Health effects of indoor nitrogen dioxide and passive smoking on urban asthmatic children

Health care education, delivery, and quality Health effects of indoor nitrogen dioxide and passive smoking on urban asthmatic children Meyer Kattan, MD, CM,a Peter J. Gergen, MD,b Peyton Eggleston, MD,c Cynthia M. Visness, MA, MPH,d and Herman E. Mitchell, PhDd New York, NY, Baltimore and Bethesda, Md, and Chapel Hill, NC

Health care education, delivery, and quality

Background: Nitrogen dioxide (NO2) and environmental tobacco smoke (ETS) have been associated with adverse respiratory effects. Objective: We sought to assess the effect of NO2 and ETS on asthma morbidity among children in inner-city environments. Methods: Asthmatic children between the ages of 4 and 9 years had exposure to NO2 and ETS measured by using Palmes tubes in the home and urinary cotinine. A baseline interview and telephone assessments at 3, 6, and 9 months evaluated health service use, asthma symptoms, and peak flow rates. Results: Gas stoves were present in 87.8% of 469 homes. The median level of indoor NO2 was 29.8 ppb compared with the US national outdoor median of 18 ppb. Of 1444 children, 48% had urinary cotinine/creatinine ratios of greater than 30 ng/mg. The median level of the cotinine/creatinine ratio was 42.4 ng/mg in smoking homes compared with 18.0 ng/mg in nonsmoking homes. The relative risk for asthma symptoms with increased NO2 exposure was 1.75 (95% CI, 1.10-2.78) in children who did not have positive skin test responses. Higher NO2 exposure resulted in lower peak flows during colder months (relative risk, 1.46; 95% CI, 1.07-1.97). Higher ETS exposure in colder months was weakly associated with lower peak flows (relative risk, 1.21; 95% CI, 0.99-1.47). There was no effect of ETS exposure on symptoms or use of health care services. Conclusion: Higher levels of indoor NO2 are associated with increased asthma symptoms in nonatopic children and decreased peak flows. From athe Department of Pediatrics, Mt Sinai School of Medicine, New York; b the Asthma, Allergy, and Inflammation Branch, Division of Allergy, Immunology, and Transplantation, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda; cthe Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore; and dRho Federal Systems Division, Inc, Chapel Hill. Supported by grants UOI A1-30751, A1-30752, A1-30756, A1-30772, A130773-01, A1-30777, A1-30779, A1-30780, and N01-A1-15105 from the National Institutes of Allergy and Infectious Disease (National Institutes of Health, Bethesda, Md). Disclosure of potential conflict of interest: M. Kattan is on the speakers’ bureau for AstraZeneca. P. Eggleston has consulting arrangements with the Chlorine Chemistry Council, Proctor and Gamble, SC Johnson, Nexcura, and Church and Dwight and is on the speakers’ bureau for AstraZeneca, Merck, and GlaxoSmithKline. The rest of the authors have declared that they have no conflict of interest. Received for publication January 18, 2007; revised March 30, 2007; accepted for publication May 3, 2007. Available online June 22, 2007. Reprint requests: Meyer Kattan, MD, CM, Department of Pediatrics, Children’s Hospital of New York-Presbyterian, The University Hospitals of Columbia and Cornell, 3959 Broadway, New York, NY 10032. E-mail: [email protected]. 0091-6749 doi:10.1016/j.jaci.2007.05.014

618

Clinical implications: Interventions to reduce NO2 exposure, such as venting of gas stoves, might help reduce asthma morbidity. (J Allergy Clin Immunol 2007;120:618-24.) Key words: Asthma, nitrogen dioxide, tobacco smoke, pollution, passive smoking

