http://informahealthcare.com/jas ISSN: 0277-0903 (print), 1532-4303 (electronic) J Asthma, 2014; 51(4): 355–359 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/02770903.2013.823446
ENVIRONMENTAL DETERMINANTS
Low-level environmental tobacco smoke exposure and inflammatory biomarkers in children with asthma Ramneet Gill, MD1, Sankaran Krishnan, MD, MPH2, and A.J. Dozor, MD2 Division of Pulmonary & Critical Care and Sleep Medicine, Department of Medicine, Wayne State University, Detroit, MI, USA and 2Division of Pediatric Pulmonology, Allergy, and Sleep Medicine, Department of Pediatrics, Maria Fareri Children’s Hospital at Westchester Medical Center and New York Medical College, Valhalla, NY, USA Abstract
Keywords
Objective: The effects of low-level environmental tobacco smoke (ETS) exposure, on asthma control, lung function and inflammatory biomarkers in children with asthma have not been well studied. The objective of the study was to assess ETS exposure in school-age children with asthma whose parents either deny smoking or only smoke outside the home, and to assess the impact of low-level ETS exposure on asthma control, spirometry and inflammatory biomarkers. Methods: Forty patients age 8–18 years with well-controlled, mild-to-moderate persistent asthma treated with either inhaled corticosteroids (ICS) or montelukast were enrolled. Subjects completed an age-appropriate Asthma Control Test and a smoke exposure questionnaire, and exhaled nitric oxide (FeNO), spirometry, urinary cotinine and leukotriene E4 (LTE4) were measured. ETS-exposed and unexposed groups were compared. Results: Only one parent reported smoking in the home, yet 28 (70%) subjects had urinary cotinine levels 1 ng/ml, suggesting ETS exposure. Seven subjects (18%) had FeNO levels 425parts per billion, six of whom were in the ETS-exposed group. In the ICS-treated subjects, but not in the montelukasttreated subjects, ETS exposure was associated with higher urinary LTE4, p ¼ 0.04, but had no effect on asthma control, forced expiratory volume in 1 s or FeNO. Conclusions: A majority of school-age children with persistent asthma may be exposed to ETS, as measured by urinary cotinine, even if their parents insist they don’t smoke in the home. Urinary LTE4 was higher in the ETS-exposed children treated with ICS, but not in children treated with montelukast.
Asthma, inflammation, nitric oxide, tobacco smoke exposure, urinary leukotriene E4
Introduction Active smoking and exposure to secondhand smoke (SHS) worsen asthma symptom control [1,2] and pulmonary function in children [2,3]. Cigarette smoke exposure has also been implicated in blunting the therapeutic response to inhaled [4,5] and oral corticosteroids [6]. Many parents are aware of the potential risks to their children of passive smoking and try to minimize exposure by smoking outdoors or in other rooms, opening windows or turning on fans [7,8]. In addition to SHS exposure, investigators have recently recognized the possibility of thirdhand smoke, which generally refers to exposure to tobacco smoke that previously settled onto furniture, clothes and inanimate objects and subsequently becomes re-suspended [9–11]. There can be significant nicotine residue in the air of homes in which smoking previously occurred [9,11,12], while surface oxidation of nicotine can produce toxic compounds that could significantly influence asthma [10]. Thus, environmental tobacco smoke Correspondence: Dr Sankaran Krishnan, MD, Division of Pediatric Pulmonology, Allergy and Sleep Medicine, New York Medical College, 106, Munger Pavilion, Valhalla, NY 10595, USA. Tel: +1-914-4937585. Fax: þ1-914-594-4336. E-mail: [email protected]
History Received 24 January 2013 Revised 23 June 2013 Accepted 5 July 2013 Published online 7 March 2014
(ETS) exposure may include SHS as well as thirdhand smoke exposure. The amount of ETS exposure of children due to thirdhand smoke has not been established, nor the effects of low-level ETS exposure on asthma symptoms, control or airway inflammation [9,10,13]. Non-invasive biomarkers of airway inflammation have not yet found their place in the routine care of patients with asthma [14–17]. Two biomarkers commonly studied are fractional concentration of exhaled nitric oxide (FeNO) [15] and urinary leukotriene E4 (uLTE4) [16]. FeNO is increased in children with asthma, correlates with severity [18,19], and decreases with treatment with inhaled corticosteroids (ICS) [20] though not with leukotriene receptor antagonists (LTRAs) [21]. FeNO is often increased in children with poorly controlled asthma [18,19,22], but levels can be misleading [23]. FeNO is lower in adult smokers with asthma, though the relationship between FeNO and exposure to SHS in children with asthma is less clear [24–26]. uLTE4 is an attractive biomarker, since it has been shown in both experimental and clinical settings that cysteinyl leukotrienes (CysLTs) function as key mediators and modulators in the pathogenesis of allergic airway disease [16]. LTE4, the end product of the CysLT pathway, can be quantified through
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urinalysis [16] or in exhaled breath [27]. uLTE4 is elevated in children with asthma [16], is associated with decreased lung function [28], and decreases with treatment with ICS [16]. Studies of the effect of montelukast on uLTE4 are inconclusive [29–31]. Airway inflammation in smokers is associated with enhanced production of leukotrienes [32,33], and urinary excretion of LTE4 is closely correlated with the number of cigarettes smoked daily [34]. Data quantifying LTE4 levels in children exposed to ETS is limited [32]. There is some evidence that children with asthma exposed to ETS are more likely to respond to montelukast than ICS, and that montelukast responders tend to have a relatively higher uLTE4/FeNO ratio [35,36]. The objective of this study was to examine the effects of exposure to very low-levels of ETS on children with stable persistent asthma. The hypothesis was that school-age children with parents that either don’t smoke or smoke predominantly outside the home have measurable nicotine exposure, as determined by urinary cotinine levels, a metabolite of nicotine [37,38]. The secondary hypothesis was that there is a relationship between low-level ETS exposure and inflammatory biomarkers in children with asthma, and that uLTE4 but not FeNO, is elevated in ETS-exposed children with asthma compared to non-ETS exposed children irrespective of therapy. The tertiary hypothesis was that uLTE4 is higher in ETS-exposed children treated with ICS than in ETS-exposed children treated with montelukast.
