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Year : 2011  |  Volume : 5  |  Issue : 2  |  Page : 42-47

Exhaled nitric oxide in the diagnosis and management of bronchial asthma: From bench to bedside?

Division of Pulmonology, Department of Medicine, Ahmadu Bello University, Zaria, Nigeria

Date of Web Publication17-Feb-2012

Correspondence Address:
Abdullah A Abba
Department of Medicine, Ahmadu Bello University Teaching Hospital, P M B 06, Shika, Zaria, Kaduna State
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0331-3131.92949

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The identification of nitric oxide in exhaled breath and its role as a surrogate marker of eosinophilic inflammation of the airways led to rapid development in the area of its measurement. Standardized measurement techniques have been developed as well as simple, cheap, and reliable equipments. Although a number of factors have been identified as affecting its assay, fractional exhaled nitric oxide (FENO) can reliably be used to distinguish eosinophilic from non-eosinophilic airway inflammation. Unlike the other indirect measures of airway inflammation such as FEV1 reversibility and bronchoprovocative tests, FENO is noninvasive and gives a direct measure of inflammation. There are sufficient data supporting its role in the diagnosis of asthma, monitoring of disease, prediction of relapse, and level of compliance. Measurement of FENO has therefore made the transition from the bench to the bedside. Of recent, there are attempts at devising interpretative strategies for its use in day to day clinical practice.

Keywords: Asthma, diagnosis, management, nitric oxide

How to cite this article:
Abba AA, Adeiza MA. Exhaled nitric oxide in the diagnosis and management of bronchial asthma: From bench to bedside?. Ann Nigerian Med 2011;5:42-7

How to cite this URL:
Abba AA, Adeiza MA. Exhaled nitric oxide in the diagnosis and management of bronchial asthma: From bench to bedside?. Ann Nigerian Med [serial online] 2011 [cited 2021 Apr 18];5:42-7. Available from: https://www.anmjournal.com/text.asp?2011/5/2/42/92949

   Introduction Top

In 1987, Ignarro and Palmer and their coworkers independently demonstrated that the substance referred to as endothelium-derived relaxing factor had the same biological and chemical properties as nitric oxide (NO). [1],[2] The biology of NO was extensively studied during this period. [3] Later in 1991, Gustafsson confirmed the presence of this substance in exhaled air which subsequently led to the proclamation of the molecule as "the molecule of the year" by the journal Science in 1992 [4],[5] and the award of the Nobel Prize for science to the investigators. NO is a small, endogenous easily diffusible simple free radical. Mammals synthesize NO by way of the NO synthase (NOS) enzyme, which converts the amino acid L-arginine into L-citrulline and NO. [6] It acts as a biological mediator in a number of physiological processes in the body including smooth muscle relaxation, neurotransmission, apoptosis, immune regulation, and platelet inhibition. [7] In the lungs it plays a part in the pathophysiology of many conditions including asthma, chronic obstructive pulmonary disease, bronchiectasis, primary ciliary dyskinesia, pulmonary hypertension, infections, lung injury, and transplant. [8] It has been shown by many workers that the degree of eosinophilic inflammation in the airways is mirrored by the fraction of exhaled nitric oxide (FENO) in breath of humans and that the levels are elevated in asthmatics. [9],[10]

In asthma, there is no correlation between the degree of symptoms, physical signs, physiological measures of airway obstruction, and the severity of inflammation. [11],[12],[13],[14] Direct measures such as bronchial biopsy and bronchoalveolar lavage are invasive and not practical for routine use. The measurement of NO in exhaled breath by chemiluminescence and electrochemical analyzers has made it easy to apply this tool in the management of many respiratory disorders particularly in asthma where eosinophilic inflammation plays a predominant role. It therefore makes this marker of inflammation a valuable, noninvasive, and easily repeatable tool in the management of asthmatic adults and children. [15] Furthermore, there have been significant strides in the manufacture of portable, cheap, hand-held, and easy-to-use equipment for the determination of values of FENO. Such equipments are reliable and have yielded figures that are comparable to those obtained by using larger machines. [16],[17],[18] While not completely replacing other physiological measures, it is conceivable that the diagnosis, management, and even day to day monitoring of asthma will hinge on the measurement of FENO. This is because inflammation and its control is the cornerstone in the pathogenesis and management of asthma. This review outlines the methodology of assay, confounding factors, interpretation, and clinical utility of FENO as a biomarker in the management of asthma.

