Clinical utility of exhaled nitric oxide fraction in the management of asthma and COPD

Steve W. Turner, Anne B. Chang, Ian A. Yang
Breathe 2019 15: 306-316; DOI: 10.1183/20734735.0268-2019

Abstract

Exhaled nitric oxide fraction (FENO) values can be easily measured using portable analysers and are a surrogate marker of airway eosinophilia. FENO may be useful in diagnosing and monitoring conditions characterised by airway eosinophilia, i.e. asthma and possibly COPD. Many factors other than asthma and COPD affect FENO, especially atopy, which is associated with elevated FENO. One guideline recommends that FENO should be used as part of the diagnostic pathway for asthma diagnosis in adults and children aged >5 years. The role of FENO in monitoring asthma is even less clear, and most guidelines do not recommend its use outside of specialist asthma clinics. Currently, FENO is not recommended for diagnosis or monitoring of COPD. Although FENO is starting to find a place in the management of asthma in children and adults, considerably more research is required before the potential of FENO as an objective measurement in asthma and COPD can be realised.

Key points

  • For individuals aged ≥12 years, FENO is not recommended by all guidelines as a test to diagnose asthma (recommended only by the UK National Institute for Health and Care Excellence guideline for asthma symptoms, which are likely to respond to corticosteroid treatment).

  • FENO may be used in conjunction with other investigations to diagnose asthma in 5–16-year-olds where there is diagnostic uncertainty, but further evidence is required.

  • FENO is not recommended as a routine test to monitor all patients with asthma or to titrate asthma treatment.

  • FENO is not recommended for routine clinical testing in adults with COPD.

  • FENO may be useful to identify patients with COPD who could benefit from the use of inhaled corticosteroids (asthma–COPD overlap).

Educational aims

  • To understand what factors other than asthma and COPD affect FENO

  • To understand the current controversies in the application of FENO to diagnosis and management of asthma in children

  • To understand the current controversies in the application of FENO to diagnosis and management of asthma and COPD in adults

Abstract

Exhaled nitric oxide fraction (FENO) may be a useful test for diagnosing asthma in adults and in children but is currently not recommended for monitoring all patients with asthma or COPD
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30 years ago, it was realised that nitric oxide was protean and regulates almost every bodily function, including neuronal function important in laying down memories and regulating the tone of muscles in the walls of the coronary artery. Subsequent research into the role of nitric oxide in various diseases was associated with a rapid increase the nitric oxide literature [1]. Nitric oxide is produced by nitric oxide synthetase (NOS), which is a family of enzymes [1]. Briefly, NOS can be considered as having two isoforms: constitutive (cNOS), which constantly produces relatively small quantities of nitric oxide; and inducible (iNOS), which responds to various stimuli and is able to quickly produce large quantities of nitric oxide. iNOS is considered more important than cNOS to various diseases, including those of the respiratory system.

Why might exhaled nitric oxide fraction be a useful marker of respiratory disease?

In the respiratory tract, nitric oxide is produced by a variety of structural and inflammatory cells, including eosinophils, macrophages, epithelial cells and smooth muscle cells [2]. During inflammation, the concentration of nitric oxide increases in the lungs and nitric oxide can be measured in the exhaled breath as the exhaled nitric oxide fraction (FENO). Elevated FENO levels generally reflect eosinophilic airway inflammation [2] and patients likely to benefit from corticosteroids [2]; monitoring levels of eosinophilic airway inflammation using FENO as a noninvasive surrogate should theoretically aid clinical management [2, 3]. In the current era, in which we aspire to personalised medicine [4], FENO may be crucial to categorising asthma pheno/endotypes, although these is remain to be determined. This review explores the current thinking of how FENO should be applied in the respiratory clinical setting, and focuses on the potential role of FENO in diagnosing and monitoring asthma and COPD.