Methods Children ages 8–18 years were enrolled over a 9-month period, from the predominantly suburban outpatient practice of the Division of Pediatric Pulmonology, Allergy and Sleep Medicine, New York Medical College at the time of a routinely scheduled visit. Inclusion criteria were: (i) physician diagnosis of asthma; (ii) at least one of the following: bronchial hyper-responsiveness confirmed by a 12% or greater improvement in forced expiratory volume in 1 s (FEV1) with an inhaled bronchodilator, one or more hospitalizations for asthma during their lifetime, or one or more courses of prednisone for asthma within the last year; (iii) mild-to-moderate persistent asthma treated with either daily montelukast or low-to-medium dose ICS, defined by the National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI) Expert Panel Report 3 [39] and (iv) clinically stable at the time of the study visit. Subjects were excluded if they had received a course of oral corticosteroids or had an emergency department or unscheduled physician visit for asthma within the previous 8 weeks. Subjects on treatment with high-dose ICS, combination therapy of ICS with long-acting b-agonists or both ICS and montelukast were also excluded. Additional exclusion criteria included preterm birth 534 weeks gestational age; other chronic lung diseases such as restrictive lung disease, cystic fibrosis or bronchiectasis; cardiovascular disease or musculoskeletal deformities. Active smokers were excluded from participation. Following approval from the Institutional Review Board, written informed consent and assent were obtained by each
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patient and their parent or legal guardian. All subjects completed the study during one visit in the following sequence: (i) spirometry was performed following European Respiratory Society/American Thoracic Society (ERS/ATS) guidelines [40], and results were compared to the National Health and Nutrition Examination Survey III reference equations [41]. The highest value for FEV1 of at least three acceptable forced expiratory maneuvers was used for data analysis. (ii) Asthma control was assessed with the Asthma Control Test (ACT) if 412 years of age, or the Child Asthma Control Test (cACT) if between 8 and 12 years of age [42,43]. The presence of atopy was established by documentation of either two positive skin tests or two positive specific immunoglobulin E in vitro tests. (iii) Exposure to ETS was assessed by two methods: a validated ETS exposure questionnaire that ascertained exposure to smoking within 24 h and within 2 weeks [44], and the urinary concentration of cotinine measured by enzyme-linked immunosorbent assay (ELISA) (Calbiotech, Inc., Spring Valley, CA), which reflects exposure to nicotine within 24–36 h [37,45]. Cotinine levels were measured in duplicate, and the mean of the two values are reported as unadjusted concentrations (in nanogram per milliliter). Urinary cotinine levels 1 ng/ml were considered consistent with ETS exposure [38,46]. (iv) uLTE4 was measured with an ELISA-based assay from Cayman Chemical Company (Ann Arbor, MI). (v) FeNO was measured using a single-breath on-line method using the NIOXÕ Flex System (Aerocrine, Inc., Morrisville, NC) according to ATS guidelines [18,47]. Patients performed FeNO measurements 1 h after spirometry was completed. The mean FeNO from three acceptable exhalations was used for analysis. A power analysis was not performed a priori since there were no comparable published studies evaluating the effects of such low-level ETS exposure on FeNO and uLTE4. Medians and interquartile ranges (IQR) were calculated for all ordinal data and the two groups compared with Mann– Whitney U-tests. Proportions were compared with Fisher’s exact tests. Two-tailed p values of 50.05 were considered significant.