Nitrogen dioxide (NO2) and environmental tobacco smoke (ETS) are known respiratory irritants. The levels of exposure indoors are of concern because children spend nearly 70% of their time indoors at home.1 Children with asthma living in inner cities are exposed to higher levels than in other environments. In the National Cooperative Inner-City Asthma Study (NCICAS) cohort, 24% were exposed to NO2 levels of greater than 40 ppb,2 which is near the 95th percentile for outdoor averages in the United States in the same time period.3 More than 58% of NCICAS children were exposed to a smoker in the home compared with 25% in the general US population.4 In population studies the use of gas appliances, a primary source of NO2, and exposure to indoor or outdoor NO2 have increased the risk of lower respiratory tract symptoms in both general population samples and asthmatic subjects.5-11 NO2 might potentiate airway responsiveness of asthmatic subjects to inhaled allergens.12 Children with increased total IgE levels and bronchial hyperreactivity have been found to be more sensitive to outdoor ambient NO2.13 Exposure to ETS increases the prevalence of both upper and lower respiratory tract illnesses.14 In longitudinal and case-control population studies, a higher incidence of wheezing illness and asthma is associated with exposure to ETS.15-18 Most studies in asthmatic subjects observe a diminishing effect of ETS on morbidity in older children.19-23 We investigated the association between these respiratory irritants and asthma morbidity in children from the NCICAS. This cohort is representative of a population of asthmatic children with low socioeconomic status and high asthma morbidity. A better understanding of how these environmental exposures contribute to the asthma morbidity in the inner city will allow interventions to be more effectively designed and implemented. This study takes advantage of the comprehensive data collection in the NCICAS, including the large sample size with objective measures of NO2 and ETS, and characterization of the

Kattan et al 619

J ALLERGY CLIN IMMUNOL VOLUME 120, NUMBER 3

atopic status to examine potential confounders and effect modifiers and to elucidate the independent contributions of NO2 and ETS.

METHODS The NCICAS (1992-1994) included 1528 children ages 4 through 9 years from 8 inner-city areas in the United States (Bronx, NY; East Harlem, NY; St Louis, Mo; Washington, DC; Baltimore, Md; Chicago, Ill; Cleveland, Ohio; and Detroit, Mich). The full design and methodology have been published and are summarized here.2,24,25 Children were recruited from emergency departments and clinics based on physician-diagnosed asthma and the presence of symptoms in the previous 12 months or cough, wheeze, or shortness of breath that lasted for more than 6 weeks in the previous 12 months. The protocol received institutional review board approval at each site. A baseline assessment included questions about morbidity, the home environment, and cigarette smoking by household members. All questionnaires were completed as interviews, with the exception of some of the psychological measures. These were self-administered, as long as the caretaker passed a short literacy exercise; otherwise, they were interviewer administered. Urine samples were collected for cotinine. Prick-puncture skin tests were performed to Dermatophagoides pteronyssinus, Dermatophagoides farinae, cat pelt, dog pelt, rat pelt, mouse pelt, a mixture of German and American cockroach, Alternaria species, Penicillium species, mixed grasses, orchard grass, white oak, maple, and giant and short ragweed (Greer Laboratories, Lenoir, NC) by using a Multi Test device (Lincoln Diagnostics, Decatur, Ill). Home visits were conducted between February and July in a subset (n 5 663) of families. NO2 was sampled by means of a Palmes tube taped to a wall in the child’s sleeping area for 7 days. Standard quality control procedures were maintained with use of more than 10% laboratory blanks, field blanks, and replicate samplers for quality assurance evaluation.24 Professional telephone interviewers, who had no information about the families’ NO2 levels or cotinine levels, contacted the families at 3, 6, and 9 months after the baseline assessment. The families reported unscheduled asthma visits (emergency department visits plus clinic visits scheduled <24 hours in advance) over the previous 3 months and days of wheeze over the previous 2 weeks. Follow-up was 90%, 92%, and 94% complete for the 3-month, 6-month, and 9-month calls. Morning and evening peak flows were recorded for 2 weeks before each of the follow-up calls. The rate of return of peak flow diaries at the 3 follow-up periods was 61%, 60%, and 59%.2 NO2 and ETS levels were expected to be greater during the colder months.5 To account for geographic variation in temperature, months in which the average temperature was less than 608F were classified as the cooler season, and months in which the average temperature was 608F or greater were classified as the warmer season. NO2 and ETS levels vary by month, but homes with higher levels remain in the higher relative level groupings across seasons.5 NO2 and cotinine levels were analyzed as percentiles to maintain this relative ranking across months. The 75th percentile was chosen to define high

