Less Air Pollution Leads to Rapid Reduction of Airway Inflammation and Improved Airway Function in Asthmatic Children
OBJECTIVE. Air pollution can promote airway inflammation, posing significant health risks for children with chronic respiratory problems. However, it is unknown whether this process is reversible, so that limiting pollution will benefit these children. We measured the short-term response of allergic asthmatic children exposed to a real-life reduction in outdoor air pollution by using noninvasive biomarkers of airway inflammation and function.
PATIENTS AND METHODS. Thirty-seven untreated allergic children with mild persistent asthma were recruited from a highly polluted urban environment and relocated to a less polluted rural environment. Air pollution, pollen counts, and meteorological conditions were carefully monitored at both sites. Nasal eosinophils, fractional exhaled nitric oxide, peak expiratory flow, and urinary leukotriene E4 were measured first in the urban environment and then again 7 days after relocation to the rural environment.
RESULTS. One week after relocation to the rural environment, we measured, on average, a fourfold decrease in nasal eosinophils and significant decrease in fractional exhaled nitric oxide. We also noted an improvement in lower airway function, reflected by highly significant increase in peak expiratory flow. In contrast, mean urinary leukotriene E4 concentration remained unchanged after 1 week of exposure to the rural environment.
CONCLUSIONS. Better air quality is associated with a rapid reduction of airway inflammation in allergic asthmatic children. Nasal eosinophils and fractional exhaled nitric oxide are sensitive indicators of this effect, and their rapid decline is paralleled by improved airway function measured by peak expiratory flow. Leukotriene synthesis has a more variable response to environmental modifications.
In recent decades, we have experienced a global increase in the prevalence of asthma and other allergic diseases, particularly among children living in the urban areas of economically developed countries. This has led to the hypothesis that environmental factors, especially indoor and outdoor air quality, play an important role in the inception of allergy and asthma early in life, and later trigger acute exacerbations of respiratory symptoms.1–3 Specifically, several studies have shown that exposure to particulate matter (PM10) increases the use of asthma medications and the rate of hospital admissions for asthma.4–8 Ozone worsens airway inflammation and resistance in patients with asthma.9–11 Nitrogen oxides predispose to respiratory infections, wheezing exacerbations, and stronger response to inhaled allergens.12 Carbon monoxide (CO)13 and benzene14 are strong independent risk factors for emergency department and hospital admissions of asthmatic children.
In light of the epidemiologic evidence outlined previously, and assuming that the inflammatory response of the airways to airborne irritants is reversible, it is reasonable to hypothesize that limiting outdoor air pollution will benefit airway inflammation, thereby improving the clinical and functional manifestations of asthma and other chronic respiratory disorders. However, little scientific evidence is available to support this hypothesis, and also it is not known how rapidly a favorable change in air quality can lead to measurable reduction in airway inflammation and to improvement in airway function. To address these questions, the present study sought to determine whether a 1-week exposure to a less polluted environment affects the expression of specific noninvasive biomarkers used to monitor airway inflammation and airflow limitation in allergic children with physician-diagnosed asthma.
Previous studies have shown that exposure to ozone increases the number of eosinophils in nasal secretions,15 and more recent work found that personal and ambient air pollution correlate with increased fractional exhaled nitric oxide (FENO) concentration from the lower airways of children with asthma.16 Therefore, we measured the response of these sensitive biomarkers of upper and lower airway inflammation to real life, carefully monitored environmental exposures to airborne pollutants and allergens, and explored the correlation between airway inflammation and function measured by peak expiratory flow (PEF). Furthermore, in light of the role played by cysteinyl leukotrienes (cysLTs) in the pathophysiology of allergic inflammation of the upper and lower airways,17 we measured the excretion of their terminal metabolite leukotriene E4 (LTE4) in the urine.
PATIENTS AND METHODS
All subjects were recruited between June 1 and July 31, 2006, from the Asthma Clinic of the Department of Pediatrics of the Civil Hospital in Pescara, Italy. This study was approved by the local institutional review board, and informed consent was obtained from the parents of each subject.
