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(Chest. 2003;124:639-643.)
© 2003 American College of Chest Physicians

Exhaled Nitric Oxide as a Predictor of Exercise-Induced Bronchoconstriction*

Samy M. ElHalawani, DO; Nam T. Ly, MD; Richard T. Mahon, MD and Dennis E. Amundson, DO

* From the Department of Internal Medicine (Drs. ElHalawani, Mahon, and Amundson), Division of Pulmonary and Critical Care Medicine, Naval Medical Center San Diego, San Diego, CA; and National Naval Medical Center (Dr. Ly), Bethesda, MD.

Correspondence to: Richard T. Mahon, MD, c/o Clinical Investigation Department (KCA), Naval Medical Center San Diego, 34800 Bob Wilson Dr, Ste. 5, San Diego, CA 92134-1005; e-mail: rtmahon{at}nmcsd.med.navy.mil


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Introduction: Exercise-induced bronchoconstriction (EIB) is present in 40 to 90% of patients with asthma. Exhaled NO (eNO) levels have been correlated with bronchial hyperresponsiveness to methacholine, and have correlated with the degree of decrease in FEV1 with exercise. The purpose of our study was to examine whether eNO measurements prior to or after exercise could be used as a surrogate marker of exertional bronchoconstriction in a population referred specifically for the evaluation of EIB.

Methods: We studied 50 consecutive subjects without a history of asthma who were referred for the clinical evaluation of EIB. eNO levels were measured prior to exercise challenge and every 5 min for a total of 30 min after exercise. Forced expiratory flows were measured prior to and serially after exercise challenge.

Results: Seven subjects had a decrease in FEV1 of >= 15% with exercise. The mean eNO level prior to exercise was 41 parts per billion (ppb) [median ± SD, 23 ± 42.2 ppb] in the EIB group and 25.6 ppb (median, 19.95 ± 18.47 ppb) in the group without EIB. A receiver operator characteristic curve yielded a value of 0.636. When using an eNO level of < 12 ppb, the sensitivity, specificity, negative predictive value, and positive predictive value for EIB were 1.0, 0.31, 0.19, and 1.0, respectively; therefore, no one with a baseline eNO of < 12 ppb demonstrated EIB.

Conclusions: No subjects with very low pre-exercise eNO levels (< 12 ppb) demonstrated bronchial hyperresponsiveness to exercise. eNO measurement may obviate the need for bronchoprovocation testing in patients who complain of exertional dyspnea.

Key Words: asthma • dyspnea • exercise-induced bronchoconstriction • nitric oxide


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Nitric oxide (NO) is a product of the NO synthase (NOS) enzyme found in both normal and asthmatic human airways. The precise role of NO in airway disease remains uncertain. Exhaled NO (eNO) can be measured by a simple noninvasive method utilizing chemiluminescence. In studies of chronic asthma, eNO is elevated and treatment with inhaled corticosteroids decreases eNO levels.1 2 3 4 5 Additionally, eNO levels have been correlated with bronchial hyperresponsiveness to methacholine and have correlated with the degree of decrease in FEV1 with exercise.6 7 8 Also, eNO levels rise after bronchoprovocation.9 These data suggest that eNO may be a useful marker of airway responsiveness.1 2

Exercise-induced bronchoconstriction (EIB) is present in 40 to 90% of patients with asthma,10 and may be the sole manifestation of airway disease.11 One current theory suggests that bronchoconstriction occurs as a result of airway cooling during hyperpnea followed by warming when ventilation diminishes.10 12 The role of airway inflammation and NO in EIB is poorly characterized.

The purpose of our study was to examine whether eNO measurements prior to or after exercise could be used as a surrogate marker of exertional bronchoconstriction in a population referred specifically for the evaluation of EIB. Such a surrogate marker could potentially obviate the need for the significant materials, facilities, and human resources required for standard EIB testing.13 In contrast to previous studies, we excluded patients with previously diagnosed airway disease and those who were receiving anti-inflammatory therapy.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patients
After approval from our institutional review board and using an information sheet explaining the project, we studied 50 consecutive patients between the ages of 18 years and 40 years referred to the pulmonary clinic with a suspected diagnosis of EIB. This age range was chosen in an effort to eliminate individuals with emphysema and chronic bronchitis. Subjects completed a questionnaire that included demographic information, smoking history, respiratory symptoms, atopy history, and medication use. All patients were current nonsmokers, and none reported a history of atopy to include no seasonal allergic rhinitis or eczema. At the time of recruitment, all the subjects were in stable condition as assessed by a pulmonary physician. We excluded patients who were receiving long-term medications including inhaled corticosteroids, mast-cell stabilizers, antihypertensives, nonsteroidal anti-inflammatory drugs, or oral corticosteroids. As-needed use of inhaled ß-agonists was not exclusionary.

