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Original Research: ASTHMA |

Investigation of Occupational Asthma: Sputum Cell Counts or Exhaled Nitric Oxide? FREE TO VIEW

Catherine Lemière, MD, MSc; Vinciane D’Alpaos, MSc; Simone Chaboillez, RT; Mélanie César, MSc; Mathieu Wattiez, MSc; Samah Chiry, MD; Olivier Vandenplas, MD, MSc
Author and Funding Information

From the Hôpital du Sacré-Coeur de Montréal, Université de Montréal (Drs Lemière and Chiry and Ms Chaboillez), Montreal, QC, Canada; and the Department of Chest Medicine (Mss D’Alpaos, César, and Wattiez, and Dr Vandenplas), Mont-Godinne Hospital, Université Catholique de Louvain, Yvoir, Belgium.

Correspondence to: Catherine Lemière, MD, MSc, Department of Chest Medicine, Sacré-Coeur Hospital, 5400 Gouin West, Montreal, QC, Canada, H4J 1C5; e-mail: catherine.lemiere@umontreal.ca


Funding: The project was funded by the Institut Robert Sauvé en Santé et sécurité au travail, the Asthma in the Workplace Centre (Canadian Institute of Health Research), and the Actions de Recherche Concertées de la Communauté Française de Belgique. Dr Lemière holds a scholarship from the Fonds de la recherche en santé du Québec.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestpubs.org/site/misc/reprints.xhtml).


© 2010 American College of Chest Physicians


Chest. 2010;137(3):617-622. doi:10.1378/chest.09-2081
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Published online

Background:  The measure of sputum eosinophil counts is a useful tool in the investigation of occupational asthma (OA), but processing sputum is time consuming. Measuring the fractional concentration of exhaled nitric oxide (FENO) may be an alternative in clinical practice. The aim of this study was to assess the respective changes of sputum eosinophil counts and FENO following exposure to occupational agents in the routine practice of two tertiary centers in North America and Europe.

Methods:  Workers undergoing specific inhalation challenges (SICs) for possible OA in tertiary clinics in both Canada and Belgium were enrolled. Sputum cell counts and FENO were collected at the end of the control day and at 7 and 24 h after exposure to the offending agent.

Results:  Forty-one subjects had a negative SIC; 26 subjects had OA proven by a positive SIC. In subjects with positive SIC, there was a significant increase in sputum eosinophils at 7 h (9.0 [9.9]%) and 24 h (11.9 [14.9]%) after exposure compared with the baseline (2.8 [4.2]%), whereas there was a significant increase in FENO only 24 h after exposure (26.0 [30.5] ppb) compared with the baseline (16.6 [18.5] ppb). A 2.2% change in sputum eosinophil counts achieved a much higher sensitivity and positive predictive value than a 10-ppb change in FENO with similar specificity and negative predictive value for predicting a 20% decrease in FEV1 during SICs.

Conclusions:  Sputum eosinophil counts constitute a more reliable tool than FENO to discriminate positive and negative SICs.

Figures in this Article

Inflammometry has been increasingly used in the management of asthma during the last 10 years. Tailoring asthma treatment according to sputum eosinophil counts has been shown to reduce the occurrence of severe asthmatic exacerbations in patients with moderate to severe asthma compared with the usual management of asthma based upon symptoms and spirometry.1 However, sputum induction and processing are time consuming and usually restricted to tertiary centers. Exhaled nitric oxide is considered as a surrogate marker of eosinophilic inflammation in asthma.2 When used to guide asthma treatment, the monitoring of fractional concentrations of exhaled nitric oxide (FENO) enabled maintenance of an adequate control of asthma with lower doses of inhaled corticosteroids (ICS)3 than the usual approach for controlling asthma. The assessment of FENO levels is totally noninvasive, rapid, and relatively simple to perform compared with sputum induction and processing. However, FENO is a very sensitive measure that can be affected by a number of factors, especially by treatment with ICS and smoking.4 In subjects treated with ICS and in those with severe asthma, the correlation between FENO and sputum eosinophils appears to be poor.5,6

Sputum cell count monitoring has also been used successfully in the investigation of occupational asthma (OA).7,8 In contrast, the results of the studies reporting the changes in FENO levels after exposure to occupational agents in the investigation of OA are somewhat contradictory9,10. Therefore, the aim of this study was to assess the respective changes in sputum eosinophil counts and FENO following exposure to occupational agents in the routine practice of two tertiary centers in both North America and Europe.

