Friendships or peer relationships represent the next level of social connection. These are often close others who provide an important source of social support and companionship. At the broadest level are neighborhood connections. Neighbors provide a source of social contact, but may not be as close as family and friends. In addition, neighborhoods often provide a sense of social identity and community for many individuals. In this article, we discuss the role of the social environment at each of these levelsdneighborhood, peer, and family levelsdin affecting asthma. Neighborhood effects on asthma We highlight two social factors at the neighborhood level that have been linked to asthma: socioeconomic status (SES) and exposure to violence. Socioeconomic status Although SES likely reflects a number of nonsocial factors [5,6], including material resources, access to health care, and housing quality, it also contains a social component in that it indicates a person’s relative standing within a larger social community. This in turn affects how people perceive themselves within their social group [7], as well as how others interact toward them [8]. Across numerous studies, evidence shows that lower SES increases risk for morbidity among patients with asthma. For example, poor children and children from lower income families are significantly more likely to be hospitalized for asthma, to have greater asthma symptoms, and to have more severe asthma episodes compared with nonpoor and higher income children with asthma [9–11]. Fewer years of parent education also have been associated with greater risk of asthma hospitalizations and emergency department visits in children with asthma [12,13]. Longitudinal studies show similar patterns. For example, children whose fathers had less
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prestigious occupations were more likely to be hospitalized because of asthma during the following 6 years compared with those whose fathers had more prestigious occupations [14]. In addition, neighborhoods with lower income levels and higher unemployment rates have been found to have higher rates of asthma hospitalizations [15–17]. Finally, populationbased studies (which are distinct from the above studies that focus on children with pre-existing asthma) have also found that lower SES (as indicated by either parental education or neighborhood characteristics) is associated with greater risk of asthma-related emergency room visits, asthma hospitalizations, and more severe asthma in children [18,19]. In contrast, relationships between low SES and asthma onset are less clear. Some studies have shown that low SES is associated with an increased prevalence of asthma. For example, children whose parents have fewer years of education are more likely to have a physician diagnosis of asthma [19]. Children from poorer families are also more likely to have a diagnosis of asthma [9,11]. Children who live in inner-city or low-income neighborhoods are more likely to have current asthma [16,18,20,21]. However, other studies have found no evidence for an association between neighborhood SES and childhood asthma prevalence rates [22,23]. Meanwhile, some studies have found individuals in higher SES groups to be more likely to have an asthma diagnosis [24,25]. In sum, evidence that living in a low-SES environment increases the risk for morbidity among those already diagnosed with asthma is fairly strong, but evidence that low-SES environments contribute to asthma onset is less clear-cut. Neighborhood characteristics Intriguing evidence has emerged recently to suggest that certain negative social characteristics of neighborhoods may be detrimental to asthma. For example, exposure to violence represents a community-level stressor that can take a toll on health [26]. Previous research has documented that greater exposure to violence is associated with a greater number of symptom days in children with asthma, as well as a greater number of nights of lost sleep for caretakers because of their child’s asthma [27]. Similarly, greater problems in one’s neighborhood, such as problems with crime and gangs, have been associated with greater asthma symptoms in children [28]. In addition, exposure to violence moderated the relationship between physical environment exposures and asthma. Children were at greater risk for being diagnosed with asthma if they had high levels of exposure to both traffic-related air pollution and violence [29]. Explaining neighborhood effects Why would the neighborhoods that people live in affect asthma? One possibility is that life in a low-SES or high-violence neighborhood is more stressful on a day-to-day basis. Life in a low-SES household may involve
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multiple competing demands that are often unpredictable. For example, low-SES families may experience multiple pulls on their limited resources, such as trying to pay bills so that services to their home do not get shut off while trying to put enough food on the table and while trying to deal with problems in the house, such as a plumbing leak. Demands may also spill over from one domain into another, creating conflicts between domains for families. For example, parents may need to work additional shifts to make extra money for the family, but this takes away from time with children and creates pressures to find additional childcare options. Demands in low-SES households may also create unpredictability in families’ dayto-day lives. For example, low-SES children may not be able to count on a consistent schedule if parents must depend on unreliable public transportation for getting between work and home. Similarly, families that live in high-violence neighborhoods may also experience greater stress in their day-to-day lives. This may be because they have to constantly be vigilant for threats to their safety. This vigilance may be activated every time they leave their home, and may even extend to feeling unsafe in their home environment. As a result, families may have to change their pattern of activities. For example, if they do not feel safe, they might not leave the house to shop or for social activities. Hence life in low-SES or unsafe neighborhoods may be more stressful on a day-to-day basis [30]. In addition, families who live in low-SES or unsafe neighborhoods may have fewer material and social resources for coping with stressors when they arise, adding to the overall burden of stress for these individuals. In the section below on biological mechanisms, we discuss the notion that the experience of stress may directly influence biological systems in a way that has implications for asthma. A second possibility is that neighborhood factors have effects on asthma by changing behaviors. For example, low-SES neighborhoods may have different social norms about the acceptability of certain health behaviors, such as smoking. If smoking is more prevalent and accepted in low-SES neighborhoods, individuals with asthma are more likely to both be exposed to secondhand smoke, as well as to be smokers themselves. Hence low-SES neighborhoods might increase the risk for health behaviors that are detrimental to asthma. In addition, neighborhoods with high levels of violence may create barriers to asthma management behaviors. For example, unsafe neighborhoods may make it difficult to fill asthma prescription medications in a timely fashion [31]. Finally, living in a neighborhood with frequent violence could affect asthma if individuals with asthma are more likely to spend time inside their homes, resulting in greater exposure to indoor allergens as well as more sedentary behaviors [31]. Social networks and asthma A number of studies have asked whether the types of social networks or social support an individual has can impact asthma morbidity. Social
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support can come from a number of sources, including friends, colleagues, teachers, physicians, and other asthma patients. Moreover, social support can be conceptualized both in terms of the perceived quality, or closeness, of social relationships, as well as the quantitydthat is, the diversity or extensivenessdof one’s social networks. Patients with asthma report that social networks are quite valuable and helpful when it comes to managing their asthma [32,33]. Although patients perceive their social networks to be beneficial, the studies that have examined whether they are related to asthma outcomes have mixed conclusions. On the positive end, a number of studies have found social support to be associated with asthma outcomes. For example, poor confidant support and negative support were related to a greater likelihood of hospital admissions in adult patients with asthma [34]. Conversely, having better social contacts predicted fewer asthma symptoms and, to a lesser degree, better peak expiratory flow rate over the course of 3 weeks [35]. Social support may also be most effective as a buffer against stress. For example, individuals who experienced both more negative life events and low social support reported the most episodes of cold-induced asthma exacerbations [36]. Finally, Levy and colleagues [37] reported that after an unrelated intervention in youth with asthma in one of three housing developments studied, those whose social networks improved were more likely to experience a decrease in asthma symptoms relative to baseline measures. Similarly, among children with asthma, the social networks of parents are related to clinical outcomes in their children. For example, parents who reported low social support were more likely to have children who were admitted to the emergency department [38] and who were at greater risk for continued atopic illness [39]. Conversely, families reporting good social support had children at reduced risk of both wheezing and asthma [40] and more likely to recover from atopic illness between the ages of 18 months and 3 years [39]. Weil and colleagues [41] also reported some evidence of an association between good social support in parents and marginally fewer days of wheeze in their children. That social support to the family can work in very practical ways was demonstrated in a Norwegian study that found that access to a specialized asthma health care facility was in part influenced by whether families of children with asthma had a physician in their social network [42]. Finally, in addition to morbidity outcomes, social support also may affect behaviors relevant to asthma. Two studies of youth with asthma found that receiving social support was related to better asthma self-management behaviors, such as greater medication adherence and more willingness to seek immediate help from other people in response to breathing problems [32,33]. Adults with asthma also reported their social network to be the main factor facilitating exercise and an active and healthy lifestyle [43].
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In contrast to the above studies, a handful of studies have found no relationship between social support and asthma. Ngamvitroj and Kang [44] reported that social support was not a significant predictor of greater peak expiratory flow rate self-monitoring over the subsequent 3 months even though participants’ satisfaction with their social support was very good. A study of youth with asthma found that, whereas family support was associated with better pulmonary functioning and fewer asthma symptoms, peer support was not related to either of those factors [28]. Finally, one study investigating the risk factors for asthma mortality matched adults who died of asthma with a comparison group of patients with asthma who were hospitalized but did not die. None of the factors relating to people’s social networks, including bereavement, separation, or isolation, was found to be a significant risk factor for asthma mortality [45]. Finally, it is important to also consider the possibility that social networks may, in some circumstances, exert negative influences. For example, in certain situations, social networks may create peer pressure to engage in detrimental health behaviors. Precht and colleagues [46] found that high school students with asthma, in particular boys, were more likely than healthy students to smoke because of peer pressure, although the overall occurrence was rare. Chen and colleagues [28] also found that stronger peer support in youth with asthma was related to lower medication adherence. This too may reflect the desire of youth to fit in with their peers and not stand out because of their asthma, potentially resulting in their neglecting to take medications appropriately. Explaining social network effects Social support and social networks may affect asthma through a variety of pathways. For example, social networks are important sources of tangible support (ie, concrete assistance with tasks). This may take the form of providing rides to the doctor, watching siblings so that a parent can take a child with asthma to the doctor, or offering to pick up important medications from the pharmacy. The larger one’s social network, the more options one has to draw on for this type of help. These types of assistance with asthma management behaviors may help explain one way in which social networks can be beneficial for coping with asthma. Living with a chronic illness such as asthma can require a number of changes to daily routines, and it can be difficult for many families to balance asthma management with the other daily responsibilities in life. Hence, social networks may provide additional sources of support for managing with all these tasks. Second, social networks may also provide tangible support in the form of knowledge and advice. For example, patients with asthma may learn new information from others with asthma, such as information about new medications or helpful sources of care for asthma. Patients with asthma may also learn from others different strategies for better managing their asthma (eg,
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for remembering to take their medications) and may find others to be helpful role models for both daily management and responses to symptom exacerbations. Another form of support offered by social networks is emotional support. In contrast to the concrete assistance of tangible support, emotional support refers to providing empathy and understanding for another person’s emotional reactions and feelings. This type of support could affect asthma outcomes in a number of ways. First, emotional support may help patients with asthma be more accepting of their illness. This may lead to more positive mental health states, with implications down the line for physical health. Second, support from others with respect to one’s emotional responses may help patients with asthma remain calm during times of symptom exacerbations. This in turn may facilitate appropriate implementation of asthma action plans and optimal responses to asthma symptoms. Third, support from others may increase positive emotional states and decrease negative emotional states more generally in patients with asthma. In turn, these emotional experiences could alter physiologic states in ways that have implications for asthma. As we described above, social networks can sometimes have negative influences on asthma, particularly among youth. It is possible that youth with asthma are more susceptible to negative peer pressure because their asthma already makes them socially vulnerable. For example, if youth have activity limitations due to asthma that make them feel different and less accepted, they may be more likely to engage in maladaptive behaviors, such as smoking, to fit in or gain approval from peers. Thus, even if they are aware of the negative impact of such behaviors, knowledge alone may not be sufficient to drive behavior, particularly if there are competing pulls from peers that conflict with this knowledge.