Results Forty subjects were enrolled, of which only one parent reported smoking in the home in the past 2 weeks. Of the four subjects whose parents reported any smoking exposure, all reported that smoking took place outside the home. Despite denials of recent exposure to SHS, 28 (70%) subjects had urinary cotinine concentrations 1 ng/ml and 12 (30%) had urinary cotinine 51 ng/ml. The highest urinary cotinine was 9.0 ng/ml. Median urinary cotinine level for the group considered ETS exposed was 1.67 ng/ml (IQR: 1.37–2.44) compared to 0.45 ng/ml (IQR: 0.00–0.68) for the unexposed group, p50.001. Twenty-eight subjects (70%) had mild and 12 (30%) had moderate persistent asthma. Twenty (71%) subjects in the ETS-exposed group and nine (75%) subjects in the unexposed group were prescribed daily ICS. Twenty-seven (67%) subjects were atopic. All subjects were well-controlled, with a median ACT of 23.5 (IQR: 22–25). Median FEV1 was
ETS exposure, FeNO & uLTE4 in children with asthma
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98.4% of predicted value (IQR: 89.5–107.4), ranging from 76.3 to 127%. There were no significant differences between the ETS-exposed and non-exposed groups in age, sex, race or ethnicity, FEV1, presence of atopy, asthma severity or asthma control (Table 1). Data on inflammatory biomarkers are summarized in Table 2. Results are shown for each group and stratified based on treatment with ICS or montelukast. One subject was unable to adequately perform the maneuvers required to measure FeNO. There were no significant differences in FeNO between ETS-exposed and non-exposed subjects, though six of the seven subjects with FeNO levels 425 parts per billion (ppb) were in the ETS-exposed group. Among ETS-exposed subjects, there were no differences in median FeNO between the ICS-treated group (9.0 ppb, IQR: 7.2–29.8) and the montelukast-treated group (12.7 ppb, IQR: 9.7–15.8), p ¼ 0.77. Both groups had significantly higher uLTE4 levels than previously reported normal ranges in children [45,46]. In the ICS-treated subjects, ETS exposure was associated with significantly higher uLTE4, 576 pg/ml (IQR: 486–636) Table 1. Patients’ characteristics.
Characteristics Age (years)* Sex: male, n (%) Race/ethnicity White African-American Hispanic FEV1, % predicted* Atopic, n (%) Asthma severity, n (%) Mild persistent Moderate persistent ACT* Daily therapy ICS, n (%) Montelukast, n (%) Urinary cotinine (ng/ml)*
Urinary cotinine 51 ng/ml (n ¼ 12) 12 (9–16.5) 7 (58)
Urinary cotinine 1 ng/ml (n ¼ 28) 11.5 (9–13) 16 (57)
p Value 0.44 1.00 0.06**
12 0 0 99.5 (94–110.5) 7 (58)
18 6 4 95 (87–107) 20 (71)
0.57 0.48
7 (58) 5 (42) 22.5 (20.5–24)
21 (75) 7 (25) 24 (22–25)
0.45 0.45 0.23
9 (75) 3 (25) 0.45 (0–0.68)
20 (71) 1.00 8 (29) 1.00 1.66 (1.37–2.44) 50.001
*Median and IQR; ** 2 test.
Table 2. Inflammatory biomarkers.
Biomarkers
Urinary cotinine Urinary cotinine 51 ng/ml 1 ng/ml p Value
All subjects FeNO (ppb)* uLTE4 (pg/ml)* uLTE4/FeNO* Subjects on ICS FeNO (ppb)* uLTE4 (pg/ml)* uLTE4/FeNO* Subjects on montelukast FeNO (ppb)* uLTE4 (pg/ml)* uLTE4/FeNO*
n ¼ 12 10.5 (8.3–15.3) 406 (247–553) 42.8 (23.7–52.0) n¼9 10.7 (8.8–15.3) 367 (249–549) 41.6 (24.0–50.8) n¼3 10.5 (8.6–18.2) 550 (395–557) 53.9 (31.5–67.8)
*Median and IQR.
n ¼ 28 12.1 (7.9–23.8) 571 (384–652) 48.1 (18.9–60.3) n ¼ 20 9.0 (7.2–29.8) 576 (486–636) 50.1 (20.2–66.4) n¼8 12.7 (9.7–15.8) 330 (156–685) 33.3 (14.8–57.7)
0.42 0.11 0.72 0.42 0.04 0.59 0.78 0.80 0.40
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compared to 367 pg/ml (IQR: 249–549) in the non-exposed group, p ¼ 0.04. Median uLTE4 for the ICS-treated ETSexposed group was 576 pg/ml (IQR: 486–636) compared to 330 pg/ml (IQR: 156–685) for the montelukast-treated ETS-exposed group, p ¼ 0.25. There were no differences between the two groups in the ratio of uLTE4/FeNO. Median uLTE4/FeNO for the ICS-treated ETS-exposed group was 50.1 (IQR: 20.2–66.4) and 33.3 (IQR: 14.8–58.0) for the montelukast-treated ETS-exposed group, p ¼ 0.35. There were no differences in the montelukast-treated group in uLTE4, FeNO or uLTE4/FeNO ratio associated with ETS exposure. There were no significant differences in any of the measurements between ICS-treated subjects and montelukasttreated subjects if ETS exposure was not taken into account (data not shown).