exposure of NO2 because it approached the US Environmental Protection Agency criterion for outdoor NO2 levels of 53 ppb. For cotinine, the 50th percentile was chosen because it approximated the cutoff for ETS exposure of a cotinine/creatinine ratio of 30 ng/mg.20 Differences in median NO2 and cotinine levels by sociodemographic and environmental characteristics were tested by using the Wilcoxon rank sum statistic. We examined the effect of NO2 and cotinine on morbidity (ie, 4 or more days of asthma symptoms in 2 weeks, any unscheduled medical visit for asthma in the past 3 months, and peak flow of less than 80% of predicted value) by using a longitudinal binomial regression model with a generalized estimating equation function for correlated observations among individuals and a log link.26 Binomial regression has the advantage of directly estimating relative risk, whereas logistic regression models estimate odds ratios. All models are adjusted for study site, family income, sex, psychosocial status of the caretaker and the child, caretaker education, family history of asthma, household smoking (NO2 model only), and use of steroid medications at baseline. These model covariates were specified a priori, based on presumed risk, to avoid the model estimation biases that occur with a posteriori covariate selection.27 The variables that were controlled as confounders are variables that have been shown in previous work in inner-city populations to be related to asthma morbidity.28 Atopic status and season were found to have significant interactions with NO2 levels, and therefore stratified models are presented.

RESULTS A total of 1528 caretaker and child pairs completed the baseline interview. The population was predominantly low-income African American and Latino. A large proportion of the participants had high-level social and psychological stress, allergen skin test reactivity, and exposure to NO2 and ETS in the home (Table I). Of the 525 Palmes tubes returned, 56 were missing duration of exposure, resulting in an analyzable sample of 469 (71%) of the 663 placed during the home visit. Valid cotinine measurements were obtained for 1444 (95%) children at the baseline visit. Sociodemographic data for those participants with cotinine samples and Palmes tube samples and the total NCICAS sample were highly comparable (Table I). Of the children who had Palmes tubes assayed for NO2, 15.6% (73/469) had levels greater than 53 ppb (100 mg/ m3), the upper limit of the US Environmental Protection Agency outdoor air quality standard.29 The overall median level of NO2 was 29.8 ppb (range, 0.5-480.1 ppb). As seen in Table II, the strongest influence on NO2 values was the presence of a gas stove in the house. Higher NO2 values were also found in cooler weather, measured either by month or average temperature per month. Presence of a vent with a gas stove reduced levels of NO2, a result that approached statistical significance. In 48% (691/1444) of the children, the urinary cotinine/ creatinine ratio was greater than 30 ng/mg, the generally accepted cutoff point for exposure to ETS.20 The overall median level of the cotinine/creatinine ratio was 28.3 (range, 2.9-672.7). Median values of the cotinine/creatinine ratio by subgroups of interest are shown in Table II. The strongest influence on cotinine values was the presence

Health care education, delivery, and quality

Abbreviations used ETS: Environmental tobacco smoke NCICAS: National Cooperative Inner-City Asthma Study NO2: Nitrogen dioxide

620 Kattan et al

J ALLERGY CLIN IMMUNOL SEPTEMBER 2007

TABLE I. Characteristics of the study population Total NCICAS sample (n 5 1528)

NO2 sample (n 5 469)

Cotinine sample (n 5 1444)

6.2 (1.7) 62.4%

6.2 (1.7) 63.8%

6.2 (1.7) 62.7%

19.5% 73.5% 7.0% 61.2% 42.5% 58.9% 33.1%

22.7% 71.0% 6.3% 64.2% 46.2% 57.6% 32.3%

19.5% 73.8% 6.7% 61.3% 42.8% 59.3% 33.1%

49.8%

50.6%

50.0%

76.9% 58.6% 88.6%

80.9% 56.4% 87.8%

76.9% 58.7% 88.4%

Mean age (y [SD]) Male sex Race or ethnic group Hispanic Black Other Household income <$15,000 Inadequate social support Stressful life events Child Behavior Checklist score above clinical cutoff point Caretaker Brief Symptom Inventory score above clinical cutoff At least 1 positive skin test response Any smokers in the home Gas stove in the home* *Among home visit subsample.

Health care education, delivery, and quality

of a smoker in the house. Higher cotinine values were also found in cooler weather (measured either by month or average temperature), among girls, and in homes in which the caretaker had less than a high school education. Neither NO2 nor cotinine levels varied by allergen skin test reactivity in the child, family history of asthma, or household income but varied significantly by site. As shown in Table III, children with no positive skin test responses had a significantly increased risk of symptoms in the highest NO2 exposure category (relative risk, 1.75; 95% CI, 1.10-2.78). In colder months peak flow was significantly reduced in the highest NO2 exposure category (relative risk, 1.46; 95% CI, 1.07-1.97). The risk of symptoms equal to or more than 4 times per 2 weeks or unscheduled visits was not significantly increased in the highest cotinine level category when analyzed on the basis of skin test status or season. The relative risk of a reduction in peak flow rates with higher cotinine/creatinine ratios in colder weather approached statistical significance (Table IV).