Family effects on asthma Evidence suggests that both the quality of family relationships and the psychosocial traits that family members possess affect asthma outcomes. Much of this research has focused on children with asthma and has investigated how family factors affect them. We will review evidence for links between family relationship quality and asthma, as well as links between parent traits, such as parental depression and stress, and childhood asthma. Family relationships The quality of relationships with family members affects not only a child’s psychologic well-being but also his or her physical well-being. For example, family relationships early in life predict the likelihood of children getting diagnosed with asthma years later. In a sample of children at risk for developing asthma, researchers measured parenting difficulties when infants were
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3 weeks old. During home visits, clinicians assessed parenting difficulties by observing attitudes and behaviors parents exhibited toward their child, parents’ ability to regulate their child’s arousal and emotions, the supportiveness of parents’ relationship with each other, and the balance in the home between childcare and other demands. Children were then followed for several years to track the development of asthma. Greater parenting difficulties when an infant was 3 weeks old prospectively predicted a greater likelihood of that child being diagnosed with asthma, both by the age of 3 and by the age of 8 [47,48]. In addition, among children already diagnosed with asthma, family relationship quality contributes to morbidity and mortality. One classic example of this is a case-control study that recruited two groups of children hospitalized for asthma. One group consisted of children who died of asthma following hospital discharge. The second group was made up of children who did not die, despite having similar severity of illness. A number of psychologic and social factors distinguished these two groups, including parent-patient conflict and family dysfunction. Children in the group who died from asthma were more likely to have persistent and severe arguments with parents, as well as to have families with greater dysfunction (eg, intense marital conflict) [49]. Similar types of relationships were found with respect to asthma morbidity outcomes. Among a sample of children with asthma, those who reported receiving less support from their parents had more asthma symptoms and poorer daily pulmonary function [28]. Parent characteristics The psychosocial characteristics of a parent can also affect asthma outcomes in a child. For example, higher levels of maternal depression have consistently been linked to childhood asthma. Shalowitz and colleagues [50] documented that parents who reported greater symptoms of depression had children who were more likely to use health care services and who experienced more severe asthma symptoms. Similarly, among a sample of children hospitalized for asthma, depression in parents was associated with a greater number of unscheduled physician visits as well as a greater number of hospitalizations for asthma in their children [51]. Longitudinal studies show similar patterns. Weil and colleagues [41] found that children of parents having clinically significant levels of mental health problems (including depression) at baseline had twice the rate of hospitalization for asthma during a 9-month follow-up period compared with children of parents without mental health problems. Inner-city mothers with high levels of depressive symptoms at baseline were 30% more likely than nondepressed mothers to report taking their children to the emergency department for asthma during the following 6 months [52]. These longitudinal data suggest that depression precedes poor asthma outcomes, rather than the opposite explanationdthat having a child with poorer asthma causes parents to become more depressed.
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Evidence linking parental depression to childhood asthma appears to be stronger for morbidity outcomes among those already diagnosed with asthma than for predicting asthma onset [53]. Greater parental stress also has been linked to increased asthma morbidity in children. For example, Shalowitz and colleagues [50] documented that caregivers with more negative life stressors were more likely to have children who used health care services and who experienced more severe asthma symptoms. Longitudinal studies show similar effects. Among a sample of children diagnosed with asthma, reports indicating greater life stress for parents predicted a greater likelihood of asthma hospitalization as well as poorer daily functioning in children over the following 9 months [41]. High levels of caregiver stress when infants were 2 to 3 months old predicted a higher likelihood of repeated wheezing in children by 14 months of age [54]. As with maternal depression, evidence suggests that parental stress may not predict asthma diagnosis [48,53]. However, parental stress may interact with family relationship problems to predict asthma. Parents who experienced a combination of both parenting difficulties (when the child was 3 weeks of age) and high stress at the end of pregnancy were five times more likely to have a child who developed asthma by the age of 3 compared with those without parenting difficulties (with or without high stress), and 2.5 times as likely to develop asthma compared with those with parenting difficulties but with low stress [55]. Explaining family effects How does the psychologic state of one individual (a parent) come to affect asthma outcomes in another individual (the child)? One possibility is that the difficulties that children experience early in life may program their biological systems in a way that increases their vulnerability to asthma later in life. For example, difficulties bonding with parents may lead to insecure attachments and difficulties regulating emotions, which in turn may enhance the biological responses to stresses in children [56]. Certain family characteristics may also influence the amount of stress a child perceives. For example, family conflict or a poor quality family relationship can be a source of stress in and of itself. In addition, parental depression or stress may create stress for the child by affecting how parents interact with their child or because children are sensitive in picking up on the psychologic states of their parents. Another possibility is that the family environment influences how children cope with events in their own lives. Coping refers to cognitive and behavioral efforts aimed at dealing with external demands from the environment [57]. One important type of coping strategy is to draw on close others to help you with your problems. A parent struggling with depression or significant life stressors may be less available to help a child deal with his or her problems. Hence, having low levels of family support may heighten
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the impact of a stressor, given that these children will have more limited resources for getting help with their problems. In addition, children from difficult family circumstances may have parents who model maladaptive coping strategies. For example, children may observe parents with depression or stress struggling to cope with their own problems, and may attempt similar ineffective coping strategies for their problems. Or, such parents may use less effective coping strategies when parenting their child, leading children to have greater difficulty regulating their own emotional responses in daily life. Another possibility is that family factors affect the health behaviors a child engages in, which in turn affects asthma morbidity. For example, parents who have high levels of depression or stress may be less available to supervise their child’s behaviors. This could lead to a greater influence of peers in shaping detrimental health behaviors, such as smoking. These parents may also have a more difficult time monitoring and ensuring their child’s compliance with asthma medications. This could mean that, among children whose parents are depressed or stressed, asthma is more likely to be improperly managed on a daily basis, leading to greater asthma morbidity over time.
Biological mechanisms The above studies have linked social environment factors to clinical asthma outcomes. However, the question still remains of how the larger social environment gets ‘‘under the skin’’ to influence disease. Is there evidence that social environment factors are linked to biological processes implicated in asthma? In this section, we first briefly overview the types of inflammatory mechanisms relevant to asthma, and then address whether social factors are associated with these pathways. Other articles have provided broader overviews of biological systems implicated in biopsychosocial models of asthma [58–60]. Inflammatory pathways in asthma One pathway to airway inflammation in asthma involves the activation of certain T helper cells, which in turn release cytokines that coordinate inflammatory responses. These cells, known as Th-2 cells, promote B cell proliferation and differentiation, leading to a humoral response involving antibody synthesis. For example, the Th-2 cytokines IL-4 and IL-13 bind to B cells, inducing them to synthesize and release IgE antibodies. IgE then binds to mast cells residing in the airways, causing them to degranulate and release allergic mediators, such as histamines and leukotrienes. Histamines and leukotrienes cause edema, smooth muscle constriction, and mucus production. A second type of inflammatory response is generated when Th-2 cells release IL-5. This cytokine recruits eosinophils into the airways, where they bring about inflammation and obstruction. Eosinophils also release mediators,
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such as eosinophil cationic protein and major basic protein, which can bring about damage to airway cells, and leukotrienes, which cause edema and further bronchial constriction. Social factors and inflammatory responses At the neighborhood level, low SES has been linked to asthma-related inflammatory markers in children with asthma. In one study, adolescents diagnosed with persistent asthma were recruited from either low-SES or highSES neighborhoods (based on the percentage of people living below poverty in each neighborhood). Peripheral blood was drawn from adolescents, and their cells were stimulated with a combination of phorbol myristate acetate and ionomycin to induce the production of cytokines. Adolescents with asthma from low-SES neighborhoods displayed significantly greater production of IL-5 compared with adolescents with asthma from high-SES neighborhoods, despite their cells having been exposed to an equivalent dose of mitogens [61]. In a subsequent study, children with asthma were recruited from a range of SES backgrounds. A linear relationship was found, such that as family SES decreased, production of IL-5, IL-13, and eosinophil counts all increased in children with asthma, but not among healthy children [62]. These findings suggest that low-SES children with asthma exhibit heightened inflammatory responses, and that the direction of these responses may help explain why low SES is linked to more severe exacerbations of asthma. At the level of social networks and social support, one previously mentioned study [28] found that unlike family and neighborhood factors, peer support was not related to any of the biological variables investigated, including the production of cytokines implicated in asthma or eosinophil counts, in youth with asthma. These findings suggest that the link between peer support and biological processes in children with asthma is weak, perhaps consistent with the fact that the link between social support and clinical asthma outcomes is mixed. Another study examining the effect of social support on stress before and after examinations in high school students found that perceived social support decreased during examination time and that this decrease was accompanied by a decrease in natural killer cells [63]. However, this pattern for natural killer cells was found in both adolescents with asthma and in healthy adolescents, suggesting that social support may not activate immune pathways specific to asthma. At the family level, recent evidence suggests that parent psychologic states are associated with child biological profiles. Higher levels of parental depression have been associated with eosinophil cationic protein (ECP), a substance released when eosinophils are activated. Specifically, greater parental depression at baseline predicted increases in ECP over the following 6 months in a sample of children with asthma and a sample of healthy children [64]. With respect to parental stress, higher levels of parental
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perceived stress at baseline predicted greater increases over the following 6 months both in ECP as well as in stimulated production of IL-4 in these same samples of children [64]. Among young children, high levels of parental stress during the first 6 months of the child’s life predicted higher IgE levels at 2 years of age, as well as an increased proliferation of children’s lymphocytes after in vitro exposure to selected allergens [65]. These findings suggest that poorer parent mental health is associated with inflammatory profiles in children in a direction detrimental to asthma. In earlier sections, we hypothesized that one reason why larger social environmental factors influence health outcomes is because environmental factors, such as low SES and poor family relationships, affect the stress that an individual experiences. In turn, clinical evidence indicates individuals who experience greater stress also are at risk for poorer asthma outcomes [35,66,67]. Recent evidence corroborates this clinical data, suggesting that stress affects inflammatory processes of individuals with asthma. For example, in one study, college students with asthma were tested during periods of high stress (final examination period) and during periods of low stress (no major examination) [68]. Each time, participants inhaled increasing dosages of allergens to which they were sensitized (ragweed, cat, or dust mite) until their pulmonary functioning declined by 20% or more. There was evidence of a greater immune response to this challenge during times of stress. During final examinations, the allergen challenge elicited greater numbers of eosinophils in both sputum and blood compared with periods outside of examination time. A parallel finding emerged for in vitro production of IL-5 in sputum treated with phytohemagglutinin. In a separate series of studies, high school students were studied before an examination (baseline period of low stress) and after examinations (highstress period), and their peripheral blood cells were stimulated in vitro with various mitogens. In one study, students with asthma had greater production of IL-5 postexamination compared with students who were healthy. In contrast, there were no group differences in IL-5 production at baseline. This suggests that under conditions of low stress, individuals with asthma do not differ from healthy individuals in their responsiveness to mitogens, but that periods of stress heighten the responsiveness of Th-2 immune cells to mitogens in individuals with asthma [69]. A second study from this group documented that examination stress was associated with reduced production of the Th-1 cytokines IFN-g and IL-2, but increased production of the proinflammatory cytokine IL-6 (argued by this group to represent Th-2) across both a sample of students with asthma and a sample of healthy students [70]. Collectively, these studies suggest that, among patients with asthma, stress can amplify the Th-2 cytokine response to asthma triggers and mitogens. Over time, such an inflammatory pattern could lead to more frequent or severe symptoms of asthma. Taken together, the studies reviewed in this section provide intriguing evidence that the larger social environmentdin particular at the family and
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neighborhood levelsdcan alter biological systems in individuals. This link between the social environment and biology is important to provide plausible explanations for how it is that social environments come to influence the course of diseases. With additional empiric evidence from future studies, researchers can begin to develop more comprehensive models of how larger social factors affect individuals psychologically and behaviorally, and in turn what the biological and long-term health implications of these effects are. Summary In this article, we addressed the question of whether the social environment affects the onset or course of asthma. We reviewed evidence showing that neighborhood-level factors, such as low SES and community violence, are associated with greater asthma morbidity. In addition, family-level factors, such as poor quality family relationships, parental depression, and parental stress, are associated with poorer asthma outcomes. In contrast, peer-level factors, such as social support, were more mixed in their association with asthma, with some studies finding that support is beneficial for asthma, and others finding no relationship or even detrimental effects of peers on asthma. Longitudinal studies indicate that neighborhood and family social factors precede asthma, rather than being a consequence of asthma. The strongest evidence exists for social factors predicting morbidity among those already diagnosed with asthma, with evidence being more mixed for social factors predicting the development of asthma. Social factors likely operate via direct effects on physiologic systems, as well as by changing health behaviors in individuals with asthma. In sum, while exposure to factors in the physical environment has long been recognized as contributing to asthma, the studies reviewed in this article highlight the importance of also considering social exposures in asthma. To push the field forward in developing more comprehensive models of asthma, the concept of environmental exposures in asthma needs to be more broadly defined. Exposures, both physical and social, affect asthma in significant ways. References [1] Sigurs N, Gustafsson PM, Bjarnason R, et al. Severe respiratory syncytial virus bronchiolitis in infancy and asthma and allergy at age 13. Am J Respir Crit Care Med 2005;171(2):137–41. [2] Nelson HS, Szefler SJ, Jacobs J, et al. The relationships among environmental allergen sensitization, allergen exposure, pulmonary function, and bronchial hyperresponsiveness in the childhood asthma management program. J Allergy Clin Immunol 1999;104:775–85. [3] Ober C, Hoffjan S. Asthma genetics 2006: the long and winding road to gene discovery. Genes Immun 2006;7(2):95–100. [4] Weiss ST. Gene by environment interaction and asthma. Clin Exp Allergy 1999;29(2):96–8. [5] Yen IH, Yelin EH, Katz P, et al. Perceived neighborhood problems and quality of life, physical functioning, and depressive symptoms among adults with asthma. Am J Public Health 2006;96(5):873–9.