Discussion Seventy percent of school-age children with persistent asthma in this study had urinary cotinine levels 1 ng/ml, a level unlikely to be secondary to non-environmental exposure to nicotine [37,46]. This was despite the fact that none of the subjects smoked and parents of 39 of 40 subjects denied any smoking in the home during the last 2 weeks; though nonparental smoke exposures cannot be excluded. Urinary cotinine reflects nicotine exposure within 24–36 h [45], suggesting that these subjects were either exposed to SHS outside the home or thirdhand smoke within the home [10–13]. Overall, there were no significant differences in uLTE4 between the ETS-exposed and non-exposed groups, though both groups had elevated levels compared to normal ranges for children [48]. The relationship between urinary leukotriene concentrations and exposure to tobacco smoke is not fully understood. In smokers, uLTE4 levels correlate with the number of cigarettes smoked [34]. Kott et al. [32] found in a significant increase in uLTE4 excretion in infants with bronchiolitis and ETS exposure. Similar to our results, Rabinovitch et al. [35] did not find any differences in uLTE4 levels between ETS exposed and those who were not, though there were clinical differences, including albuterol usage. Rabinovitch et al. [49], however, reported that elevated uLTE4 levels in SHS exposed children were associated with increased emergency room/urgent care visits. In our crosssectional study of very low-level exposure, there were no significant differences in lung function, asthma severity or control between ETS-exposed and non-exposed subjects. There were no significant differences between ICS-treated and montelukast-treated subjects, if ETS exposure was not taken into account, consistent with data reported by Zeiger et al. [29] in the CARE Network/NHLBI study [29] and Sorkness et al. [50] in the PACT study. Active smokers were excluded in these trials, but exposure to SHS was not accounted for. Rabinovitch et al. [36] analyzed the results of these two studies [29,50], and suggested that the uLTE4/FeNO ratio could perhaps be a predictor of which patients were more likely to respond to montelukast than ICS [35,36]. uLTE4 concentrations were significantly higher in ETSexposed children treated with ICS than non-exposed children treated with ICS, a difference not found in montelukasttreated subjects. Cigarette smoke exposure is known to affect
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responses to corticosteroids. Chalmers et al. [4] found that non-smoking subjects on inhaled fluticasone had better lung function than smokers. Chaudhuri et al. [6] demonstrated a poor response to short-term oral corticosteroids in smokers with mild asthma as compared to never smokers. There are reports in children of decreased FeNO with ICS [20–22,38], but it remains unclear if montelukast significantly decreases FeNO [21,37,51]. The effect of montelukast therapy on uLTE4 levels is not well understood. Karaman et al. [31] described lower uLTE4 levels in three groups of children with mild asthma treated with ICS, montelukast or both, after 3 months of therapy. Cai et al. [30] reported no changes in uLTE4 levels in 25 ‘‘montelukast responders’’. It has been suggested that montelukast and other LTRAs could alter (lower) uLTE4 levels by a negative feedback loop mechanism [16], independent of their effect on inflammation. A major limitation of this study is the small sample size. All subjects in this study were clinically stable and relatively well-controlled. Perhaps the effects of low-level ETS exposure might be more apparent in children with poorly controlled asthma or during asthma exacerbations. Normal controls were not obtained, but the purpose of this study was to compare ETS-exposed and non-exposed children with asthma, not to compare to healthy children. Our study was cross-sectional; perhaps serial measures of cotinine as well as biomarkers may have yielded more impressive data. In our subjects with lowlevel exposure, it was not possible to differentiate between SHS or thirdhand smoke exposure. We also cannot determine if increased uLTE4 in ETS-exposed ICS-treated subjects reflects airway inflammation, inflammation elsewhere, or is due to an entirely different mechanism. In conclusion, school-age children with persistent asthma may be exposed to ETS, even if their parents insist they don’t smoke in the home. Low-level ETS exposure did not affect FeNO. There was an association between ETS exposure and higher uLTE4 concentrations in ICS-treated children but not in montelukast-treated children.
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Acknowledgements We thank the Children’s Environmental Health Center of the Hudson Valley and the Division of Pediatric Pulmonology, Allergy and Sleep Medicine, New York Medical College for their support. We also acknowledge Dr Lance A. Parton and the staff of his laboratory for their assistance in the performance of the ELISA tests.
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Declaration of interest
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The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article. We thank the Westchester Community Foundation and the Children’s Health and Research Foundation for the funding of this research.
