The Journal of Allergy and Clinical Immunology
Volume 117, Issue 2 , Pages 259-262, February 2006

Nitric oxide as a clinical guide for asthma management

  • D. Robin Taylor, MD, FRCPC

      Affiliations

    • Corresponding Author InformationReprint requests: D. Robin Taylor, MD, FRCPC, Department of Medicine, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.

From the Department of Medicine, Dunedin School of Medicine, University of Otago

Received 1 November 2005; received in revised form 7 November 2005; accepted 7 November 2005.

Dunedin, New Zealand

Article Outline

Asthma is a pathologically heterogeneous disease, and the phenotype is characterized by different types of airway inflammation. Exhaled nitric oxide (FENO) measurements are a surrogate marker specific for eosinophilic airway inflammation. The latter is usually associated with steroid responsiveness, and hence, FENO may be used to guide steroid requirements in certain clinical situations. High FENO levels may be used to predict likely benefits with inhaled corticosteroid (ICS) therapy. Both high and low FENO levels are prognostically significant when withdrawal of ICS treatment is being considered. Studies have shown that, just as for induced sputum, repeated FENO measurements improve the cost-effectiveness of ICS therapy when used to guide dose requirements. In practice, FENO measurements are useful in the management of severe or difficult asthma. High and low FENO levels in symptomatic patients provide the clinician with information that enables active eosinophilic airway inflammation to be included or excluded. Either outcome is helpful in decision making. FENO measurements complement the use of other tests in asthma, but more work is required to determine reference values and cut-points for appropriate interpretation.

Key words: Asthma, exhaled nitric oxide, FENO, pulmonary function

Abbreviations used: FENO, Fraction of nitric oxide in exhaled air, ICS, Inhaled corticosteroid

 

Asthma is increasingly recognized as a syndrome rather than a specific disease, and its underlying pathology, clinical manifestations, natural history, and responses to treatment exhibit considerable heterogeneity. Conventional measurements of functional abnormalities, such as airway obstruction and reversibility and bronchial hyperresponsiveness, provide information that describes the physiological phenotype. However, because of considerable overlap between asthma and other airways diseases, these data provide only limited guidance to the clinician, both diagnostically and in terms of treatment choices.

More recently, the technique of induced sputum analysis has offered insights into the different pathological phenotypes of asthma. Although characterized predominantly by eosinophilic airway inflammation, in some cases neutrophilic and pauci-granulocytic cell populations occur.1 The key issue appears to be not only that these entities are different but also that they define the differing capacity to respond—or not—to anti-inflammatory treatment. Airways diseases characterized by eosinophilic inflammation are more likely to benefit from corticosteroid therapy.2

It is against this background that the advent of exhaled nitric oxide (FENO) measurements represents a significant advance in practice. In contrast with induced sputum induction, FENO measurements are easy to perform and are reproducible. Standards for measurement have been agreed.3 Importantly, measuring FENO provides a useful surrogate marker for airway eosinophilia.4 This feature is critical to the clinical interpretation of FENO measurements. In atopic asthma, FENO levels are increased compared with healthy controls, increase further when asthma becomes unstable, and are reduced with steroid treatment. Just as importantly, levels are likely to be low in the absence of eosinophilic airway inflammation. This is diagnostically helpful: in such circumstances, alternative diagnoses should be considered. These include neutrophilic asthma, anxiety/hyperventilation, vocal cord dysfunction, rhinosinusitis, gastroesophageal reflux, chronic obstructive pulmonary disease, or even cardiac disease.

The role of FENO measurements in the management of asthma per se is still an evolving one. However, recent studies now provide a sufficient body of evidence to support this application in clinical practice.

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Starting and stopping inhaled steroid therapy 

The decision to commence inhaled corticosteroid (ICS) therapy in patients with chronic symptoms of cough, wheeze, and shortness of breath is often empiric. The assumption is made that these symptoms are a result of uncontrolled airway inflammation, and in turn, that anti-inflammatory treatment is appropriate. However, this approach is flawed. First, the correlation between respiratory symptoms and airway inflammation is very weak,5 and second, not all airway inflammation is steroid-responsive.6

Recently, Smith et al7 showed that FENO measurements provide a useful guide about whether benefits will be obtained from a trial of ICS treatment. Among 52 steroid-naive patients with chronic respiratory symptoms, the response to inhaled fluticasone for 4 weeks was significantly greater than placebo and occurred predominantly in the ⅓ of subjects whose FENO was greater than 47 ppb (Fig 1). The negative predictive values were high (77% for symptoms; 89% for improvement on spirometry); that is, in the absence of high FENO levels, a response to steroid was much less likely. These results are consistent with those of Szefler et al,8 who demonstrated that the mean FENO levels in children who were steroid-responsive (54 ppb; 95% CI, 19-90) were significantly greater than in those who did not respond (mean FENO, 23 ppb; 95% CI, 10-41).