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[6] Yen IH, Yelin E, Katz P, et al. Impact of perceived neighborhood problems on change in asthma-related health outcomes between baseline and follow-up. Health Place 2008;14: 468–77. [7] Adler NE, Epel ES, Castellazzo G, et al. Relationship of subjective and objective social status with psychological and physiological functioning: preliminary data in health white women. Health Psychol 2000;19:586–92. [8] Blascovich J, Mendes WB, Hunter SB, et al. Perceiver threat in social interactions with stigmatized others. J Pers Soc Psychol 2001;80:253–67. [9] Miller JE. The effects of race/ethnicity and income on early childhood asthma prevalence and health care use. Am J Public Health 2000;90:428–30. [10] Wood PR, Smith LA, Romero D, et al. Relationships between welfare status, health insurance status, and health and medical care among children with asthma. Am J Public Health 2002;92(9):1446–52. [11] Simon PA, Zeng ZW, Wold CM, et al. Prevalence of childhood asthma and associated morbidity in Los Angeles County: impacts of race/ethnicity and income. J Asthma 2003;40(5): 535–43. [12] Dales RE, Choi B, Chen Y, et al. Influence of family income on hospital visits for asthma among Canadian school children. Thorax 2002;57(6):513–7. [13] Maziak W, Von Mutius E, Keil U, et al. Predictors of health care utilization of children with asthma in the community. Pediatr Allergy Immunol 2004;15(2):166–71. [14] Amre DK, Infante-Rivard C, Gautrin D, et al. Socioeconomic status and utilization of health care services among asthmatic children. J Asthma 2002;39:625–31. [15] Goodman DC, Stukel TA, Chang C. Trends in pediatric asthma hospitalization rates: regional and socioeconomic differences. Pediatrics 1998;101:208–13. [16] Claudio L, Stingone JA, Godbold J. Prevalence of childhood asthma in urban communities: the impact of ethnicity and income. Ann Epidemiol 2006;16(5):332–40. [17] Castro M, Schechtman KB, Halstead J, et al. Risk factors for asthma morbidity and mortality in a large metropolitan city. J Asthma 2001;38(8):625–35. [18] Persky VW, Slezak J, Contreras A, et al. Relationships of race and socioeconomic status with prevalence, severity, and symptoms of asthma in Chicago school children. Ann Allergy Asthma Immunol 1998;81(3):266–71. [19] Cesaroni G, Farchi S, Davoli M, et al. Individual and area-based indicators of socioeconomic status and childhood asthma. Eur Respir J 2003;22(4):619–24. [20] Grant EN, Wagner R, Weiss KB. Observations on emerging patterns of asthma in our society. J Allergy Clin Immunol 1999;104(2):S1–9. [21] Webber MP, Carpiniello KE, Oruwariye T, et al. Prevalence of asthma and asthma-like symptoms in inner-city elementary schoolchildren. Pediatr Pulmonol 2002;34(2):105–11. [22] Saha C, Riner ME, Liu G. Individual and neighborhood-level factors in predicting asthma. Arch Pediatr Adolesc Med 2005;159(8):759–63. [23] Juhn YJ, St Sauver J, Katusic S, et al. The influence of neighborhood environment on the incidence of childhood, asthma: a multilevel approach. Soc Sci Med 2005;60(11): 2453–64. [24] Yawn BP, Wollan P, Kurland M, et al. A longitudinal study of the prevalence of asthma in a community population of school-age children. J Pediatr 2002;140(5):576–81. [25] Graham PJ, Rutter ML, Yule W, et al. Childhood asthma: a psychosomatic disorder? Br J Prev Soc Med 1967;21:78–85. [26] Wright RJ. Health effects of socially toxic neighborhoods: the violence and urban asthma paradigm. Clin Chest Med 2006;27(3):413–21. [27] Wright RJ, Mitchell H, Visness CM, et al. Community violence and asthma morbidity: the inner-city asthma study. Am J Public Health 2004;94(4):625–32. [28] Chen E, Chim LS, Strunk RC, et al. The role of the social environment in children and adolescents with asthma. Am J Respir Crit Care Med 2007;176:644–9.
DOES THE SOCIAL ENVIRONMENT CONTRIBUTE TO ASTHMA?
663
[29] Clougherty JE, Levy JI, Kubzansky LD, et al. Synergistic effects of traffic-related air pollution and exposure to violence on urban asthma etiology. Environ Health Perspect 2007;115: 1140–6. [30] Brady SS, Matthews KA. The effect of socioeconomic status and ethnicity on adolescents’ exposure to stressful life events. J Pediatr Psychol 2002;27:575–83. [31] Wright RJ, Steinbach SF. Violence: an unrecognized environmental exposure that may contribute to greater asthma morbidity in high risk inner-city populations. Environ Health Perspect 2001;109:1085–9. [32] Sin MK, Kang DH, Weaver M. Relationships of asthma knowledge, self-management, and social support in African American adolescents with asthma. Int J Nurs Stud 2005;42(3): 307–13. [33] Knight D. Beliefs and self-care practices of adolescents with asthma. Issues Compr Pediatr Nurs 2005;28:71–81. [34] Wainwright NW, Surtees PG, Wareham NJ, et al. Psychosocial factors and incident asthma hospital admissions in the EPIC-Norfolk cohort study. Allergy 2007;62(5):554–60. [35] Smyth JM, Soefer MH, Hurewitz A, et al. Daily psychosocial factors predict levels and diurnal cycles of asthma symptomatology and peak flow. J Behav Med 1999;22(2):179–93. [36] Smith A, Nicholson K. Psychological factors, respiratory viruses and exacerbation of asthma. Psychoneuroendocrinology 2001;26:411–20. [37] Levy JI, Brugge D, Peters JL, et al. A community-based participatory research study of multifaceted in-home environmental interventions for pediatric asthmatics in public housing. Soc Sci Med 2006;63(8):2191–203. [38] Rand CS, Butz AM, Kolodner K, et al. Emergency department visits by urban African American children with asthma. J Allergy Clin Immunol 2000;105:83–90. [39] Gustafsson PA, Kjellman NI, Bjorksten B. Family interaction and a supportive social network as salutogenic factors in childhood atopic illness. Pediatr Allergy Immunol 2002; 13(1):51–7. [40] Berz JB, Carter AS, Wagmiller RL, et al. Prevalence and correlates of early onset asthma and wheezing in a healthy birth cohort of 2- to 3-year olds. J Pediatr Psychol 2007;32(2): 154–66. [41] Weil CM, Wade SL, Bauman LJ, et al. The relationship between psychosocial factors and asthma morbidity in inner-city children with asthma. Pediatrics 1999;104:1274–80. [42] Finnvold JE. Access to specialized, health care for asthmatic children in Norway: the significance of parents’ educational background and social network. Soc Sci Med 2006;63(5): 1316–27. [43] Mancuso CA, Sayles W, Robbins L, et al. Barriers and facilitators to healthy physical activity in asthma patients. J Asthma 2006;43(2):137–43. [44] Ngamvitroj A, Kang DH. Effects of self-efficacy, social support and knowledge on adherence to PEFR self-monitoring among adults with asthma: a prospective repeated measures study. Int J Nurs Stud 2007;44(6):882–92. [45] Sturdy PM, Victor CR, Anderson HR, et al. Psychological, social and health behaviour risk factors for deaths certified as asthma: a national case-control study. Thorax 2002;57(12): 1034–9. [46] Precht DH, Keiding L, Nielsen GA, et al. Smoking among upper secondary pupils with asthma: reasons for their smoking behavior: a population-based study. J Adolesc Health 2006;39(1):141–3. [47] Mrazek DA, Klinnert M, Mrazek PJ, et al. Prediction of early-onset asthma in genetically atrisk children. Pediatr Pulmonol 1999;27:85–94. [48] Klinnert MD, Nelson HS, Price MR, et al. Onset and persistence of childhood asthma: predictors from infancy. Pediatrics 2001;108:e69. [49] Strunk RC, Mrazek DA, Fuhrmann GS, et al. Physiologic and psychological characteristics associated with deaths due to asthma in childhood. J Am Med Assoc 1985;254:1193–8.
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CHEN & SCHREIER
[50] Shalowitz MU, Berry CA, Quinn KA, et al. The relationship of life stressors and maternal depression to pediatric asthma morbidity in a subspecialty practice. Ambul Pediatr 2001; 1(4):185–93. [51] Brown ES, Gan V, Jeffress J, et al. Psychiatric symptomatology and disorders in caregivers of children with asthma. Pediatrics 2006;118(6):E1715–20. [52] Bartlett SJ, Kolodner K, Butz AM, et al. Maternal depressive symptoms and emergency department use among inner-city children with asthma. Arch Pediatr Adolesc Med 2001; 155(3):347–53. [53] Horwood LJ, Fergusson DM, Shannon FT. Social and familial factors in the development of early childhood asthma. Pediatrics 1995;75:859–68. [54] Wright RJ, Cohen S, Carey V, et al. Parental stress as a predictor of wheezing in infancy: a prospective birth-cohort study. Am J Respir Crit Care Med 2002;165:358–65. [55] Klinnert MD, Mrazek PJ, Mrazek DA. Early asthma onset: the interaction between family stressors and adaptive parenting. Psychiatry 1994;57:51–61. [56] Taylor SE, Lerner JS, Sage RM, et al. Early environment, emotions, responses to stress, and health. J Pers 2004;72(6):1365–93. [57] Lazarus RS, Folkman S. Stress, appraisal, and coping. New York: Springer Publishing Company; 1984. [58] Wright RJ, Rodriguez M, Cohen S. Review of psychosocial stress and asthma: an integrated biopsychosocial approach. Thorax 1998;53:1066–74. [59] Wright RJ. Stress and atopic disorders. J Allergy Clin Immunol 2005;116:1301–6. [60] Chen E, Miller GE. Stress and inflammation in exacerbations of asthma. Brain Behav Immun 2007;21:993–9. [61] Chen E, Fisher EB Jr, Bacharier LB, et al. Socioeconomic status, stress, and immune markers in adolescents with asthma. Psychosom Med 2003;65:984–92. [62] Chen E, Hanson MD, Paterson LQ, et al. Socioeconomic status and inflammatory processes in childhood asthma: the role of psychological stress. J Allergy Clin Immunol 2006;117(5): 1014–20. [63] Kang DH, Coe CL, Karaszewski J, et al. Relationship of social support to stress responses and immune function in healthy and asthmatic adolescents. Res Nurs Health 1998;21(2): 117–28. [64] Wolf JM, Miller GE, Chen E. Parent psychological states predict changes in inflammatory markers in children with asthma and healthy children. Brain Behav Immun 2008;22:433–41. [65] Wright RJ, Finn P, Contreras JP, et al. Chronic caregiver stress and IgE expression, allergeninduced proliferation, and cytokine profiles in a birth cohort predisposed to atopy. J Allergy Clin Immunol 2004;113(6):1051–7. [66] Sandberg S, Paton JY, Ahola S, et al. The role of acute and chronic stress in asthma attacks in children. Lancet 2000;356:982–7. [67] Kilpelainen M, Koskenvuo M, Helenius H, et al. Stressful life events promote the manifestation of asthma and atopic diseases. Clin Exp Allergy 2002;32(2):256–63. [68] Liu LY, Coe CL, Swenson CA, et al. School examinations enhance airway inflammation to antigen challenge. Am J Respir Crit Care Med 2002;165:1062–7. [69] Kang D, Coe C, McCarthy DO, et al. Cytokine profiles of stimulated blood lymphocytes in asthmatic and healthy adolescents across the school year. J Interferon Cytokine Res 1997;17: 481–7. [70] Kang DH, Fox C. Th1 and Th2 cytokine responses to academic stress. Res Nurs Health 2001;24(4):245–57.
