Randomized controlled trial of unflued gas heater replacement on respiratory health of asthmatic schoolchildren

Louis S Pilotto1, Monika Nitschke2, Brian J Smith3, Dino Pisaniello4, Richard E Ruffin5, Heather J McElroy6, James Martin7 and Janet E Hiller4

1 Department of General Practice and Flinders Centre for Epidemiology and Biostatistics, Flinders University of South Australia, Australia
2 Environmental Health Branch, Department of Human Services, Australia
3 Respiratory Medicine, North Western Adelaide Health Service, Australia
4 Department of Public Health, University of Adelaide, Australia
5 Department of Medicine, University of Adelaide, Australia
6 Clinical Epidemiology and Health Outcomes Unit, North Western Adelaide Health Service, Australia
7 Women's and Children's Hospital, Adelaide, South Australia, Australia

Correspondence: Professor Louis Pilotto, Department of General Practice, Level 7, Flinders Medical Centre, Bedford Park, SA, 5042, Australia. E-mail: louis.pilotto{at}flinders.edu.au


    Abstract
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 Abstract
 Methods
 References
 
Background Previous studies do not provide a clear picture of the relationship between nitrogen dioxide (NO2) exposure and asthma.

Methods Eighteen schools using unflued gas heating in winter were randomly allocated to either retain their heaters (10 control schools) or to have replacement flued gas or electric heaters installed at the beginning of winter (8 intervention schools). Fortnightly telephone interviews were used to record daily individual asthma symptoms that occurred over 12 weeks (including winter). Lung function and histamine challenge tests were performed at baseline and the end of the study. NO2 was measured in each school classroom on 9 days and in each household on 3 days spread over the study period.

Results From 199 primary school children that met the eligibility criteria, 45 intervention and 73 control children agreed to participate. Baseline characteristics were similar between groups. Difficulty breathing during the day (Relative Risk [RR] = 0.41; 95% CI: 0.07, 0.98) and night (RR = 0.32; 95% CI: 0.14, 0.69), chest tightness during the day (RR = 0.45; 95% CI: 0.25, 0.81), and daytime asthma attacks (RR = 0.39; 95% CI: 0.17, 0.93) were significantly reduced in the intervention group. Percentage predicted forced expiratory volume in one second (FEV1), the concentration of histamine inducing a 20% fall in FEV1 (PD20), and the dose–response slope (DRS) were similar between groups at follow-up. Mean (standard deviation) NO2 levels were 15.5 (6.6) parts per billion (ppb) and 47.0 (26.8) ppb in the intervention and control schools respectively (P < 0.001).

Conclusions Asthma symptoms were reduced following a replacement intervention that removed high exposure to NO2. Such replacement should be considered a public health priority for schools using unflued gas heating during winter.


Keywords Respiratory disease, asthma, indoor air pollution, nitrogen dioxide

Accepted 15 August 2003

Australia has one of the highest asthma symptom prevalence rates in children anywhere in the world.1 Up to 28% of primary school children living in seven regions in New South Wales reported wheeze occurring within the preceding 12 months.2 Epidemiological evidence suggests that the wide variation in asthma prevalence between different countries is due mainly to environmental and not genetic factors.3 Air pollution is associated with many signs of asthma aggravation.4 Nitrogen dioxide (NO2), an air pollutant formed by the combustion of fossil fuels, and its relationship to asthma has been the focus of considerable research.5 Unflued gas cooking and heating appliances have been shown to produce indoor levels of NO2 considerably higher than those occurring outdoors. One study conducted in Western Sydney found one-hour levels in school classrooms heated by unflued gas heaters reached up to seven times the current recommended WHO level of 110 parts per billion (ppb).6

In controlled clinical studies, NO2 had mixed effects on lung function tests,7,8 including non-specific airways responsiveness. However, a meta analysis by Folinsbee concluded that increased bronchial hyperresponsiveness occurred in asthmatics after exposure to NO2 levels of 100–200 ppb/hr.9

Two case-control and one cohort study, using measured levels of indoor NO2 to classify exposure, have been conducted involving children with asthma. One study found no association,10 while the other found a dose–response relationship between increasing NO2 concentrations of exposure and asthma.11 A recently reported cohort study found a significant association between daily NO2 exposure and a range of asthma symptoms on the same and the next day.12