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37. Benowitz N. Biomarkers of environmental tobacco smoke exposure. Environ Health Perspect 1999;107:349–355. 38. Benowitz NL. Cotinine as a biomarker of environmental tobacco smoke exposure. Epidemiol Rev 1996;18:188–202. 39. National Heart, Lung, and Blood Institute. Expert Panel 3 (EPR3): Guidelines for the Diagnosis and Management of Asthma. NIH/ NHLBI. Full Report 2007. Available from: www.nhlbi.nih.gov/ guidelines/asthma/asthgdln.htm. 40. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, et al. ATS/ERS Task Force. Standardisation of spirometry. Eur Respir J 2005;26:319–338. 41. Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of the general US population. Am J Respir Crit Care Med 1999;159:179–187. 42. Nathan RA, Sorkness CA, Kosinski M, Schatz M, Li JT, Marcus P, Murray JJ, et al. Development of the Asthma Control Test: a survey for assessing asthma control. J Allergy Clin Immunol 2004;113: 59–65. 43. Liu AH, Zeiger R, Sorkness C, Mahr T, Ostrom N, Burgess S, Rosenzweig JC, et al. Development and cross-sectional validation of the Childhood Asthma Control Test. J Allergy Clin Immunol 2007;119:817–825. 44. Gehring U, Leaderer BP, Heinrich J, Oldenwening M, Giovannangelo ME, Nordling E, Merkel G, et al. Comparison of parental reports of smoking and residential air nicotine concentrations in children. Occup Environ Med 2006;63:766–772. 45. Matt G, Hovell MF, Quintana PJE, Zakarian J, Liles S, Meltzer SB, Benowitz NL. The variability of urinary cotinine levels in young children: implications for measuring ETS exposure. Nicotine and Tob Res 2007;9:83–92. 46. Oddoze C, Dubus JC, Badier M, Thirion X, Pauli AM, Pastor J, Bruguerolle B. Urinary cotinine and exposure to parental smoking in a population of children with asthma. Clin Chem 1999;45: 505–509. 47. ATS/ERS. recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide. Am J Respir Crit Care Med 2005;171: 912–930. 48. Dal Negro RW, Visconti M, Micheletto C, Tognella S, Guerriero M. Reference urinary LTE4 levels in normal individuals: a pilot study. Eur Ann Allergy Clin Immunol 2011;43:22–28. 49. Rabinovitch N, Reisdorph N, Silveira L, Gelfand EW. Urinary leukotriene E4 levels identify children with tobacco smoke exposure at risk for asthma exacerbation. J Allergy Clin Immunol 2011;128:323–327. 50. Sorkness CA, Lemanske Jr RF, Mauger DT, Boehmer SJ, Chinchilli VM, Martinez FD, Strunk RC, et al. Long-term comparison of 3 controller regimens for mild-moderate persistent childhood asthma: the Pediatric Asthma Controller Trial. J Allergy Clin Immunol 2007;119:64–72. 51. Fritscher LG, Rodrigues MT, Zamel N, Chapman KR. The effect of montelukast on exhaled nitric oxide of alveolar and bronchial origin in inhaled cortico-steroid treated asthma. Respir Med 2009;103: 296–300.
ENVIRONMENTAL DETERMINANTS
Low-level environmental tobacco smoke exposure and inflammatory biomarkers in children with asthma Ramneet Gill, MD1, Sankaran Krishnan, MD, MPH2, and A.J. Dozor, MD2 Division of Pulmonary & Critical Care and Sleep Medicine, Department of Medicine, Wayne State University, Detroit, MI, USA and 2Division of Pediatric Pulmonology, Allergy, and Sleep Medicine, Department of Pediatrics, Maria Fareri Children’s Hospital at Westchester Medical Center and New York Medical College, Valhalla, NY, USA Abstract
Keywords
Objective: The effects of low-level environmental tobacco smoke (ETS) exposure, on asthma control, lung function and inflammatory biomarkers in children with asthma have not been well studied. The objective of the study was to assess ETS exposure in school-age children with asthma whose parents either deny smoking or only smoke outside the home, and to assess the impact of low-level ETS exposure on asthma control, spirometry and inflammatory biomarkers. Methods: Forty patients age 8–18 years with well-controlled, mild-to-moderate persistent asthma treated with either inhaled corticosteroids (ICS) or montelukast were enrolled. Subjects completed an age-appropriate Asthma Control Test and a smoke exposure questionnaire, and exhaled nitric oxide (FeNO), spirometry, urinary cotinine and leukotriene E4 (LTE4) were measured. ETS-exposed and unexposed groups were compared. Results: Only one parent reported smoking in the home, yet 28 (70%) subjects had urinary cotinine levels 1 ng/ml, suggesting ETS exposure. Seven subjects (18%) had FeNO levels 425parts per billion, six of whom were in the ETS-exposed group. In the ICS-treated subjects, but not in the montelukasttreated subjects, ETS exposure was associated with higher urinary LTE4, p ¼ 0.04, but had no effect on asthma control, forced expiratory volume in 1 s or FeNO. Conclusions: A majority of school-age children with persistent asthma may be exposed to ETS, as measured by urinary cotinine, even if their parents insist they don’t smoke in the home. Urinary LTE4 was higher in the ETS-exposed children treated with ICS, but not in children treated with montelukast.