Currently, in the clinical setting, eosinophilia can be defined in blood, lower airway cells (from sputum or bronchoalveolar lavage) and FENO levels [5]. As recently highlighted, these measures do not always correlate in children, especially in young children [5]. In children with stable asthma, induced sputum eosinophil counts vary over time and have a variable relationship with FENO levels, with discordant values in 25% of paired sputum–FENO measurements [6]. Furthermore, induced sputum-based phenotypes [7] vary considerably in the same individual over time in mild–moderate and severe asthma in children. Nevertheless, measuring FENO levels is increasingly available and advocated. As it adds an additional cost of ∼US$8.50 per test (which equates to ∼US$17.00 per occasion, excluding the cost of labour) above current universal practice [2], evidence for its application in routine clinical practice requires evaluation.

How is FENO measured?

Nasal and exhaled breath nitric oxide can be measured using widely available nitric oxide analysers. Nasal nitric oxide is not used for asthma or COPD-related diagnosis or monitoring and hence, this article is restricted to FENO.

Like other lung function tests, standardised methods of measuring FENO need to be adhered to for reliable results [2]. The online test is simple, requiring the individual to exhale to reach an acceptable plateau with online visual feedback and tests are performed at least twice to achieve results within 10% of each other [2]. With the wide availability of portable FENO analysers, the offline method, where breath was collected in a bag and then, at a later stage, taken to a machine and analysed, is now not used in the clinical setting

FENO levels provided by nitric oxide analysers are not equivalent, with differences as large as 30% [8]. A study comparing FENO levels measured by NIOX VERO (Aerocrine AB, Solna, Sweden) described significantly lower values than that measured with the NOA280i (Sievers Instruments, Boulder, CO, USA), where the median values were 29 parts per billion (ppb) and 41 ppb respectively [8], i.e. the portable NIOX values were 30% lower than the standard chemiluminescence stationary electrochemical analyser; and between portable FENO analysers, there was variability among devices (limits of agreement is up to 10 ppb) [9]. Portable FENO analysers have cartridges which need changing after a preset number of measurements are made, and different cartridges can deliver slightly different FENO concentrations when the same patient uses the same analyser.

Factors other than asthma that affect FENO

FENO levels are affected by various external factors [2] (e.g. nitric oxide analyser variability, air pollutants, season and ambient nitric oxide). In addition to the external factors, clinicians need to be cognisant of the many factors that influence these levels above and beyond clinical disease when using and/or interpreting studies involving FENO and its levels in patients [10]. Atopy is an important factor that is associated with elevated FENO independent of asthma. Other factors include ethnicity, height, age, recent dietary intake, exercise and tobacco exposure. Inhaled corticosteroids (ICS) and leukotriene receptor antagonists both lower FENO [2]. Interestingly, age is the only factor that many guidelines suggest should be considered when interpreting FENO [2, 9].

Interpretation of FENO

FENO can be interpreted in at one of at least three ways:

  • As a percentage of the predicted value for the population, but this is not a preferred method [2], in part due to a lack of data and in part due to the many factors (previously discussed) that may affect FENO independent of asthma.

  • As a single “one-size fits all” cut-off value, and this is currently the preferred value [2] although there are some limitations to this including the low values in people with nonatopic asthma and individuals with values close to a single cut-off may find their treatment varies as FENO values fall just above or just below the threshold concentration.

  • As a use percentage change from a previous value, and this may have merit for monitoring of asthma over time [2].

  • Currently, FENO results are classified as either normal, intermediate or abnormal positive for diagnostic of eosinophilic airway inflammation (note that this is not diagnostic of asthma). FENO values below the reference (cut-offs) indicate a likely absence of eosinophilic inflammation and a lower likelihood of response to corticosteroids [2]. Importantly, these statements are acknowledged to be based on low-quality evidence [2] and several guidelines interpret the available literature in different ways an recommend different cut-offs in adults and children [2, 9, 11, 12] (table 1).

View this table:
Table 1

A summary of the recommended FENO cut-off values for use in asthma diagnosis and management from international guidelines

Exhaled nitric oxide in childhood asthma

Feasibility

FENO can be measured using commercially available equipment in most children aged ≥6 years and values are reproducible over a 24-h period [13]. Unfortunately, at present, although the challenge of diagnosing asthma and the overall burden of asthma symptoms is in children aged 5 years and younger, FENO cannot be measured outside of research setting in this age group.