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Asthma in the Inner City and the Indoor Environment Elizabeth C. Matsui, MD, MHSa, Nadia N. Hansel, MD, MPHb, Meredith C. McCormack, MD, MHSb, Robert Rusher, MDb, Patrick N. Breysse, PhDc, Gregory B. Diette, MD, MHSb,* a Johns Hopkins University School of Medicine, Department of Pediatrics, Division of Allergy/Immunology, 600 N. Wolfe Street, CMSC 1102, Baltimore, MD 21287, USA b Johns Hopkins University School of Medicine, Department of Medicine, Division of Pulmonary and Critical Care Medicine, 1830 East Monument St., 5th Floor, Baltimore, MD 21205, USA c Johns Hopkins University Bloomberg School of Public Health, Department of Environmental Health Sciences, 615 N. Wolfe Street, Rm E6630, Baltimore, MD 21287, USA
Inner-city residents continue to suffer disproportionate asthma morbidity despite recent progress in reducing asthma morbidity and mortality in other strata of the United States population. Although many factors are likely responsible for these disparities, studies conducted over the past decade indicate that the indoor environment is a strong contributor to poor asthma control and asthma-related health care use in inner-city populations. The term ‘‘inner city’’ generally refers to impoverished urban neighborhoods where housing is often very old and dilapidated, so that certain indoor exposures are more common and occur in higher concentrations than in suburban communities [1]. Identification of ‘‘asthmagenic’’ indoor exposures has paved the way for the development of intervention strategies aimed at reducing asthma morbidity, principally by reducing these This work is supported by the National Institutes of Health grants R18 HL73833 and 1P50ES015903-01; the Environmental Protection Agency grant R8267240); and the National Institutes of Health Disease Investigation Through Specialized Clinically-Oriented Ventures in Environmental Research (DISCOVER) grant 1P50ES015903). * Corresponding author. E-mail address:
[email protected] (G.B. Diette). 0889-8561/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.iac.2008.03.004 immunology.theclinics.com
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exposures. This article reviews the growing body of evidence that certain indoor environmental exposures contribute to the burden of asthma in the inner city. The major categories of indoor exposures include allergens and other biologics, such as endotoxin, as well as pollutants. The major indoor allergens include those associated with dust mites, cats, dogs, mice, rats, cockroaches, and molds. Important indoor air pollutants include particulate matter (PM), nitrogen dioxide (NO2), secondhand tobacco smoke, and ozone. Indoor allergens and endotoxin Overview Allergic sensitization is an important risk factor for asthma for both children and adults. One recent study that included children and adults estimated the population-attributable risk for allergic sensitization to be 56%. In other words, more than half of asthma cases in the United States can be attributed to allergic sensitization [2]. In the pediatric population, about 80% of school-age children with asthma have evidence of allergic sensitization to at least one common environmental allergen [3,4]. Allergic sensitization to the predominant allergen in a community confers a 4- to 20-fold increase in the risk of asthma [5–7], suggesting a causal relationship between allergen exposure and the development of asthma. Moreover, populations with more poorly controlled asthma have higher prevalence rates of sensitization than populations with well-controlled asthma. In one recent inner-city study of children with poorly controlled asthma, a staggering 94% of children had evidence of allergic sensitization [8], highlighting the potential importance of allergic sensitization as a risk factor for poorly controlled asthma. Studies have also clearly demonstrated that exposure can lead to both acute and chronic symptoms in sensitized patients with asthma [4,9–13]. Although seasonal allergens are known triggers of asthma, overall exposure to indoor allergens may be greater given the substantial amount of time spent indoors as well as the year-round presence of many indoor allergens. In addition, among innercity children with asthma, sensitivity to indoor allergens is more prevalent than sensitivity to outdoor allergens, underscoring the relevance of indoor allergen exposure in this population [14]. Although all of the major allergens can be found in inner-city homes, the distribution of allergens depends somewhat on the geographic region of the inner city [8,15,16]. For example, the dust mite is the predominant allergen in inner-city homes of southern and northwestern United States. In contrast, pest allergens, such as rodent and cockroach allergens, are the predominant allergens in northeastern inner-city homes where dust mite allergens are less common. Some of these regional differences in allergen ecology appear to be due to differences in climate and housing stock. As such, it is important to understand which allergens are most important in a given geographic area
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so that appropriate allergy testing can be performed, and tailored environmental control recommendations can be provided to patients. Rodent allergens Mice and rats excrete urinary allergens that are carried on small particles that readily become airborne [17–19]. The allergens are pheromone-binding proteins that are thought to have a role in mating practices [20] and are excreted in very large quantities in the urine. Although these allergens have long been known to cause occupational asthma, their role in nonoccupational asthma has only recently been described [12,21]. In fact, in some inner cities, mouse allergen appears to be an important contributor to asthma morbidity. The domestic house mouse (Mus musculus) is very common, particularly in urban areas where multifamily dwellings and poorly maintained housing are common [16,22]. Mouse allergen can be found in virtually all inner-city homes, and one study found detectable airborne mouse allergen in 84% of bedrooms of inner-city children with asthma [23]. Airborne mouse allergen levels in as many as 25% of inner-city homes are similar to levels measured in occupational settings, where mouse allergen is a known cause of asthma symptoms. Mouse allergen is surprisingly prevalent in suburban communities as well, with as many as 75% of middle-class, suburban households having detectable mouse allergen levels in settled dust samples [16,24]. However, the levels in these suburban homes are 100-fold lower than the levels observed in inner-city settings. For example, the median settled-dust mouse allergen level in inner-city bedrooms is approximately 2.5 mg/g as compared with 0.02 mg/g in suburban bedrooms. Overall, as many as 75% of homes in inner cities may have clinically relevant levels of mouse allergen [12]. Sensitization to mice is also common, with 18% to 28% of inner-city children with asthma having evidence of allergic sensitization to mice [8,12,21]. Since most of these children are also exposed to clinically relevant levels of mouse allergen, more than 20% of inner-city children with asthma may be at risk for increased morbidity from mouse allergen exposure. Recent studies have linked exposure to mouse allergen to poorer asthma control and an increased risk of asthma-related health care use among mouse-sensitized, inner-city children with asthma [10,12]. In a Baltimore study, mouse-sensitized children with more than 0.5 mg/g of mouse allergen in bedroom settled dust had more symptom days and more days of rescue medication use than children who either were nonsensitized or had lower levels of mouse allergen in their bedrooms. The sensitized and more highly exposed children were also more likely to visit the emergency department or be hospitalized for asthma than children who were either not sensitized or were exposed to lower levels of mouse allergen [12]. Any patient who reports mouse sightings or evidence of mice, such as droppings, is very likely to be exposed to significant levels of mouse allergen
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in the home [22–24]. However, as with cockroach allergen, patients and families may be reluctant to admit a rodent infestation, so that a negative history is not a good predictor of lack of exposure. In addition, substantial levels of mouse allergen can be found in homes with little or no evidence of infestation, because mice nest in hidden spaces and are active at night. Reducing exposure to mouse allergen is feasible, but can be difficult. Although several studies have found an association between the presence of a cat and lower mouse allergen levels [22,23,25], acquisition of a cat as a means of lowering mouse allergen levels has not been studied. In addition, acquisition of a cat should not be recommended as a means of reducing mouse allergen levels in patients who are allergic to both mice and cats. Integrated pest management is the best approach and includes a combination of extermination, vigorous cleaning, meticulous disposal of food remains, and sealing of holes and cracks in walls, doors, and ceilings. Using this approach, the allergen source is eliminated, the allergen reservoirs are cleaned up, and reinfestation is discouraged. In one study, integrated pest management resulted in a 75% reduction in mouse allergen levels in settled dust, while levels increased in the control group [26]. Although no studies have been conducted to determine the impact of mouse allergen reduction on asthma, the evidence to date indicates that reduction of exposure has the potential to improve asthma control and prevent asthma-related morbidity. Rats are also common in urban areas and, although they typically do not venture indoors, rat allergen has been found in 33% of inner-city homes. In one multicenter study, 21% of inner-city children with asthma were sensitized to rats, and the children who were sensitized and exposed to rat allergen in their homes were at greater risk for asthma-related hospitalization and unscheduled medical visits than children who either were not sensitized or not exposed [13]. No published studies have examined methods of reducing household rat allergen, but a reasonable approach would include sealing holes and cracks in the home’s structure, vigorous cleaning to remove reservoir allergen, and extermination. Cockroach allergen The two most common cockroaches found in United States homes are the German cockroach (Blatella germanica) and the American cockroach (Periplaneta americana). Cockroach allergens are carried on relatively large particles (10–40 mm) that quickly settle to dependent surfaces so that the allergens are easiest to detect in settled dust samples, but very difficult to detect in air samples. Multiple allergens from each of these cockroach species have been characterized, but inner-city asthma studies have primarily focused on the German cockroach (Bla g) allergens. Several studies have found that at least half of inner-city homes have clinically relevant levels of cockroach allergen [4,8]. Although as many as 30% of suburban, middleclass homes also contain detectable levels of cockroach allergen, the levels in
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suburban homes are much lower than levels found in inner-city homes [15,27]. For example, approximately half of homes in the inner city have a Bla g 1 level greater than 8 U/g, a level associated with asthma morbidity, but only 10% to 12% of suburban homes have levels that exceed this threshold [27,28]. In inner-city populations, 30% to 70% of children with asthma are sensitized to cockroaches [8,29], and in suburban populations, sensitization rates are about 21% [27]. Cockroach allergen has also been directly linked to poorer asthma outcomes in inner-city children with asthma, including asthma-related health care use [4,8]. In the National Cooperative InnerCity Asthma Study, cockroach-sensitized children with more than 8 U/g of cockroach allergen in their bedrooms had greater morbidity than either nonsensitized or less exposed children [4]. These findings were replicated in the Inner-City Asthma Study for exposure to cockroach allergen levels greater than 2 U/g [8], suggesting that levels below 8 U/g may be sufficient to trigger asthma symptoms. In light of these findings, it is important to assess risk of exposure in sensitized patients and make recommendations for reducing cockroach allergen exposure. Although patient report of cockroach infestation is a good indicator of significant levels of cockroach allergen exposure [15], one cannot be reassured that a patient is not exposed to significant levels of allergen if they fail to report cockroach infestation. Patients may be reluctant to admit pest infestation, and homes without evidence of active infestation often contain substantial levels of the allergen. Substantial reductions in cockroach allergen levels can be achieved using an integrated pest management approach. Several studies have demonstrated that a combination of extermination, vigorous cleaning aimed at reducing reservoir allergen, and meticulous care in disposing of food remains can result in 80% to 90% reductions in cockroach allergen levels [30,31], although not all studies have had this degree of success [32]. One recent study pointed out the importance of using certain pest management techniques, including use of traps, to monitor and direct treatments. This same study showed that methods used by some pest management companies may be inadequate to achieve substantial and lasting reductions in allergen levels [33]. It remains unknown if cockroach allergen reduction alone has a clinical impact. However, the strong evidence that cockroach allergen exposure is linked with asthma morbidity supports recommending an integrated pest management approach to reduce exposure in cockroach-sensitized patients with asthma. Pet allergens Unlike cockroach allergens, cat and dog allergens are carried on small particles that remain airborne and are very adherent to surfaces and clothing [34]. These properties lead to widespread distribution, such that cat and dog
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allergen can even be detected in public buildings, such as schools [35,36]. Allergen is brought to school on the clothing of children with pets at home, and the highest airborne allergen levels occur around the desks of those children with pets [35]. Cat and dog allergens are obviously found in homes with these pets, but the allergens can also be found in homes without pets, though the concentrations are typically 10 to 1000 times lower than homes with a pet [37,38]. The practice of pet keeping occurs across almost all communities in the United States, so that, in general, studies of pet allergen exposure have not focused explicitly on inner-city environments. However, a few innercity studies, particularly recent multicenter inner-city asthma studies, provide some insight into levels of pet allergens and their potential impact on asthma in these communities. These studies have found that there is somewhat less pet ownership in inner-city homes than in suburban homes [39]. Approximately 15% of inner-city families report having a dog, and approximately 13% to 25% report having a cat [8,40], while more than half of suburban families keep pets [39,41]. Not surprisingly, cat and dog allergen levels tend to be lower in inner-city homes than in suburban homes [39]. Sensitization to cats and dogs is also common in inner-city populations with asthma. In the Inner-City Asthma Study, 44% of children were sensitized to cats and 21% to dogs [8], and the prevalence rates of sensitization in suburban or non–inner-city populations range from 50% to 80% for cats and 20% to 30% for dogs [3,39]. For both cat and dog allergens, considerable evidence supports a relationship between allergen exposure and exacerbation of asthma in sensitized individuals. Epidemiologic studies have demonstrated an increased risk of exacerbations among patients who are both sensitized and highly exposed to cat allergen [8,42]. In addition, allergen challenge studies demonstrate that cat-sensitized asthmatics develop asthma symptoms and decreased lung function in response to airborne cat allergen, even at low levels [37,43,44]. An atopic child with asthma who is sensitized to cat or dog allergen should not live with the respective pet in the home. Pet removal reduces airway responsiveness in those with pet allergic asthma [45]. Once a pet has been removed, allergen levels in settled dust fall in 4 to 6 months to those seen in homes without cats [46]. Levels fall more rapidly if extensive environmental controls are undertaken, such as removal of carpets, upholstered furniture, and other reservoirs, as well as thorough and repeated cleaning. Cat allergen may persist in mattresses for years after a cat has been removed from a home [47], so the purchase of new bedding or impermeable encasements is also recommended. Because so many sensitized patients are unwilling to remove a pet, many compromise measures have been suggested. The use of high-efficiency particulate air (HEPA) filters and vacuum cleaners results in short-term reductions in airborne cat and dog allergen levels, but no change in settled dust allergen concentrations [48–52]. No studies