  • View full-size image.
  • Fig 1. 

    Changes in FEV1 (% improvement) following 4 weeks of treatment with inhaled fluticasone 500 μg/d in 52 subjects with chronic nonspecific respiratory symptoms, stratified by baseline FENO (tertiles). The changes in FEV1 were significantly higher in the group with the highest FENO (greater than 47 ppb) using 1-way ANOVA for trends across all 3 groups (P < .01). Data are also given after stratifying by clinical diagnosis made at the time of initial presentation based on symptoms, bronchodilator response, and/or a positive test for airway hyperresponsiveness (asthma versus nonasthma).7

Measurements of FENO are also helpful when considering stopping ICS therapy if asthma appears to be in remission. Is remission the result of ICS treatment or independent of it? Can treatment be discontinued safely? Pijnenburg et al9 have recently addressed this issue in a study of 40 children with stable asthma. ICS treatment was withdrawn, and 9 relapsed during the 24-week follow-up interval. In contrast with the nonrelapsers, their FENO levels rose steadily during the postwithdrawal period, from a mean FENO at baseline of 14.8 ppb to 40.8 ppb at 4 weeks. The values were 10.5 ppb and 15.9 ppb, respectively, in the nonrelapsers (P = .01). Optimum positive and negative predictive values for subsequent relapse were obtained at a FENO of 49 ppb, which is remarkably similar to the cut-point for “steroid-responsiveness” obtained in the study by Smith et al.7 In a similar study, Zacharasiewicz et al10 concluded that the absence of sputum eosinophils, with simultaneously low FENO levels, predicted successful withdrawal of ICS therapy in children.

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Optimizing inhaled steroid therapy 

At least in this country, there has been a trend over recent years for increasingly high doses of ICS therapy to be prescribed in patients with persistent asthma. In addition to the economic cost, the risk of adverse systemic effects also increases significantly with higher doses.11 Clearly, any practical strategy that might improve the cost-benefit ratio for ICS prescribing would be an advance.

The concept that “inflammometry” might be used to guide anti-inflammatory therapy in asthma—as an alternative to a conventional approach based on symptoms, bronchodilator use, and peak flows—is entirely rational. Anti-inflammatory treatment ought to be guided by ongoing assessment of airway inflammation or appropriate surrogates. Previously, Sont et al12 and Green et al13 have investigated the use of regular bronchial hyperresponsiveness testing and induced sputum eosinophil counts, respectively, as the basis for ICS dose adjustment in asthma. Both investigators demonstrated that using the alternative strategy, outcomes with ICS treatment were improved. In the study by Green et al,13 a 68% reduction in asthma exacerbation rates was obtained in the strategy group compared with the conventional group. However, this was achieved using comparable doses of ICS in both treatment groups.

The results of these studies indicate the potential advantages of adjusting ICS dose on the basis of regular “inflammometry” rather than clinical parameters. However, their application is clearly limited: frequent bronchial hyperresponsiveness testing or sputum induction is impractical. So what about FENO? In a recent study by Smith et al,14 a similar hypothesis was tested, namely that repeated measurements of FENO as a guide to treatment would improve the cost-effectiveness of ICS use. In that study, a somewhat different but nonetheless significant outcome was achieved. In the FENO group, there was a 46% reduction in the number of exacerbations, but this was nonsignificant. However, simultaneously, there was a highly significant reduction in the mean daily dose of inhaled fluticasone (over 12 months): 370 μg/d for the FENO group (95% CI, 263-477) versus 641 μg/d for the control group (95% CI, 526-756), a difference of 270 μg/d (95% CI, 112-430; P = .003). The distribution of dose requirements was strikingly different between the 2 groups (Fig 2).

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  • Fig 2. 

    Distribution of mean inhaled fluticasone doses (over 12 months) in 2 asthma management groups, one using FENO measurements (n = 46) and the other conventional group in which symptoms, bronchodilator use, and lung function were used in accordance with a priori criteria (n = 48). There was a highly significant difference between the 2 groups (P = .008). Downward dose adjustments were made in the FENO group if the FENO level was less than 35 ppb.14

There are a number of explanations for these results. First, the choice of cut-point for FENO may have been inappropriately high (it was 35 ppb). If a lower cut-point for downward dose titration had been used in the FENO group, then the mean daily fluticasone dose would have been increased, and arguably the exacerbation rate in that group would have been reduced, possibly to the point of statistical significance. The overall result might then have mirrored that of Green et al.13 Alternatively, it could be argued that the between-group dose difference resulted from the control group receiving inappropriately high doses of ICS—but this calls into question the thresholds for ICS dose adjustment that are currently specified in conventional guidelines to determine poor asthma control and hence the need for increased anti-inflammatory treatment.15

Whatever the interpretation, the study by Smith et al7 provides evidence to support the view that “inflammometry,” this time using FENO measurements, rather than the use of clinical parameters, may provide for more effective management in chronic persistent asthma.

