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(Chest. 2000;117:695-701.)
© 2000 American College of Chest Physicians

Increased Exhaled Nitric Oxide in Chronic Bronchitis*

Comparison With Asthma and COPD

Frank M. Delen, MD; Jeffrey M. Sippel, MD, MPH; Molly L. Osborne, MD, PhD, FCCP; Sandra Law, BS; Nundhini Thukkani, BS and William E. Holden, MD

* From the Portland Veterans Administration Medical Center, Portland, OR.

Correspondence to: William E. Holden, MD, Pulmonary and Critical Care Section, P3-Pulm, Portland VA Medical Center, 3710 SW US Veterans Rd, Portland, OR 97201; e-mail: holden.william{at}portland.va.gov


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: To test the hypothesis that exhaled nitric oxide (NO) is increased in patients with chronic bronchitis, and to compare the results with exhaled NO in patients with asthma and COPD.

Study design: Cross-sectional survey.

Setting and patients: Veterans Administration pulmonary function laboratory. Patients (n = 179) were recruited from 234 consecutive patients. Two nonsmoking control groups of similar age, with normal spirometry measurements and no lung disease, were used (18 patient control subjects and 20 volunteers).

Measurements: Participants completed questionnaires and spirometry testing. Exhaled NO was measured by chemiluminescence using a single-breath exhalation technique.

Results: Current smoking status was associated with reduced levels of exhaled NO (smokers, 9.2 ± 0.9 parts per billion [ppb]; never and ex-smokers, 14.3 ± 0.6 ppb; p < 0.0001). Current smokers (n = 57) were excluded from further analysis. Among nonsmokers, the levels of exhaled NO were significantly higher in patients with chronic bronchitis (17.0 ± 1.1 ppb; p = 0.035) and asthma (16.4 ± 1.3 ppb; p = 0.05) but not in those with COPD (14.7 ± 1.0 ppb; p = 0.17) when compared with either control group (patient control subjects, 11.1 ± 1.6 ppb; outside control subjects, 11.5 ± 1.5 ppb). The highest mean exhaled NO concentration occurred in patients with both chronic bronchitis and asthma (20.2 ± 1.6 ppb; p = 0.005 vs control subjects).

Conclusions: Exhaled NO is increased in patients with chronic bronchitis. The increase of exhaled NO in patients with chronic bronchitis was similar to that seen in patients with asthma. The highest mean exhaled NO occurred in patients with both chronic bronchitis and asthma. Exhaled NO was not increased in patients with COPD. Although chronic bronchitis and asthma have distinct histopathologic features, increased exhaled NO in patients with both diseases suggests common features of inflammation.

Key Words: asthma • chronic bronchitis • COPD • nitric oxide


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Exhaled nitric oxide (NO) is increased in diseases of the airways associated with inflammation such as asthma1 2 and bronchiectasis,3 suggesting that NO may play a role in the pathophysiology of inflammatory airway diseases.4 There is less information on exhaled NO in other chronic lung diseases associated with airway inflammation and obstruction, including chronic bronchitis and COPD.5 6 7 Although there are distinguishing clinical and epidemiologic features that allow the classification of COPD, chronic bronchitis, and asthma as separate entities,8 they are all characterized by variable degrees of airways inflammation, and considerable overlap exists between these syndromes. Studies of exhaled NO in patients with COPD are somewhat conflicting, suggesting either that exhaled NO is not increased5 6 or that it is increased only during an unstable exacerbation.7 To date, no studies have characterized exhaled NO in patients with chronic bronchitis.

In this study, we tested the hypothesis that the levels of exhaled NO are increased in patients with chronic bronchitis. We tested this hypothesis and compared the results with levels of exhaled NO in patients with asthma and COPD in a cross-sectional survey of consecutive patients referred to our pulmonary function laboratory. Our patient population has a high prevalence of chronic airflow obstruction, present or past smoking, and environmental tobacco smoke (ETS) exposure. Because smoking is known to reduce the values of exhaled NO,9 we also characterized the effects of smoking and ETS on exhaled NO measurements. Our findings confirm that exhaled NO is increased in patients with chronic bronchitis to concentrations comparable to those seen in patients with asthma. The highest concentrations of exhaled NO were found in patients with features of both chronic bronchitis and asthma. In contrast, exhaled NO is not increased in patients with COPD.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study Design and Subjects
We conducted a cross-sectional survey of exhaled NO in consecutive patients referred for routine pulmonary function testing to the Veterans Administration Medical Center in Portland, OR. We administered a standardized demographic and pulmonary symptom questionnaire to each subject, and measured exhaled carbon monoxide (CO) and exhaled NO concentrations using standard techniques that are described below. Each subject then performed spirometry before and after receiving an aerosolized bronchodilator. Two hundred thirty-four patients were seen during the study period (July 1 to August 31, 1997), and 179 subjects (76%) agreed to participate. No patient had acute pulmonary symptoms at the time of study, and all were outpatients. The institutional review board approved the research protocol, and written informed consent was obtained from all subjects.