   Measurement of Fractonal Exhaled NO Top

Both the European Respiratory Society and the American Thoracic Society (ATS) have published the technical details of measurement of FENO and have regularly updated these documents. [19] NO in the airway reacts with ozone in a cooled chamber to form NO 2 . This photochemical reaction emits infrared light that can be detected by a photomultiplier tube with a linear response. Measurement can be done online, where the patient breathes directly into the analyzer, or offline where he breathes into a bag and the breath is analyzed later. The former is suitable for adults and children who can co-operate. Subject breathes NO-free air (<5 ppb) for 2-3 seconds before exhaling fully into the mouthpiece. Expiration is against a closed palate to avoid contamination by nasal NO. Expiratory flow rates have been shown to dramatically affect the FENO levels with levels rising at higher expiratory flow rates. [20],[21] The standard expiratory flow rate for online measurement is therefore set at 50 L/sec. A variability of no more than 10% over three measurements or no more than 5% over two measurements is recommended. Offline measurement has the advantage of remote collection with a convenient use of a centralized analyzer. It is, however, considered second choice as it does not allow for monitoring of flow rate and there is a possibility of contamination.

   Factors Affecting FENO Measurement Top

A number of factors affect the measurement of FENO and therefore the interpretation of values obtained may be difficult. In children, where there is age-body size relationship, the values of FENO bear a consistent positive correlation with age. In adults on the other hand, there are conflicting data. The largest study showed a 40% difference between the oldest group (over 64 years) and the youngest group (35-44 years) with FENO increasing with age. [22] Other workers have, however, found no relationship between age and FENO in adults. [23],[24]

There are also conflicting data on the effect of gender on measured FENO. While some studies show an increase in FENO in males to the tune of 25%, [23],[24] others show no difference when anthropometric factors are taken into consideration. [22],[25] A [more recent study by Taylor et al., however, showed lower values of about 25% among females. [26] The difference among females may well be as a result of differences in the airway size affecting flow rates, and therefore just an artifact.

Smoking and ingestion of alcohol have both been shown to reduce the level of FENO both acutely and on long-term basis. [27],[28] Conversely, the intake of nitrate-rich foods (such as lettuce and radishes), fats, antioxidants, and drinking of water and coffee tend to give higher levels of FENO. [29],[30],[31],[32] It is recommended to abstain from eating and drinking for at least 1 hour before measurement.

It is also important to obtain a proper drug history as a number of drugs have an effect on the level of FENO. Steroids, both oral and inhaled, as well as leukotriene-axis modifiers have been shown to reduce the levels of FENO. [33] Bronchodilatation as with use of beta-2 agonist increases the levels. [34] It is not certain whether there is a circadian rhythm in the levels of FENO, but it is advisable to take measurements at the same time of the day. [35] A number of respiratory maneuvers such as spirometry, sputum induction, and bronchoprovocation tend to decrease the levels. [36],[37] Therefore, reasonable time should be given between carrying out these maneuvers and measuring FENO.