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to date show an effect of air filters on disease activity [46], although one study demonstrated a reduction in airway responsiveness, without change in any other clinical measure [53]. Dust mite allergens The major dust mite allergens are carried on relatively large particles (10–30 mm) that only briefly remain airborne [54]. The mites infest fabrics and are not particularly mobile, and disturbance is required to detect the allergens in the air. The distribution of house dust mite allergens varies widely among different homes [55,56], with highest concentrations found in the bedroom, especially in the bed. Higher allergen levels are associated with increased moisture, such as in damp houses and basement bedrooms [57]. Because dust mites require higher relative humidity for survival, there are striking geographic differences in dust mite allergen levels. For example, multicenter inner-city asthma studies have found that the highest dust mite allergen levels are found in southern cities, such as Dallas, and northwestern cities, such as Seattle, where two thirds of inner-city homes have clinically relevant levels of mite allergen [8]. In contrast, only 8% to 20% of inner-city homes in New York, Chicago, and Baltimore have clinically relevant dust mite allergen levels. There also appears to be differences between suburban and inner-city homes in the same region of the United States. For example, dust mite allergen levels are approximately five-fold higher in suburban Maryland homes than in inner-city Baltimore homes. The median bedroom dust mite allergen level is 66 ng/g in inner-city Baltimore homes [58], but is 360 ng/g in suburban Maryland homes [59]. Because of these regional and community differences in dust mite allergen levels, few published studies have focused explicitly on dust mite allergen and asthma in inner-city communities. However, based on all studies to date, the 2000 Institute of Medicine Report concluded that there are causal relationships between (1) dust mite allergen exposure and the development of asthma in susceptible children and (2) exposure and asthma exacerbations in sensitized individuals [60]. The evidence cited includes studies in various countries demonstrating an association between dust mite sensitization and asthma (with odds ratios of 6 or more) [5], bronchial provocation experiments showing allergic response [61], and studies of clinical outcomes after mite allergen avoidance [62–69]. Evidence supports dust mite allergen control measures as a reasonable approach to improving asthma in children, though whether to recommend the practices on a larger scale remains controversial. The most effective method of control is the use of allergen-proof encasings fitted to the mattress and pillow [63,70]. Of more than a dozen clinical trials of allergen-proof encasings, seven have demonstrated a reduction in mite allergen and a clinical effect [64–69]. Dust mite covers are available by mail or in retail stores, are
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breathable and comfortable, and exclude nearly 100% of particles carrying mite allergen [71]. Although prior studies have found that allergen-proof bed covers can reduce mite allergen levels and improve clinical outcomes in selected populations, one recent study of over 1100 adults suggests that providing encasings to all patients with asthma may not be an effective public health intervention [72]. Washing sheets, pillowcases, blankets, and mattress pads at least weekly in warm water with detergent and with 8- to 10-minute cycles removes virtually all mite allergen [73]. Dry cleaning [74] and prolonged tumble drying [75] effectively kill mites, but are less effective at removing allergens. Vacuum cleaning reduces the bulk of household dust and reduces the overall exposure burden, but does not change the concentration of mite allergen in settled dust [76]. Second line measures for which there is evidence of mite allergen reduction include removal of wall-to-wall carpeting [77] and steam cleaning [78]. Other measures without supporting evidence include relocation of the bedroom [78] and application of acaracides [79]. The evidence surrounding dehumidifiers is inconsistent, with some studies showing a reduction in mite allergen levels [80], and others not [81]. Mold Mold, a saprophytic fungus, requires moisture, elevated temperatures, and nutrients to grow. These conditions are often found in homes. Mold spores are small (2–10 um), and therefore can remain airborne for extend periods. Hundreds of species of mold can be found indoors. Although there has been a great deal of interest in mold exposure and its impact on respiratory health, studies have been hampered by the complexity of the assessment of mold exposure. Molds can be quantified by measuring spore counts, culturable spores, allergens, or fungal products, and it is not entirely clear which method is best for examining the impact of mold exposure on asthma. In addition, molds can cause adverse health effects through multiple mechanisms, adding to the challenge of studying the impact of mold exposure on asthma. Despite these challenges, a growing body of evidence shows that allergic responses to inhaled mold allergens do result in increased asthma symptoms. Most of these published studies focus on the role of outdoor mold exposure and asthma symptoms, but more recent studies have focused on indoor mold exposure. The best-studied mold in asthma is Alternaria. Exposure to outdoor Alternaria has been associated with asthma symptoms, bronchial hyperresponsiveness, and severe asthma in sensitized individuals in several reports [82–85]. In a recent study, levels of indoor Alternaria were associated with an increased risk of asthma symptoms [86]. Mold exposure has been comprehensively assessed in only a few innercity asthma studies. In the Inner-City Asthma Study, indoor culturable airborne fungi levels were correlated with outdoor levels, underscoring the importance of considering outdoor levels when assessing the relative degree
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of indoor fungal exposure [87]. Homes with dampness, a cat, and cockroach infestation were more likely to have indoor fungal levels that were higher than outdoor fungal levels. The National Academy of Sciences review of asthma and indoor air exposures [60] concluded that there is sufficient evidence of an association between fungal exposure and symptom exacerbation in sensitized asthmatics. The National Academy of Sciences also concluded that evidence is inadequate or insufficient to determine whether there is an association between fungal exposures and the development of asthma. In addition, a large body of literature suggests that damp housing, assessed by evidence of water damage or excessive moisture, is associated with respiratory symptoms and asthma severity [88]. While it is often inferred from this literature that mold is the likely culprit, damp housing is potentially a surrogate for increased pests and their allergens as well as bacteria, viruses, and fungi [88,89]. Patients with asthma should be evaluated for mold sensitization by skin testing or specific IgE testing and, if indoor fungal sources are present, steps should be taken to remove the indoor mold. Although detailed information about abatement strategies are beyond the scope of this article, information about abatement can be found in the 2004 Institute of Medicine’s report, ‘‘Damp Indoor Spaces and Health’’ [89]. Allergen abatement recommendations in clinical care In clinical practice, each patient must be assessed for allergic sensitization using skin testing or serum-specific IgE tests. In fact, many inner-city asthma patients have multiple allergic sensitivities and identification of the specific sensitivities will guide exposure-reduction recommendations. For example, a patient with dust mite and cockroach sensitization should be counseled to concentrate on environmental-control practices aimed at reducing exposure to these allergens, while another patient with cat and mouse sensitizations should concentrate on implementing measures to reduce exposure to these allergens. In general, strategies aimed at reducing a single allergen [32] have been less successful than multimodal interventions in reducing exposures and, consequently, improving asthma control [90,91]. The most recent National Asthma Education and Prevention Program guidelines also support a multimodal approach over a single allergen approach as an integral part of asthma management [92]. Endotoxin Endotoxin is a proinflammatory lipopolysaccharide that makes up the outer membrane of gram-negative bacteria and produces reversible airway inflammation in animal models and human challenge studies [93–95]. Though some epidemiologic evidence in early life suggests that endotoxin exposure may protect against the development of allergic disease [96,97], other studies have found higher levels of endotoxin in homes of children
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with asthma compared with control homes, suggesting that endotoxin may be a risk factor for the development of asthma [98,99]. In some farming communities, high indoor endotoxin exposure is associated with a decreased risk of wheezing and atopic asthma [96]. However, endotoxin levels in these communities may be several-fold higher than levels seen in nonfarming environments, including the inner city. In fact, several studies that have focused on nonfarming communities have reported seemingly contradictory findings. These studies demonstrated a link between increasing endotoxin concentrations and increased prevalence of wheeze in individuals at risk of developing asthma [94,100–102]. Perzanowski and colleagues specifically studied an inner-city birth cohort and demonstrated that children in homes with higher endotoxin concentration were more likely to wheeze at age 2 years (odds ratio 1.34; 95% CI 1.01–1.78) compared with children with lower endotoxin concentrations. Taken together, it appears that endotoxin is a risk factor for wheeze in nonfarming communities, including the inner city, but may protect against wheeze in early-life exposures at the highest levels seen in farming communities. Many studies have shown that, among subjects with asthma, domestic endotoxin exposure is associated with greater asthma severity and increased morbidity, as measured by symptoms, lung function, and medication use [103–106]. Although these findings have not been replicated in inner-city populations, endotoxin levels in inner-city homes are comparable to those in other nonfarming communities where endotoxin has been associated with adverse asthma outcomes [102,107]. However, endotoxin levels in lower-income homes may be higher than those in higher-income homes. For example, in a study conducted in Denver, Colorado, lower-income homes had higher endotoxin concentrations compared with those in higher-income homes [107]. This finding may suggest that endotoxin has some link to increased asthma morbidity in lower socioeconomic homes, though further research is needed to address this hypothesis. Despite the evidence supporting a link between endotoxin exposure and asthma morbidity, no intervention studies specifically evaluating the effectiveness of reducing endotoxin concentration on asthma morbidity have been performed. However, in a prospective randomized controlled trial, a home remediation strategy aimed at moisture reduction noted a decrease in endotoxin concentrations as well as asthma symptom days and health care use [108]. Thus, efforts at reducing endotoxin may eventually be shown to reduce asthma morbidity. However, evidence is now insufficient to support that practice. Indoor air pollution Indoor air pollution is a complex mixture of pollutants migrating indoors from outdoor air and pollutants generated by unique sources indoors. Even though Americans spend nearly 90% of their time indoors [109], most
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scientific investigation of pollutant effects on asthma has focused on outdoor rather than indoor air pollution. Exposure to outdoor air pollutants has been associated with increased airway reactivity, asthma exacerbations, respiratory symptoms, and decreased lung function [110–113]. For some pollutants, indoor air concentrations can greatly exceed outdoor air concentrations [58,114]. Although the link between asthma and indoor air pollutants has not yet been thoroughly studied for all pollutants, research to date suggests that indoor air pollution may play a significant role in asthma morbidity. We summarize the findings of the effects of indoor air pollutants, including ozone, particulate matter, NO2, and secondhand tobacco smoke, on asthma morbidity. Particulate matter PM consists of solid and liquid particles suspended in the air. For outdoor air, the Environmental Protection Agency regulates particulate concentrations through the National Ambient Air Quality Standards. These standards define acceptable outdoor particulate concentrations based on particle size, and outdoor air quality is monitored through a network of national monitoring sites. Until recently, one standards applied to particles with an aerodynamic diameter of less than 2.5 mm (PM2.5) and another applied to particles with an aerodynamic diameter of less than 10 mm (PM10). However, in the latest update, PM2.5 standards were made more stringent and the PM10 annual standard was repealed with a new goal of implementing standards for the coarse PM fraction, defined as particles measuring from 2.5 to 10 mm (PM2.5-10). One reason that regulations for PM2.5-10 may supplant those for PM10 is that PM2.5-10 does not overlap with the PM2.5 measurement while the majority of PM10 is accounted for by particles that are smaller than 2.5 mm in diameter. Individual consideration of acceptable concentrations of both fine PM (PM2.5) and coarse PM (PM2.5-10) is important as particles of different sizes have different sources, composition, and deposition properties. Studies have consistently shown an association between elevated outdoor concentrations of PM and asthma morbidity, and most of these have focused on populations living in major cities [115–119]. Activities associated with elevated indoor PM include smoking, as well as cleaning (eg, sweeping) and cooking (eg, use of the stove, frying foods) [120,121]. Cigarette smoking is a substantial contributor to indoor PM as one study found that smoking households had average PM2.5 and PM10 concentrations that were 33 to 54 mg/m3 greater than those of nonsmoking households, with each cigarette smoked adding 1.0 mg/m3 to indoor PM concentrations [58]. The observation that smoking is a major source of indoor PM is a consistent observation across numerous studies [120,122,123]. A few studies have examined the health effects of indoor PM exposure in study populations living near large cities, though it is not clear from the
