Exhaled nitric oxide levels correlate with measures of disease control in asthma

Transcription

1 Exhaled nitric oxide levels correlate with measures of disease control in asthma Jeffrey M. Sippel, MD, MPH, a William E. Holden, MD, a Stephen A. Tilles, MD, b Mark O Hollaren, MD, c Justin Cook, BS, a Nundhini Thukkani, BS, a James Priest, a Bella Nelson, BS, a and Molly L. Osborne, MD, PhD a Portland, Ore Background: Asthma guidelines emphasize maintaining disease control. However, objective measures of asthma disease control are lacking. Objective: We sought to examine the relationship between exhaled nitric oxide (NO) levels and measures of asthma disease control versus asthma disease severity. Methods: We performed a cross-sectional study of 100 patients (age range, 7-80 years) with asthma. We administered a questionnaire to identify characteristics of asthma, performed spirometric testing before and after administration of a bronchodilator, and measured exhaled NO levels in all participants. Results: Exhaled NO was significantly correlated with the following markers of asthma disease control: asthma symptoms within the past 2 weeks (P =.02), dyspnea score (P =.02), daily use of rescue medications (P =.01), and reversibility of airflow obstruction (P =.02). Exhaled NO levels were not correlated with the following markers of asthma disease severity: history of respiratory failure (P =.20), health care use (P =.08), fixed airflow obstruction (P =.91), or a validated asthma severity score (P =.19). Markers with relevance to both disease control and severity showed either a weak correlation (FEV 1 and FEV 1 percent predicted) or no correlation (controller drug use) with exhaled NO. Conclusion: We conclude that exhaled NO levels are correlated predominantly with markers of asthma control rather than asthma severity. Monitoring of exhaled NO may be useful in outpatient asthma management. (J Allergy Clin Immunol 2000;106: ) Key words: Asthma, nitric oxide, exhaled nitric oxide, disease control, epidemiology Recently published National Asthma Education and Prevention Program (NAEPP) guidelines for the management of asthma emphasize the importance of maintaining disease control by preventing chronic symptoms and recurrent exacerbations, minimizing the need for rescue medications such as short-acting β-agonists, and From a Pulmonary and Critical Care Section, Portland Veterans Administration Medical Center; b Oregon Health Sciences University; and c Portland Allergy Clinic, Portland. Supported by The American Lung Association of Oregon. Received for publication Mar 15, 2000; revised June 19, 2000; accepted for publication June 20, Reprint requests: Molly L. Osborne, MD, PhD, Oregon Health Sciences University, 3181 SW Sam Jackson Park Rd #L102, Portland, OR Copyright 2000 by Mosby, Inc /2000 $ /1/ doi: /mai Abbreviations used FVC: Forced vital capacity NAEPP: National Asthma Education and Prevention Program NO: Nitric oxide ppb: parts per billion. maintaining pulmonary function and activity levels. 1 These characteristics of asthma disease control can vary over a wide range of disease severity. Indeed, asthma disease control and disease severity are conceptually separate. For example, a patient with severe asthma receiving appropriate controller therapy might have few symptoms and exacerbations, require little use of rescue medications, and have minimal reversibility of airflow obstruction. Such a patient would have good disease control by NAEPP definitions and require little change in therapy despite underlying severe asthma. In contrast, a patient with mild asthma might have periods of troublesome symptoms, require frequent rescue medications, and demonstrate robust reversibility of airflow obstruction indicative of poor disease control requiring more aggressive therapy. In these examples the adequacy of asthma control guides the intensity of therapy, and assessment of disease control depends heavily on patient report of symptoms. Objective measures of disease control would be useful to clinicians in tailoring therapy for individual patients. Current concepts of the pathogenesis of asthma emphasize the central role of airways inflammation in both initiating and sustaining the disease. 2 Exhaled nitric oxide (NO) has been identified as a potential marker to monitor airways inflammation in asthma. Exhaled NO is increased in patients with asthma compared with control subjects, 2-4 increased in allergen-induced late asthmatic reactions, 5 and reduced when asthma exacerbations are treated with corticosteroids. 6 Although the precise relationship between airways inflammation and the natural history of asthma remains a topic of debate, improvement in markers of inflammation is associated with improvement in asthma control. 7,8 We therefore hypothesized that exhaled NO, a marker of airways inflammation, would correlate with indicators of disease control in asthmatic subjects. In this study we examined the distribution of several epidemiologic markers of asthma control and severity in a cross-sectional analysis of asthmatic subjects in an out- 645