The mixed results based on the studies conducted to date do not provide a clear picture of the relationship between NO2 exposure and asthma. Misclassification of NO2 levels and possible confounding may explain the absence of an exposure–disease link in some of the studies. Here we report on the first randomized controlled trial of unflued gas heater replacement (intervention), with either flued gas or electric heating, on the respiratory health of asthmatic primary school children in South Australia over winter. Unflued combustion sources are known to also produce nitrous acid (HONO) indoors. However, indoor HONO levels have been shown to be closely correlated with indoor NO2 levels, but at about 17% of the NO2 concentrations.13 The main hypotheses tested were (1) asthma symptoms would be less over winter in the intervention children compared with control children, and (2) that lung function would be improved and bronchial responsiveness decreased at the end of winter in these children.


    Methods
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 Abstract
 Methods
 References
 
School selection and randomization
A metropolitan survey of primary schools in Adelaide identified a total of 19 schools that used unflued gas heating in school classrooms during winter, making them eligible to participate in this study. Prior to their recruitment (January–February 2000) a letter was sent to the school principals to seek their support and involvement in the study. Principals were asked to maintain confidentiality about the link between replacement of heaters and this study, which was identified as a study of the indoor environment of the school and asthma. This was to make blind school staff, our research staff, the research participants, and their families to the intervention.

Schools were numbered and then randomly allocated for unflued gas heater replacement by flued gas or electric heaters using the random number generator in Stata 6.0. The use of either flued gas or electric heating in an intervention school was determined by cost limitation and school requirements. Heaters were replaced in April/May 2000, at the beginning of the winter heating period. Installation of heaters was organized through the usual school authorities to appear as a normal upgrade and to maintain normal procedures so as to avoid the link between heater replacement and this study. This process was to maintain blinding.

Child recruitment
School support officers (SSO), who are employed by the schools to support teachers, assisted with the study. They provided lists of all students in unflued gas heated classrooms, organized distribution of written materials to parents, and promoted participation among children. After initial training, they placed and collected NO2 monitors in classrooms, and helped with the organization of objective lung measurements.

In the first instance, an information letter and short questionnaire were distributed to all children listed by the SSO to identify eligible children. Eligibility criteria were (1) a history of doctor-diagnosed asthma and (2) the absence of unflued appliances in their household. Children whose questionnaires were not returned to the SSO within a week received at least two reminders.

A second information letter with study details and consent form (for both parent and child) were sent to parents of eligible children, inviting them to participate by keeping daily diaries of their children's respiratory state, to be reported fortnightly by telephone interview. The daily diaries employed have been successfully used in previous studies.12,14 In the same letter, children were invited to undertake lung function, histamine challenge, and skin prick tests. Results of these tests were to be made available to participants' nominated general practitioners on request.

Demographic and clinical factors
Age, gender, household smoking, ethnic background, and education level of parents were recorded at the first telephone interview. The extent of asthma medication use in the 4 weeks prior to the intervention, and over the previous 12 months, birthweight, chest illness before the age of 2, and hayfever status in the last 12 months were also recorded.

Skin prick testing
Skin prick tests for rye grass, cat hair, dog hair, plantain, alternaria, and house dust mite allergy, with appropriate controls, were conducted at the end of the study. The standardized protocol for performing skin prick tests in population studies was used.15

Outcomes
Daily diaries
A market research company, blinded to the purpose of the study and the allocation of schools, conducted the fortnightly telephone interviews of parents over 12 weeks from 1 June to 20 August 2000. These were conducted to compile the symptom database based on the diaries. Symptom rates for each child were calculated as the number of days of symptom occurrence divided by the number of days recording.

Lung function
Lung function measurements were taken on entry into the study when gas heaters were in use but the intervention was not yet in place, and at the end of the study when heater use was minimal. Lung function testing, pre- and post-Ventolin®, was performed using the Jaeger Toennis Master Scope direct reading spirometer with Software version 4.34 using a standardized protocol outlined by the Australian Asthma Council.15 Percentage predicted forced expiratory volume in one second (FEV1) (= measured FEV1/predicted FEV1) was used in the analysis.