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reports how many of the studied homes would be considered ‘‘inner city’’ [119,124,125]. These studies suggest that there is a relationship between indoor PM exposure and asthma morbidity. Indoor PM has been shown to be inversely associated with lung function among children with asthma [119,124], and PM2.5 originating from indoor sources may be more potent per unit mass in decreasing lung function compared with outdoor-derived PM [124]. Furthermore, among asthmatic children not taking inhaled corticosteroids, increases in exposure to indoor fine PM has been associated with increases in exhaled nitric oxide levels, suggesting that indoor PM may stimulate airway inflammation [124]. While these studies suggest that PM is associated with decreased lung function and increased airway inflammation, the studies to date have been relatively small and have not yet clarified whether or not there is an association with asthma exacerbations and acute health care encounters. Ultimately, studies examining the effect of PM reduction are necessary to more fully understand the potential impact of indoor PM on asthma. Although no intervention studies have explicitly targeted indoor PM, a handful of studies have incorporated HEPA filters as part of multifaceted approaches to environmental modification. These studies have demonstrated that HEPA filters are effective in lowering the concentration of indoor PM in homes of children with asthma and that, as part of a multimodality intervention to improve the home environment, they may have a modest effect in reducing asthma morbidity [91,126]. Studies that isolate the independent effect of PM reduction, and that evaluate the effectiveness of comprehensive PM reduction strategies, including source modification, ventilation, and HEPA filter placement, are still needed to better elucidate the potential benefit of PM reduction as a strategy to improving asthma health. Nitrogen dioxide NO2, a common ambient air pollutant, is a product of high temperature combustion. There are many potential indoor sources of NO2, including gas stoves, space heaters, furnaces, and fireplaces [127,128]. The National Cooperative Inner-City Asthma Study conducted in eight inner-city areas in the United States showed a link between higher levels of indoor NO2 and increased asthma symptoms in children and decreased peak flows [129]. Similarly, Hansel and colleagues [130] showed a consistent association between higher NO2 concentrations and increased asthma symptoms in preschool children in inner-city Baltimore. Meanwhile, another study found that indoor NO2 exposure was associated with chest tightness and wheezing, but only in individuals living in multifamily housing units. Since this living arrangement is an indicator of lower socioeconomic status, this finding highlights the complex interaction of this exposure with poverty [131]. NO2 may be a particular problem in the inner city where many households use gas stoves and, perhaps as indications of limited financial
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resources, many of these stoves are unvented [40,58] and used for prolonged periods as a source of household heat [130]. In fact, studies assessing NO2 concentrations in inner-city homes have demonstrated that they can be higher than those generally reported in other residential settings in the United States [40,58,129,132]. Since some evidence suggests low levels of NO2 are not harmful but that higher levels of exposure are linked to increased asthma morbidity [129], inner-city populations may be uniquely at risk for adverse effects of indoor NO2. When high NO2 concentrations are suspected, general control strategies can include source modification and ventilation. A randomized controlled trial studying the effects of reducing NO2 in schools by replacing unflued gas heaters with flued gas or electric heaters showed a lower indoor NO2 concentration in schools receiving the intervention compared with schools that retained the unflued gas heaters (15.5 ppb versus 47.0 ppb, P!.001) with a concordant lower risk of asthma symptoms (difficulty breathing [relative risk 0.41; 95% CI 0.07–0.98], chest tightness [relative risk 0.45; 95% CI 0.25–0.81] and asthma attacks [relative risk 0.39; 95% CI 0.17– 0.93]) in schoolchildren [133]. While not an intervention study, observations by Kattan and colleagues [129] found a protective effect of stove vents on indoor NO2 levels that approached statistical significance. Though definitive intervention studies in inner-city homes are warranted, we would recommend that individuals with asthma, if afforded the opportunity to choose housing, choose residences without gas stoves and heaters. For those who already have these appliances, they should be cautioned at least about the need for proper venting of the exhaust gases. Secondhand smoke Secondhand smoke is involuntarily inhaled tobacco smoke that contains particles and gases generated by the combustion of tobacco, paper, and additives [134]. The most recent and most comprehensive review of secondhand smoke, smoking, and asthma was published in the 2006 Report of the US Surgeon General on the Health Consequences of Involuntary Exposure to Tobacco Smoke. The surgeon general concluded that there is sufficient evidence for a causal relationship between secondhand smoke exposure from parental smoking and the onset of wheeze illness in early childhood and that there is suggestive evidence of a causal relationship between secondhand smoke exposure from parental smoking and the onset of childhood asthma [134]. The surgeon general’s report also concluded that clear evidence demonstrates that secondhand smoke exposure makes childhood asthma more severe clinically. With respect to adults, the report concluded that the evidence is suggestive but not sufficient to infer a causal relationship between secondhand smoke exposure and acute respiratory symptoms, including cough, wheeze, chest tightness, and difficulty breathing, among persons with asthma [134]. There is published evidence, however, that
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asthma health outcomes are worse in adults with secondhand smoke, when exposure is measured directly using nicotine badges and hair measures of cotinine and nicotine [135]. This topic is reviewed in depth in another article by Eisner elsewhere in this issue. The prevalence of tobacco use in some urban families is alarmingly high. Data from inner-city neighborhoods in Baltimore, for example, indicate that more than 55% of homes of young asthmatics have at least one active smoker in the home [40,136]. While most exposure for young children is typically in the child’s own home, 34% of children who live in nonsmoking homes may nevertheless spend time in other homes (eg, grandparents) where smoking is reported, according to another study [137]. The surgeon general’s report states that ‘‘eliminating smoking in indoor spaces fully protects nonsmokers from exposure to secondhand smoke. Separating smokers from nonsmokers, cleaning the air, and ventilating buildings cannot eliminate exposures of nonsmokers to secondhand smoke’’ [134]. There is substantial evidence suggesting that secondhand smoke avoidance should result in improved asthma outcomes. However, studies examining the effectiveness of interventions to reduce secondhand smoke exposure show relatively insignificant effects of interventions on the smoking patterns of those who smoke near children with asthma [138,139]. There have not, to our knowledge, been clinical trials of secondhand smoke reduction in adults with asthma [134]. Recently published asthma guidelines recommend that patients who are active smokers be referred to smoking cessation programs and that all patients with asthma be counseled concerning the negative effects of smoking and secondhand smoke [92]. Substantial evidence suggests that secondhand smoke avoidance can result in improved asthma outcomes. However, effectiveness of home intervention studies attempting to reduce secondhand smoke exposure show relatively small differences in the subsequent number of cigarettes smoked in the home [138,139]. Evidence from studies of restaurants, hospitals, and other public places indicates that bans on indoor smoking can substantially reduce secondhand smoke exposure even with incomplete compliance [140]. To our knowledge, there is no evidence regarding the degree of reduction in secondhand smoke exposure that can be achieved through ventilation and air cleaning in the homes of smokers who continue to smoke indoors. Ozone Ambient ozone is the main contributor to indoor ozone concentrations. Therefore, indoor concentrations of ozone are directly related to outdoor concentrations and show significant seasonal variability [58]. Indoor sources of ozone are uncommon, but include ionizers or ozone generators, which are sold as air freshening or air cleaning devices, and xerographic copy machines found in offices, schools, and some home offices [60]. Epidemiologic studies of ambient ozone and experimental studies show a significant
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association with asthma-related morbidity, including increases in symptoms, health care use, and airway inflammation and decreases in lung function [141–145]. The effect of indoor ozone levels on asthma morbidity has not been well studied. Similarly, the benefits of indoor ozone reduction on asthma morbidity are unknown. However, because ozone is a highly reactive gas, concentrations are generally much lower indoors relative to outdoors, even in peak ozone season, and evidence suggests that indoor ozone levels may be reduced by keeping windows and doors closed [146]. Furthermore, ozone-generating ‘‘air cleaners,’’ ‘‘air filters,’’ ‘‘air purifiers,’’ and similar equipment should be avoided in the home of patients with asthma. Summary There is growing recognition of the importance of the indoor environment in the asthma burden in inner cities. Certain indoor allergens and pollutants are found in higher concentrations in inner-city homes, suggesting that any impact that these exposures have on asthma may be more pronounced in inner-city populations. Mouse and cockroach allergens in particular are prominent allergens in inner-city environments and contribute to asthma morbidity. Among indoor pollutants, PM, secondhand smoke, and NO2 in particular, are found in higher concentrations in inner-city homes than in non–inner-city homes and are also known to contribute to asthma morbidity. Because multiple exposures are found in any given inner-city home, it is critical to understand how allergens, biologic pollutants, such as endotoxin, and pollutants interact. More detailed epidemiologic studies comprehensively evaluating the indoor pollutants and allergen exposures are warranted to investigate this interaction further. In addition to this line of investigation, more work still needs to be done to develop and evaluate interventions aimed at reducing indoor exposures in inner-city homes to refine current recommendations regarding environmental control practices. References [1] Breysse P, Farr N, Galke W, et al. The relationship between housing and health: children at risk. Environ Health Perspect 2004;112:1583–8. [2] Arbes SJ Jr, Gergen PJ, Vaughn B, et al. Asthma cases attributable to atopy: results from the third National Health and Nutrition Examination Survey. J Allergy Clin Immunol 2007;120:1139–45. [3] Huss K, Adkinson NF Jr, Eggleston PA, et al. House dust mite and cockroach exposure are strong risk factors for positive allergy skin test responses in the Childhood Asthma Management Program. J Allergy Clin Immunol 2001;107:48–54. [4] Rosenstreich DL, Eggleston P, Kattan M, et al. The role of cockroach allergy and exposure to cockroach allergen in causing morbidity among inner-city children with asthma. N Engl J Med 1997;336:1356–63.
680
MATSUI
et al
[5] Sporik R, Holgate ST, Platts-Mills TA, et al. Exposure to house-dust mite allergen (Der p I) and the development of asthma in childhood. A prospective study. N Engl J Med 1990;323: 502–7. [6] Squillace SP, Sporik RB, Rakes G, et al. Sensitization to dust mites as a dominant risk factor for asthma among adolescents living in central Virginia. Multiple regression analysis of a population-based study. Am J Respir Crit Care Med 1997;156:1760–4. [7] Call RS, Smith TF, Morris E, et al. Risk factors for asthma in inner city children. J Pediatr 1992;121:862–6. [8] Gruchalla RS, Pongracic J, Plaut M, et al. Inner city asthma study: relationships among sensitivity, allergen exposure, and asthma morbidity. J Allergy Clin Immunol 2005;115: 478–85. [9] Litonjua AA, Carey VJ, Burge HA, et al. Exposure to cockroach allergen in the home is associated with incident doctor-diagnosed asthma and recurrent wheezing. J Allergy Clin Immunol 2001;107:41–7. [10] Phipatanakul W, Celedon JC, Sredl DL, et al. Mouse exposure and wheeze in the first year of life. Ann Allergy Asthma Immunol 2005;94:593–9. [11] Almqvist C, Wickman M, Perfetti L, et al. Worsening of asthma in children allergic to cats, after indirect exposure to cat at school. Am J Respir Crit Care Med 2001;163:694–8. [12] Matsui EC, Eggleston PA, Buckley TJ, et al. Household mouse allergen exposure and asthma morbidity in inner-city preschool children. Ann Allergy Asthma Immunol 2006; 97:514–20. [13] Perry T, Matsui E, Merriman B, et al. The prevalence of rat allergen in inner-city homes and its relationship to sensitization and asthma morbidity. J Allergy Clin Immunol 2003;112: 346–52. [14] Kang BC, Johnson J, Veres-Thorner C. Atopic profile of inner-city asthma with a comparative analysis on the cockroach-sensitive and ragweed-sensitive subgroups. J Allergy Clin Immunol 1993;92:802–11. [15] Cohn RD, Arbes SJ Jr, Jaramillo R, et al. National prevalence and exposure risk for cockroach allergen in U.S. households. Environ Health Perspect 2006;114:522–6. [16] Cohn RD, Arbes SJ Jr, Yin M, et al. National prevalence and exposure risk for mouse allergen in US households. J Allergy Clin Immunol 2004;113:1167–71. [17] Schumacher MJ, Tait BD, Holmes MC. Allergy to murine antigens in a biological research institute. J Allergy Clin Immunol 1981;68:310–8. [18] Ohman JL Jr, Hagberg K, MacDonald MR, et al. Distribution of airborne mouse allergen in a major mouse breeding facility. J Allergy Clin Immunol 1994;94:810–7. [19] Eggleston PA, Ansari AA, Ziemann B, et al. Occupational challenge studies with laboratory workers allergic to rats. J Allergy Clin Immunol 1990;86:63–72. [20] Sharrow SD, Vaughn JL, Zidek L, et al. Pheromone binding by polymorphic mouse major urinary proteins. Protein Sci 2002;11:2247–56. [21] Phipatanakul W, Eggleston PA, Wright EC, et al. Mouse allergen. II. The relationship of mouse allergen exposure to mouse sensitization and asthma morbidity in inner-city children with asthma. J Allergy Clin Immunol 2000;106:1075–80. [22] Chew GL, Perzanowski MS, Miller RL, et al. Distribution and determinants of mouse allergen exposure in low-income New York city apartments. Environ Health Perspect 2003;111:1348–51. [23] Matsui EC, Simons E, Rand C, et al. Airborne mouse allergen in the homes of inner-city children with asthma. J Allergy Clin Immunol 2005;115:358–63. [24] Matsui EC, Wood RA, Rand C, et al. Mouse allergen exposure and mouse skin test sensitivity in suburban, middle-class children with asthma. J Allergy Clin Immunol 2004;113: 910–5. [25] Matsui EC, Eggleston PA, Breysse P, et al. Mouse allergen levels vary over time in inner-city homes. J Allergy Clin Immunol 2007;120:956–9.