We included children 7 years of age or older, with physician-diagnosed mild persistent asthma as defined by the Global Initiative for Asthma, positive skin-prick test for allergy to dust mites, who were able to perform PEF and FENO measurements. Exclusion criteria included symptoms or any medical treatment in the 3 weeks preceding relocation to the rural environment. Throughout the study, the children were closely monitored by medical and nursing staff but received no medications.
A total of 60 children were approached, but 16 could not be enrolled because their parents declined consent. Five subjects experienced respiratory symptoms before relocation, resumed therapy with inhaled corticosteroids and short-acting β-agonists, and withdrew from the study. During the study, we also excluded 1 child who developed fever and another who had problems performing reproducible PEF measurements.
All participating families implemented in their homes environmental control strategies for avoiding indoor allergens and pollutants, particularly dust mites by encasing pillows and mattresses in air-tight covers and washing bed linens and blankets weekly in hot water. All exposure and clinical measurements were performed first in the urban environment on the day before relocation (day 0), and then again 7 days after relocation to the rural environment (day 7).
A network of 6 fixed air quality monitoring stations operates continuously in the city of Pescara, Italy, under the Regional Agency for Environmental Protection (ARTA). These stations are located in densely populated urban areas and collect hourly data on PM10, ozone, nitrous oxide (NO2), CO, and benzene. These data were used to extrapolate the mean daily exposure to each pollutant during the week preceding relocation, and the mean of these daily values was used for our analysis. PM10 levels were measured by B-ray atomic absorption, ozone by ultraviolet photometry, NO2 by chemiluminescence, CO by infrared photometry, and benzene by gas chromatography. We also monitored local meteorological conditions at the same time points, and allergen levels were measured by using a portable volumetric sampler (VPPS 2000 [Lanzoni, Bologna, Italy]).18
This part of the study was conducted during a school camp held in Ovindoli, Italy, a rural area located 1500 m above sea level with very low motor vehicle traffic. During the 7 days of the study, the children were housed in a hotel without their families and were supervised by members of the Department of Pediatrics' medical and nursing staff. Air quality was monitored from the parking lot of the hotel where the children were housed by a mobile station certified by ARTA to obtain measurements comparable with the urban data. These data were used to extrapolate the mean daily exposure to each pollutant during the week after relocation, and the mean of these daily values was used for our analysis. PM10 levels were measured with an oscillating microbalance, ozone and NO2 by differential optical absorption spectrometry, CO by infrared photometry, and benzene by gas chromatography. Meteorological conditions were monitored at the same time points, and allergen levels were measured by using the same VPPS air sampler used for the urban environment.
The mucosa was scraped with a plastic curette from the medium third of the inferior nasal turbinate on days 0 and 7 of the study period. The specimens were stained with the May-Grunwald-Giemsa method and were examined under microscope by a blinded investigator.
The FENO concentration from the lower airways was measured with a handheld analyzer (Niox Mino [Aerocrine, New Providence, NJ])19 at 5 pm on days 0 and 7 of the study period using a methodology compliant with the current American Thoracic Society (ATS)/European Respiratory Society (ERS) international guidelines.20,21
PEF was measured with a standard device at 8 am, 3 pm, and 10 pm on days 0 and 7 of the study period. The mean of the 3 measurements was used for our analysis.
Urine samples were collected on days 0 and 7 of the study period and were analyzed in duplicate using a competitive enzyme-linked immunoassay (Cayman Chemical, Ann Arbor, MI), as described previously.22
Data are expressed as mean ± SEM, unless indicated otherwise. Exposure and clinical measurements obtained in the urban versus rural environment were compared by using the paired Student's t test, and Pearson's correlation coefficients were used to assess the relationship between inflammatory biomarkers and functional measures. Statistical analysis was performed by using StatView 5.0.1 software (SAS Institute, Cary, NC). Differences having a P value of <.05 were considered significant.
We studied 37 allergic children (25 males and 12 females; age: 9.9 ± 0.3 years) with physician-diagnosed mild persistent asthma. Seventy percent (26 of 37) of these children also had clinical diagnosis of allergic rhinitis, 16% (6 of 37) atopic dermatitis, and 5% (2 of 37) allergic conjunctivitis. Results of their skin-prick tests for common airborne allergens are summarized in Table 1. All subjects were allergic to dust mites. Of the tests for pollens, 43% were positive to Gramineae, 30% to Oleaceae, and 19% to Urticaceae, whereas positivity to Cupressaceae and Betullaceae was rare.