Bronchial responsiveness
Bronchial responsiveness testing was offered to children aged >=7 years. Testing, using histamine challenge, was conducted on either the day before or after lung function testing, using a standardized protocol.16 Trained respiratory technical personnel carried out these tests in schools in the presence of a medical practitioner. Bronchial responsiveness was expressed as (1) the concentration of histamine inducing a 20% fall in FEV1 (PD20) and (2) a dose–response slope (DRS) expressed as the ratio of the overall per cent fall in FEV1 by the final histamine concentration.16

Nitrogen dioxide measurements
NO2 levels in school classrooms were measured using passive diffusion badge monitors in accordance with the Australian Standard (AS 2365.1.2, 1990).17 Measurements took place over 9 weeks during the winter heating period. Schools were evenly grouped into three batches. Each school in a batch was monitored for 3 days (Tuesday, Wednesday, Thursday) in a week, rotated over three cycles. So each classroom had NO2 levels recorded on 9 days spread over the study period.

On each day of measurement, three exposure badges were used in gas heated classrooms, and two in electrically heated classrooms. The decision to use two monitors was based on prior exposure measurements that showed minimal variation in monitors placed in electrically heated classrooms.6 All monitors were exposed for 6 hours during the active school day. Primary school children in any one classroom essentially spent their entire school days in the same room.

NO2 was measured in each child's household each evening over 3 days (Tuesday, Wednesday, Thursday) using the same passive diffusion badge monitors. Two badges were placed on each kitchen benchtop, and each child wore a personal monitor. Monitors were exposed from the time of arrival at home until bedtime.

Approval for this study was received from the North Western Adelaide Health Service Human Ethics Committee.

Statistical analyses
Sample size was calculated with Win Episcope 2.0. A sample size of 86 asthmatic participants (43 per group) was needed to determine a 50% reduction in mean symptom rates, based on a SD of 80%, with 95% confidence and 80% power in a two-tailed test. This allowed the detection of a clinically significant reduction in mean symptom rates in children over a winter heating period.

The estimated sample sizes for objective lung measurements were smaller. For example, the sample size required to detect a 10% shift in PD20 based on a mean PD20 of 0.9 (SD: 0.1) with 95% confidence and 80% power was 44 children (22 per group).

Percentage predicted FEV1, PD20, and DRS were compared between the intervention and control children using linear regression analysis with log transformation for PD20 and DRS, and including baseline covariates.18 To allow for overdispersion of symptom data, negative binomial regression analysis was used to compare symptom rates between the two groups of children.19 Robust standard errors were used to allow for clustering by school.20 T-tests of log transformed NO2 were used to assess differences in NO2 levels in classrooms and at home between groups.

Results
Recruitment
From the 18 of the 19 eligible schools that agreed to participate, randomization resulted in 10 control (with no heater replacement) and 8 intervention (4 with electric and 4 with flued gas heaters) schools involving 44 and 29 classrooms respectively. Only 199 children from 555 identified asthmatic children were eligible for this study due to the presence of unflued gas appliances at home. Of these, 118 (59%) agreed to participate (Flow diagram). The different rates of participation of these children in the different aspects of the trial are shown in the flow diagram. Eligible children who did not participate were similar in respect to gender and age. Parental refusal for objective measurements reduced participation in lung function and bronchial responsiveness testing.

Baseline data, including medication use, were similar between children in the two groups, apart from hayfever and parental education for which adjusted analyses were conducted (Table 1). Of the 114 participants with recorded diary information, 84% of the intervention children and 87% of the controls provided data for 84 days (entire period), 11 and 10% for between 70 and 84 days, and 5 and 3% for 28 days.


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Table 1 Baseline characteristics of participants (percentage unless otherwise stated)

 
Difficulty breathing during the day and night, chest tightness during the day, and daytime asthma attacks were significantly reduced in the intervention group (Table 2). This represented a reduction in asthma attacks during the day in an average child from occurring on 3 days to one day over the winter period due to the intervention. Difficulty breathing during the day fell in an average child from occurring on 5 days to 2 days, difficulty breathing during the night from 3 days to one day and chest tightness during the day from 5 days to 2 days (Table 2). Relative risks showed reduced asthma attacks during the night (P = 0.07) and visits to a health care facility due to asthma (P = 0.07) in the intervention group were of borderline significance. Following adjustment for hayfever and parental education at baseline, results remained substantially unchanged except that difficulty breathing during the day assumed borderline significance (RR = 0.46: 95% CI: 0.19, 1.08) while the reduction in asthma attacks during the night reached statistical significance (RR = 0.33; 95% CI: 0.13, 0.84).