2 646 Sippel et al J ALLERGY CLIN IMMUNOL OCTOBER 2000 FIG 1. Concept of asthma disease control versus disease severity used in this study. Selected characteristics of asthmatic patients were separated into those expected to indicate disease control (left panel) and those indicating disease severity (right panel), as suggested by the NAEPP guidelines and past studies (see text). Baseline pulmonary function studies and anti-inflammatory medication use provide information with relevance to both disease severity and disease control. patient setting. Our concept of asthma disease control versus severity used in this study is shown in Fig 1. In keeping with the NAEPP guidelines, we chose magnitude of current symptoms, 9 use of rescue medications, 1 and degree of reversibility of airflow obstruction after administration of a bronchodilator 10 as measures of asthma control. Indicators of asthma severity included a history of respiratory failure with mechanical ventilation caused by asthma, health care use, irreversible airflow obstruction, and a previously validated asthma severity score. 9 Indicators with relevance to both asthma disease control and severity included baseline spirometry and use of controller medications. We examined the correlation between these markers of asthma disease control and disease severity and exhaled NO as a marker of airways inflammation. We found that exhaled NO correlates predominantly with several markers of disease control rather than disease severity, suggesting that serial measurement of exhaled NO in individual patients over time may assist clinicians in the management of asthma disease control. METHODS We conducted a cross-sectional survey of patients with physician-diagnosed asthma whose cases were followed by allergy specialists in two community-based practices in Portland, Oregon. Our institutional review board approved the research protocol, and written informed consent was obtained from all subjects. Inclusion criteria included both a history of physician-diagnosed asthma 11 and current use of antiasthma medications. Patients were excluded if they were currently smoking or if they had visited a physician within the past month for an exacerbation of asthma. Complete identification data were available for 368 patients who were then contacted by phone. Of the eligible patients, 192 (52%) refused and 176 (48%) agreed to participate. Of those who agreed to participate, we eliminated 24 who failed to keep one or more scheduled appointments and 51 for whom data were incomplete. One subject was excluded from analysis because of current smoker status. The remaining 100 subjects were included in the analysis. Selection of asthma characteristics Our choices of asthma characteristics as indicative of either asthma disease control or asthma severity (or both) were guided by the most recent NAEPP guidelines 1 and prior work in our laboratory 9,12-16 and are illustrated in Fig 1. The NAEPP guidelines emphasize the importance of symptoms and use of rescue medications as important indicators of asthma control. In contrast, we reasoned that a prior history of respiratory failure caused by asthma or health care use as a result of asthma would more likely be indicators of asthma disease severity. We reasoned that reversibility of airflow obstruction after an inhaled bronchodilator would more likely characterize poor control of asthma, whereas fixed airflow obstruction would more likely indicate disease severity. The NAEPP guidelines also recommend that baseline spirometry and medication use should be followed longitudinally in asthma. Baseline spirometry (before administration of a bronchodilator) would be expected to worsen, and anti-inflammatory medication (especially oral corticosteroid use) should increase as disease severity worsens in asthma, but these variables might also change in a patient with mild intermittent asthma with poor disease control. Therefore we chose baseline spirometry and anti-inflammatory medication use as indicators of both asthma disease control and severity. Questionnaire A standardized demographic and pulmonary symptoms questionnaire based on the National Heart, Lung and Blood Institute Epidemiology Standardization Project 11 was administered to all subjects by a trained technician. The questionnaire focused on respiratory symptoms, history of past and present respiratory diseases,