DISCUSSION High levels of NO2 and ETS were found in the indoor environments of inner-city children with asthma. Increased NO2 exposure was associated with increased asthma symptoms among nonatopic children. Higher NO2 exposure resulted in decreased peak flow during colder months. We found no association between the level of exposure to ETS and symptoms or unscheduled visits for asthma exacerbations. High levels of ETS were weakly associated with lower peak flow rates during colder months. The median NO2 level of 29.8 ppb in the NCICAS population is increased compared with that seen in previous reports. It substantially exceeds the 90th percentile (14.8 ppb) reported in homes of children with asthma in

Southampton, England,30 and the median level of 10.2 ppb in single-family homes and 22.9 ppb in multiple-family homes in Connecticut.11 Of note, the NCICAS indoor NO2 levels are considerably higher than the US national outdoor median values of 18 ppb.3 These high levels are not surprising given the predominance of gas stoves used for cooking in the NCICAS homes. Although outdoor NO2 contributes to indoor levels, it is evident that the presence of gas stoves doubles the indoor levels. This is consistent with previous studies that report gas stoves as the major source of indoor NO2 levels.5,8,31 We observed a protective effect of stove vents on indoor NO2 levels that approached statistical significance.31 The higher NO2 exposure observed in winter months has been noted previously.5,32 In this inner-city population this most likely reflects the greater use of gas stoves and alternate heating sources in colder months and reduced ventilation in the homes because of closed windows. Data on the effect of smoking on NO2 levels are conflicting. Some reports have found higher NO2 levels in the homes of smokers,31 others have found higher NO2 levels in the homes of nonsmokers,7 and others are consistent with our findings and show no effect of smoking on NO2 levels.33 NO2 has been previously reported to be associated with symptoms in both asthmatic and nonasthmatic subjects.5,7-9,11,30,32,34,35 The type of effect varies: some find an effect on respiratory symptoms and not pulmonary function,5 whereas others find effects on pulmonary function but not on symptoms.33 However, these studies vary widely in the level of NO2 exposure, as well as the types of asthma outcomes measured. Clearly, it is only at the highest levels that NO2 has an effect on asthma symptoms. Linaker et al30 observed an effect only at the 90th percentile of NO2 exposure, and Belanger et al11 found an effect only in multifamily homes, which served as a marker for high NO2 levels. In this study the winter season served

Kattan et al 621

J ALLERGY CLIN IMMUNOL VOLUME 120, NUMBER 3

TABLE II. Median NO2 and cotinine levels by various characteristics

Overall Sex Girls Boys Household income <$15,000/y >%$15,000/y Caretaker—high school No Yes Family history of asthma No Yes One or more positive skin test responses No Yes Smoking in the home Smoking homes Nonsmoking homes Gas stove in the home  Gas stove Electric stove Gas stove ventedà No Yes Site Baltimore Bronx Chicago Cleveland Detroit New York St Louis Washington, DC Season (average monthly temperature) <608F 608F By month January February March April May June July August September October

Median NO2 (ppb)

469

29.8

170 299

29.1 30.0

263 147

Cotinine* P value

N

Median C/C ratio

P value

1444

28.3

.50

539 905

32.6 25.6

.002

30.5 28.5

.10

791 500

28.9 25.6

.17

174 288

29.7 29.9

.61

488 938

33.3 25.7

.001

197 261

28.7 30.4

.10

610 819

26.3 28.9

.24

76 321

29.5 29.8

.68

285 946

31.2 27.8

.07

260 201

29.6 29.9

.54

840 591

42.4 18.0

<.0001

404 56

31.4 15.9

<.0001

543 71

32.6 28.2

.40

358 48

31.7 28.7

.07

476 69

32.0 37.9

.13

60 72 52 49 58 58 74 46

28.5 33.1 36.9 29.4 30.4 31.7 27.7 23.6

.0006

145 208 225 182 150 156 208 170

37.5 18.2 30.8 37.5 42.2 25.7 24.9 23.5

<.0001

265 204

31.8 28.2

.0002

671 771

34.4 24.7

<.0001

32.1 29.9 33.0 30.6 27.8 26.6

.001

97 117 170 211 220 234 196 119 37 41

33.8 32.9 37.6 35.0 24.1 27.2 24.3 23.1 23.5 27.8

.008

57 97 97 93 89 36

C/C ratio, Cotinine/creatinine ratio. *Variation in sample size is due to missing values.  Among home visit subsample. àAmong those with gas stoves in home visit subsample.