Subjects

The study included subjects older than 18 years of age who had been referred to the laboratories of Sacré-Coeur Hospital, Montreal, Canada, or/and Mont-Godinne Hospital, Yvoir, Belgium, for the investigation of possible OA through the performance of specific inhalation challenges (SICs) between 2007 and 2009. In accordance with the routine clinical practice of both centers, ICS were given once daily at bedtime in Canada, but were halted 72 h prior to the test in Belgium. Long-acting β-2 agonists were halted 72 h before the SICs in both centers. Sputum cell counts and FENO were collected at the end of the control day and at 7 and 24 h after exposure to the offending agent.

All procedures used in this study were in accordance with the recommendations found in the Helsinki Declaration of 1975. The study was approved by the research ethics committees of Sacré-Coeur Hospital and Mont-Godinne Hospital. An appropriate written informed consent was obtained from all subjects.

Procedures
Skin Prick Tests:

Subjects underwent skin prick tests with common inhalants, including house dust mites, cat, dog, ragweed, weeds, tree pollen, molds, and cockroaches. Atopy was defined by the presence of at least one positive skin test with a wheal diameter ≥ 3 mm.11

Respiratory Function Tests:

The spirometry was assessed in accordance with the standards of the American Thoracic Society.12 The level of nonspecific bronchial hyperresponsiveness was assessed through the inhalation of doubling concentrations of methacholine in Montreal and histamine in Yvoir using a Wright nebulizer (Roxon Medi-Tech; Montreal, Canada) (output 0.14 mL/min) at tidal volumes for 2-min periods. The results were expressed as the concentration of methacholine/histamine inducing a 20% decrease in FEV1 (PC20).13

Sputum Induction and Examination:

Sputum was induced using inhalations of increasing concentrations (3%, 4%, and 5%) of hypertonic saline14 and processed as previously described.15 Briefly, all portions of the sample collected that macroscopically looked more opaque and/or dense and unlike saliva were selected. The sample selected was treated with dithiothreitol, and an additional four volumes of Dulbecco phosphate-buffered saline were added. The suspension was filtered. Cytospins were prepared. Slides were dried and Wright stained. Cell differential counts were performed. To assess the repeatability of the cell-count reading between both centers, 33 sputum slides made in Belgium were read in both centers. The research assistants who read the slides were blind to the diagnosis and unaware of the counting originating from the other center.

FENO Measurements:

FENO was measured using chemiluminescent analyzers (280i Sievers; GE; Boulder, CO), using the off-line method4 in Canada. In Belgium, FENO was measured using the online method (NiOX; Aerocrine AB; Solna, Sweden), also in accordance to the standards of the American Thoracic Society.4

SICs:

As previously described,16 the SICs were performed in the laboratories of both centers. On the first day, the subjects were exposed to a sham substance. The FENO measurement, the methacholine/histamine inhalation challenge, and the sputum induction were performed at the end of the day. The FENO measurements, the methacholine/histamine inhalation challenge, and the sputum induction were repeated 7 h after the end of exposure to the offending agent on the day when an asthmatic reaction occurred (20% fall in FEV1) or on the last day of exposure in the case of a negative result. Sputum induction and exhaled NO were repeated 24 h after the last day of exposure. The exhaled NO was always measured prior to the performance of the methacholine/histamine challenge and the sputum induction. An SIC was considered positive if a reproducible fall in FEV1 of 20% or more occurred after exposure to the offending agent along with a characteristic pattern of an asthmatic reaction.

Data Analysis

Results were expressed as mean and standard deviation, except for PC20, which was expressed as a geometric mean with minimum and maximum values. The sputum cell counts and the exhaled NO values were expressed as the median and interquartile range as they did not follow a normal distribution. Comparisons between the groups were performed using a Student t test for normally distributed data or using a Mann-Whitney U test for the data that did not follow a normal distribution. Correlation analyses were performed using a Pearson correlation test or a Spearman correlation test if the data did not follow a normal distribution. To assess the repeatability of sputum eosinophil counts between both centers, an intraclass correlation coefficient was calculated for this variable. Receiver operating characteristics (ROC) curves were built to study the respective sensitivity and specificity of sputum eosinophil counts and exhaled NO associated with the occurrence of a positive asthmatic reaction during an SIC. Significance was accepted at the level of 95%. The analysis was performed using the SPSS 12.0 statistical package (SPSS, Inc.; Chicago, IL).