3 J ALLERGY CLIN IMMUNOL VOLUME 106, NUMBER 4 Sippel et al 647 and smoking history. All medication use, including over-the-counter medications, was documented. Inhaled and oral corticosteroids, leukotriene modifiers, cromolyn, and nedocromil were considered controller asthma medications. Hospital-based health care use was defined as hospitalizations, emergency department visits, or urgency care clinic visits during the past year for exacerbations of asthma. A history of past respiratory failure with mechanical ventilation caused by asthma was documented. Spirometry All subjects withheld short-acting bronchodilators for at least 4 hours and long-acting β-agonists for at least 12 hours before spirometry. Spirometric findings (FEV 1 and forced vital capacity [FVC]) were measured by a trained technician using a portable spirometer (Koko Trek Spirometer; Pulmonary Data Service Instrumentation, Inc, Louisville, Colo) according to American Thoracic Society standards. 17 The best of 3 maneuvers was recorded and expressed as an absolute value and as a percentage of the predicted value by using the reference values of Crapo. 18 Bronchodilator responsiveness was determined by means of spirometry performed after 4 actuations of an isoproterenol metered-dose inhaler were administered through an aerosol holding chamber. Pulmonary function tests were repeated 20 minutes after bronchodilator administration, and improvement in spirometry values was expressed as a percentage change in FEV 1 or FVC from the baseline value. A 12% or greater increase in either FEV 1 or FVC was considered a positive bronchodilator response. We defined fixed airflow obstruction as FEV 1 percent predicted of less than 70% and absence of a positive bronchodilator response. Perception of dyspnea Sensation of dyspnea was assessed before and 5 minutes after inhalation of two puffs of isoproterenol. Each participant rated the degree of difficulty breathing (dyspnea) according to a modified scale developed in the early 1970s This is a linear scale of numbers ranking the magnitude of difficulty in breathing from 0 (none) to 10 (maximal). Standard spirometry was done immediately after each assessment. Asthma severity To provide a rough stratification for severity, we classified participants on a 3-point spirometry scale (FEV 1 percent predicted >60%, 60%-79%, or 80%) and a 4-point oral steroid use scale (never, occasional burst use, frequent burst use, or daily use). We then classified patients as having less severe asthma if the sum of these two indices was 0 to 2 and more severe asthma if this sum was 3 to 5. This simple severity score has been shown to correlate with self-assessed severity and separates participants into more and less severe groups. 9 Exhaled NO analysis We measured exhaled NO by using chemiluminescence (Model 280; Sievers Instruments, Boulder, Colo) in seated subjects without nose clips. The NO analyzer has a 0% to 90% response time of 200 ms. We calibrated the instrument and verified linearity over the range of interest (0-200 parts per billion [ppb]) with a certified mixture of 30 parts per million NO in nitrogen, making precise dilutions with NO-free compressed air in a 2-L syringe. In a separate experiment 5% helium was added to the NO/N 2 mixture, and the dilution was repeated. Helium was measured with a mass spectrometer, and the accuracy of the dilution maneuver was verified. A restricted flow exhaled breath technique was used to exclude nasopharyngeal NO from exhaled air. Details of this technique have been published elsewhere. 