Control Groups
For comparison, we used two control groups of nonsmokers who had no respiratory diseases, allergies, or ETS exposure. The first control group consisting of 18 patients was defined within the cross-sectional study population. These patient control subjects were referred to the pulmonary function laboratory for either preoperative evaluation or as part of a disability examination. The second control group (outside control subjects) consisted of 20 subjects who were of similar age and sex to the patient population and were recruited from staff and volunteer workers in our hospital. None of the control subjects were taking prescription medications, and all had normal spirometry.

Questionnaire
A standardized demographic and pulmonary symptoms questionnaire based on the National Heart, Lung, and Blood Institute Epidemiology Standardization Project8 was administered to all subjects by a trained technician. The questionnaire focused on respiratory symptoms, history of past and present respiratory diseases, and smoking history. All medication use, including prescription and over-the-counter medications, was documented.

CO Analysis
Smoking status was verified by measuring exhaled CO with a CO monitor (Discover; Multispiro, Inc; San Clemente, CA). The instrument has a resolution of 1 ppm and is sensitive from 0 to 500 ppm of CO. Participants inhaled deeply, held their breath for 15 s, then exhaled in a slow, steady manner through a mouthpiece to residual volume. CO concentrations > 5 ppm were considered consistent with current smoking.

Exhaled NO Analysis
We measured exhaled NO by chemiluminescence (model 280; Sievers Instruments; Boulder, CO) in seated subjects who were not using nose clips. The instrument has a 0 to 90% response time of 200 ms. We calibrated the instrument and verified linearity over the range of interest (0 to 200 ppb) with a certified mixture of 30 ppm NO in nitrogen, making precise dilutions with NO-free compressed air in a 2-L syringe. A restricted-flow, exhaled-breath technique was used to exclude nasopharyngeal NO from exhaled air.10 11 Subjects exhaled from total lung capacity to residual volume while maintaining a mouth pressure of 10 cm H2O by observing a biofeedback display of the pressure signal displayed graphically on a video monitor. The plateau value of exhaled NO, also displayed graphically, was recorded. Maneuvers not resulting in an exhaled NO plateau or those with irregular pressure tracings were rejected. Participants repeated the maneuver until three acceptable tests were performed. The average of the three plateau values was recorded. Ambient NO concentrations for each maneuver also were recorded. Although there is conflicting evidence as to whether ambient NO concentrations affect exhaled NO measurements,12 13 there was no correlation between ambient NO and exhaled NO values in this study (r = 0.10; p = 0.19).

Spirometry
Spirometry measurements (FEV1 and FVC) were performed by a trained technician using either a desktop automated system (Vmax22 Pulmonary Function Analysis Instrument; SensorMedics Corporation; Yorba Linda, CA) or a portable spirometer (Koko Trek Spirometer; Pulmonary Data Service Instrumentation, Inc; Louisville, CO). Using American Thoracic Society standards,14 the best of three maneuvers was recorded and was expressed as an absolute value and as a percentage of the predicted value using the reference values of Crapo.15 Bronchodilator responsiveness was determined by administering four inhalations of ipratropium bromide and albuterol (Combivent; Boehringer Ingelheim Pharmaceuticals, Inc; Ridgefield, CT) through an aerosol holding chamber. Pulmonary function tests were repeated 20 min after bronchodilator administration, and any improvement in spirometry measurements was expressed as the percentage of change in FEV1 or FVC from the baseline value. An increase of >= 12% in either FEV1 or FVC was considered a positive bronchodilator response. All subjects were withheld from using short-acting bronchodilators for at least 4 h and from using long-acting ß-agonists for at least 12 h before spirometry testing and measurement of exhaled NO.