   Normal Values of FENO Top

A number of studies have reported reference values of FENO in adults and children. [23],[24],[25],[38],[39],[40] Most of these studies vary in the numbers studied as well as the inclusion and exclusion criteria, thus limiting their value. In the largest study so far, even when individuals with atopy and asthma are excluded, the upper limit of normal ranges between 27 and 57 ppb depending on sex. [25] However, in patients with stable, well-controlled asthma, the FENO levels range between 22 and 44 ppb. [22] Clearly there is considerable overlap between the values of FENO in healthy subjects and those with stable asthma. Normal values therefore do not exclude asthma. This fact plus the confounding factors mentioned above limit the application of reference or normal values in routine clinical practice. It is more relevant to apply cutoff points rather than reference values in the interpretation of FENO measurements. These cutoff points have been mentioned below in relation to various clinical settings. For an individual therefore, the interpretation is determined by the context in which the measurement is made. Serial measurement of FENO values in stable and unstable state can be used in individual patient as "personal best" to determine the need to keep the dose of ICS the same, decrease or increase. Low FENO in the setting of an exacerbation calls for attention to other factors causing the exacerbation rather than eosinophilic inflammation.

   FENO in the Diagnosis of Aasthma Top

Alving et al. first described the relationship between asthma and exhaled NO in 1993 when they demonstrated a rise in FENO in asthmatics. [41] This has been confirmed by other studies [42],[43] and followed by hundreds of studies in the utility of FENO in the diagnosis of asthma. Salome et al. in a study of 306 adults demonstrated that airway hyper-responsiveness (AHR) defined as a dose of histamine that provoked a 20% fall in forced expiratory volume in one second (FEV1) equal to or less than 3.9 μmol of histamine or a positive bronchodilator response, correlated positively with the FENO levels. Atopic adults without AHR had significantly higher FENO levels than nonatopic adults without AHR suggesting that there is mild airway inflammation in atopic subjects. [44] Atopic asthma is characterized by an inflammatory infiltrate in the airways, with a predominance of mast cells and eosinophils. Many studies confirm that FENO levels correlate well with airway eosinophilia in induced sputum, [45] biopsy material, [46] and bronchoalveolar lavage fluid. [47] A direct relationship has also been observed with blood eosinophilia. [48] Elevated FENO is observed in conditions characterized by eosinophilic airway inflammation irrespective of the diagnosis. For example, it has been observed in patients who did not fulfill the criteria for asthma or whose asthma has been in remission for many years but who had eosinophilic bronchitis, [46],[49] and in atopic patients with allergic rhinitis but no asthma. [48],[50] It is therefore a reliable marker of airway eosinophilic inflammation but has limitations as a test for asthma. In various studies, FENO had a high predictive value for the diagnosis of asthma with a sensitivity of between 85% and 88% and a specificity of between 79% and 90%. [43],[51] The figures are comparable to induced sputum cell counts. In one of the studies, [51] FENO performed much better when compared with other "conventional" diagnostic tests indicating that in unselected cases most will have mild disease and normal lung function. A combination of raised FENO (>33 ppb) and abnormal spirometry had greater sensitivity (94%) and specificity (93%) for the diagnosis of asthma. [51],[52] It should however be noted that a patient may fulfill the criteria for the diagnosis of asthma and yet have normal values of FENO. This is especially so in nonatopic subjects. This is because the background pathology of asthma is often but not invariably due to eosinophilic inflammation. Therefore, FENO levels may be low in asthma where there is no eosinophilic inflammation. In a study of 115 adults, Franklin et al. demonstrated that elevated FENO was only associated with a phenotype characterized by atopy and increased AHR regardless of the presence of asthma or asthma-like symptoms. Thus, FENO measurements supplement rather than substitute the measurement for AHR in the diagnosis of asthma.

The ATS recently released guidelines recommending the use of the test for the diagnosis of eosinophilic airway inflammation and to support the diagnosis of asthma in situations where objective evidence is needed. [53] The test is also recommended in identifying patients with chronic respiratory symptoms possibly arising from airway inflammation that may be responsive to corticosteroids. According to this document, an FENO level of <25 ppb in adults or <20 ppb in children indicates that eosinophilic inflammation and responsiveness to steroids is not likely. On the other hand, a level >50 ppb in adults and >35 ppb in children and with symptoms indicates that response to corticosteroids is likely. A level between these two figures should be interpreted with caution and with reference to the clinical context.