as a marker for the higher NO2 levels. This seasonal difference, however, was rather small (3.6 ppb, Table II) and is unlikely to completely account for the observation that children with higher NO2 exposure had significantly

reduced peak flow during the colder months. The greater effect during the winter season could be explained by NO2 lowering the threshold for viral-induced asthma exacerbations.30,36,37 In the absence of personal exposure

Health care education, delivery, and quality

Nitrogen dioxide* N

622 Kattan et al

J ALLERGY CLIN IMMUNOL SEPTEMBER 2007

TABLE III. Proportion with asthma morbidity by atopy and season for houses with high NO2 levels (>75th percentile) versus those without Low NO2 levels Outcome

By atopy No positive skin test responses Maximum symptom days >4/past 2 wk Any unscheduled visit Peak flow <80% of predicted value One or more positive skin test responses Maximum symptom days >4/past 2 wk Any unscheduled visit Peak flow <80% of predicted value By season  <608F Maximum symptom days >4/past 2 wk Any unscheduled visit in the season Peak flow <80% of predicted value 608F Maximum symptom days >4/past 2 wk Any unscheduled visit in the season Peak flow <80% of predicted value

High NO2 levels

N

Percentage

N

Percentage

Adjusted* risk ratio

95% CI

58 58 48

16.1 11.0 25.6

18 18 14

28.1 9.9 26.6

1.75 0.90 1.04

1.10-2.78 0.42-1.92 0.54-2.00

239 239 188

15.9 17.3 20.5

80 80 66

16.1 14.2 26.5

1.02 0.82 1.29

0.76-1.39 0.62-1.08 0.94-1.78

348 347 237

24.5 17.6 23.2

115 114 80

27.4 14.1 33.8

1.12 0.80 1.46

0.86-1.45 0.60-1.07 1.07-1.97

335 335 234

18.2 11.0 27.3

108 108 81

21.3 9.9 28.6

1.17 0.90 1.05

0.80-1.71 0.60-1.36 0.75-1.46

*Models are adjusted for study site, family history of asthma, sex, steroid use at baseline, household smoking, household income, caretaker education, caretaker Brief Symptom Inventory score, and Child Behavior Checklist score. Each model is also adjusted for atopy and season when not used for stratification.  A child can be included in more than 1 season.

TABLE IV. Proportion with asthma symptoms by atopy and season for children with high cotinine/creatinine ratio levels (>50th percentile) versus those without Low CCR levels Outcome

Health care education, delivery, and quality

By atopy No positive skin test responses Maximum symptom days >4/past 2 wk Any unscheduled visit Peak flow <80% of predicted value One or more positive skin test responses Maximum symptom days >4/past 2 wk Any unscheduled visit Peak flow <80% of predicted value By season  <608F Maximum symptom days >4/past 2 wk Any unscheduled visit in the season Peak flow <80% of predicted value 608F Maximum symptom days >4/past 2 wk Any unscheduled visit in the season Peak flow <80% of predicted value

High CCR levels

N

Percentage

N

Percentage

Adjusted* risk ratio

95% CI

127 127 96

20.0 14.1 32.0

149 149 87

21.3 14.0 33.8

1.07 1.00 1.06

0.82-1.39 0.70-1.42 0.70-1.60

462 462 340

19.2 18.0 35.7

466 466 318

20.8 17.4 41.2

1.08 0.97 1.15

0.93-1.25 0.83-1.12 0.95-1.40

698 698 465

23.9 19.9 28.9

692 691 390

26.5 19.8 34.9

1.11 0.99 1.21

0.96-1.28 0.85-1.16 0.99-1.47

597 594 358

20.7 14.7 32.5

588 587 316

20.6 13.3 33.8

0.99 0.91 1.04

0.81-1.22 0.72-1.14 0.84-1.29

CCR, Cotinine/creatinine ratio. *Models are adjusted for study site, family history of asthma, sex, steroid use at baseline, household income, caretaker education, caretaker Brief Symptom Inventory score, and Child Behavior Checklist score. Each model is also adjusted for atopy and season when not used for stratification.  A child can be included in more than 1 season.