FENO and asthma diagnosis

Epidemiological papers published since 1997 [14] that have described elevated FENO in children with asthma compared individuals with established asthma to controls. Although these studies provided proof of the concept that FENO may be useful in diagnosing asthma, they do not provide valid cut-off FENO values for asthma diagnosis. Comparing differences in FENO between groups who have “typical” asthma and controls does not help in the clinical encounter with a child who may have asthma. The absence of a gold standard diagnostic test for asthma also gives researchers a challenge in establishing the role of FENO in diagnosing asthma.

There have been at least four studies that measured FENO in children being considered for a diagnosis of asthma as part of observational, “real-life” asthma diagnosis programmes in hospital clinics [15–18]. These studies identified FENO cut offs of between 16 and 22 ppb as having the best combination of sensitivity and specificity for a later asthma diagnosis. An important confounder for interpreting FENO in the context of asthma diagnosis is prior asthma treatment since both ICS [19] and leukotriene receptor antagonists [20] reduce FENO by up to one third. The study with the highest cut-off was the only one to include only steroid-naïve children [16], whereas other studies included 11% [18] to 33% [15] on ICS or children who had their ICS withheld for 4 weeks [17].

As previously described, there is uncertainty about which precise cut-off value should be applied to asthma diagnosis in children but despite their limitations, these four studies would support a cut off value of 15–20 ppb for diagnosing asthma. A key question for clinicians to consider after having taken a history and then measuring FENO is whether they believe an asthma diagnosis is likely or not; if the history suggests that asthma is likely then a FENO value >15 ppb could be supportive of a diagnosis and if asthma seems unlikely, then a FENO value <20 ppb would be helpful in excluding an asthma diagnosis. Two European Respiratory Society task forces are currently exploring, from different perspectives, the role of FENO in diagnosing childhood asthma and, collectively, will bring more clarity to clinicians in this area.

FENO and monitoring childhood asthma

In principle, FENO offers everything that an objective test should have for monitoring asthma in children since it has the following characteristics:

  • sensitivity to symptoms

  • sensitivity to treatment

  • a known biomarker for airway eosinophilia

  • reproducibility

  • results are available almost immediately

  • apparatus is portable and affordable

Not surprisingly, at least eight clinical trials [10] have evaluated the role of FENO in guiding treatment to reduce asthma exacerbations and improve asthma control. There were important differences between these trials in several aspects, as described elsewhere [10], summarised in table 2 and discussed here.

  • Inclusion criteria: atopy is a key determinant of FENO and four trials selected only participants who were atopic; by including a mix of participants, it is not surprising that the results were heterogeneous.

  • Primary outcomes: the primary outcome determines a study sample size, and such outcomes include exacerbations, control (as evidenced by a symptom score) and change in lung function; the presence of different primary outcomes makes it hard to directly compare results between studies.

  • Population size: this varied between 47 and 546 with a median of 88 participants; many trials are likely to have been underpowered and reported false-negative findings.

  • FENO values used to trigger treatment changes: the trials were published between 2005 and 2015, and during this decade, our understanding of FENO changed. It was increasingly recognised that FENO behaves differently to percentage of predicted forced expiratory volume in 1 s (FEV1); for example, FENO is much more variable than FEV1 % pred and worse asthma outcomes are associated with increasing FENO but falling FEV1 % pred. The earlier studies used a single FENO value to trigger changes in treatment whereas some later studies had a “sliding scale” and used two or more values, and one had different values for nonatopic and atopic children. The pioneering trials may have been too simplistic when applying FENO to treatment.

  • Inclusion of FEV1: three trials used a cut-off of FEV1 <80% pred to influence treatment decisions in addition to rising FENO values. This means that decision making in these trials was not solely influenced by FENO.

  • Treatment changes made: studies had different treatment steps triggered by different FENO cut-offs. Some studies only changed ICS dose and different dose changes were applied.