22,23 Subjects exhaled from total lung capacity to residual volume while maintaining a mouth pressure of 10 mm Hg by observing the pressure signal displayed graphically on a video monitor, thus maintaining a stable flow rate during exhalation (0.03 L/s or 1.8 L/min). The plateau value of exhaled NO, also displayed graphically, was recorded. Maneuvers not resulting in an exhaled NO plateau or with irregular pressure tracings were rejected. Participants repeated the maneuver until 3 acceptable tests were performed. The average of the 3 plateau values was recorded. Exhaled NO concentration (parts per billion or nanoliters per liter) can be converted to NO output (nanoliters per minute) by multiplying NO concentration by the constant flow rate (liters per minute). Ambient NO levels for each maneuver were also recorded. Although there is conflicting evidence whether ambient NO levels affect exhaled NO measurements, 24,25 there was no correlation between ambient NO and exhaled NO values in this study (r = 0.20, P =.12). Statistical analysis Statistical analysis was performed by using JMP software (SAS Institute, Cary, NC). ANOVA was used to compare exhaled NO concentrations between groups. Univariate linear regression analysis was used to determine correlations between continuous variables and exhaled NO levels. Multiple regression analysis was used to control for multiple variables where appropriate. All values are reported as means ± SEM. Probability (P) values are two-sided, and values less than or equal to.05 were considered statistically significant. RESULTS The mean age of participants was 41.8 ± 18 years (range, 7-80 years), and the majority of subjects were female (Table I). Over half the subjects reported using inhaled corticosteroids during the previous year, and most had less severe asthma, as defined by a validated asthma severity score. 9 The mean exhaled NO level for the population was 59.9 ± 5.3 ppb (range, ppb). The mean ambient NO level was 13.8 ± 1.3 ppb, and there was no correlation between ambient and exhaled NO levels (r = 0.20, P =.12). There was no relationship between exhaled NO and age, sex, height, weight, or activities of daily living (data not shown). Measures of asthma disease control and exhaled NO Subjects recalled their frequency of symptoms during the past year. 11 Those who reported asthma symptoms during the prior 2 weeks had significantly higher exhaled NO levels than those without symptoms, irrespective of whether there was adjustment for inhaled corticosteroid use (Table II). However, subjects who reported asthma symptoms during the past 1 or 6 months did not have significantly higher exhaled NO levels compared with those without symptoms. In addition, subjects rated their symptoms using a dyspnea score. 21 Dyspnea scores correlated positively with exhaled NO, meaning greater dyspnea was associated with higher exhaled NO levels (P =.02). The use of daily rescue medications (short-acting β-agonist inhalers) also correlated positively with exhaled NO, as did a positive bronchodilator response (Table II). The mean exhaled NO level was 80.8 ± 10 ppb in patients with a positive bronchodilator response and 52.6 ± 6 ppb in patients without a positive response (P <.02).

4 648 Sippel et al J ALLERGY CLIN IMMUNOL OCTOBER 2000 TABLE I. Baseline demographic characteristics of the study group (n = 100) Variable Age, y (mean ± SD) 41.8 ± 18 Sex, F (%) 72 Race, white (%) 97 Hospital-based asthma care during past year (%) 15 Burst of prednisone during past year (%) 38 Current steroid inhaler use (%) 55 Less severe asthma (validated asthma severity score*; %) 89 Ever smoker (%) 19 Current smoker (%) 0 Atopy (self-reported hay fever, nasal polyps, aspirin hypersensitivity, or eczema; %) 88 Daily rescue medication use (%) 37 FEV 1 % predicted (± SD) 85.2 ± 18 Pack-years for exsmokers (mean ± SD) 18.4 ± 19.8 (range, ) * See reference 9. TABLE II. Measures of asthma disease control and exhaled NO concentration (n = 100) Exhaled NO level (mean ppb ± SE) Yes No P value Adjusted P value * Symptoms within: Past 2 wk 74.1 ± 8 (n = 43) 49.2 ± 7 (n = 57) Past 1 mo 56.9 ± 15 (n = 15) 61.5 ± 5 (n = 85) Past 6 months 64.3 ± 6 (n = 70) 49.6 ± 10 (n = 30) Daily rescue medication use 77.0 ± 9 (n = 37) 49.9 ± 7 (n = 63) Positive bronchodilator response 80.8 ± 10 (n = 26) 52.6 ± 6 (n = 74) * Multiple regression analysis adjusting for inhaled corticosteroid use. TABLE III. Measures of asthma disease severity and exhaled NO concentration Exhaled NO level (ppb ± SEM) Severity measures Yes No P value Respiratory failure with mechanical ventilation 29.8 ± 31 (n = 3) 60.8 ± 5 (n = 97).20 Any hospital-based health care use in past year * 38.0 ± 14 (n = 15) 63.8 ± 6 (n = 85).08 Fixed airflow obstruction 61.9 ± 18 (n = 9) 57.9 ± 5.6 (n = 91).91 Validated severity score High 40 ± 16 (n = 11).19 Low 62.4 ± 6 (n = 89) *Hospital-based health care use is defined as hospitalizations, emergency department visits, or urgency care clinic visits during the past year for exacerbations of asthma. High indicates more severe asthma, and low indicates less severe asthma, as defined elsewhere. 