The rural environment was located 1500 m above the urban environment, which explains the lower atmospheric pressure (P = .003) and temperature (P < .0001), whereas humidity (P = .84) and wind speed (P = .85) were similar (Table 2). All of the pollutants tested (Table 3) were present at significantly lower concentrations in the rural environment compared with the urban environment (P < .001). The largest differences were measured in the concentrations of benzene and NO2 that were, respectively, 20-fold and 15-fold lower in the rural environment (Fig 1), whereas relatively smaller differences were measured for CO (sevenfold), PM10 (fourfold), and ozone (twofold). In contrast, the exposure to airborne allergens did not change significantly moving from the urban to the rural environment (Table 4), with the only exception of the Fagaceae pollen (P < .01) to which none of the study subjects was sensitized.
This environmental modification was rapidly followed by measurable changes in biomarkers of upper and lower airway inflammation. Specifically, we found an average fourfold decrease in nasal eosinophils (P = .002; Fig 2A and B). This effect was quite consistent, and eosinophils became virtually undetectable (<1%) in the upper airways of most subjects after 1-week exposure to the rural environment. Living in a less polluted environment was also associated with reduced eosinophilic inflammation of the lower airways, reflected by a significant decrease in mean FENO concentration (P = .028; Fig 3A and B), and with consistent improvement in lower airways function reflected by a highly significant increase in mean PEF (P < .0001; Fig 4A and B).
Baseline FENO concentrations measured in the urban environment were normal (5–20 ppb) in 15 subjects, intermediate (20–35 ppb) in 10 subjects, and high (>35 ppb) in 12 subjects. Rural FENO concentrations were significantly lower in subjects with high urban FENO (P = .002), whereas no significant change was measured in children with intermediate (P = .79) or normal (P = .86) urban FENO (Fig 5A). Also, the change in PEF was not correlated with FENO concentration (r = 0.18; P = .29), and a similar increase in airway function was measured in all 3 FENO subgroups (P < .001; Fig 5B).
The leukotriene response to environmental change was rather variable, increasing or decreasing sharply in some subjects while changing little in most. As a result, we found no statistically significant change in the mean urinary LTE4 concentration after 1-week exposure to the less polluted rural environment (P = .974; Fig 6, A and B). We were also unable to identify any specific factor predictive of the different patterns of leukotriene response in our subjects.
This study is the first adopting a real-life experimental approach to analyze the impact of outdoor air pollution on respiratory health in childhood. Its results suggest that lowering the exposure of allergic asthmatic children to airborne pollutants is rapidly followed by measurable improvements in airway inflammation and function. Nasal eosinophils came out as the most sensitive biomarker to monitor pollution-induced airway inflammation, decreasing to virtually normal levels just 1 week after real-life relocation from a more polluted urban environment to a less polluted rural environment. Also the FENO concentration decreased significantly after relocation in children that had more active lower airway inflammation while living in a highly polluted urban environment.
Nasal eosinophils counts are primarily a marker of allergic inflammation of the upper airways,23 whereas FENO has been shown to be closely related to the degree of eosinophilic inflammation and methacholine responsiveness of the lower airways.24 These biomarkers are well-established direct indicators of inflammation, although their clinical relevance and degree of correlation with disease activity remain controversial. Although we elected not to obtain induced sputum to minimize discomfort for our young patients and because of its lower reliability in mild asthmatic children,25,26 FENO has been shown to correlate very well with the number of eosinophils in sputum.24 As in several previous studies,26,27 we found no significant correlation between FENO and lung function measurements, suggesting that these tests reflect different pathophysiologic mechanisms of asthma.
Importantly, breathing cleaner air was associated in most children with a rapid and highly significant functional improvement in expiratory airflow. The subjects of this study were established patients of the asthma clinic and therefore they were quite experienced with the use of peak flow meters, which they were requested to use 2 to 3 times per week when clinically stable and 3 times per day during exacerbations. Therefore, it is extremely unlikely that improved performance may have contributed to the increase in PEF observed during the study.