View this table:
Table 2

Characteristics of trials that have used FENO to guide treatment in children with asthma

Despite these considerable differences, these trials collectively provide evidence that asthma treatment guided by FENO reduces the risk of asthma attacks [10, 29] and the mechanism for this might be due to an increased in ICS [10]. There is no evidence that asthma control (a primary outcome in many studies) was improved in these trials [29], and it is increasingly recognised that there are different factors driving asthma control compared to exacerbations [30]. Despite providing proof of the concept that FENO has a role in managing childhood asthma, the differences between the trials mean that there is considerable uncertainty as to how FENO can be applied to clinical practice.

The answer to question “when should FENO trigger a change in asthma treatment?” is still far from clear, and probably depends on whether the outcome is asthma control or exacerbations. A very cautious recommendation in the American Thoracic Society (ATS) guideline states “We suggest using the following values to determine a significant increase in FENO: greater than 20% for values over 50 ppb or more than 10 ppb for values lower than 50 ppb from one visit to the next” [2].

At present, FENO is considered a useful tool in diagnosing asthma in children (or symptoms that are responsive to treatment with corticosteroids) [2, 9]. In the absence of robust evidence that links a certain change in FENO to a certain change in treatment to an improved asthma outcome (exacerbation or control), FENO is not recommended for monitoring asthma in all children [9, 12]. Looking forward, the absence of evidence for the potential benefit of FENO to diagnose and monitor asthma needs to be addressed by our community. We are hopefully about to step into an era where objective measurements such as FEV1 and FENO are used to stratify treatment (perhaps alongside objective measurements of treatment adherence) with the goal of improving symptoms, reducing exacerbation and reducing treatment.

Exhaled nitric oxide in adult respiratory medicine

FENO in adults with asthma

The ATS guideline outlines potential uses for FENO in adults with asthma, including identifying eosinophilic airway inflammation, predicting responsiveness to ICS, monitoring airway inflammation and detecting nonadherence to ICS [2]. Since the publication of these guidelines in 2011, additional studies have shed further light on the utility of FENO testing in clinical practice.

Is FENO useful for the diagnosis of asthma in adults?

Asthma remains a clinical diagnosis in adults supported by evidence of variable airflow limitation, so supplementary testing may be useful for increasing the diagnostic probability of asthma in people who present with variable respiratory symptoms. In a systematic review of the use of FENO for the diagnosis of asthma in adults, FENO ≥40 ppb had a sensitivity of only 41% but a high specificity of 93%, with likelihood ratio for a positive test (high FENO) of 6.18 (95% CI 3.64–10.47) [31]. Overall, there was evidence for moderate accuracy for the diagnosis of asthma in adults (i.e. a high FENO can rule in asthma but may not be able to rule out asthma).

FENO and asthma phenotypes

Elevated FENO correlates with the presence of specific asthma phenotypes. Consequently, FENO testing may be useful to characterise treatable traits in asthma.

Sputum eosinophilia

Eosinophilic airway inflammation is an asthma phenotype that is more likely to be steroid responsive. Biomarkers to predict sputum eosinophilia were evaluated in a study of 336 adults with asthma in the Netherlands. The area under the curve for FENO was 0.82, compared with 0.83 for blood eosinophils and 0.69 for total serum IgE. Hence, FENO and blood eosinophils were similar in accuracy (and more accurate than IgE) for predicting sputum eosinophilia. Furthermore, in a prospective study of 144 adult patients with asthma in Denmark, high FENO (>50 ppb) had moderate positive predictive value (77%) for sputum eosinophilia of >3%, although one-third of patients with sputum eosinophilia >3% had intermediate FENO values (25–50 ppb) [32].

Cough-variant asthma

This asthma phenotype is represented by chronic cough, rather than wheeze or breathlessness, and often characterised by type 2 inflammation. FENO has moderate, but not high, accuracy for detection of cough-variant asthma.