9 Measures of asthma severity and exhaled NO Exhaled NO did not correlate with several measures of asthma disease severity, including a history of respiratory failure with mechanical ventilation, health care use, fixed airflow obstruction, or a validated severity score (Table III). 9 Measures of both asthma disease control and severity When analyzed as continuous variables, both FEV 1 percent predicted and the FEV 1 /FVC ratio correlated negatively with exhaled NO (P <.05, data not shown). However, the correlation was not strong for either variable (r = 0.26 or less for each). Use of controller medications (inhaled or oral corticosteroids, leukotriene modifiers, cromolyn, or nedocromil) did not correlate with exhaled NO level, although there was a trend toward lower exhaled NO with daily use of inhaled corticosteroids (P =.11). DISCUSSION The results of this study support the concept that exhaled NO levels correlate with measures of asthma control, as defined by recent symptoms or dyspnea, use of rescue medications, and reversibility of airflow

5 J ALLERGY CLIN IMMUNOL VOLUME 106, NUMBER 4 Sippel et al 649 obstruction. Exhaled NO levels did not correlate with several measures of asthma severity, including a history of mechanical ventilation, health care use in the past year, fixed airflow obstruction, or a validated asthma severity score. 9 Although our findings may suggest a clinical role for monitoring exhaled NO levels, the results must be interpreted with caution. First, this was a cross-sectional study of 100 individuals with predominantly mild and stable asthma. Individuals with recent exacerbations (within 4 weeks) were excluded from the study. The small and relatively homogeneous sample may limit generalization of the results. However, we would anticipate that the small sample size should increase the chance of type 2 (β) error (eg, not demonstrating a correlation between exhaled NO levels and measures of asthma control). Second, the exhaled NO levels seen in this crosssectional population study ranged from 4 to 270 ppb. This broad range of exhaled NO values is consistent with levels reported by other investigators, with reported population means ranging from 8 to 301 ppb. 4,26 Differences in patient clinical status at the time of evaluation, patterns of medication use, and measurement techniques may explain a portion of the variance observed between studies. The wide range of concentrations found in these studies suggests that the predictive or diagnostic value of exhaled NO, when used at a single point in time, may have limited value. However, these results are an important first step in identifying an objective measure of asthma control. A next step would be to follow levels according to individual best exhaled NO levels in a manner similar to that used for peak flow measurements. Finally, our study was not longitudinal in nature, which limits our ability to further characterize the clinical utility of monitoring exhaled NO. The NAEPP guidelines identified the goals of asthma therapy as preventing chronic symptoms and recurrent exacerbations, minimizing the need for rescue medications such as short-acting β-agonists, and maintaining pulmonary function and activity levels. This guided our choice of recent symptoms, perception of dyspnea, and medication use as indicators of the degree of disease control. In contrast, we chose a history of respiratory failure with mechanical ventilation and health care use as characteristics more clearly related to disease severity. Although it could be argued that some patients with mild intermittent asthma have catastrophic asthma with respiratory failure, in general, respiratory failure occurs in the presence of severe disease. There is obvious overlap in several traditional asthma characteristics that relate to both disease severity and disease control. For example, baseline (ie, before administration of a bronchodilator) measurements of FEV 1, FEV 1 /FVC ratio, and peak flow will worsen as the severity of asthma increases but will also worsen with an acute exacerbation of asthma in a patient with mild asthma under poor control. Hence measurements of baseline pulmonary function contain information related to both disease control and severity. Similarly, we have previously validated the use of anti-inflammatory medications (especially oral corticosteroids) as a marker of disease severity. 