Asthma, inflammation, nitric oxide, tobacco smoke exposure, urinary leukotriene E4
Introduction Active smoking and exposure to secondhand smoke (SHS) worsen asthma symptom control [1,2] and pulmonary function in children [2,3]. Cigarette smoke exposure has also been implicated in blunting the therapeutic response to inhaled [4,5] and oral corticosteroids [6]. Many parents are aware of the potential risks to their children of passive smoking and try to minimize exposure by smoking outdoors or in other rooms, opening windows or turning on fans [7,8]. In addition to SHS exposure, investigators have recently recognized the possibility of thirdhand smoke, which generally refers to exposure to tobacco smoke that previously settled onto furniture, clothes and inanimate objects and subsequently becomes re-suspended [9–11]. There can be significant nicotine residue in the air of homes in which smoking previously occurred [9,11,12], while surface oxidation of nicotine can produce toxic compounds that could significantly influence asthma [10]. Thus, environmental tobacco smoke Correspondence: Dr Sankaran Krishnan, MD, Division of Pediatric Pulmonology, Allergy and Sleep Medicine, New York Medical College, 106, Munger Pavilion, Valhalla, NY 10595, USA. Tel: +1-914-4937585. Fax: þ1-914-594-4336. E-mail: [email protected]
History Received 24 January 2013 Revised 23 June 2013 Accepted 5 July 2013 Published online 7 March 2014
(ETS) exposure may include SHS as well as thirdhand smoke exposure. The amount of ETS exposure of children due to thirdhand smoke has not been established, nor the effects of low-level ETS exposure on asthma symptoms, control or airway inflammation [9,10,13]. Non-invasive biomarkers of airway inflammation have not yet found their place in the routine care of patients with asthma [14–17]. Two biomarkers commonly studied are fractional concentration of exhaled nitric oxide (FeNO) [15] and urinary leukotriene E4 (uLTE4) [16]. FeNO is increased in children with asthma, correlates with severity [18,19], and decreases with treatment with inhaled corticosteroids (ICS) [20] though not with leukotriene receptor antagonists (LTRAs) [21]. FeNO is often increased in children with poorly controlled asthma [18,19,22], but levels can be misleading [23]. FeNO is lower in adult smokers with asthma, though the relationship between FeNO and exposure to SHS in children with asthma is less clear [24–26]. uLTE4 is an attractive biomarker, since it has been shown in both experimental and clinical settings that cysteinyl leukotrienes (CysLTs) function as key mediators and modulators in the pathogenesis of allergic airway disease [16]. LTE4, the end product of the CysLT pathway, can be quantified through
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urinalysis [16] or in exhaled breath [27]. uLTE4 is elevated in children with asthma [16], is associated with decreased lung function [28], and decreases with treatment with ICS [16]. Studies of the effect of montelukast on uLTE4 are inconclusive [29–31]. Airway inflammation in smokers is associated with enhanced production of leukotrienes [32,33], and urinary excretion of LTE4 is closely correlated with the number of cigarettes smoked daily [34]. Data quantifying LTE4 levels in children exposed to ETS is limited [32]. There is some evidence that children with asthma exposed to ETS are more likely to respond to montelukast than ICS, and that montelukast responders tend to have a relatively higher uLTE4/FeNO ratio [35,36]. The objective of this study was to examine the effects of exposure to very low-levels of ETS on children with stable persistent asthma. The hypothesis was that school-age children with parents that either don’t smoke or smoke predominantly outside the home have measurable nicotine exposure, as determined by urinary cotinine levels, a metabolite of nicotine [37,38]. The secondary hypothesis was that there is a relationship between low-level ETS exposure and inflammatory biomarkers in children with asthma, and that uLTE4 but not FeNO, is elevated in ETS-exposed children with asthma compared to non-ETS exposed children irrespective of therapy. The tertiary hypothesis was that uLTE4 is higher in ETS-exposed children treated with ICS than in ETS-exposed children treated with montelukast.
Methods Children ages 8–18 years were enrolled over a 9-month period, from the predominantly suburban outpatient practice of the Division of Pediatric Pulmonology, Allergy and Sleep Medicine, New York Medical College at the time of a routinely scheduled visit. Inclusion criteria were: (i) physician diagnosis of asthma; (ii) at least one of the following: bronchial hyper-responsiveness confirmed by a 12% or greater improvement in forced expiratory volume in 1 s (FEV1) with an inhaled bronchodilator, one or more hospitalizations for asthma during their lifetime, or one or more courses of prednisone for asthma within the last year; (iii) mild-to-moderate persistent asthma treated with either daily montelukast or low-to-medium dose ICS, defined by the National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI) Expert Panel Report 3 [39] and (iv) clinically stable at the time of the study visit. Subjects were excluded if they had received a course of oral corticosteroids or had an emergency department or unscheduled physician visit for asthma within the previous 8 weeks. Subjects on treatment with high-dose ICS, combination therapy of ICS with long-acting b-agonists or both ICS and montelukast were also excluded. Additional exclusion criteria included preterm birth 534 weeks gestational age; other chronic lung diseases such as restrictive lung disease, cystic fibrosis or bronchiectasis; cardiovascular disease or musculoskeletal deformities. Active smokers were excluded from participation. Following approval from the Institutional Review Board, written informed consent and assent were obtained by each
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patient and their parent or legal guardian. All subjects completed the study during one visit in the following sequence: (i) spirometry was performed following European Respiratory Society/American Thoracic Society (ERS/ATS) guidelines [40], and results were compared to the National Health and Nutrition Examination Survey III reference equations [41]. The highest value for FEV1 of at least three acceptable forced expiratory maneuvers was used for data analysis. (ii) Asthma control was assessed with the Asthma Control Test (ACT) if 412 years of age, or the Child Asthma Control Test (cACT) if between 8 and 12 years of age [42,43]. The presence of atopy was established by documentation of either two positive skin tests or two positive specific immunoglobulin E in vitro tests. (iii) Exposure to ETS was assessed by two methods: a validated ETS exposure questionnaire that ascertained exposure to smoking within 24 h and within 2 weeks [44], and the urinary concentration of cotinine measured by enzyme-linked immunosorbent assay (ELISA) (Calbiotech, Inc., Spring Valley, CA), which reflects exposure to nicotine within 24–36 h [37,45]. Cotinine levels were measured in duplicate, and the mean of the two values are reported as unadjusted concentrations (in nanogram per milliliter). Urinary cotinine levels 1 ng/ml were considered consistent with ETS exposure [38,46]. (iv) uLTE4 was measured with an ELISA-based assay from Cayman Chemical Company (Ann Arbor, MI). (v) FeNO was measured using a single-breath on-line method using the NIOXÕ Flex System (Aerocrine, Inc., Morrisville, NC) according to ATS guidelines [18,47]. Patients performed FeNO measurements 1 h after spirometry was completed. The mean FeNO from three acceptable exhalations was used for analysis. A power analysis was not performed a priori since there were no comparable published studies evaluating the effects of such low-level ETS exposure on FeNO and uLTE4. Medians and interquartile ranges (IQR) were calculated for all ordinal data and the two groups compared with Mann– Whitney U-tests. Proportions were compared with Fisher’s exact tests. Two-tailed p values of 50.05 were considered significant.