measurements of NO2, we cannot rule out the possibility that personal exposures were higher during colder months because more time was spent indoors. Atopy was observed to be an important effect modifier of the relationship between NO2 and asthma symptoms in

this study. Asthma morbidity was greater in children without a positive skin test response compared with atopic children. The data regarding the effects of air pollution in atopic and nonatopic individuals are conflicting.8,10,33 In a study of adult asthmatic subjects, a small but

Kattan et al 623

J ALLERGY CLIN IMMUNOL VOLUME 120, NUMBER 3

In inner cities, where asthma prevalence is high, there is a need to reduce exposure of young children to ETS. However, in children with asthma, the findings of the NCICAS cohort suggest that other risk factors in addition to NO2 contribute more strongly to asthma morbidity than ETS. These factors include limited access to care, psychosocial problems, and environmental allergens, such as cockroach.2,25 This study found an association between indoor NO2 exposure and morbidity. The widespread use of gas appliances in inner-city homes might therefore have a considerable public health effect. Educational interventions aimed at reducing asthma morbidity in inner-city children should include strategies to reduce indoor NO2 exposure. Despite the finding that NO2 levels were lower in homes with vented stoves, the levels remained relatively high. This might reflect the fact that we only had data on the presence of vents but not their actual use. Instructing families to operate vents when using gas appliances as part of asthma education programs would be a simple and immediate intervention. Long-term efforts should be aimed at advocating for installing vents with gas appliances and the manufacture of pilotless stoves, which are associated with lower NO2 levels.41 We thank the investigators and other staff who worked on the National Cooperative Inner-City Asthma Study and also extend our thanks to the study participants. In addition, we thank Robert James and Dr Henry Lynn for statistical guidance and preliminary analyses.

REFERENCES 1. Klepeis NE, Nelson WC, Ott WR, Robinson JP, Tsang AM, Switzer P, 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. 2. Kattan M, Mitchell H, Eggleston P, Gergen P, Crain E, Redline S, et al. Characteristics of inner-city children with asthma: the National Cooperative Inner-City Asthma Study. Pediatr Pulmonol 1997;24: 253-62. 3. United States Environmental Protection Agency. National air quality and emissions trends report: 2003 special studies edition. Research Triangle Park (NC): United States Environmental Protection Agency; 2003. EPA 454/R-03-005. 4. US Department of Health and Human Services. The health consequences of involuntary exposure to tobacco smoke: a report of the Surgeon General. Atlanta (GA): US Department of Health and Human Services, Centers for Disease Control and Prevention, Coordinating Center for Health Promotion, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health; 2006. 5. Neas LM, Dockery DW, Ware JH, Spengler JD, Speizer FE, Ferris BJJ. Association of indoor nitrogen dioxide with respiratory symptoms and pulmonary function in children. Am J Epidemiol 1991;134:204-19. 6. Mortimer KM, Neas LM, Dockery DW, Redline S, Tager IB. The effect of air pollution on inner-city children with asthma. Eur Respir J 2002;19: 699-705. 7. Smith BJ, Nitschke M, Pilotto LS, Ruffin RE, Pisaniello DL, Willson KJ. Health effects of daily indoor nitrogen dioxide exposure in people with asthma. Eur Respir J 2000;16:879-85. 8. Garrett MH, Hooper MA, Hooper BM, Abramson MJ. Respiratory symptoms in children and indoor exposure to nitrogen dioxide and gas stoves. Am J Respir Crit Care Med 1998;158:891-5. 9. Just J, Segala C, Sahraoui F, Priol G, Grimfeld A, Neukirch F. Shortterm health effects of particulate and photochemical air pollution in asthmatic children. Eur Respir J 2002;20:899-906.