Definitions
COPD was defined as a smoking history of >= 10 pack-years accompanied by airflow obstruction (FEV1/FVC ratio, < 0.70). Chronic bronchitis was defined by a history of productive cough that was present daily for at least 3 months of the year for 2 consecutive years.8 The presence of asthma was determined by a history of physician-diagnosed asthma8 and current use of antiasthma medications. Current smoker status was defined as self-reported daily cigarette use and an exhaled CO concentration > 5 ppm. ETS exposure was based on self-reported regular exposure to other people’s tobacco smoke.

Statistical Analysis
Statistical analysis was performed using computer software (JMP; SAS Institute; Cary, NC). Analysis of variance (ANOVA) was used to compare exhaled NO concentrations between groups. ANOVA also was used to determine correlations between categorical variables and exhaled NO concentrations. Univariate linear regression analysis was used to determine correlations between continuous variables and exhaled NO concentrations. NO values are reported as mean ± SEM in parts per billion. CO values are reported as parts per million. Two-sided tests yielding a value of p <= 0.05 were considered statistically significant.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Demographics of the Study Population
The study and control groups were predominantly older white men (Table 1 ). Most members of the study population were ex-smokers (51%) or current smokers (35%) and had ETS exposure (47%). In contrast, the control groups consisted entirely of never smokers or ex-smokers and reported no ETS exposure. As expected for patients referred to a pulmonary function laboratory, the prevalence of lung disease was high, with more than half the study group meeting the criteria for COPD and one third meeting the criteria for either chronic bronchitis or asthma. As is characteristic of patients with diseases of airflow obstruction, there was considerable overlap in the patient groups with chronic bronchitis, asthma, and COPD (Table 1) . Spirometry revealed airflow obstruction in the majority of the study population (63%) and a positive response to bronchodilator administration in slightly less than half (43%). There was no relationship between age (r = 0.12; p = 0.09) or sex (p = 0.66) and exhaled NO among the study population or control groups.


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  		Table 1.. Demographics, Smoking Status, Pulmonary Diagnoses, and Pulmonary Function of Study and Control Groups*

 
Effects of Smoking and ETS Exposure on Exhaled CO and NO
We measured exhaled CO concentrations as a method of verifying current smoking status. Current smoker status was associated with reduced exhaled NO concentrations when compared with never or ex-smokers (9.2 ± 0.9 ppb vs 14.3 ± 0.6 ppb, respectively; p < 0.0001). ETS exposure also was associated with slightly reduced exhaled NO concentrations (no exposure, 13.9 ± 0.7 ppb; ETS exposure, 11.1 ± 0.8 ppb; p = 0.006). Regression analysis using both variables demonstrated that current-smoker status was an independent predictor of reduced exhaled NO (p < 0.0001), whereas ETS exposure was not (p = 0.23). All subsequent analyses, therefore, were performed excluding current smokers.

Other investigators16 have suggested that exhaled CO may be a marker of inflammation in asthma. We found no differences in exhaled CO concentrations between nonsmoking patients with asthma (3.1 ± 0.4 ppm; n = 42), COPD (3.1 ± 0.3 ppm; n = 59), or chronic bronchitis (2.8 ± 0.4 ppm; n = 40) and our patient control group (2.4 ± 0.2 ppm; n = 18).

Exhaled NO Concentrations in Patients With Chronic Bronchitis, Asthma, and COPD
Forty nonsmoking patients had chronic bronchitis, and 36 of these patients were past smokers. Exhaled NO was increased in chronic bronchitis when compared with either the patient control group or the outside control group (Fig 1 ). Forty-two nonsmoking patients had asthma, and, consistent with the findings of other investigators,1 2 the levels of exhaled NO were increased in patients with asthma when compared with those in the control groups (Fig 1) . The magnitude of increased exhaled NO in patients with chronic bronchitis was similar to that of patients with asthma (17.0 ppb and 16.4 ppb, respectively). A subset of 21 nonsmoking patients in our study population had both chronic bronchitis and asthma, and this group had the highest mean exhaled NO concentration (20.2 ± 2 ppb; Fig 1 ). In contrast, exhaled NO was not significantly increased in 59 nonsmoking patients with COPD.



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  		Figure 1.. Comparison of exhaled NO concentrations in patients with COPD, chronic bronchitis, and asthma to concentrations in the control groups. Compared with the control groups, concentrations of exhaled NO were increased in patients with either asthma or chronic bronchitis, but not in patients with COPD. The highest concentrations of exhaled NO occurred in patients with both asthma and chronic bronchitis (see "Materials and Methods" section for descriptions of outside control subjects and patient control subjects).