Measurements
eNO was measured by the "on-line" (real-time display of eNO) technique11 using a Sievers 280A chemiluminescence analyzer (Sievers Instruments; Boulder, CO) prior to spirometric measurements. To exclude nasally produced NO, the subject exhaled against a fixed resistance resulting in closure of the velopharyngeal aperture.11 Specifically, the subject inhaled to near total lung capacity through an NO absorber that decreased inhaled NO to < 2 parts per billion (ppb). Next, subjects exhaled against a fixed resistance of 16 cm H2O with a resulting flow delivery of 50 mL/s. This level was kept constant by a graphic display of flow with patient coaching. Three measurements of eNO within 5% variance were required for acceptability,11 and the average of these levels was recorded. Ambient temperature and humidity were measured prior to testing. FEV1 was measured with a spirometer (GS Collins Gold Plus; Collins; Braintree, MA).

Exercise Challenge Test
Exercise challenge testing was performed on a treadmill with an incremental work rate protocol. The protocol consisted of up to 14 min of exercise but was symptom limited. Treadmill speed was begun at 2 miles per hour and increased 1 mile per hour every 2 min. Treadmill grade began at 10% and increased to 15% after 8 min. Targeted heart rate was 85% predicted maximum heart rate and maintained for 2 min. Following our existing laboratory protocol, spirometry was performed every 5 min after exercise for a total of 30 min. Pulmonary function testing was discontinued when a fall in FEV1 of 15% from baseline was demonstrated. eNO was measured and recorded prior to each spirometric maneuver. Treatment for wheezing and dyspnea were based on an established Naval Medical Center protocol for acute bronchoconstriction.

Statistics
Baseline characteristics were compared using t test and rank-sum test. Baseline eNO levels, eNO at each time point, the difference between time points and slopes of eNO for those who manifested EIB and those that did not were compared using analysis of variance. A receiver operator characteristic (ROC) curve was constructed from which we developed the "best discriminator" of eNO concentration to classify patients as having EIB or not having EIB. A 2 x 2 table was constructed using this discriminator against true EIB and those without EIB. We determined specificity, sensitivity, positive predictive value, and negative predictive value. Additionally correlation coefficients of baseline eNO were analyzed for those who demonstrated a significant fall in expiratory flows with exercise.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Fifty consecutive patients were tested. One patient was excluded from analysis secondary to laryngospasm during exercise and the inability to complete spirometry. Hence, data from 49 subjects were analyzed. All subjects had complete eNO and spirometry data. Seven subjects had a decrease in FEV1 of >= 15% with exercise (EIB group), while 42 subjects had a < 15% decrease in expiratory flows with exercise (no-EIB group). Patients with and without EIB were not significantly different in demographics, and ambient relative humidity in the test environment was similar in both groups (Table 1 ).


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  		Table 1. Baseline Characteristics in Patients With and Without EIB

 
The mean eNO level prior to exercise was 41 ppb (median ± SD, 23 ± 42.2 ppb) in the EIB group and 25.6 ppb (median, 19.95 ± 18.47 ppb) in the group without EIB. This difference between groups did not reach statistical significance (p = 0.25). Serial eNO measurements after the exercise challenge did not reveal significant changes in the eNO level prior to and at any time points after exercise to include comparison between baseline and final eNO concentration.

An ROC curve yielded a value of 0.636 (Fig 1 ). When using an eNO level of < 12 ppb, the sensitivity, specificity, negative predictive value, and positive predictive value for EIB were 1.0, 0.31, 0.19, and 1.0, respectively. Thus, no one with a baseline eNO of < 12 ppb demonstrated EIB (Fig 2 ). In patients who demonstrated EIB, the degree of eNO elevation did not correlate with the absolute fall in FEV1 (p = 0.204; r2 = 0.29).



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  		Figure 1. ROC curve for eNO predicting patients with EIB, with representative values.

 


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  		Figure 2. Scatterplot of eNO and EIB. Sensitivity = 1.0; specificity = 0.31; positive predictive value = 0.19; negative predictive value = 1.0. Line at 12 ppb is at proposed best level discriminator.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Dyspnea is a common complaint in a military population. Though often considered, EIB is found in only 6% of military personnel presenting with such complaints.14 The evaluation of EIB is a significant cost issue in dollars and personnel time. A cost-effective prediction tool for EIB would be clinically helpful and would spare the expense of performing a full EIB protocol. Reliable surrogate predictive tools for EIB have not been previously validated.