Nonspecific respiratory symptoms

In primary care, patients may present with symptoms resembling asthma but not meet the clinical criteria for asthma and not have a previous diagnosis of asthma, presenting a diagnostic challenge. FENO could add to the diagnostic testing for these patients. In a randomised controlled trial (RCT) in the UK and Singapore, 517 patients with nonspecific respiratory symptoms, but without a prior history of asthma or bronchodilator reversibility, were randomised to inhaled beclomethasone versus placebo for 4 weeks [33]. In the per-protocol analysis (214 patients), those with a greater baseline FENO had a higher improvement in asthma symptoms when on inhaled steroids, compared to the placebo group, as well as reduced cough and improved FEV1. As a simple and noninvasive tool, FENO measurement may be helpful for clinical decision making in primary care about whether to trial an ICS in patients with asthma-like symptoms who do not initially meet bronchodilator reversibility and other criteria.

Is FENO useful for the management of asthma in adults?

Current asthma clinical guidelines recommend assessment and monitoring of symptoms, exacerbations and lung function tests to optimise asthma management in individual patients. Whether routinely adding measurements of type 2 inflammation is beneficial, beyond clinical and physiological assessment, is still a matter of intense debate.

A Cochrane systematic review examined the benefits of tailored asthma management using FENO levels for adults with asthma, compared with symptom- or guideline-based approaches [34]. Seven studies of 1700 patients were reviewed. Meta-analysis demonstrated a reduction in the number of patients with one or more exacerbations in the FENO-guided approach (OR 0.60, 95% CI 0.43–0.84; moderate quality of evidence), translating to a number needed to treat to benefit over 52 weeks of 12 (95% CI 8–32). In contrast, there were no differences in other outcomes such as rates of hospitalisation, symptom scores, FENO levels or ICS dose. The authors' conclusions were that widespread FENO use for adults with asthma could not be recommended; however, this approach may be useful in patients with more frequent exacerbations. Management based on sputum analysis of airway eosinophilia similarly reduces exacerbations but does not improve asthma control or spirometric measures.

Role of FENO in patients with severe asthma

FENO testing may have a useful role in severe asthma clinics, where additional asthma phenotyping is helpful for risk stratification and tailored management. In a study of 132 adults with severe allergic asthma in Italy, patients with FENO ≥30 ppb had worse asthma symptoms and quality of life, and higher rates of hospital admission, than patients with FENO <30 ppb [35].

Oral corticosteroid (OCS)-dependent patients with severe asthma require further treatment choices for better asthma control. The question arises as to how responsive biomarkers are in these patients, especially given chronic OCS use.
FENO responds to a 7-day course of oral prednisolone, and then this and other biomarkers (blood eosinophils, periostin, interleukin (IL)-5 and IL-13) return to baseline by 1 month after an oral steroid burst.

FENO may be responsive to treatment with some biologic agents in severe asthma.

Omalizumab

In a subgroup analysis (n=394) of an RCT, patients receiving the anti-IgE monoclonal antibody omalizumab had a small reduction of FENO (mean change –4 ppb) compared to those receiving placebo [36], but reduction in exacerbation rates was much greater in the high-FENO group receiving omalizumab than in the low-FENO group [37]. FENO levels (high (≥25 ppb) versus low (<25 ppb)) do not appear to predict responders to omalizumab.

Mepolizumab

There was no statistically significant change in FENO with use of mepolizumab, an anti-IL-5 monoclonal antibody for severe eosinophilic asthma, despite a substantial reduction in blood eosinophil counts.

Lebrikizumab

Use of lebrikizumab, an anti-IL-13 monoclonal antibody, reduced FENO by 19% at week 12, compared to a reduction of 10% with placebo [38], consistent with the role of IL-13 in nitric oxide production in the airways.

Dupilumab

Dupilumab, an anti-IL-4 and anti-IL-13 monoclonal antibody, reduces FENO, compared to placebo, and a greater reduction in exacerbations occurs with baseline FENO ≥25 than <25 ppb.