9 However, corticosteroids are used in a variety of ways in the treatment of asthma. Patients with mild intermittent asthma may receive bursts of corticosteroids during asthma exacerbations. In this case the use of corticosteroids could be an indicator of poor disease control. Hence the use of corticosteroids and other anti-inflammatory medications can be an indicator of both asthma disease severity and control. Because use of either oral or inhaled corticosteroids in asthma is associated with decreased exhaled NO, 6,27 it is not surprising that corticosteroid use did not correlate with exhaled NO in this study. Most of the characteristics defining asthma severity or control rely on patient report. It would be useful for clinicians to have more objective methods on which to base clinical decisions. Exhaled NO is one of several potential markers of inflammation that could possibly be used to assess the level of current control in asthma. Importantly, it could be used even though the inflammatory changes are poorly understood and even controversial. For example, eosinophil cationic protein levels in induced sputum correlate with symptoms and airflow obstruction in asthma. 28 Also, the number of neutrophils in bronchoalveolar lavage fluid reflects the degree of inflammation in asthma. 29 Yet two recent studies did not find a correlation between exhaled NO and bronchial hyperresponsiveness. 30,31 The interpretation was that measurement of exhaled NO is not clinically useful in asthma. 32 In contrast, our data suggest that exhaled NO is only a marker for inflammatory changes related to current control in asthma. Bronchial hyperresponsiveness may be a marker for underlying severity in asthma. Perhaps severity of asthma reflects some intrinsic characteristic of airways (eg, airways remodeling) that is unrelated to exhaled NO. This would have important clinical implications because elevated exhaled NO might reflect the presence of inflammation treatable with anti-inflammatory drugs, whereas underlying severity might reflect irreversible structural changes unresponsive to anti-inflammatory drugs. Furthermore, measurement of exhaled NO level offers several advantages over these methods: it is rapid, reproducible, and noninvasive. Indeed, a recent study has demonstrated that exhaled NO correlates significantly with airways responsiveness, is highly reproducible, and discriminates well among subjects with and without asthma. 2 Prior studies by Kharitonov and coworkers 6,27,33 support the concept that exhaled NO is a marker of airways inflammation in asthma. More recent studies in our laboratory confirm that exhaled NO is increased in asthmatic subjects. 34 It is possible that measurements of exhaled NO will be used clinically, and recommendations for standard methodology in measurements of exhaled NO have been made. 23,35 The results of our study suggest that measurements of exhaled NO may reflect the degree of asthma control and thus help to identify patients requiring changes in therapy. In conclusion, our cross-sectional study of patients with predominantly mild asthma demonstrated that

6 650 Sippel et al J ALLERGY CLIN IMMUNOL OCTOBER 2000 exhaled NO levels correlated with several markers of asthma control, including recent symptoms and use of rescue medications, but not with several markers of asthma severity. Our findings suggest that measurements of exhaled NO may be useful in the management of patients with asthma. We thank the Portland, Oregon, VAMC, for the use of space and equipment provided for this study. REFERENCES 1. NHLBI USPHS. Expert panel report 2. Guidelines for the diagnosis and management of asthma. Bethesda (MD): National Institutes of Health; NIH publication No Salome CM, Roberts AM, Brown NJ, Dermand J, Marks GB, Woolcock AJ. Exhaled nitric oxide measurements in a population sample of young adults. Am J Respir Crit Care Med 1999;159: Barnes PJ, Kharitonov SA. Exhaled nitric oxide: a new lung function test. Thorax 1996;51: Kharitonov SA, Chung KF, Evans D, O Connor BJ, Barnes PJ. 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