Does Exhaled Nitric Oxide Reflect Asthma Control?
Yes, It Does!

Sergei A. Kharitonov and Peter J. Barnes

National Heart and Lung Institute, Imperial College and Royal Brompton Hospital, London, U.K.

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There has been an explosion of research into exhaled nitric oxide (eNO) since levels were found to be increased in patients with asthma. But what is the clinical value of eNO measurements in asthma? We are edging closer to the answer after the timely study by Jones and colleagues published in this issue (1).

The key findings of this article are that eNO measurements have a positive predictive value of between 80 and 90% for predicting and diagnosing loss of control in asthma, and are as useful as induced sputum eosinophils and airway hyperresponsiveness to hypertonic saline, but with the enormous advantage that they are easy to perform. In addition, it has been shown that the changes in eNO were strongly related to asthma symptoms and FEV₁, and that the levels of eNO were significantly different in patients with and without loss of control.

This is the largest longitudinal study (11 wk) to date in which the utility of repeated (once a week for 7 wk) eNO, symptoms, and spirometry measurements has been explored in 78 patients with predominantly atopic asthma. Patients maintained a good lung function (FEV₁ 92% predicted) on inhaled corticosteroids of 630 µg/d (range 100-1600 µg beclomethasone equivalent) during a 4-wk run-in period before their steroid treatment was stopped. Although a placebo-controlled study would be a better choice, the current design was simple and sufficient to pick up 78% of the patients with deterioration of their asthma within 6 wk after the cessation of steroid treatment. The median time to loss of control was 17 d, and the most frequent criteria of the loss were fall in peak expiratory flow and symptoms.

This study is a natural continuation of previous studies, which convincingly demonstrated that eNO is a useful marker of airway inflammation (2). It seems, however, that eNO reflects asthma control better than asthma severity (3). Thus, it is elevated in mild asthma, but it is almost normal in stable moderate asthma adequately treated with corticosteroids (4). However, eNO levels are often further elevated in patients with severe (5) and uncontrolled asthma (6).

An advantage of eNO as a "loss-of-control marker" (7) is that an increase in eNO and asthma symptoms may be seen before any significant deterioration in airway hyperresponsiveness, sputum eosinophils, or lung function during asthma exacerbation induced by steroid reduction (8, 9). Recently, it has been confirmed that eNO is closely related to several markers of asthma control, such as asthma symptoms, dyspnea score, daily use of rescue medication, and reversibility of airflow obstruction (6).

The results were less conclusive when single baseline eNO measurements instead of serial assessments were used. Although the high number of sputum eosinophils of patients who eventually develop exacerbations was a good predictor of asthma deterioration, the changes in eospinophils following steroid reduction were slow and insignificant (9). Similarly, a single baseline assessment of either exhaled NO (9, 10) or sputum eosinophils (10) had a low power to predict asthma deterioration during the reduction of steroid treatment.

Unfortunately, one of the main advantages of serial eNO measurements has not been fully exploited in the latter study. This is because monitoring of eNO was performed at 2, 4, and 6 mo after the dose of corticosteroids was halved (10). However, it is well known that changes in eNO can be seen within 3-5 d following either introduction (11) or discontinuation of steroids (3), and a different study design with more frequent measurements would have been more informative.

Jones and coworkers have realized the importance of assessment of the changes in eNO when measured longitudinally. Thus, eNO was measured every week for 6 wk after steroid treatment was stopped, in contrast to sputum eosinophils and airway hyperresponsiveness, which were measured twice only, at baseline and at the final visit. Importantly, the authors have calculated the differences and correlations between the changes in eNO that occurred between the first visit at which inhaled corticosteroids treatment was stopped, and the final visit at which loss of control developed, but no longer than 6 wk. In addition, the ability of eNO to predict upcoming loss of control was assessed in three ways: first, using the baseline eNO; second, using eNO measurement immediately before loss of control (the penultimate visit); and third, using the change in eNO that occurred between baseline and the penultimate visit.

The finding that changes in eNO measured over time have higher predictive values, sensitivities, and specificities both for predicting and diagnosing loss of control than did single measurements clearly indicates the need for repeated tests. When measured longitudinally the changes in eNO correlated significantly not only with changes in sputum eosinophils and hyperresponsiveness, but also with lung function and asthma symptoms.