Results Forty subjects were enrolled, of which only one parent reported smoking in the home in the past 2 weeks. Of the four subjects whose parents reported any smoking exposure, all reported that smoking took place outside the home. Despite denials of recent exposure to SHS, 28 (70%) subjects had urinary cotinine concentrations 1 ng/ml and 12 (30%) had urinary cotinine 51 ng/ml. The highest urinary cotinine was 9.0 ng/ml. Median urinary cotinine level for the group considered ETS exposed was 1.67 ng/ml (IQR: 1.37–2.44) compared to 0.45 ng/ml (IQR: 0.00–0.68) for the unexposed group, p50.001. Twenty-eight subjects (70%) had mild and 12 (30%) had moderate persistent asthma. Twenty (71%) subjects in the ETS-exposed group and nine (75%) subjects in the unexposed group were prescribed daily ICS. Twenty-seven (67%) subjects were atopic. All subjects were well-controlled, with a median ACT of 23.5 (IQR: 22–25). Median FEV1 was
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98.4% of predicted value (IQR: 89.5–107.4), ranging from 76.3 to 127%. There were no significant differences between the ETS-exposed and non-exposed groups in age, sex, race or ethnicity, FEV1, presence of atopy, asthma severity or asthma control (Table 1). Data on inflammatory biomarkers are summarized in Table 2. Results are shown for each group and stratified based on treatment with ICS or montelukast. One subject was unable to adequately perform the maneuvers required to measure FeNO. There were no significant differences in FeNO between ETS-exposed and non-exposed subjects, though six of the seven subjects with FeNO levels 425 parts per billion (ppb) were in the ETS-exposed group. Among ETS-exposed subjects, there were no differences in median FeNO between the ICS-treated group (9.0 ppb, IQR: 7.2–29.8) and the montelukast-treated group (12.7 ppb, IQR: 9.7–15.8), p ¼ 0.77. Both groups had significantly higher uLTE4 levels than previously reported normal ranges in children [45,46]. In the ICS-treated subjects, ETS exposure was associated with significantly higher uLTE4, 576 pg/ml (IQR: 486–636) Table 1. Patients’ characteristics.
Characteristics Age (years)* Sex: male, n (%) Race/ethnicity White African-American Hispanic FEV1, % predicted* Atopic, n (%) Asthma severity, n (%) Mild persistent Moderate persistent ACT* Daily therapy ICS, n (%) Montelukast, n (%) Urinary cotinine (ng/ml)*
Urinary cotinine 51 ng/ml (n ¼ 12) 12 (9–16.5) 7 (58)
Urinary cotinine 1 ng/ml (n ¼ 28) 11.5 (9–13) 16 (57)
p Value 0.44 1.00 0.06**
12 0 0 99.5 (94–110.5) 7 (58)
18 6 4 95 (87–107) 20 (71)
0.57 0.48
7 (58) 5 (42) 22.5 (20.5–24)
21 (75) 7 (25) 24 (22–25)
0.45 0.45 0.23
9 (75) 3 (25) 0.45 (0–0.68)
20 (71) 1.00 8 (29) 1.00 1.66 (1.37–2.44) 50.001
*Median and IQR; ** 2 test.
Table 2. Inflammatory biomarkers.
Biomarkers
Urinary cotinine Urinary cotinine 51 ng/ml 1 ng/ml p Value
All subjects FeNO (ppb)* uLTE4 (pg/ml)* uLTE4/FeNO* Subjects on ICS FeNO (ppb)* uLTE4 (pg/ml)* uLTE4/FeNO* Subjects on montelukast FeNO (ppb)* uLTE4 (pg/ml)* uLTE4/FeNO*
n ¼ 12 10.5 (8.3–15.3) 406 (247–553) 42.8 (23.7–52.0) n¼9 10.7 (8.8–15.3) 367 (249–549) 41.6 (24.0–50.8) n¼3 10.5 (8.6–18.2) 550 (395–557) 53.9 (31.5–67.8)
*Median and IQR.