Health care education, delivery, and quality

statistically significant increase in reactivity to an allergen challenge after exposure to high (400 ppb), but not lower (100 ppb), levels of NO2 has been observed.12 There are plausible explanations for our findings. First, the levels of NO2 in inner-city homes were far less than 400 ppb. Second, exposure to allergens, such as cockroach, in sensitized children could possibly have a stronger influence that obscures the weaker relationship of other triggers to morbidity, such as NO2.28 In those who do not have allergens as a trigger of asthma, the effect of NO2 on symptoms becomes evident. A number of factors might have influenced the NO2 associations reported in this study. We used a Palmes tube in the home to assess NO2 exposure rather than personal monitoring. This method might not precisely reflect the actual exposure of the child but should provide a reasonable estimate given the amount of time children spend at home. Exposure to short-term peak levels of NO2 might contribute more to the respiratory effects in asthmatic subjects than cumulative exposures.35 We measured levels averaged over a 1-week period and did not take into account peak exposures. It is therefore possible that we might have underestimated the effect of peak NO2 exposures in asthmatic subjects. Finally, it is possible that NO2 was merely the marker for another agent. ETS exposure was not associated with wheezing in the NCICAS cohort. The previous ETS literature provides a number of explanations for this lack of association. ETS exposure had been shown consistently to have its greatest effect on wheezing in the first 2 or 3 years of life, and the effect of ETS exposure on wheezing decreases with age.21,38 Similarly, the Third National Heath and Nutrition Examination Survey found that ETS exposure was no longer significantly associated with wheezing after age 6 years. In this national survey the odds ratio had decreased to 0.9 in the 12- to 16-year age group.39 An 11-year longitudinal study from birth in Tucson found ETS exposure only influenced the children’s respiratory symptoms at less than 3 years of age, with no effect between 3 and 11 years of age.21 A recent extensive review by the Institute of Medicine found that the existing evidence was not conclusive in regard to the role of chronic ETS exposure in exacerbations of asthma among older children but concluded that chronic ETS exposure was associated with exacerbations in younger children.40 ETS exposure misclassification could obscure a relationship between an environmental factor and a specific outcome. In this study exposure was determined by means of both questionnaires given to caretakers and by testing a biologic marker of ETS exposure, urinary cotinine. Analysis with questionnaire data only did not alter the results. This report avoids the limitations of the few previous studies on indoor air pollution in asthma resulting from small sample sizes, lack of direct measures of exposure, and/or low levels of exposures. In addition, unlike more narrowly focused studies, the well-described population of the NCICAS project2 allowed for a thorough examination of potential confounding variables.

624 Kattan et al

Health care education, delivery, and quality

10. Jarvis D, Chinn S, Luczynska C, Burney P. Association of respiratory symptoms and lung function in young adults with use of domestic gas appliances. Lancet 1996;347:426-31. 11. Belanger K, Gent JF, Triche EW, Bracken MB, Leaderer BP. Association of indoor nitrogen dioxide exposure with respiratory symptoms in children with asthma. Am J Respir Crit Care Med 2006;173:297-303. 12. Tunnicliffe WS, Burge PS, Ayres JG. Effect of domestic concentrations of nitrogen dioxide on airway responses to inhaled allergen in asthmatic patients. Lancet 1994;344:1733-6. 13. Boezen HM, van der Zee SC, Postma DS, Vonk JM, Gerritsen J, Hoek G, et al. Effects of ambient air pollution on upper and lower respiratory symptoms and peak expiratory flow in children. Lancet 1999;353:874-8. 14. DiFranza JR, Lew RA. Morbidity and mortality in children associated with the use of tobacco products by other people. Pediatrics 1996;97:560-8. 15. Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan WJ. Asthma and wheezing in the first six years of life. The Group Health Medical Associates. N Engl J Med 1995;332:133-8. 16. Lewis S, Richards D, Bynner J, Butler N, Britton J. Prospective study of risk factors for early and persistent wheezing in childhood. Eur Respir J 1995;8:349-56. 17. Ehrlich RI, Du Toit D, Jordaan E, Zwarenstein M, Potter P, Volmink JA, et al. Risk factors for childhood asthma and wheezing. Importance of maternal and household smoking. Am J Respir Crit Care Med 1996;154:681-8. 18. Henderson FW, Henry MM, Ivins SS, Morris R, Neebe EC, Leu SY, et al. Correlates of recurrent wheezing in school-age children. The Physicians of Raleigh Pediatric Associates. Am J Respir Crit Care Med 1995;151:1786-93. 19. Duff AL, Pomeranz ES, Gelber LE, Price GW, Farris H, Hayden FG, et al. Risk factors for acute wheezing in infants and children: Viruses, passive smoke, and IgE antibodies to inhalant allergens. Pediatrics 1993;92:535-40. 20. Henderson FW, Reid HF, Morris R, Wang OL, Hu PC, Helms RW, et al. Home air nicotine levels and urinary cotinine excretion in preschool children. Am Rev Respir Dis 1989;140:197-201. 21. Stein RT, Holberg CJ, Sherrill D, Wright AL, Morgan WJ, Taussig L, et al. Influence of parental smoking on respiratory symptoms during the first decade of life: the Tucson Children’s Respiratory Study. Am J Epidemiol 1999;149:1030-7. 22. Strachan DP, Cook DG. Health effects of passive smoking. 6. Parental smoking and childhood asthma: longitudinal and case-control studies. Thorax 1998;53:204-12. 23. Weitzman M, Gortmaker S, Sobol A. Racial, social, and environmental risks for childhood asthma. Am J Dis Child 1990;144:1189-94. 24. Mitchell H, Senturia Y, Gergen P, Baker D, Joseph C, McNiff-Mortimer K, et al. Design and methods of the National Cooperative Inner-City Asthma Study. Pediatr Pulmonol 1997;24:237-52. 25. Wade S, Weil C, Holden G, Mitchell H, Evans R 3rd, Kruszon-Moran D, et al. Psychosocial characteristics of inner-city children with asthma: a description of the NCICAS psychosocial protocol. National Cooperative Inner-City Asthma Study. Pediatr Pulmonol 1997;24:263-76. 26. Robbins AS, Chao SY, Fonseca VP. What’s the relative risk? A method to directly estimate risk ratios in cohort studies of common outcomes. Ann Epidemiol 2002;12:452-4.