Sixty-eight subjects were investigated. Forty-one subjects had a negative SIC, 26 subjects had OA proven by a positive SIC, and one subject was excluded because the result of his SIC could not be interpreted reliably because of severe and uncontrolled asthma. Twenty-five subjects with a positive SIC and 19 with a negative SIC agreed to complete sputum induction and FENO measurements 24 h after the end of exposure. Sputum induction was performed for 20 subjects with OA at baseline and at 7 and 24 h after exposure, whereas FENO measurements were performed for 24 subjects with OA on those three occasions.

The clinical characteristics of the subjects are presented in Table 1. The subjects investigated in Montreal and Yvoir had similar characteristics except that the baseline PC20 of the subjects investigated in Belgium (2.8 ± 7.5 mg/mL) was lower than for those in Canada (9.3 ± 6.2 mg/mL; P = .02) Additional results are presented in the online data supplement.

Table Graphic Jump Location
Table 1 —Characteristics of the Subjects Studied

Data given as mean ± SD unless otherwise noted. CS = current smoker; F = female; FENO = fractional concentration of exhaled nitric oxide; HMW = high-molecular-weight agent; ICS = inhaled corticosteroids; LMW = low-molecular-weight agent; M = male; NS = never smoker; OA = occupational asthma; PC20 = concentration of methacholine/histamine inducing a 20% fall in FEV1; SIC = specific inhalation challenge; exS = exsmoker.

a 

P < .05

Changes in Sputum Eosinophil Counts and FENO After Exposure to Occupational Agents

The sputum-eosinophil-count intraclass correlation coefficient between Belgium and Canada was 0.98 (95% CI, 0.96-0.99). At baseline, subjects with a positive SIC had a higher sputum eosinophil count than subjects with a negative SIC (P = .01) (Table 1). There was an increase in sputum eosinophil counts 7 h after exposure that was sustained 24 h after exposure in subjects with a positive SIC (P < .01), whereas no change was found in subjects with a negative SIC (P = .2) (Table 2). At baseline, subjects with a positive SIC had higher FENO levels than subjects with a negative SIC (P = .02) (Table 1). There was an increase in FENO after exposure (P = .01) in subjects with a positive SIC only at 24 h postexposure, but not in subjects with a negative SIC (P = .1).

Table Graphic Jump Location
Table 2 —Sputum Cell Counts and FENO Levels in Subjects Who Underwent Sputum Induction and FENO Measurement at Baseline, 7 h, and 24 h After Exposure

Data given as median (interquartile range). Eos = sputum eosinophil count; Neu = sputum neutrophil count; TCC = total cell count. See Table 1 for expansion of other abbreviations.

a 

P < .01 compared with baseline value.

b 

P = .01 compared with baseline value.

Impact of ICS Treatment on Sputum Eosinophil Counts and FENO

In subjects with a positive SIC, there was no significant difference in sputum eosinophil counts between steroid-naive and steroid-treated subjects at baseline (P = .3), at 7 h (P = .1), or at 24 h (P = .6) postexposure. We did not observe any difference in sputum eosinophils between steroid-naive and steroid-treated subjects in Canada or Belgium (results not shown).

Overall, we found similar levels of FENO in subjects treated with ICS compared with steroid-naive subjects (Table 3). However, when we examined each center separately, we found higher values of FENO in steroid-naive subjects (28.6 [17.0] ppb) than in steroid-treated subjects (14.7 [4.0] ppb, P = .03) at 24 h after exposure only in subjects investigated in Canada. We did not observe any difference between these two groups of subjects from Belgium (P = .3). Additional results are presented in the online data supplement.

Table Graphic Jump Location
Table 3 —Sputum Eosinophil Counts and FENO Levels in Steroid-Naive and Steroid-Treated Subjects With a Positive SIC

Data given as median (interquartile range). There were no statistically significant differences in sputum cell counts or FENO levels between steroid-naive subjects and steroid-treated subjects at any time points. See Tables 1 and 2 for expansion of abbreviations.