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Table 2 Mean rates (SD) per 100 days at risk, unadjusted relative risks (RR), 95% CI, and significant P-values for symptoms/activities over 12 weeks during the winter heating period

 
Lung function and bronchial responsiveness
Lung function tests were conducted before and after the study period on 38 (83%) children in the intervention group and 52 (71%) in the control group. Eighteen children were excluded due to a missing baseline lung function test. Another 10 were excluded due to absence of parental consent or inadequate spirometry technique.

From the 88 children aged >=7 years, 3 were excluded from histamine challenge due to lack of parental consent and 21 did not complete testing because of inability to comply with technique or being absent on the day of the test. Twenty-seven (60%) intervention and 37 (51%) control children underwent bronchial responsiveness testing before and after the study period.

The decrease in symptom rates observed in intervention children not taking part in objective lung function testing was of the same order of magnitude as that found in intervention children who participated. This suggests that the results of objective lung tests were not biased due to exclusion of participants.
Flow diagram

At baseline there was no difference in lung function or bronchial responsiveness between the intervention and control children (Table 3). At the end of the study period, percentage predicted FEV1 had risen in both groups, but there was no relevant difference between the groups (ß-coefficient: 1.2; 95% CI: −2.4, 4.9; P = 0.5). Proportions of students who responded to histamine were very similar in the two groups and remained so after the study period. Linear regression analysis in relation to post study outcomes for PD20 FEV1 (ß-coefficient: −0.2; 95% CI: −0.5, 0.1; P = 0.2) and DRS (ß-coefficient: −0.3; 95% CI: −1.3, 0.7; P = 0.7) indicated no difference between intervention and control children.


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Table 3 Lung function and bronchial responsiveness in children at baseline and at the end of the study period. Mean percentage predicted forced expiratory volume in one second (FEV1a) (SD), the concentration of histamine inducing a 20% fall in FEV1 (PD20), and a dose–response slope (DRS) expressed as the ratio of the overall per cent fall in FEV1 by the final histamine concentration (geometric mean; 95%CI)

 
Nitrogen dioxide measurements
Six-hourly NO2 measurements were made on 9 days in 21 and 33 intervention and control classrooms, on 8 days in 3 intervention and 8 control classrooms and on 6 days in 5 intervention and 3 control classrooms, respectively due to the occurrence of pupil-free days and school excursions. Mean classroom NO2 levels ranged from 7–38 ppb and 12–116 ppb respectively, with overall means (SD) of 15.5 (6.6) and 47.0 (26.8) ppb in the intervention and control schools respectively. The mean levels recorded in intervention classrooms were significantly less than those in control classrooms (P < 0.001). All measurements in the intervention classrooms were within the WHO one-hour guideline level (110 ppb), while at least one measurement in 44% of control classrooms exceeded the guideline.

Mean (SD) NO2 levels recorded in home kitchens were 13.7 (19.3) ppb and 14.6 (21.5) ppb for the intervention and control children respectively; and on personal monitors at home were 12.8 (12.2) ppb and 12.9 (13.9) ppb respectively.

Discussion
This is the first reported intervention study of unflued gas heater replacement on health effects related to asthma. Rates of difficult breathing during the day and night, chest tightness during the day, and daytime asthma attacks were reduced, and the magnitude of this reduction may be attributed to the intervention, as may the reduction in NO2 exposure levels. To a lesser extent, visits to a health care facility due to asthma were also reduced in the intervention group. More generally, the intervention group had almost all symptoms/activities reduced compared with the control group. These findings for chest tightness during the day and asthma attacks during the day and night are consistent with those reported in a previous study that used the same symptom/activity diary as the one used in this study.12 The absence of a significant reduction of symptoms with exercise in the intervention group may in part be due to the use of bronchodilator medication in both groups prior to exercise, but this was not recorded.

Randomization was successful, with little difference in asthma medication use or other characteristics at entry into the study. Blinding was maintained throughout the study at school, laboratory, and data management levels. Importantly, school principals ensured that heater replacement was not identified to be part of the study. The magnitude of the differences between the intervention and control groups was large enough to demonstrate significant differences for a number of outcomes that remained strong both with and without adjustment for parental education and hayfever at baseline. The levels of NO2 measured are consistent with these findings in that there were significantly lower levels recorded in the intervention classrooms. Home levels of NO2 were low in both groups and unlikely to be a cause of misclassification by group.