J ALLERGY CLIN IMMUNOL SEPTEMBER 2007

27. Copas JB, Long T. Estimating the residual variance in orthogonal regression with variable selection. Statistican 1991;40:51-9. 28. Rosenstreich DL, Eggleston P, Kattan M, Baker D, Slavin RG, Gergen P, 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. 29. US Environmental Protection Agency. National Ambient Air Quality Standards; June 10, 2004. Available at: http://www.epa.gov/air/criteria.html. Accessed August 10, 2004. 30. Linaker CH, Coggon D, Holgate ST, Clough J, Josephs L, Chauhan AJ, et al. Personal exposure to nitrogen dioxide and risk of airflow obstruction in asthmatic children with upper respiratory infection. Thorax 2000; 55:930-3. 31. Farrow A, Greenwood R, Preece S, Golding J. Nitrogen dioxide, the oxides of nitrogen, and infants’ health symptoms. ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and Childhood. Arch Environ Health 1997;52:189-94. 32. Shima M, Adachi M. Effect of outdoor and indoor nitrogen dioxide on respiratory symptoms in schoolchildren. Int J Epidemiol 2000;29:862-70. 33. Ponsonby AL, Glasgow N, Gatenby P, Mullins R, McDonald T, Hurwitz M, et al. The relationship between low level nitrogen dioxide exposure and child lung function after cold air challenge. Clin Exp Allergy 2001;31:1205-12. 34. Pilotto LS, Douglas RM, Attewell RG, Wilson SR. Respiratory effects associated with indoor nitrogen dioxide exposure in children. Int J Epidemiol 1997;26:788-96. 35. Ng TP, Seet CS, Tan WC, Foo SC. Nitrogen dioxide exposure from domestic gas cooking and airway response in asthmatic women. Thorax 2001;56:596-601. 36. Chauhan AJ, Inskip HM, Linaker CH, Smith S, Schreiber J, Johnston SL, et al. Personal exposure to nitrogen dioxide (NO2) and the severity of virus-induced asthma in children. Lancet 2003;361:1939-44. 37. Gergen PJ, Mitchell H, Lynn H. Understanding the seasonal pattern of childhood asthma: results from the National Cooperative Inner-City Asthma Study (NCICAS). J Pediatr 2002;141:631-6. 38. Gergen PJ, Fowler JA, Maurer KR, Davis WW, Overpeck MD. The burden of environmental tobacco smoke exposure on the respiratory health of children 2 months through 5 years of age in the United States: Third National Health and Nutrition Examination Survey, 1988 to 1994. Pediatrics 1998;101:E8. 39. Mannino DM, Moorman JE, Kingsley B, Rose D, Repace J. Health effects related to environmental tobacco smoke exposure in children in the United States: data from the Third National Health and Nutrition Examination Survey. Arch Pediatr Adolesc Med 2001;155:36-41. 40. National Institute of Medicine. Exposure to environmental tobacco smoke. In: Committee on the Assessment of Asthma and Indoor Air, editors. Clearing the air: asthma and indoor air exposures. Washington (DC): National Academy Press; 2000. p. 263-97. 41. Lee K, Levy JI, Yanagisawa Y, Spengler JD, Billick IH. The Boston residential nitrogen dioxide characterization study: classification and prediction of indoor NO2 exposure. J Air Waste Manag Assoc 1998; 48:736-42.