   FENO in the Management of Asthma Top

Traditionally, asthma management is based on symptoms and spirometry. It is known however that the relationships between airway inflammation and symptoms and/or lung functions are weak. [11],[12],[13],[14] Measures of inflammation in the lungs have been used to optimize the dose of steroids treatment. Green et al. showed that using a sputum eosinophil level of <1% and >3% to reduce or increase the dose of inhaled corticosteroids (ICS), respectively, led to a 32% reduction in the rate of exacerbations. [54] Similarly, Jayaram et al. have shown that adjusting ICS dose to maintain sputum eosinophil to <2% resulted in a 49% reduction in exacerbations and a 2/3 reduction in the need for intervention with prednisolone. [55] It is therefore expected that FENO measurement, being a marker for eosinophilic inflammation in the lungs, will serve a useful objective purpose in this regard. Several studies have been carried out to determine the value of FENO measurement in the management of asthma with variable results. These studies varied in several ways: definition of asthma exacerbations cutoff levels of FENO, the way these levels are used to adjust therapy, and the duration of study. For example, Smith et al. used a single cutoff point of 35 ppb to adjust the dose of ICS in 94 adults and showed a 40% reduction in ICS without significant increase in exacerbations. [56] On the other hand, Pijnenburg et al. used a 30 ppb cutoff point in 85 children and showed no difference in the use of ICS between the two groups. [57] Recently, Powel et al. using a cutoff point of >30 ppb in 220 pregnant women showed that asthma exacerbations during pregnancy, quality of life, and neonatal hospitalizations can be significantly reduced with a validated FENO-based treatment algorithm. [58]

Clearly, the most important reason for FENO monitoring is need for the reduction of steroids in patients who are well controlled. This has been shown to be possible in the studies quoted above. It is, however, not clear if adjusting the dose of ICS upward is beneficial in patients with persistently elevated FENO, particularly if they are asymptomatic. It is often not possible to normalize FENO levels in such patients. [59] In a recent meta-analysis of six studies as a follow-up to an earlier review, Petsky et al. concluded that the role of utilizing exhaled NO to tailor the dose of ICS cannot be routinely recommended for clinical practice at this stage and remains uncertain. [60] On the other hand, the same authors undertook a meta-analysis of three studies of patients with asthma and concluded that tailored asthma interventions based on sputum eosinophils are beneficial in reducing the frequency of asthma exacerbations in adults with asthma. [61] Further studies are needed in this area and particularly in defining cutoff points of FENO in which to increase, decrease, or keep the dose of ICS the same.

Another area of importance in the management of asthma is determining impending loss of control. Reduction in peak flow rates tends to coincide with acute exacerbations rather than precede them and therefore are of little value in predicting exacerbations. Harkins et al. reported that an increase in FENO predicted an exacerbation within the next 2 weeks. [62] Jatakanon on the other hand reported that changes in sputum eosinophils are of better predictive value than FENO. [63] Other workers, however, observed that AHR to hypertonic saline, sputum eosinophils, and FENO measurement all ranked similar as predictors of loss of control in 78 asthmatics after withdrawal of steroids. [64]

In the context of response or otherwise to corticosteroids, the ATS guidelines offer the following interpretation and recommendation. FENO increases of 20% or more for values of >50 ppb or 10 ppb or more for values less than 50 ppb indicate a significant increase from one visit to the next. Conversely, reductions >20% (or 10 ppb) indicate significant response to anti-inflammatory therapy. [53]

   Conclusions Top

The identification and measurement of exhaled NO has generated considerable research interest in its application in many respiratory diseases, particularly bronchial asthma. There is strong evidence that it can be used in differentiating between eosinophilic and noneosinophilic inflammation of the airways. Although there are many confounding factors in its measurement, the standardization of techniques has allowed for acceptance of cutoff points useful in the diagnosis and management of asthma. Further work is obviously needed to strengthen the evidence in favor of its routine application in clinical practice.

   References Top

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