A limitation of the study was the need to use either electric or flued gas heaters for the intervention, instead of the same type of heater throughout. However, the knowledge that flued gas heaters produce low levels of NO2 indoors is consistent with the significantly lower levels of NO2 found in intervention compared with control classrooms, which was the desired result for the intervention.

Clinically significant symptom reduction in the intervention group is consistent with the findings from outdoor time series studies of hospital admission for asthma worldwide2123 and for proxy studies evaluating the relationship between gas appliances and asthma symptoms indoors.2428 A very recent study has shown that high exposure to NO2 in the week before the start of a respiratory viral infection, and at levels within current air quality standards, is associated with an increase in the severity of a resulting asthma exacerbation.29

The absence of significant differences between the groups for lung function tests and bronchial responsiveness are consistent with the majority of chamber study results,30 and may indicate that these infrequently measured outcomes do not pick up the extent of morbidity experienced by individuals over time due to the reversible nature of the condition. However, two recent studies have shown a relationship between gas cooking and lung function,31 and gas cooking and bronchial responsiveness32 that may relate to a different pattern of exposure in the home. The rise in percentage predicted FEV1 over the study period might be explained by growth of children between baseline and follow-up.

This study provides evidence of a reduction in asthma symptoms following a replacement intervention (electric or flued-gas) that removes high exposure to NO2. Such a replacement intervention should be considered a public health priority for schools using unflued gas heating during winter.

It is likely these results could be extrapolated to other countries where unflued gas heating is present in schools, and it is also reasonable to suggest this is further evidence for minimizing the use of unflued gas heating in other settings such as in the home.


KEY MESSAGES

  • Unflued gas appliances produce higher nitrogen dioxide (NO2) concentrations indoors than found in ambient (outdoor) air.
  • Observational studies have shown a link between indoor NO2 exposure and asthma symptoms.
  • This first randomized controlled trial of unflued gas heater replacement confirms the association between NO2 exposure and asthma symptoms.
  • Asthma symptoms and indoor NO2 levels were substantially reduced following unflued gas heater replacement with electric or flued gas heaters.

 


    Acknowledgments
 
We wish to thank the National Health and Medical Research Council and Asthma South Australia who funded the study. We thank TAN Research Pty Ltd. who conducted the secondly weekly telephone interviews and Andrew Orfanos for assistance with laboratory assays of NO2.


    References
 Top
 Abstract
 Methods
 References
 
1 Worldwide variation in prevalence of symptoms of asthma common allergic rhino conjunctivitis, and atopic eczema: ISAAC. The International Study of Asthma and Allergies in Childhood Steering Committee. Lancet 1998;351:1225–32.[CrossRef][ISI][Medline]

2 Peat JK, Toelle BG, Gray EJ et al. Prevalence and severity of childhood asthma and allergic sensitisation in seven climatic regions in New South Wales. Med J Aust 1995;163:22–26.[ISI][Medline]

3 Peat JK. The epidemiology of asthma. Curr Opin Pulm Med 1996;2:7–15.[Medline]

4 Koenig JQ. Air pollution and asthma. J Allergy Clin Immunol 1999;104:717–22.[ISI][Medline]

5 Nitschke M, Smith BJ, Pilotto LS, Pisaniello D, Ruffin RE, Abramson M. Respiratory health effects of nitrogen dioxide exposure and current guidelines. Int J Environ Health Res 1999;9:39–53.[CrossRef][ISI]

6 Pilotto LS, Douglas RM, Attewell RG, Wilson SR. Respiratory effects associated with indoor nitrogen dioxide exposure in children. Int J Epidemiol 1997;26:788–95.[Abstract]

7 Bauer MA, Utell MJ, Morrow PE, Speers DM, Gibb FR. Inhalation of 0.30 ppm nitrogen dioxide potentiates exercise-induced bronchospasm in asthmatics. Am Rev Respir Dis 1986;134:1203–08.[ISI][Medline]

8 Utell MJ. Asthma and nitrogen dioxide: a review of the evidence. In: Utell MJ, Frank R (eds). Susceptibility to Inhaled Pollutants ASTM STP 1024. Philadelphia: American Society for Testing and Materials, 1989, pp. 218–23.