Correlation Between Sputum Cell Counts, FENO, and Functional Parameters

There was a correlation between the changes between baseline and 24 h after exposure in sputum eosinophil counts (absolute counts and percentages) and FENO (ρ = 0.4, P = .02; ρ = 0.4, P = .007, respectively), but not between baseline and 7 h after exposure (ρ = −0.07, P = .6; ρ = 0.08, P = .6, respectively). There was a negative correlation between the changes in sputum neutrophils in percentages and FENO between baseline and 24 h after exposure (ρ = −0.5, P = .03), but not when expressed as absolute counts (ρ = −0.2, P = .2). There was an inverse correlation between the change in sputum eosinophils between baseline and 7 h after exposure and the fall in FEV1 during SICs (ρ = −0.4, P = .03), as well as with the change in PC20 (ρ = −0.3, P = .04).

ROC Curves

Using ROC curves, we assessed the association between the changes in sputum eosinophil counts and FENO, and the occurrence of a 20% fall in FEV1 during SICs. The area under the curve (AUC) was significantly different from the reference line for a sputum eosinophil count change between baseline and 7 h (AUC: 0.8 [0.6-0.9], P = .003) and 24 h (AUC: 0.8 [0.7-0.9], P = .002). There was no significant difference between the changes in FENO at 7 h (AUC: 0.6 [0.4-0.7], P = .5) and 24 h postexposure (AUC: 0.6 [0.5-0.8], P = .09) compared with the reference line. (Fig 1). Using the ROC curves, a 2.2% change in sputum eosinophil counts between baseline and either 7 or 24 h after exposure was identified as the cutoff providing the best sensitivity and specificity. Since the ROC curves did not allow us to find a relevant cutoff for FENO, we calculated the sensitivity, specificity, and positive and negative predictive values for a 10-ppb change in FENO. A 2.2% change in sputum eosinophil counts achieved a much higher sensitivity and positive predictive value than a change in 10 ppb in FENO with similar specificity and negative predictive value for predicting a 20% decrease in FEV1 during SICs (Table 4).

Figure Jump LinkFigure 1. Receiver operating characteristic curves evaluating the effectiveness of changes in sputum eosinophils counts and fractional concentration of exhaled nitric oxide changes between baseline and 7 and 24 h postexposure for diagnosing occupational asthma. eNO 5 exhaled nitric oxide.Grahic Jump Location
Table Graphic Jump Location
Table 4 —Sensitivities, Specificities, and Positive and Negative Predictive Values of Sputum Eosinophil Counts and FENO Levels for Predicting a Positive SIC

NPV = negative predicted value; PPV = positive predicted value. See Table 1 legend for expansion of other abbreviations.

This study showed that both sputum eosinophil counts and FENO were increased in subjects with a positive SIC after exposure to occupational agents, which was not the case in subjects with a negative SIC. However, the time course and the magnitude of changes observed in sputum eosinophil counts and FENO levels differed significantly. The increase in sputum eosinophil counts occurred 7 h after exposure, whereas the increase in exhaled NO only occurred 24 h after exposure. This is consistent with previous studies that showed an increase in exhaled NO from 22 to 24 h17,18 and at 48 h after exposure,9 not only after exposure to occupational agents but also after exposure to common inhalants.19 However, those studies did not examine sputum cell counts 7 h after exposure to occupational agents. This late increase in FENO (24 h postchallenge) is also consistent with the kinetics of induction of nitric oxide synthase by interleukin-4 and interferon-γ in airway epithelial cells.20

Several studies examined the changes in FENO after SICs were performed in steroid-naive subjects.9,21 Although it is important to describe the maximum changes in FENO that can be expected in steroid-naive subjects after exposure to occupational agents, it is also crucial to establish whether such changes are still present in steroid-treated subjects in order to apply the results to the clinical practice. Indeed, a large proportion of the subjects investigated for OA are usually treated with ICS in clinical practice. Baur and Barbinova18 did not find a significant increase in FENO in steroid-treated subjects sensitized to latex after exposure to latex in contrast to steroid-naive subjects. It is unclear from this study whether ICS were stopped prior to the SICs. Interestingly, we observed higher levels of FENO 24 h after exposure in steroid-naive subjects with a positive SIC compared with steroid-treated subjects, but only in Canada. This is likely to be explained by the maintenance of the ICS treatment until 8 h preceding the SIC in Canada, whereas ICS were stopped 72 h before testing in Belgium. Therefore, the cessation of ICS 72 h prior to the test seems to be sufficient to avoid a major suppression of the FENO levels. In contrast, the increase in sputum eosinophil counts did not seem to be affected by the maintenance of treatment with ICS.