ASTHMA IN THE INNER CITY AND THE INDOOR ENVIRONMENT
681
[26] Phipatanakul W, Cronin B, Wood RA, et al. Effect of environmental intervention on mouse allergen levels in homes of inner-city Boston children with asthma. Ann Allergy Asthma Immunol 2004;92:420–5. [27] Matsui EC, Wood RA, Rand C, et al. Cockroach allergen exposure and sensitization in suburban middle-class children with asthma. J Allergy Clin Immunol 2003;112:87–92. [28] Arbes SJ Jr, Sever M, Vaughn B, et al. Feasibility of using subject-collected dust samples in epidemiologic and clinical studies of indoor allergens. Environ Health Perspect 2005;113: 665–9. [29] Eggleston PA, Rosenstreich D, Lynn H, et al. Relationship of indoor allergen exposure to skin test sensitivity in inner-city children with asthma. J Allergy Clin Immunol 1998;102: 563–70. [30] Eggleston PA, Wood RA, Rand C, et al. Removal of cockroach allergen from inner-city homes. J Allergy Clin Immunol 1999;104:842–6. [31] Arbes SJ Jr, Sever M, Mehta J, et al. Abatement of cockroach allergens (Bla g 1 and Bla g 2) in low-income, urban housing: month 12 continuation results. J Allergy Clin Immunol 2004;113:109–14. [32] Gergen PJ, Mortimer KM, Eggleston PA, et al. Results of the National Cooperative InnerCity Asthma Study (NCICAS) environmental intervention to reduce cockroach allergen exposure in inner-city homes. J Allergy Clin Immunol 1999;103:501–6. [33] Sever ML, Arbes SJ Jr, Gore JC, et al. Cockroach allergen reduction by cockroach control alone in low-income urban homes: a randomized control trial. J Allergy Clin Immunol 2007;120:849–55. [34] Custovic A, Green R, Fletcher A, et al. Aerodynamic properties of the major dog allergen can f 1: distribution in homes, concentration, and particle size of allergen in the air. Am J Respir Crit Care Med 1997;155:94–8. [35] Almqvist C, Larsson PH, Egmar AC, et al. School as a risk environment for children allergic to cats and a site for transfer of cat allergen to homes. J Allergy Clin Immunol 1999;103:1012–7. [36] Custovic A, Fletcher A, Pickering CA, et al. Domestic allergens in public places III: house dust mite, cat, dog and cockroach allergens in British hospitals. Clin Exp Allergy 1998;28: 53–9. [37] Bollinger ME, Eggleston PA, Flanagan E, et al. Cat antigen in homes with and without cats may induce allergic symptoms. J Allergy Clin Immunol 1996;97:907–14. [38] Wood RA, Johnson EF, Van Natta ML, et al. A placebo-controlled trial of a HEPA air cleaner in the treatment of cat allergy. Am J Respir Crit Care Med 1998;158:115–20. [39] Simons E, Curtin-Brosnan J, Buckley TJ, et al. Indoor environmental differences between inner city and suburban homes of children with asthma. J Urban Health 2007;84(4):577–90. [40] Diette GB, Hansel NN, Buckley TJ, et al. Home indoor pollutant exposures among innercity children with and without asthma. Environ Health Perspect 2007;115:1665–9. [41] Weiss ST, Horner A, Shapiro G, et al. The prevalence of environmental exposure to perceived asthma triggers in children with mild-to-moderate asthma: data from the Childhood Asthma Management Program (CAMP). J Allergy Clin Immunol 2001;107:634–40. [42] Lewis SA, Weiss ST, Platts-Mills TA, et al. The role of indoor allergen sensitization and exposure in causing morbidity in women with asthma. Am J Respir Crit Care Med 2002; 165:961–6. [43] Norman PS, Ohman JL Jr, Long AA, et al. Treatment of cat allergy with T-cell reactive peptides. Am J Respir Crit Care Med 1996;154:1623–8. [44] Sicherer SH, Wood RA, Eggleston PA. Determinants of airway responses to cat allergen: comparison of environmental challenge to quantitative nasal and bronchial allergen challenge. J Allergy Clin Immunol 1997;99:798–805. [45] Shirai T, Matsui T, Suzuki K, et al. Effect of pet removal on pet allergic asthma. Chest 2005; 127:1565–71.
682
MATSUI
et al
[46] Wood RA, Chapman MD, Adkinson NF Jr, et al. The effect of cat removal on allergen content in household-dust samples. J Allergy Clin Immunol 1989;83:730–4. [47] van der Brempt X, Charpin D, Haddi E, et al. Cat removal and Fel d I levels in mattresses. J Allergy Clin Immunol 1991;87:595–6. [48] de BF, Chapman MD, Platts-Mills TA. Airborne cat allergen (Fel d I). Environmental control with the cat in situ. Am Rev Respir Dis 1991;143:1334–9. [49] Avner DB, Perzanowski MS, Platts-Mills TA, et al. Evaluation of different techniques for washing cats: quantitation of allergen removed from the cat and the effect on airborne Fel d 1. J Allergy Clin Immunol 1997;100:307–12. [50] Green R, Simpson A, Custovic A, et al. The effect of air filtration on airborne dog allergen. Allergy 1999;54:484–8. [51] Gore RB, Bishop S, Durrell B, et al. Air filtration units in homes with cats: can they reduce personal exposure to cat allergen? Clin Exp Allergy 2003;33:765–9. [52] Francis H, Fletcher G, Anthony C, et al. Clinical effects of air filters in homes of asthmatic adults sensitized and exposed to pet allergens. Clin Exp Allergy 2003;33:101–5. [53] van der Heide S, van Aalderen WM, Kauffman HF, et al. Clinical effects of air cleaners in homes of asthmatic children sensitized to pet allergens. J Allergy Clin Immunol 1999; 104:447–51. [54] Tovey ER, Chapman MD, Wells CW, et al. The distribution of dust mite allergen in the houses of patients with asthma. Am Rev Respir Dis 1981;124:630–5. [55] Tovey E, Marks G. Methods and effectiveness of environmental control. J Allergy Clin Immunol 1999;103:179–91. [56] Wickman M, Nordvall SL, Pershagen G, et al. Sensitization to domestic mites in a cold temperate region. Am Rev Respir Dis 1993;148:58–62. [57] Platts-Mills TA, Hayden ML, Chapman MD, et al. Seasonal variation in dust mite and grass-pollen allergens in dust from the houses of patients with asthma. J Allergy Clin Immunol 1987;79:781–91. [58] Breysse PN, Buckley TJ, Williams D, et al. Indoor exposures to air pollutants and allergens in the homes of asthmatic children in inner-city Baltimore. Environ Res 2005;98:167–76. [59] Perry TT, Wood RA, Matsui EC, et al. Room-specific characteristics of suburban homes as predictors of indoor allergen concentrations. Ann Allergy Asthma Immunol 2006;97: 628–35. [60] Institute of Medicine Committee on the Assessment of Asthma and Indoor Air. Clearing the air: asthma and indoor air exposures. Washington, DC: National Academy Press; 2000. [61] Shaver JR, Zangrilli JG, Cho SK, et al. Kinetics of the development and recovery of the lung from IgE-mediated inflammation: dissociation of pulmonary eosinophilia, lung injury, and eosinophil-active cytokines. Am J Respir Crit Care Med 1997;155:442–8. [62] Eggleston PA, Bush RK. Environmental allergen avoidance: an overview. J Allergy Clin Immunol 2001;107:S403–5. [63] Ehnert B, Lau-Schadendorf S, Weber A, et al. Reducing domestic exposure to dust mite allergen reduces bronchial hyperreactivity in sensitive children with asthma. J Allergy Clin Immunol 1992;90:135–8. [64] Walshaw MJ, Evans CC. Allergen avoidance in house dust mite sensitive adult asthma. Q J Med 1986;58:199–215. [65] Carswell F, Birmingham K, Oliver J, et al. The respiratory effects of reduction of mite allergen in the bedrooms of asthmatic childrenda double-blind controlled trial. Clin Exp Allergy 1996;26:386–96. [66] van der Heide S, Kauffman HF, Dubois AE, et al. Allergen-avoidance measures in homes of house-dust-mite-allergic asthmatic patients: effects of acaricides and mattress encasings. Allergy 1997;52:921–7. [67] Shapiro GG, Wighton TG, Chinn T, et al. House dust mite avoidance for children with asthma in homes of low-income families. J Allergy Clin Immunol 1999;103:1069–74.
ASTHMA IN THE INNER CITY AND THE INDOOR ENVIRONMENT
683
[68] Htut T, Higenbottam TW, Gill GW, et al. Eradication of house dust mite from homes of atopic asthmatic subjects: a double-blind trial. J Allergy Clin Immunol 2001;107:55–60. [69] Frederick JM, Warner JO, Jessop WJ, et al. Effect of a bed covering system in children with asthma and house dust mite hypersensitivity. Eur Respir J 1997;10:361–6. [70] Eggleston PA. Methods and effectiveness of indoor environmental control. Ann Allergy Asthma Immunol 2001;87:44–7. [71] Vaughan JW, McLaughlin TE, Perzanowski MS, et al. Evaluation of materials used for bedding encasement: effect of pore size in blocking cat and dust mite allergen. J Allergy Clin Immunol 1999;103:227–31. [72] Woodcock A, Forster L, Matthews E, et al. Control of exposure to mite allergen and allergen-impermeable bed covers for adults with asthma. N Engl J Med 2003;349:225–36. [73] McDonald LG, Tovey E. The role of water temperature and laundry procedures in reducing house dust mite populations and allergen content of bedding. J Allergy Clin Immunol 1992;90:599–608. [74] Vandenhove T, Soler M, Birnbaum J, et al. Effect of dry cleaning on mite allergen levels in blankets. Allergy 1993;48:264–6. [75] Miller JD, Miller A. Ten minutes in a clothes dryer kills all mites in blankets. J Allergy Clin Immunol 1996;97(1):423. [76] Munir AK, Einarsson R, Dreborg SK. Vacuum cleaning decreases the levels of mite allergens in house dust. Pediatr Allergy Immunol 1993;4:136–43. [77] Sporik R, Hill DJ, Thompson PJ, et al. The Melbourne House Dust Mite Study: long-term efficacy of house dust mite reduction strategies. J Allergy Clin Immunol 1998;101:451–6. [78] Woodfolk JA, Hayden ML, Miller JD, et al. Chemical treatment of carpets to reduce allergen: a detailed study of the effects of tannic acid on indoor allergens. J Allergy Clin Immunol 1994;94:19–26. [79] Hayden ML, Rose G, Diduch KB, et al. Benzyl benzoate moist powder: investigation of acaricidal [correction of acarical] activity in cultures and reduction of dust mite allergens in carpets. J Allergy Clin Immunol 1992;89:536–45. [80] Arlian LG. Dust mites: update on their allergens and control. Curr Allergy Asthma Rep 2001;1:581–6. [81] Custovic A, Taggart SC, Kennaugh JH, et al. Portable dehumidifiers in the control of house dust mites and mite allergens. Clin Exp Allergy 1995;25:312–6. [82] Pulimood TB, Corden JM, Bryden C, et al. Epidemic asthma and the role of the fungal mold Alternaria alternata. J Allergy Clin Immunol 2007;120:610–7. [83] Bush RK, Prochnau JJ. Alternaria-induced asthma. J Allergy Clin Immunol 2004;113: 227–34. [84] Downs SH, Mitakakis TZ, Marks GB, et al. Clinical importance of Alternaria exposure in children. Am J Respir Crit Care Med 2001;164:455–9. [85] Delfino RJ, Zeiger RS, Seltzer JM, et al. The effect of outdoor fungal spore concentrations on daily asthma severity. Environ Health Perspect 1997;105:622–35. [86] Salo PM, Arbes SJ Jr, Sever M, et al. Exposure to Alternaria alternata in US homes is associated with asthma symptoms. J Allergy Clin Immunol 2006;118:892–8. [87] O’Connor GT, Walter M, Mitchell H, et al. Airborne fungi in the homes of children with asthma in low-income urban communities: the inner-city asthma study. J Allergy Clin Immunol 2004;114:599–606. [88] Bornehag CG, Blomquist G, Gyntelberg F, et al. Dampness in buildings and health. Nordic interdisciplinary review of the scientific evidence on associations between exposure to ‘‘dampness’’ in buildings and health effects (NORDDAMP). Indoor Air 2001;11:72–86. [89] Institute of Medicine Damp indoor spaces and health 2001 Washington, DC: The National Academies Press; 2000. [90] Morgan WJ, Crain EF, Gruchalla RS, et al. Results of a home-based environmental intervention among urban children with asthma. N Engl J Med 2004;351:1068–80.