We deliberately limited our study to children with mild persistent asthma and without therapy to avoid the possibility that antiinflammatory medications would mask environment-driven effects on inflammatory and functional biomarkers, and that our data would be confounded by variable adherence to therapy. On the other hand, recent studies in adults28 suggest that the magnitude of the changes measured in our end points would be much larger in patients with more severe asthma and more compromised airway function. Also, some inflammatory and functional changes may lag several days behind the causative environmental modifications29 and may therefore be missed in a short-term study, although again similar real-life studies have shown significant changes within hours from exposure.28
All children included in this study met Global Initiative for Asthma criteria for the diagnosis of mild persistent asthma, and consistent with these guidelines they were treated with regular inhaled corticosteroid therapy, which was suspended at least 3 weeks before the study. The protocols adopted by the asthma clinic where these children were recruited prescribe a 6-month cycle of inhaled corticosteroid therapy after the diagnosis of mild persistent asthma. If the patient is clinically stable after this cycle, controller therapy is suspended and it is resumed in combination with a rescue short-acting β-agonist only if symptoms recur. Although management guidelines recommend the continued use of inhaled corticosteroids for patients with mild persistent asthma, recent studies indicate that these patients may not require regular treatment. Rather, the symptom-driven use of inhaled corticosteroids would be as effective as its regular use and would allow the use of lower cumulative doses.30,31
Therefore, we feel that the management of our subjects was appropriate and based on sound scientific evidence, although it may have not adhered strictly to the adopted guidelines.
Our results are consistent with recent studies showing that traffic-related exposures are associated with increased airway inflammation and reduced lung function in children with asthma,32 and contribute the notion that this negative influence may be rapidly reversible. Another study conducted in Atlanta during the 1996 Summer Olympic Games concluded that decreased air pollution resulting from the implementation of alternative transportation strategies coincided with a transient reduction of asthma morbidity in children.33 Collectively, these investigations underscore the impact of outdoor air pollution on allergic airways during childhood, whereas in the past more emphasis was placed on indoor pollution because of the fact that average children spend most of their time indoors. However, it is now recognized that outdoor air pollutants, particularly ozone and fine particles, can penetrate the building shell and enter the indoor environment,34–37 which provides another key to explain our findings. The reversible nature of pollution-induced airway inflammation emphasizes the importance of air quality for patients with asthma and allergic rhinitis, and suggests that pharmacological interventions could be minimized or abolished when allergic asthmatic children live in a cleaner environment.
The impact of air pollution on asthma morbidity in children is of particular concern in Italy and other European countries. In recent years the concentration of some pollutants like CO, sulfur dioxide, and benzene has declined significantly in most European cities because of the improved efficiency of engines and fuels. However, differently from the declining national trends reported by the US Environmental Protection Agency, the concentrations of ozone, NO2, and especially PM10 remain high in most urban areas of both northern and southern Europe, rising frequently above the safety thresholds mandated by the European Union. Despite the improvement in air quality achieved in the United States by the pollution control programs instituted under the Clean Air Act, air pollution problems continue in many parts of the country and compel the development of new strategies to reduce emissions further.
Our findings cannot be explained by different patterns of allergic stimulation, as the only significant difference was an increase of Fagaceae pollens in the rural environment without correspondent sensitization. Also unlikely is a role of the indoor environment, because these children lived in families educated by the asthma clinic staff and their home environment was highly controlled with strategies for avoiding exposures to common allergens and pollutants, particularly dust mites. Such level of indoor environmental control would be logistically impossible in a hotel, and therefore if the indoor influences were predominant we should have observed worse airway inflammation and function in the rural area, rather than the actual improvement we measured.
Surprisingly, the improvement in airway inflammation and function observed after relocation to the rural environment was not reflected by predictable changes in the urinary concentration of LTE4, which is the end-product of cysLTs metabolism in activated mast cells, eosinophils, and monocytes.38–40 The lack of a consistent response to environmental modulation suggests that the production of cysLTs is strictly controlled by mechanisms intrinsic to the pathophysiology of allergic inflammation, or alternatively that this pathway has a slower response to extrinsic environmental changes.