 
Because exhaled NO was increased in patients with chronic bronchitis, we examined possible relationships between exhaled NO and specific clinical characteristics of these patients (Table 2 ). We found no relationship between exhaled NO and symptoms during the day or night or with self-reported allergies. There were also no relationships between exhaled NO and daily use of ß-agonists, oral or inhaled corticosteroids, ipratropium bromide, or theophylline. Exhaled NO also was not associated with the severity of pulmonary function abnormality or with bronchodilator reversibility. The only characteristic of chronic bronchitis patients with higher exhaled NO was the concomitant diagnosis of asthma (p < 0.04).


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  		Table 2.. Relationship of Selected Clinical Characteristics to Exhaled NO in 40 Nonsmoking Patients With Chronic Bronchitis*

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The most important finding of this study was that exhaled NO concentrations are elevated in patients with chronic bronchitis. As expected, subjects with asthma had elevated exhaled NO concentrations, similar in magnitude to those with chronic bronchitis; and the highest NO concentrations were seen in subjects with both chronic bronchitis and asthma. In contrast, exhaled NO concentrations were not elevated in subjects with COPD. Current-smoker status was associated with reduced NO concentrations, so active smokers were not included in our analyses.

There are several factors that limit the generalization of these results to other patient populations. First, this study was a cross-sectional survey conducted in veterans referred for pulmonary function testing. The population was characterized by a relatively high frequency of smokers and ex-smokers, and the overall prevalence of lung disease was very high (90%). Although this provided a rich sample of subjects with lung diseases and airways inflammation, the population characteristics are unique. Second, results of this descriptive study are partly dependent on comparing exhaled NO concentrations in disease states with those of a control population. Inasmuch as normal exhaled NO concentrations are not well defined for any population and may be influenced by control subject selection, we chose two control groups. The first group was defined within the cross-sectional study population and consisted of nonsmokers with normal pulmonary function and no pulmonary disorders. Even though these 18 subjects had no detectable lung disease, patients referred for pulmonary function testing may not be representative of the general population. Therefore, we selected a volunteer control group of similar age for use as a second reference. Both control groups had similar exhaled NO concentrations, and the findings of elevated exhaled NO concentrations in patients with chronic bronchitis, asthma, or both was true regardless of which control group was used.

We measured ambient NO concentrations before each measurement of exhaled NO in our control subjects and patients. Currently, there is controversy about whether ambient NO affects measurements of exhaled NO. Piacentini and coworkers12 examined the influence of environmental NO concentrations in the range of 0 to 150 ppb on exhaled NO concentrations and found no relationship between ambient NO and exhaled NO. Others5 17 also have reported no effect of lower concentrations of ambient NO (< 20 ppb) on exhaled NO. In contrast, Corradi et al13 found a relationship between high ambient NO (> 35 ppb) and increased concentrations of exhaled NO. There was no correlation between ambient concentrations of NO and exhaled NO in our study (r = 0.10; p = 0.19). To further evaluate the possibility of an effect of high ambient NO on exhaled NO, we recalculated our results by eliminating subjects whose measurements were made when the ambient NO was > 35 ppb (Table 3 ). The values of exhaled NO were similar, and the comparisons between groups were unchanged.


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  		Table 3.. Exhaled NO Concentrations in Patients With Chronic Bronchitis, Asthma, and COPD and Comparison With Control Groups Based on Ambient NO Concentrations*

 
The nature of our patient population created difficulty in defining distinct groups (ie, those without overlap) of patients with asthma, chronic bronchitis, or COPD. Our study population was composed of elderly patients, the majority of whom had a history of tobacco smoking. It is particularly difficult to diagnose asthma and to differentiate asthma from chronic bronchitis and COPD in this group of patients because of incomplete reversibility after administration of a bronchodilator, persistent airflow obstruction, and chronic symptoms. To address the possibility that our definition of asthma was too broad, we reanalyzed our data using more strict definitions of asthma. If the criteria were expanded to include episodic cough, wheezing, or shortness of breath, the number of patients with asthma decreased from 40 to 38, but the concentration of exhaled NO was still significantly increased compared with the control groups (p < 0.03 for each). If the criteria were further expanded to include significant reversibility of airflow obstruction after the administration of a bronchodilator, the number of subjects in the asthmatic group decreased to 18, but exhaled NO still trended to a higher concentration compared with control subjects (outside control subjects, p < 0.06; patient control subjects, p < 0.07).