n ¼ 28 12.1 (7.9–23.8) 571 (384–652) 48.1 (18.9–60.3) n ¼ 20 9.0 (7.2–29.8) 576 (486–636) 50.1 (20.2–66.4) n¼8 12.7 (9.7–15.8) 330 (156–685) 33.3 (14.8–57.7)
0.42 0.11 0.72 0.42 0.04 0.59 0.78 0.80 0.40
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compared to 367 pg/ml (IQR: 249–549) in the non-exposed group, p ¼ 0.04. Median uLTE4 for the ICS-treated ETSexposed group was 576 pg/ml (IQR: 486–636) compared to 330 pg/ml (IQR: 156–685) for the montelukast-treated ETS-exposed group, p ¼ 0.25. There were no differences between the two groups in the ratio of uLTE4/FeNO. Median uLTE4/FeNO for the ICS-treated ETS-exposed group was 50.1 (IQR: 20.2–66.4) and 33.3 (IQR: 14.8–58.0) for the montelukast-treated ETS-exposed group, p ¼ 0.35. There were no differences in the montelukast-treated group in uLTE4, FeNO or uLTE4/FeNO ratio associated with ETS exposure. There were no significant differences in any of the measurements between ICS-treated subjects and montelukasttreated subjects if ETS exposure was not taken into account (data not shown).
Discussion Seventy percent of school-age children with persistent asthma in this study had urinary cotinine levels 1 ng/ml, a level unlikely to be secondary to non-environmental exposure to nicotine [37,46]. This was despite the fact that none of the subjects smoked and parents of 39 of 40 subjects denied any smoking in the home during the last 2 weeks; though nonparental smoke exposures cannot be excluded. Urinary cotinine reflects nicotine exposure within 24–36 h [45], suggesting that these subjects were either exposed to SHS outside the home or thirdhand smoke within the home [10–13]. Overall, there were no significant differences in uLTE4 between the ETS-exposed and non-exposed groups, though both groups had elevated levels compared to normal ranges for children [48]. The relationship between urinary leukotriene concentrations and exposure to tobacco smoke is not fully understood. In smokers, uLTE4 levels correlate with the number of cigarettes smoked [34]. Kott et al. [32] found in a significant increase in uLTE4 excretion in infants with bronchiolitis and ETS exposure. Similar to our results, Rabinovitch et al. [35] did not find any differences in uLTE4 levels between ETS exposed and those who were not, though there were clinical differences, including albuterol usage. Rabinovitch et al. [49], however, reported that elevated uLTE4 levels in SHS exposed children were associated with increased emergency room/urgent care visits. In our crosssectional study of very low-level exposure, there were no significant differences in lung function, asthma severity or control between ETS-exposed and non-exposed subjects. There were no significant differences between ICS-treated and montelukast-treated subjects, if ETS exposure was not taken into account, consistent with data reported by Zeiger et al. [29] in the CARE Network/NHLBI study [29] and Sorkness et al. [50] in the PACT study. Active smokers were excluded in these trials, but exposure to SHS was not accounted for. Rabinovitch et al. [36] analyzed the results of these two studies [29,50], and suggested that the uLTE4/FeNO ratio could perhaps be a predictor of which patients were more likely to respond to montelukast than ICS [35,36]. uLTE4 concentrations were significantly higher in ETSexposed children treated with ICS than non-exposed children treated with ICS, a difference not found in montelukasttreated subjects. Cigarette smoke exposure is known to affect
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responses to corticosteroids. Chalmers et al. [4] found that non-smoking subjects on inhaled fluticasone had better lung function than smokers. Chaudhuri et al. [6] demonstrated a poor response to short-term oral corticosteroids in smokers with mild asthma as compared to never smokers. There are reports in children of decreased FeNO with ICS [20–22,38], but it remains unclear if montelukast significantly decreases FeNO [21,37,51]. The effect of montelukast therapy on uLTE4 levels is not well understood. Karaman et al. [31] described lower uLTE4 levels in three groups of children with mild asthma treated with ICS, montelukast or both, after 3 months of therapy. Cai et al. [30] reported no changes in uLTE4 levels in 25 ‘‘montelukast responders’’. It has been suggested that montelukast and other LTRAs could alter (lower) uLTE4 levels by a negative feedback loop mechanism [16], independent of their effect on inflammation. A major limitation of this study is the small sample size. All subjects in this study were clinically stable and relatively well-controlled. Perhaps the effects of low-level ETS exposure might be more apparent in children with poorly controlled asthma or during asthma exacerbations. Normal controls were not obtained, but the purpose of this study was to compare ETS-exposed and non-exposed children with asthma, not to compare to healthy children. Our study was cross-sectional; perhaps serial measures of cotinine as well as biomarkers may have yielded more impressive data. In our subjects with lowlevel exposure, it was not possible to differentiate between SHS or thirdhand smoke exposure. We also cannot determine if increased uLTE4 in ETS-exposed ICS-treated subjects reflects airway inflammation, inflammation elsewhere, or is due to an entirely different mechanism. In conclusion, school-age children with persistent asthma may be exposed to ETS, even if their parents insist they don’t smoke in the home. Low-level ETS exposure did not affect FeNO. There was an association between ETS exposure and higher uLTE4 concentrations in ICS-treated children but not in montelukast-treated children.
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Acknowledgements We thank the Children’s Environmental Health Center of the Hudson Valley and the Division of Pediatric Pulmonology, Allergy and Sleep Medicine, New York Medical College for their support. We also acknowledge Dr Lance A. Parton and the staff of his laboratory for their assistance in the performance of the ELISA tests.
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Declaration of interest
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The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article. We thank the Westchester Community Foundation and the Children’s Health and Research Foundation for the funding of this research.
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