Clinical recommendations regarding FENO in adults with asthma

The 2017 UK National Institute for Health and Care Excellence guidelines for asthma recommend use of FENO testing in adults with asthma [9]. In contrast, the 2019 Global Strategy for Asthma Management and Prevention [11] from the Global Initiative for Asthma (GINA) does not currently recommend FENO-guided treatment for all adults with asthma. The GINA strategy notes that elevated FENO can be used to guide initiation of ICS in adults with asthma, but that ICS should not necessarily be withheld in patients with suspected asthma despite a low initial FENO measurement. The GINA strategy also suggests that FENO can be used in adult patients with moderate to severe asthma, in experienced severe asthma centres, as a potential biomarker to predict response to certain biologics.

Future developments

Further definition of the clinical utility of FENO in a range of mild, moderate and severe asthma phenotypes should be undertaken in large prospective studies. In addition, characterisation of interacting clinical and biological factors on FENO levels should be undertaken, including the role of the lung microbiome in influencing FENO. Comparative studies are needed to test novel molecular biomarkers such as sputum gene expression as predictors of asthma outcomes [39] compared to FENO and other inflammatory markers. Remote, web-based monitoring of suppression of FENO with ICS treatment may improve adherence issues in patients with severe asthma.

FENO in adults with COPD

Role of FENO in patients with COPD

Some patients with COPD may have type 2 inflammation, which increases during exacerbations. Furthermore, increased blood eosinophils may predict ICS-responsiveness in patients with COPD; hence, there has been some interest in using FENO to characterise COPD phenotypes.

COPD versus non-COPD controls

Patients with COPD may have a mildly elevated FENO compared to non-COPD, healthy controls.

Frequent exacerbators

FENO was used to predict frequency of exacerbations in 226 stable COPD patients in Spain. Patients with FENO consistently ≥20 ppb over a 12-month period had a greater risk of exacerbations [40].

Exacerbations

In a study of 163 patients during a COPD exacerbation, elevated FENO was associated with higher sputum and blood eosinophil levels, although the sensitivity and specificity of FENO were relatively low for sputum eosinophilia (sensitivity 65% and specificity 56% for sputum eosinophilia with FENO ≥17.5 ppb) [41].

Hospitalisations

In a cohort study of 50 patients hospitalised with a COPD exacerbation, patients with asthma–COPD overlap had higher FENO levels than other COPD phenotypes. FENO correlated with blood eosinophils at admission, but not when measured at discharge or stability [42].

Response to ICS treatment

A systematic review of five studies of 171 patients with COPD found a decrease in FENO in patients treated with ICS, predominantly in former smokers [43]. COPD patients with high FENO (defined as ≥25 ppb), when given ICS/long-acting β2-agonists, had the greatest reduction in FENO and largest improvement in COPD Assessment Test score, compared to those receiving long-acting muscarinic antagonists or low-FENO patients [44].

Asthma–COPD overlap

Patients with COPD may have features of asthma such bronchodilator reversibility and eosinophilia. In 80 patients with severe COPD (Global Initiative for Chronic Obstructive Lung Disease grade 4, group D) in Germany, 33% had FENO ≥22.5 ppb [45]. In a study of 121 patients with COPD in Japan, FENO was higher in patients with features of asthma–COPD overlap (median 24.5 ppb) than in patients with COPD (median 16.0 ppb) [46]. When combined with blood eosinophil count, a FENO level of ≥25 ppb, when combined with blood eosinophil count ≥250 per μL, had 96% specificity for asthma–COPD overlap.

Clinical recommendations regarding FENO in COPD

FENO testing is not routinely recommended in international or national clinical guidelines for patients with COPD alone. However, COPD patients may, at times, have some features of asthma, or some patients may have coexisting asthma and COPD (asthma–COPD overlap), when FENO may be more useful to identify a potential asthma component, as a treatable trait.

Future FENO research in adults and children

There is currently an absence of evidence for clinicians to confidently apply FENO into routine clinical practice. There are many chronic noncommunicable diseases where there is a “standalone” test for diagnosis and monitoring (e.g. blood pressure for hypertension and blood glucose for diabetes) but currently, FENO is not likely to be a standalone test for airway disease. Instead, FENO is likely to be part of an overall evaluation of symptoms and objective measurements for the diagnosis and stratification of treatment for airway disease.