We did not find any difference in FENO levels before or after SICs between steroid-naive smokers and nonsmokers with a positive SIC. Smoking did not prevent the increase of FENO 24 h after challenge in those subjects. Although smoking has been reported to decrease FENO levels in several instances,22-24 clinically significant changes in FENO related to changes in asthma control can still be observed in smokers.24 Furthermore, our results are consistent with those from Baur and Barbinova,18 who found similar levels of FENO after latex challenge in smokers and nonsmokers. The changes observed in FENO after exposure to occupational agents have been reported to depend on the baseline value (low or high) prior to the exposure to those agents.25 In the present study, we did not find a higher increase in FENO levels in subjects with low baseline levels of FENO compared with subjects with high baseline levels.

Subjects with a positive SIC showed higher baseline sputum eosinophil counts and FENO levels (P = .02) than subjects with a negative SIC. Twelve of the 24 subjects with OA were still exposed at their workplace during the investigation. Since occupational exposure induces a sputum eosinophilia in the majority of the subjects with OA in contrast to the subjects without OA,26 the persistent work exposure in half of the OA group is likely to explain the higher baseline sputum eosinophil counts and FENO levels in this group of subjects.

As previously described,9 we found a correlation between the changes in sputum eosinophil counts and the FENO levels 24 h after exposure to occupational agents. Although there was a statistically significant increase in FENO 24 h after exposure to occupational agents, it is unlikely that this increase would have provided a substantial help in interpreting the results of the SICs. Indeed, using the ROC curve, FENO levels failed to achieve discriminating sensitivities and specificities that may have been helpful as a diagnostic test in the majority of circumstances. However, an increase in FENO of 10 ppb after exposure to occupational agents achieved good specificity and negative predictive values, which may help the interpretation of SICs in some instances. In contrast, sputum eosinophil counts achieved good sensitivities and specificities in association with a 20% fall in FEV1 during SICs. The lower discriminating capability of FENO compared with sputum eosinophil counts is likely to be explained by the important influence of external factors such as ICS treatment on FENO, but not on sputum eosinophil counts.

In conclusion, we believe that this study brings important insight for the interpretation of FENO and sputum eosinophil counts during SICs in clinical practice. Sputum eosinophil counts constitute a more reliable tool than FENO for facilitating the interpretation of SICs.

Author contributions:Dr Lemière: was responsible for the design of the study, the supervision of the study in Montreal, and the writing of the manuscript in collaboration with Dr Vandenplas and the coauthors.

Ms D’Alpaos: was responsible for the recruitment of the subjects and the performance of the study in Belgium as well as the review of the manuscript.

Ms Chaboillez: was responsible for the recruitment of the subjects and the performance of the study in Montreal, the performance of sputum induction and processing, and the review of the manuscript.

Ms César: was responsible for performing sputum induction and processing in Belgium as well as the review of the manuscript.

Ms Wattiez: was responsible for performing sputum induction and processing in Belgium as well as the review of the manuscript.

Dr Chiry: was responsible for a part of the recruitment of the subjects in Montreal and the management of the data as well as the review of the manuscript.

Dr Vandenplas: collaborated on the design of the study and was responsible for the supervision of the study in Belgium and the writing of the manuscript in collaboration with Dr Lemière.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Other contributions: This work was performed at Sacré-Coeur Hospital and Mont-Godinne Hospital. The authors thank Mr James Hatch for reviewing the manuscript.

AUC

area under the curve

FENO

fractional concentration of exhaled nitric oxide

ICS

inhaled corticosteroids

OA

occupational asthma

PC20

concentration of methacholine/histamine inducing a 20% fall in FEV1

ROC

receiver operating characteristics

SIC

specific inhalation challenge

Green RH, Brightling CE, McKenna S, et al. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet. 2002;3609347:1715-1721. [CrossRef] [PubMed]
 
Bates CA, Silkoff PE. Exhaled nitric oxide in asthma: from bench to bedside. J Allergy Clin Immunol. 2003;1112:256-262. [CrossRef] [PubMed]
 
Smith AD, Cowan JO, Brassett KP, Herbison GP, Taylor DR. Use of exhaled nitric oxide measurements to guide treatment in chronic asthma. N Engl J Med. 2005;35221:2163-2173. [CrossRef] [PubMed]
 