Clinical tools for predicting exertional bronchoconstriction in known asthmatics have been evaluated. It has been shown that blood and sputum eosinophils correlate with the severity of EB.15 16 Yoshikawa et al15 demonstrated that sputum eosinophilia correlated with EIB severity better than methacholine bronchoprovocation. Additionally, Koh and Choi16 noted that the presence of blood eosinophilia yielded a specificity of 88% and a positive predictive value of 93% for EIB. Both of these studies evaluated patients with known asthma or excluded patients without bronchial hyperresponsiveness; therefore, the predictors used by the above-mentioned authors are generally limited to known asthmatics. Whether the assessment of eNO has a potential as a marker for EIB in a population of patients without a definite history of asthma or airway hyperresponsiveness was previously unknown.

NO is a highly reactive molecule that participates in many biological processes primarily through an enzymatic reaction with guanylate cyclase.17 18 This activation serves to provide an important second messenger between vascular endothelium and smooth muscle as well as between nerve cells. The enzymatic generation of NO by NOS in both vascular endothelial cells and neurons is achieved by two isoforms of NOS and are modulated through calcium-channel–dependent mechanisms. Both endothelial-derived NOS and neuronal NOS are expressed constitutively.19 NO is also formed de novo by a third inducible isoform of NOS through gene activation. Expression of this inducible form of NOS is stimulated by endogenous cytokines resulting in the synthesis of NO and is a calcium-independent process. Inducible NOS can be found in a number of cells within the respiratory epithelium such as monocytes and macrophages in addition to the respiratory epithelium.1 20 21 All three forms of NOS have been identified in airway epithelium.19

The measurement of eNO is a simple noninvasive method that has shown utility in chronic asthma. eNO is elevated in patients with asthma, and treatment with inhaled corticosteroids decreases eNO levels.4 Additionally, eNO levels have been correlated with bronchial hyperresponsiveness to methacholine, and have correlated with the degree of decrease in FEV1 with exercise.6 7 8

eNO levels have been previously studied during exercise in both healthy individuals and in patients with chronic, stable respiratory illnesses.6 22 23 24 25 Articles evaluating the relationship of EIB and eNO have yielded conflicting results. Scollo and colleagues7 did not find a significant change in eNO during exercise in children with asthma and EIB. Terada and coworkers,6 however, demonstrated a significant decrease in eNO with exercise in patients with EIB, while normal control subjects in this study had an increase in eNO. However, Kotaru et al24 measured eNO using hyperventilation as a surrogate for exercise and documented an increase in eNO in asthmatic subjects with EIB. Both authors concluded that baseline eNO was elevated in the asthmatic groups prior to testing. A correlation between the elevation in baseline eNO and the percentage of maximal decrease in FEV1 with EIB was also observed.6 7 Importantly, the participants in these prior studies were known asthmatics, and the majority of them were treated with anti-inflammatory therapy.

We have demonstrated that a low baseline eNO level (< 12 ppb) is unlikely to be associated with EIB. Though this level of eNO was only observed in approximately 30% of our patients, the cost savings in technician and laboratory time would be substantial. Though others have demonstrated a correlation between eNO elevation and the decrease in FEV1 in those with EIB,6 7 we have not demonstrated such results.

There are several potential weaknesses in this study. Its design is one of looking at the clinical utility of eNO as a screening test for potential EIB. In our study, we excluded subjects with conditions that might affect eNO levels (tobacco abuse, asthma, and atopy) based on historical grounds only in an effort to better define the utility of the test. Clearly, within our population it is likely that true atopics and potential tobacco abusers were included.

Additionally, the wide range of eNO in this study is noted. In our clinic, patients without cardiopulmonary complaints have median baseline eNO levels of 13.3 ± 1.8 ppb; our study only analyzed subjects with a suspicion of EIB. Though the final cause of this dyspnea is not reported, cardiopulmonary disorders that affect eNO are likely present. In a recent study of exertional dyspnea in a military population, Morris et al26 reported that in addition to EIB, other conditions were certainly present to include sarcoidosis and gastroesophageal reflux. Additionally, despite their extensive evaluation that included cardiopulmonary exercise testing, chest radiography, and echocardiography, 24% of cases were undiagnosed. Data of eNO levels in patients with idiopathic exertional dyspnea have not been reported in the literature.

In summary, eNO measurement is an attractive marker for predicting and monitoring airway disease because of its simplicity and potential for off-line collection. Despite the wide range and significant overlap of eNO among the study groups, EIB was not seen in patients with low initial eNO levels. This finding may negate the need for further evaluation of exertional bronchoconstriction in a patient with exertional dyspnea; however, caution should be exercised in extrapolating these findings to populations that were not included in this study.


   Footnotes
 
Abbreviations: EIB = exercise-induced bronchoconstriction; eNO = exhaled nitric oxide; NO = nitric oxide; NOS = nitric oxide synthase; ppb = parts per billion; ROC = receiver operator characteristic

The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Navy, Department of Defense, or the United States Government.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: permissions@chestnet.org).

Received for publication July 30, 2002. Accepted for publication February 6, 2003.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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