9 Folinsbee LJ. Does nitrogen dioxide exposure increase airways responsiveness? Toxicol Ind Health 1992;8:273–83.[ISI][Medline]

10 Hoek G, Brunekreef B, Meijer R, Scholten A, Boleij J. Indoor nitrogen dioxide pollution and respiratory symptoms of schoolchildren. Int Arch Occup Environ Health 1984;55:79–86.[ISI][Medline]

11 Infante Rivard C. Childhood asthma and indoor environmental risk factors. Am J Epidemiol 1993;137:834–44.[Abstract]

12 Smith BJ, Nitschke M, Pilotto LS, Ruffin RE, Pisaniello DL, Willson K. Health effects of daily indoor nitrogen dioxide exposure in people with asthma. Eur Respir J 2000;16:879–85.[Abstract/Free Full Text]

13 Lee K, Xue J, Geyh AS et al. Nitrous acid, nitrogen dioxide, and ozone concentrations in residential environments. Environ Health Perspect 2002;110:145–50.

14 Creer TL, Kotses H, Reynolds RVC. Living with asthma: part II. Beyond CARIH. J Asthma 1989;26:31–51.[ISI][Medline]

15 Spirometry: the measurement and interpretation of ventilatory function in clinical practice. Pierce RJ, Johns DP. National Asthma Campaign 1995. (www.nationalasthma.org.au)

16 Yan K, Salome C, Woolcock AJ. Rapid measurement of bronchial responsiveness. Thorax 1983;38:760–65.[Abstract]

17 Australian Standard (AS 2365.1.2, 1990). Methods for the Sampling and Analysis of Indoor Air. Method 1.2: Determination of Nitogen Dioxide–Spectrophotometric Method–Treated Filter/Passive Badge Sampling Procedure. Standards Australia.

18 Frison L, Pocock SJ. Repeated measures in clinical trials: analysis using mean summary statistics and its implications for design. Stat Med 1992;11:1685–704.[ISI][Medline]

19 Glynn RJ, Buring JE. Ways of measuring rates of recurrent events. BMJ 1996;312:364.

20 Stata Statistical Software. Release 7.0. College Station TX: Stata Corporation.

21 Anderson HR, Limb ES, Bland JM, Ponce de Leon A, Strachan DP, Bower JS. Health effects of an air pollution episode in London, December 1991. Thorax 1995;50:1188–93.[Abstract]

22 Castellsague J, Sunyer J, Saez M, Anto JM. Short-term association between air pollution and emergency room visits for asthma in Barcelona. Thorax 1995;50:1051–56.[Abstract]

23 Walters S, Phupinyokul M, Ayres J. Hospital admission rates for asthma and respiratory disease in the West Midlands: their relationship to air pollution levels. Thorax 1995;50:948–54.[Abstract]

24 Kuhr J, Hendel Kramer A, Karmaus W et al. Air pollutant burden and bronchial asthma in school children. Soz Praeventivmed 1991;36:67–73.

25 Dekker C, Dales R, Bartlett S, Brunekreef B, Zwanenburg H. Childhood asthma and the indoor environment. Chest 1991;100:922–26.[Abstract]

26 Ostro BD, Lipsett MJ, Mann JK, Wiener MB, Selner J. Indoor air pollution and asthma. Results from a panel study. Am J Respir Crit Care Med 1994;149:1400–06.[Abstract]

27 Volkmer RE, Ruffin RE, Wigg NR, Davies N. The prevalence of respiratory symptoms in South Australian preschool children. II. Factors associated with indoor air quality. J Paediatr Child Health 1995;31:116–20.[ISI][Medline]

28 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.[ISI][Medline]

29 Chauhan AJ, Inskip HM, Linaker CH et al. Personal exposure to nitrogen dioxide (NO2) and the severity of virus-induced asthma in children. Lancet 2003;361:1939–44.[CrossRef][ISI][Medline]

30 Samet JM, Utell MJ. The risk of nitrogen dioxide: what have we learned from epidemiological and clinical studies. Toxicol Ind Health 1990;6:247–62.[ISI][Medline]

31 Corbo GM, Forastiere F, Agabiti N et al. Effect of gas cooking on lung function in adolescents: modifying role of sex and immunoglobulin e. Thorax 2001;56:536–40.[Abstract/Free Full Text]

32 Kerkhof M, de Monchy JG, Rijken B, Schouten JP. The effect of gas cooking on bronchial hyperresponsiveness and the role of immunoglobulin E. Eur Respir J 1999;14:839–44.[Abstract/Free Full Text]