The utility of eNO measurements in relation to sputum analysis or airway hyperresponsiveness is important. Methodologically, standardized eNO measurements (12) have obvious advantages over sputum induction and airway hyperresponsiveness or any other bronchial provocation tests due to their simplicity, reproducibility, and entirely noninvasive nature. It is vital that this technique can be used repeatedly in patients with severe disease and to assess disease in children, making it a suitable test for use in the clinical as well as the research practice. The scope for using sputum analysis to monitor asthma control in clinical practice is limited not only by the resources required, but also by the well-documented proinflammatory action of hypertonic saline.

In conclusion, the available evidence suggests that eNO, especially when repeated, as longitudinal measurements, reflects control of asthma. Because the technique is noninvasive, it is possible to make repeated measurements without disturbing the system, in contrast to the invasive or semiinvasive procedures currently used. Individual eNO values, like individual peak expiratory flows, should be established and monitored, and when the levels are above or below a certain reference level, steroid treatment should be either reduced or increased. We clearly need further clinical research on eNO to be able to tailor strategies for effective treatment and early intervention in asthma. As eNO analyzers become more widely available and miniaturized, it is likely that this measurement will become routine in monitoring asthma control, particularly in patients with unstable and difficult to control asthma.

	References

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1. Jones SL, Kittelson J, Cowan JO, Flannery EM, Hancox RJ, McLachlan CR, Taylor DR. The predictive value of exhaled nitric oxide measurements in assessing changes in asthma control. Am J Respir Crit Care Med 2001; 164: 738-743 [Abstract/Free Full Text].

2. Kharitonov SA, Barnes PJ. Exhaled markers of pulmonary disease. Am J Respir Crit Care Med 2001; 163: 1693-1722 [Free Full Text].

3. Kharitonov SA, Barnes PJ. Clinical aspects of exhaled nitric oxide. Eur Respir J 2000; 16: 781-792 [Abstract].

4. Kharitonov SA, Yates DH, Robbins RA, Logan-Sinclair R, Shinebourne EA, Barnes PJ. Increased nitric oxide in exhaled air of asthmatic patients. Lancet 1994; 343: 133-135 [Medline].

5. Stirling RG, Kharitonov SA, Campbell D, Robinson D, Durham SR, Chung KF, Barnes PJ. Exhaled NO is elevated in difficult asthma and correlates with symptoms and disease severity despite treatment with oral and inhaled corticosteroids. Thorx 1998; 53: 1030-1034 . [Abstract/Free Full Text]

6. Sippel JM, Holden WE, Tilles SA, O'Hollaren M, Cook J, Thukkani N, Priest J, Nelson B, Osborne ML. Exhaled nitric oxide levels correlate with measures of disease control in asthma. J Allergy Clin Immunol 2000; 106: 645-650 [Medline].

7. Kharitonov SA. Exhaled nitric oxide and carbon monoxide in asthma. Eur Respir J 1999; 9: 212-218 .

8. Kharitonov SA, Yates DH, Chung KF, Barnes PJ. Changes in the dose of inhaled steroid affect exhaled nitric oxide levels in asthmatic patients. Eur Respir J 1996; 9: 196-201 [Abstract].

9. Jatakanon A, Lim S, Barnes PJ. Changes in sputum eosinophils predict loss of asthma control. Am J Respir Crit Care Med 2000; 161: 64-72 [Abstract/Free Full Text].

10. Leuppi JD, Salome CM, Jenkins CR, Anderson SD, Xuan W, Marks GB, Koskela H, Brannan JD, Freed R, Andersson M, et al . . Predictive markers of asthma exacerbation during stepwise dose reduction of inhaled corticosteroids. Am J Respir Crit Care Med 2001; 163: 406-412 [Abstract/Free Full Text].

11. Kharitonov SA, Yates DH, Barnes PJ. Inhaled glucocorticoids decrease nitric oxide in exhaled air of asthmatic patients. Am J Respir Crit Care Med 1996; 153: 454-457 [Abstract].

12. Recommendations for Standardized Procedures for the Online and Offline Measurement of Exhaled Lower Respiratory Nitric Oxide and Nasal Nitric Oxide in Adults and Children. Am J Respir Crit Care Med 1999;160:2104-2117.