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Difficult asthma 

We have recently introduced FENO measurements into the range of tests provided in our local pulmonary function laboratory. Apart from their diagnostic role in the work-up of patients with nonspecific respiratory symptoms, they are also helpful in ongoing asthma management, particularly if it is severe, difficult, or both.

There are now sufficient data16 to provide a provisional schema for interpreting FENO results in patients with asthma. To summarize, low FENO levels (<25 ppb) in an asymptomatic individual indicate that ICS dose may be reduced, or even withdrawn altogether. Low levels in a symptomatic patient indicate that whatever the cause of persistent symptoms, it is unlikely that eosinophilic airway inflammation is one of them. The diagnosis of atopic asthma ought therefore to be questioned, and/or other factors should be sought, to explain ongoing symptoms such as uncontrolled rhinosinusitis, gastroesophageal reflux, and anxiety-hyperventilation. Often these factors coexist, but having FENO measurements provides a helpful alternative to guessing which of them is the most important. Why? Because none of these other entities will benefit from increased doses of ICS treatment.

High FENO levels (>45-50 ppb) in an asymptomatic individual do not necessarily imply the need for clinical intervention and should be interpreted strictly with reference to the clinical history. Unfortunately, in a patient with active asthma, they do not necessarily predict an imminent exacerbation,17 although as previously stated, they appear to be relevant in predicting the outcome with steroid withdrawal if the asthma is in remission.9, 10 High levels in a symptomatic patient imply inadequate ICS treatment. In the first instance, poor compliance and/or poor inhaler technique are the most likely explanations. Thereafter, high levels indicate the need for increasing the dose of inhaled or even oral corticosteroid therapy. Only rarely do they indicate true steroid resistance.

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Practical problems 

A number of important questions regarding the application of FENO measurements in asthma still remain to be resolved. Perhaps the most important of these is the issue of clinically meaningful cut-points. This is an important issue in the design and interpretation of clinical studies. It is also problematic in practice. The interpretation of intermediate values (in the range 25-50 ppb) remains unclear. The suggested cut-points for low and high FENO have been obtained in either healthy populations or those with mild to moderate asthma. Do they apply in severe or difficult asthma? In the study by Kharitonov et al,18 the upper limit of normal for FENO was 33 ppb, and the between-sitting variability was ±4 ppb. However, in the study by Jones et al,17 changes in FENO between stability and poor control in 77 patients ranged from −10 ppb to +141 ppb (mean, 24.9 ppb), indicating very high interindividual variation with deteriorating asthma. Thus, using group mean data to derive meaningful thresholds for clinical decision making may be inappropriate. An individual FENO type may be more relevant for determining what constitutes a clinically important change in specific patients.

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Conclusion 

Measurements of FENO provide a perspective on airway pathology that complements conventional assessment of airway function in the diagnosis and ongoing management of asthma. They shed light on whether symptoms are attributable to uncontrolled eosinophilic airway inflammation, and in turn on whether the patient may benefit from more or less inhaled corticosteroid—or none at all. The technique is coming of age, and FENO measurements now have a useful place in day-to-day practice. But we are still learning.

All numeric references to FENO are reported in parts per billion at or corrected for the recommended expiratory flow rate of 50 mL/s.

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References 

  1. Douwes J, Gibson P, Pekkanen J, Pearce N. Non-eosinophilic asthma: importance and possible mechanisms. Thorax. 2002;57:643–648
  2. Brightling CE, Monteiro W, Ward R, Parker D, Morgan MD, Wardlaw AJ, et al. Sputum eosinophilia and short-term response to prednisolone in chronic obstructive pulmonary disease: a randomised controlled trial. Lancet. 2000;356:1480–1485
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 Guest editors: William W. Busse, MD, and Stanley J. Szefler, MD

 Disclosure of potential conflict of interest: D. Taylor has received money and has spoken on behalf of Aerocrine.

PII: S0091-6749(05)02524-8

doi:10.1016/j.jaci.2005.11.010

The Journal of Allergy and Clinical Immunology
Volume 117, Issue 2 , Pages 259-262, February 2006

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