Distinct histopathologic features are seen in COPD, asthma, and chronic bronchitis, which may provide an explanation for the differences in exhaled NO concentrations seen in this study. In COPD, there is limited airways inflammation and the destruction of lung parenchyma predominates.18 Conversely, asthma is characterized by the presence of numerous inflammatory mediators, including leukotrienes, prostaglandins, histamine, eosinophilic basic proteins, and lymphokines.19 Chronic bronchitis is characterized by neutrophil and monocyte-predominant inflammation, with mucous gland and goblet cell hypertrophy.18 Inducible NO synthase is present in epithelial cells, macrophages, neutrophils, smooth muscle cells, fibroblasts, and mast cells20 and may be induced by cytokines and endotoxins.21 The fact that the highest exhaled NO concentrations seen in this study were in subjects with concomitant chronic bronchitis and asthma suggests that the inflammatory milieu of both conditions may contribute to the activation of inducible NO synthase.

The relatively small differences in exhaled NO concentrations seen in this study may limit the utility of exhaled NO monitoring in populations similar to those studied here. For example, the difference between nonsmokers with chronic bronchitis and control subjects was only approximately 6 ppb. Although this represents a difference of approximately 50%, there was considerable overlap between the groups, which may limit the predictive value of exhaled NO for any given subject. Nonetheless, observations such as those seen here may provide stimulus for further research into disease pathophysiology and disease management.

Few studies have investigated exhaled NO concentrations in patients with COPD or chronic bronchitis. Studies published elsewhere, with 43 or fewer total subjects, conclude that exhaled NO concentrations in patients with COPD are no different from those of selected control subjects.5 6 Rutgers and colleagues6 compared exhaled NO concentrations in 16 subjects with COPD and in 8 healthy nonsmokers and found no difference in exhaled NO concentrations, regardless of smoking status. Robbins and colleagues5 also found no difference in exhaled NO concentrations when comparing 14 subjects with COPD with 23 healthy control subjects. Maziak and colleagues7 compared exhaled NO in 43 unstable and stable patients with COPD and showed significantly higher NO concentrations in their unstable population, comprising subjects experiencing an exacerbation of disease or having severe airways obstruction. However, no comparison was made between subjects with COPD or chronic bronchitis and healthy nonsmokers. Our finding that exhaled NO concentrations in patients with COPD are no different from those of two control groups supports the conclusions of other investigators. The finding of elevated NO concentrations in subjects with chronic bronchitis has not been demonstrated previously.

We did not find that exhaled NO concentrations correlated with the degree of airway obstruction in chronic bronchitis (Table 2) . This finding may reflect the variable presence of emphysema occurring concurrently with chronic bronchitis in our patients. Emphysema is pathologically characterized by parenchymal damage with minimal airways inflammation. Because emphysema often occurs together with chronic bronchitis, it is possible that emphysema may contribute to airways obstruction without affecting airways inflammation and exhaled NO concentration. Alternatively, the airways inflammation associated with chronic bronchitis may have caused fibrosis, which also could contribute to airways obstruction without concomitant airways inflammation and increased exhaled NO concentration.

Previous studies of patients with asthma have demonstrated a correlation between levels of exhaled NO and airways hyperresponsiveness as measured by histamine challenge.22 23 These findings have strengthened the concept that both airways hyperresponsiveness and exhaled NO are markers of airways inflammation in patients with asthma. Within our group of 40 patients with chronic bronchitis, only 18 demonstrated a positive bronchodilator response, and there was no correlation between exhaled NO concentrations and bronchodilator responses. Although both bronchodilator reversibility and histamine responsiveness are thought to reflect airways hyperresponsiveness in patients with asthma, we are not aware of studies correlating bronchodilator responsiveness and exhaled NO concentrations in patients with either asthma or chronic bronchitis. The lack of such a correlation in our patients with chronic bronchitis may reflect a differing disease process compared with asthma or simply that exhaled NO is not as sensitive as histamine challenge in the detection of airways hyperresponsiveness.