Self-assessment questions

1) In adult patients with asthma, which one of the following statements is true?

  • a. A low FENO level can rule out asthma.

  • b. All adult patients with asthma and sputum eosinophilia have high FENO >50 ppb.

  • c. All biologic agents for asthma significantly reduce FENO levels.

  • d. FENO testing in adults with asthma leads to a reduction in rates of hospitalisation.

  • e. Patients with nonspecific respiratory symptoms and high FENO may show clinical response to ICS.

2)In patients with COPD, for which of the following could FENO testing potentially be useful for?

  • a. Detecting type I inflammation in COPD airways.

  • b. Diagnosing severe emphysema.

  • c. Diagnosing viral exacerbations.

  • d. Identifying great likelihood of asthma–COPD overlap.

  • e. Predicting response to long-acting bronchodilators.

3)Increased FENO levels occur in all the following situations except?

  • a. Child with allergic rhinitis

  • b. Post-exertion.

  • c. Diagnosing respiratory viral exacerbations.

  • d. During an infection.

  • e. African Americans.

4)In children, for which of the following is FENO clinically useful?

  • a. Screening for asthma

  • b. Definitive diagnoses of asthma

  • c. Predicting risk of future exacerbation

  • d. Predicting airway obstruction

  • e. Monitoring asthma in a small subset of children with asthma

Suggested answers

  • 1) e.

  • 2) d.

  • 3) d.

  • 4) e.

Footnotes

  • Conflict of interest: S.W. Turner has received apparatus at no cost from Circassia (and formerly Aerocrine) for measuring nitric oxide in three research studies.

  • Conflict of interest: A.B. Chang reports grants from National Health and Medical Research Council, Australia related to the submitted work (multiple grants relating to cough, bronchiectasis and PBB). Other grants and interests from GSK (member of a data monitoring committee relating to an unlicensed vaccine), Up to Date (author of sections on paediatric cough) and BMJ Evidence Centre (author of two chapters on paediatric asthma with monies received (to Institution)) are outside the submitted work.

  • Conflict of interest: I.A. Yang has nothing to disclose.