684
MATSUI
et al
[91] Eggleston PA, Butz A, Rand C, et al. Home environmental intervention in inner-city asthma: a randomized controlled clinical trial. Ann Allergy Asthma Immunol 2005;95: 518–24. [92] National Heart, Lung and Blood Institute Guidelines for the diagnosis and management of asthma: expert panel report 3, 2007. Bethesda (MD): 2007. [93] Michel O, Ginanni R, Le BB, et al. Inflammatory response to acute inhalation of endotoxin in asthmatic patients. Am Rev Respir Dis 1992;146:352–7. [94] Park JH, Gold DR, Spiegelman DL, et al. House dust endotoxin and wheeze in the first year of life. Am J Respir Crit Care Med 2001;163:322–8. [95] Pauwels RA, Kips JC, Peleman RA, et al. The effect of endotoxin inhalation on airway responsiveness and cellular influx in rats. Am Rev Respir Dis 1990;141:540–5. [96] Braun-Fahrlander C, Riedler J, Herz U, et al. Environmental exposure to endotoxin and its relation to asthma in school-age children. N Engl J Med 2002;347:869–77. [97] Gereda JE, Leung DY, Thatayatikom A, et al. Relation between house-dust endotoxin exposure, type 1 T-cell development, and allergen sensitisation in infants at high risk of asthma. Lancet 2000;355:1680–3. [98] Tavernier G, Fletcher G, Gee I, et al. IPEADAM study: indoor endotoxin exposure, family status, and some housing characteristics in English children. J Allergy Clin Immunol 2006; 117:656–62. [99] Tavernier GO, Fletcher GD, Francis HC, et al. Endotoxin exposure in asthmatic children and matched healthy controls: results of IPEADAM study. Indoor Air 2005;15(Suppl 10): 25–32. [100] Bolte G, Bischof W, Borte M, et al. Early endotoxin exposure and atopy development in infants: results of a birth cohort study. Clin Exp Allergy 2003;33:770–6. [101] Litonjua AA, Milton DK, Celedon JC, et al. A longitudinal analysis of wheezing in young children: the independent effects of early life exposure to house dust endotoxin, allergens, and pets. J Allergy Clin Immunol 2002;110:736–42. [102] Perzanowski MS, Miller RL, Thorne PS, et al. Endotoxin in inner-city homes: associations with wheeze and eczema in early childhood. J Allergy Clin Immunol 2006;117:1082–9. [103] Michel O, Kips J, Duchateau J, et al. Severity of asthma is related to endotoxin in house dust. Am J Respir Crit Care Med 1996;154:1641–6. [104] Michel O, Ginanni R, Duchateau J, et al. Domestic endotoxin exposure and clinical severity of asthma. Clin Exp Allergy 1991;21:441–8. [105] Montealegre F, Fernandez B, Delgado A, et al. Exposure levels of asthmatic children to allergens, endotoxins, and serine proteases in a tropical environment. J Asthma 2004;41: 485–96. [106] Thorne PS, Kulhankova K, Yin M, et al. Endotoxin exposure is a risk factor for asthma: the national survey of endotoxin in United States housing. Am J Respir Crit Care Med 2005; 172:1371–7. [107] Gereda JE, Klinnert MD, Price MR, et al. Metropolitan home living conditions associated with indoor endotoxin levels. J Allergy Clin Immunol 2001;107:790–6. [108] Kercsmar CM, Dearborn DG, Schluchter M, et al. Reduction in asthma morbidity in children as a result of home remediation aimed at moisture sources. Environ Health Perspect 2006;114:1574–80. [109] Klepeis NE, Nelson WC, Ott WR, et al. The National Human Activity Pattern Survey (NHAPS): a resource for assessing exposure to environmental pollutants. J Expo Anal Environ Epidemiol 2001;11:231–52. [110] Bates DV, Sizto R. Air pollution and hospital admissions in southern Ontario: the acid summer haze effect. Environ Res 1987;43:317–31. [111] Lioy PJ, Vollmuth TA, Lippmann M. Persistence of peak flow decrement in children following ozone exposures exceeding the national ambient air quality standard. J Air Pollut Control Assoc 1985;35:1069–71.
ASTHMA IN THE INNER CITY AND THE INDOOR ENVIRONMENT
685
[112] Schwartz J, Slater D, Larson TV, et al. Particulate air pollution and hospital emergency room visits for asthma in Seattle. Am Rev Respir Dis 1993;147:826–31. [113] Peters A, Dockery DW, Heinrich J, et al. Short-term effects of particulate air pollution on respiratory morbidity in asthmatic children. Eur Respir J 1997;10:872–9. [114] Wallace L. Indoor particles: a review. J Air Waste Manag Assoc 1996;46:98–126. [115] Romieu I, Meneses F, Ruiz S, et al. Effects of air pollution on the respiratory health of asthmatic children living in Mexico city. Am J Respir Crit Care Med 1996;154:300–7. [116] Lin M, Chen Y, Burnett RT, et al. The influence of ambient coarse particulate matter on asthma hospitalization in children: case-crossover and time-series analyses. Environ Health Perspect 2002;110:575–81. [117] Mar TF, Larson TV, Stier RA, et al. An analysis of the association between respiratory symptoms in subjects with asthma and daily air pollution in Spokane, Washington. Inhal Toxicol 2004;16:809–15. [118] McConnell R, Berhane K, Gilliland F, et al. Prospective study of air pollution and bronchitic symptoms in children with asthma. Am J Respir Crit Care Med 2003;168:790–7. [119] Delfino RJ, Quintana PJ, Floro J, et al. Association of FEV1 in asthmatic children with personal and microenvironmental exposure to airborne particulate matter. Environ Health Perspect 2004;112:932–41. [120] Wallace LA, Mitchell H, O’Connor GT, et al. Particle concentrations in inner-city homes of children with asthma: the effect of smoking, cooking, and outdoor pollution. Environ Health Perspect 2003;111:1265–72. [121] McCormack MC, Breysse PN, Hansel NN, et al. Common household activities are associated with elevated particulate matter concentrations in bedrooms of inner-city Baltimore pre-school children. Environ Res 2008;106:148–55. [122] Spengler JD, Dockery DW, Reed MP, et al. Long-term measurements of respirable sulfate and particle inside and outside homes. Atmos Environ 1990;15:23–30. [123] Ozkaynak H, Xue J, Spengler J, et al. Personal exposure to airborne particles and metals: results from the particle TEAM study in Riverside, California. J Expo Anal Environ Epidemiol 1996;6:57–78. [124] Koenig JQ, Mar TF, Allen RW, et al. Pulmonary effects of indoor- and outdoor-generated particles in children with asthma. Environ Health Perspect 2005;113:499–503. [125] Trenga CA, Sullivan JH, Schildcrout JS, et al. Effect of particulate air pollution on lung function in adult and pediatric subjects in a Seattle panel study. Chest 2006;129: 1614–22. [126] Reisman RE, Mauriello PM, Davis GB, et al. A double-blind study of the effectiveness of a high-efficiency particulate air (HEPA) filter in the treatment of patients with perennial allergic rhinitis and asthma. J Allergy Clin Immunol 1990;85:1050–7. [127] Spengler JD, Schwab M, McDermott A, et al. Nitrogen dioxide and respiratory illness in children. Part IV: effects of housing and meteorologic factors on indoor nitrogen dioxide concentrations. Res Rep Health Eff Inst 1996;58:1–29. [128] Marbury MC, Harlos DP, Samet JM, et al. Indoor residential NO2 concentrations in Albuquerque, New Mexico. JAPCA 1988;38:392–8. [129] Kattan M, Gergen PJ, Eggleston P, et al. Health effects of indoor nitrogen dioxide and passive smoking on urban asthmatic children. J Allergy Clin Immunol 2007;120:618–24. [130] Hansel NN, McCormack MC, Breysse PN, et al. Indoor NO2 concentrations are associated with increased asthma morbidity in pre-school inner city children. Am J Respir Crit Care Med 2008;177:A712. [131] Belanger K, Gent JF, Triche EW, et al. Association of indoor nitrogen dioxide exposure with respiratory symptoms in children with asthma. Am J Respir Crit Care Med 2006; 173:297–303. [132] Zota A, Adamkiewicz G, Levy JI, et al. Ventilation in public housing: implications for indoor nitrogen dioxide concentrations. Indoor Air 2005;15:393–401.
686
MATSUI
et al
[133] Pilotto LS, Nitschke M, Smith BJ, et al. Randomized controlled trial of unflued gas heater replacement on respiratory health of asthmatic schoolchildren. Int J Epidemiol 2004;33: 208–14. [134] Samet JM, Norman LA, Wilbanks C, et al. US Department of Health and Human Services, Centers for Disease Control and Prevention. The health consequences of involuntary exposure to tobacco smoke: a report of the surgeon general. Washington DC: US Department of Health and Human Services; 2008 [135] Eisner MD, Klein J, Hammond SK, et al. Directly measured second hand smoke exposure and asthma health outcomes. Thorax 2005;60:814–21. [136] Stillman FA, Bone L, vila-Tang E, et al. Barriers to smoking cessation in inner-city African American young adults. Am J Public Health 2007;97:1405–8. [137] Hopper JA, Craig KA. Environmental tobacco smoke exposure among urban children. Pediatrics 2000;106:E47. [138] Wilson SR, Yamada EG, Sudhakar R, et al. A controlled trial of an environmental tobacco smoke reduction intervention in low-income children with asthma. Chest 2001;120: 1709–22. [139] Klerman L. Protecting children: reducing their environmental tobacco smoke exposure. Nicotine Tob Res 2004;6(Suppl 2):S239–53. [140] Eisner MD. Banning smoking in public places: time to clear the air. JAMA 2006;296: 1778–9. [141] Kim JJ. Ambient air pollution: health hazards to children. Pediatrics 2004;114:1699–707. [142] Mortimer KM, Neas LM, Dockery DW, et al. The effect of air pollution on inner-city children with asthma. Eur Respir J 2002;19:699–705. [143] Graham DE, Koren HS. Biomarkers of inflammation in ozone-exposed humans. Comparison of the nasal and bronchoalveolar lavage. Am Rev Respir Dis 1990;142:152–6. [144] Lin M, Chen Y, Burnett RT, et al. Effect of short-term exposure to gaseous pollution on asthma hospitalisation in children: a bi-directional case-crossover analysis. J Epidemiol Community Health 2003;57:50–5. [145] Ross MA, Persky VW, Scheff PA, et al. Effect of ozone and aeroallergens on the respiratory health of asthmatics. Arch Environ Health 2002;57:568–78. [146] Gold DR, Allen G, Damokosh A, et al. Comparison of outdoor and classroom ozone exposures for school children in Mexico city. J Air Waste Manag Assoc 1996;46:335–42.