Previous studies of patients with asthma have demonstrated decreased exhaled NO concentrations after corticosteroid therapy,24 25 suggesting that the anti-inflammatory effects of corticosteroids reduced the exhaled NO concentration through a reduction in airways inflammation. In contrast, we found no relationship between exhaled NO concentration and the use of inhaled or oral corticosteroids in patients with chronic bronchitis (Table 2) . Our study did not monitor either compliance or dosages of corticosteroids, so it is possible that these factors may have influenced the findings. An alternative explanation is that differences in the type and magnitude of inflammation in patients with asthma and chronic bronchitis may explain the lack of a correlation of corticosteroid use and exhaled NO concentration in patients with chronic bronchitis compared with those with asthma.

One recently published study has suggested that exhaled CO concentrations are elevated in patients with asthma and may correlate with underlying inflammation.16 Exhaled CO was measured in all our study subjects, but we found no correlation between CO concentrations and underlying disease state. Subjects with a positive bronchodilator response had slightly increased exhaled CO concentrations when compared with those without a bronchodilator response, but this was not statistically significant (3.3 ± 0.4 ppb vs 2.5 ± 0.3 ppb, respectively; p = 0.08).

In conclusion, patients with chronic bronchitis have elevated exhaled NO concentrations when compared with control subjects. The magnitude of increased NO was similar to that seen in subjects with asthma; and the highest NO concentrations were seen in subjects with both chronic bronchitis and asthma. Although chronic bronchitis and asthma have distinct histopathologic features, further research into the pathophysiology of these illnesses may elucidate common inflammatory pathways and mediators involving NO.


   Acknowledgements
 
The authors thank Gary Sexton, PhD, for assistance with data analysis.


   Footnotes
 
Abbreviations: ANOVA = analysis of variance; CO = carbon monoxide; ETS = environmental tobacco smoke; NO = nitric oxide; ppb = parts per billion

Supported by the American Lung Association of Oregon.

Received for publication March 22, 1999. Accepted for publication September 21, 1999.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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  5. Robbins, RA, Floreani, AA, Von Essen, SG, et al (1996) Measurement of exhaled nitric oxide by three different techniques. Am J Respir Crit Care Med 153,1631-1635[Abstract]
  6. Rutgers, SR, Postma, DS, van der Mark, TW, et al (1996) Nitric oxide in exhaled air in COPD. Eur Respir J 9(suppl 23),13S
  7. Maziak, W, Loukides, S, Culpitt, S, et al (1998) Exhaled nitric oxide in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 157,998-1002[Abstract/Free Full Text]
  8. Ferris, BG (1978) Epidemiology Standardization Project (American Thoracic Society). Am Rev Respir Dis 118(suppl 6),1-120[ISI][Medline]
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  10. Kimberly, B, Nejadnik, B, Giraud, GD, et al (1996) Nasal contribution to exhaled nitric oxide at rest and during breathholding in humans. Am J Respir Crit Care Med 153,829-836[Abstract]
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  12. Piacentini, GL, Bodini, A, Vino, L, et al (1998) Influence of environmental concentrations of NO on the exhaled NO test. Am J Respir Crit Care Med 158,1299-1301[Abstract/Free Full Text]
  13. Corradi, M, Pelizzoni, A, Majori, M, et al (1998) Influence of atmospheric nitric oxide concentration on the measurement of nitric oxide in exhaled air. Thorax 53,673-676[Abstract/Free Full Text]
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 Am. J. Respir. Crit. Care Med.Home page
S. A. KHARITONOV and P. J. BARNES
Exhaled Markers of Pulmonary Disease
Am. J. Respir. Crit. Care Med., June 1, 2001; 163(7): 1693 - 1722.
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P. E. Silkoff, D. Martin, J. Pak, J. Y. Westcott, and R. J. Martin
Exhaled Nitric Oxide Correlated With Induced Sputum Findings in COPD
Chest, April 1, 2001; 119(4): 1049 - 1055.
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C. ADRIE, M. MONCHI, A. TUAN DINH-XUAN, J. DALL'AVA-SANTUCCI, J.-F. DHAINAUT, and M. R. PINSKY
Exhaled and Nasal Nitric Oxide as a Marker of Pneumonia in Ventilated Patients
Am. J. Respir. Crit. Care Med., April 1, 2001; 163(5): 1143 - 1149.
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Is there Increased Exhaled Nitric Oxide in Chronic Bronchitis?
S K Agarwal
Chest Online, 27 Jun 2000 [Full text]
Is there Really Increased Exhaled Nitric Oxide in Chronic Bronchitis
S K Agarwal
Chest Online, 20 Jun 2000 [Full text]
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