Of course, there are some limitations to our study, largely deriving from the approach we and others28 have adopted to mimic real life as close as possible and avoid the many artifacts inherent to the use of exposure chambers. In particular, it is impossible to rule out a potentially beneficial contribution of psycogenic factors associated with the change in environment. However, this interaction is less likely because, for most of the children involved in our study, the school camp coincided with their first experience away from home and their parents; therefore, more likely to increase rather than decrease stress. Furthermore, previous studies on the effect of psychological stress in asthmatic children failed to show significant changes in lung function,41 whereas our study shows a clear improvement in expiratory airflow.
School camp costs for the subjects and personnel involved in this study (total: 12500 euro) were paid by the families of the participants (90%) and by a small grant (10%) from a nonprofit foundation (Aspra Onlus, Pescara, Italy). The same foundation provided educational material on allergic diseases (500 euro) and an expense reimbursement for the medical staff (1000 euro). Funds and technology for all environmental measurements were provided by the ARTA of Pescara, Italy. All clinical tests were paid by the Department of Pediatrics of the Civil Hospital in Pescara, Italy. Dr Giovanni Piedimonte is funded, in part, by grants from the US National Institutes of Health (National Heart, Lung, and Blood Institute HL-61007 and National Institute of Child Health and Human Development NCS-07-11).
- Accepted July 23, 2008.
- Address correspondence to Giovanni Piedimonte, MD, West Virginia University School of Medicine, Department of Pediatrics, Robert C. Byrd Health Sciences Center, 1 Medical Center Dr, PO Box 9214, Morgantown, WV 26506-9214. E-mail:
Drs Renzetti and Silvestre contributed equally to this work.
The authors have indicated they have no financial relationships relevant to this article to disclose.
What's Known on This Subject
Air pollution can promote airway inflammation and negatively affect lung function, posing significant health risks for children with chronic respiratory problems like asthma. However, it is unknown whether this process is reversible, so that limiting pollution will benefit these children.
What This Study Adds
This study provides the first objective evidence that limiting real-life exposure of allergic asthmatic children to outdoor air pollution is followed by measurable reduction in airway inflammation and improved airway function, implying that better air quality may rapidly lead to clinical improvement.
- ↵Rasmussen F, Taylor DR, Flannery EM, et al. Risk factors for airway remodeling in asthma manifested by a low postbronchodilator FEV1/vital capacity ratio: a longitudinal population study from childhood to adulthood. Am J Respir Crit Care Med.2002;165 (11):1480– 1488
- ↵Anderson HR, Ponce de Leon A, Bland JM, Bower JS, Emberlin J, Strachan DP. Air pollution, pollens, and daily admissions for asthma in London 1987–92. Thorax.1998;53 (10):842– 848
- Atkinson RW, Anderson HR, Strachan DP, Bland JM, Bremner SA, Ponce de Leon A. Short-term associations between outdoor air pollution and visits to accident and emergency departments in London for respiratory complaints. Eur Respir J.1999;13 (2):257– 265
- Peters A, Dockery DW, Heinrich J, Wichmann HE. Short-term effects of particulate air pollution on respiratory morbidity in asthmatic children. Eur Respir J.1997;10 (4):872– 879
- ↵van der Zee S, Hoek G, Boezen HM, Schouten JP, van Wijnen JH, Brunekreef B. Acute effects of urban air pollution on respiratory health of children with and without chronic respiratory symptoms. Occup Environ Med.1999;56 (12):802– 812
- ↵Fusco D, Forastiere F, Michelozzi P, et al. Air pollution and hospital admissions for respiratory conditions in Rome, Italy. Eur Respir J.2001;17 (6):1143– 1150
- ↵Taylor DR, Pijnenburg MW, Smith AD, De Jongste JC. Exhaled nitric oxide measurements: clinical application and interpretation. Thorax.2006;61 (9):817– 827
- ↵Jatakanon A, Lim S, Kharitonov SA, Chung KF, Barnes PJ. Correlation between exhaled nitric oxide, sputum eosinophils, and methacholine responsiveness in patients with mild asthma. Thorax.1998;53 (2):91– 95
- ↵Gibson PG, Henry RL, Thomas P. Noninvasive assessment of airway inflammation in children: induced sputum, exhaled nitric oxide, and breath condensate. Eur Respir J.2000;16 (5):1008– 1015
- Copyright © 2009 by the American Academy of Pediatrics