American Thoracic SocietyAmerican Thoracic SocietyEuropean Respiratory Society ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005. Am J Respir Crit Care Med. 2005;1718:912-930. [CrossRef] [PubMed]
 
Berlyne GS, Parameswaran K, Kamada D, Efthimiadis A, Hargreave FE. A comparison of exhaled nitric oxide and induced sputum as markers of airway inflammation. J Allergy Clin Immunol. 2000;1064:638-644. [CrossRef] [PubMed]
 
Lemière C, Ernst P, Olivenstein R, et al. Airway inflammation assessed by invasive and noninvasive means in severe asthma: eosinophilic and noneosinophilic phenotypes. J Allergy Clin Immunol. 2006;1185:1033-1039. [CrossRef] [PubMed]
 
Girard F, Chaboillez S, Cartier A, et al. An effective strategy for diagnosing occupational asthma: use of induced sputum. Am J Respir Crit Care Med. 2004;1708:845-850. [CrossRef] [PubMed]
 
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Lemière C, Chaboillez S, Malo JL, Cartier A. Changes in sputum cell counts after exposure to occupational agents: what do they mean? J Allergy Clin Immunol. 2001;1076:1063-1068. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1. Receiver operating characteristic curves evaluating the effectiveness of changes in sputum eosinophils counts and fractional concentration of exhaled nitric oxide changes between baseline and 7 and 24 h postexposure for diagnosing occupational asthma. eNO 5 exhaled nitric oxide.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Characteristics of the Subjects Studied

Data given as mean ± SD unless otherwise noted. CS = current smoker; F = female; FENO = fractional concentration of exhaled nitric oxide; HMW = high-molecular-weight agent; ICS = inhaled corticosteroids; LMW = low-molecular-weight agent; M = male; NS = never smoker; OA = occupational asthma; PC20 = concentration of methacholine/histamine inducing a 20% fall in FEV1; SIC = specific inhalation challenge; exS = exsmoker.

a 

P < .05

Table Graphic Jump Location
Table 2 —Sputum Cell Counts and FENO Levels in Subjects Who Underwent Sputum Induction and FENO Measurement at Baseline, 7 h, and 24 h After Exposure

Data given as median (interquartile range). Eos = sputum eosinophil count; Neu = sputum neutrophil count; TCC = total cell count. See Table 1 for expansion of other abbreviations.

a 

P < .01 compared with baseline value.

b 

P = .01 compared with baseline value.

Table Graphic Jump Location
Table 3 —Sputum Eosinophil Counts and FENO Levels in Steroid-Naive and Steroid-Treated Subjects With a Positive SIC

Data given as median (interquartile range). There were no statistically significant differences in sputum cell counts or FENO levels between steroid-naive subjects and steroid-treated subjects at any time points. See Tables 1 and 2 for expansion of abbreviations.

Table Graphic Jump Location
Table 4 —Sensitivities, Specificities, and Positive and Negative Predictive Values of Sputum Eosinophil Counts and FENO Levels for Predicting a Positive SIC

NPV = negative predicted value; PPV = positive predicted value. See Table 1 legend for expansion of other abbreviations.

References

Green RH, Brightling CE, McKenna S, et al. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet. 2002;3609347:1715-1721. [CrossRef] [PubMed]
 
Bates CA, Silkoff PE. Exhaled nitric oxide in asthma: from bench to bedside. J Allergy Clin Immunol. 2003;1112:256-262. [CrossRef] [PubMed]
 
Smith AD, Cowan JO, Brassett KP, Herbison GP, Taylor DR. Use of exhaled nitric oxide measurements to guide treatment in chronic asthma. N Engl J Med. 2005;35221:2163-2173. [CrossRef] [PubMed]
 
American Thoracic SocietyAmerican Thoracic SocietyEuropean Respiratory Society ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005. Am J Respir Crit Care Med. 2005;1718:912-930. [CrossRef] [PubMed]
 
Berlyne GS, Parameswaran K, Kamada D, Efthimiadis A, Hargreave FE. A comparison of exhaled nitric oxide and induced sputum as markers of airway inflammation. J Allergy Clin Immunol. 2000;1064:638-644. [CrossRef] [PubMed]
 
Lemière C, Ernst P, Olivenstein R, et al. Airway inflammation assessed by invasive and noninvasive means in severe asthma: eosinophilic and noneosinophilic phenotypes. J Allergy Clin Immunol. 2006;1185:1033-1039. [CrossRef] [PubMed]
 
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