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References

  1. ↵
    1. Nathan C,
    2. Xie QW
    . Nitric oxide synthases: roles, tolls, and controls. Cell 1994; 78: 915–918. doi:10.1016/0092-8674(94)90266-6
    OpenUrlCrossRefPubMed
  2. ↵
    1. Dweik RA,
    2. Boggs PB,
    3. Erzurum SC, et al.
    An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications. Am J Respir Crit Care Med 2011; 184: 602–615. doi:10.1164/rccm.9120-11ST
    OpenUrlCrossRefPubMed
  3. ↵
    1. Petsky HL,
    2. Cates CJ,
    3. Lasserson TJ, et al.
    A systematic review and meta-analysis: tailoring asthma treatment on eosinophilic markers (exhaled nitric oxide or sputum eosinophils). Thorax 2012; 67: 199–208. doi:10.1136/thx.2010.135574
    OpenUrlAbstract/FREE Full Text
  4. ↵
    1. Pavord ID,
    2. Beasley R,
    3. Agusti A, et al.
    After asthma: redefining airways diseases. Lancet 2018; 391: 350–400. doi:10.1016/S0140-6736(17)30879-6
    OpenUrlCrossRefPubMed
  5. ↵
    1. Bush A
    . Pathophysiological mechanisms of asthma. Front Pediatr 2019; 7: 68. doi:10.3389/fped.2019.00068
    OpenUrl
  6. ↵
    1. Fleming L,
    2. Tsartsali L,
    3. Wilson N, et al.
    Longitudinal relationship between sputum eosinophils and exhaled nitric oxide in children with asthma. Am J Respir Crit Care Med 2013; 188: 400–402. doi:10.1164/rccm.201212-2156LE
    OpenUrlCrossRefPubMed
  7. ↵
    1. Fleming L,
    2. Tsartsali L,
    3. Wilson N, et al.
    Sputum inflammatory phenotypes are not stable in children with asthma. Thorax 2012; 67: 675–681. doi:10.1136/thoraxjnl-2011-201064
    OpenUrlAbstract/FREE Full Text
  8. ↵
    1. Tanabe Y,
    2. Harada N,
    3. Ito J, et al.
    Difference between two exhaled nitric oxide analyzers, NIOX VERO electrochemical hand-held analyzer and NOA280i chemiluminescence stationary analyzer. J Asthma 2019; 56: 167–172. doi:10.1080/02770903.2018.1439953
    OpenUrl
  9. ↵
    National Institute for Health and Care Excellence. Asthma: diagnosis, monitoring and chronic asthma management. www.nice.org.uk/guidance/ng80. 2017. Date last accessed: January 28, 2018.
  10. ↵
    1. Turner S
    . Exhaled nitric oxide and the management of childhood asthma – yet another promising biomarker “has been” or a misunderstood gem. Paediatr Respir Rev 2015;
    16: 88–96.
    OpenUrl
  11. ↵
    Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. https://ginasthma.org/gina-reports/. 2019. Date last accessed: July 26, 2019.
  12. ↵
    British Thoracic Society and Scottish Intercollegiate Guidelines Network. SIGN 158. The British Guideline on the Management of Asthma. www.brit-thoracic.org.uk/quality-improvement/guidelines/asthma/. 2019. Date last accessed: July 27, 2019.
  13. ↵
    1. Napier E,
    2. Turner SW
    . Methodological issues related to exhaled nitric oxide measurement in children aged four to six years. Pediatr Pulmonol 2005; 40: 97–104. doi:10.1002/ppul.20249
    OpenUrlCrossRefPubMed
  14. ↵
    1. Nelson BV,
    2. Sears S,
    3. Woods J, et al.
    Expired nitric oxide as a marker for childhood asthma. J Pediatr 1997; 130: 423–427. doi:10.1016/S0022-3476(97)70204-X
    OpenUrlCrossRefPubMed
  15. ↵
    1. Sivan Y,
    2. Gadish T,
    3. Fireman E, et al.
    The use of exhaled nitric oxide in the diagnosis of asthma in school children. J Pediatr 2009; 155: 211–216. doi:10.1016/j.jpeds.2009.02.034
    OpenUrlCrossRefPubMed
  16. ↵
    1. Woo S,
    2. Lee J,
    3. Kim H, et al.
    Utility of fractional exhaled nitric oxide (FENO) measurements in diagnosing asthma. Respir Med 2012; 106: 1103–1109. doi:10.1016/j.rmed.2012.03.022
    OpenUrlCrossRefPubMed
  17. ↵
    1. Brouwer AFJ,
    2. Visser CAN,
    3. Duiverman EJ, et al.
    Is home spirometry useful in diagnosing asthma in children with nonspecific respiratory symptoms? Pediatr Pulmonol 2010; 45: 326–332.
    OpenUrlPubMed
  18. ↵
    1. Grzelewski T,
    2. Witkowski K,
    3. Makandjou-Ola E, et al.
    Diagnostic value of lung function parameters and FeNO for asthma in schoolchildren in large, real-life population. Pediatr Pulmonol 2014; 49: 632–640. doi:10.1002/ppul.22888
    OpenUrlCrossRefPubMed
  19. ↵
    1. Beck-Ripp J,
    2. Griese M,
    3. Arenz S, et al.
    Changes of exhaled nitric oxide during steroid treatment of childhood asthma. Eur Respir J 2002; 19: 1015–1019. doi:10.1183/09031936.02.01582001
    OpenUrlAbstract/FREE Full Text
  20. ↵
    1. Montuschi P,
    2. Mondino C,
    3. Koch P, et al.
    Effects of a leukotriene receptor antagonist on exhaled leukotriene E4 and prostanoids in children with asthma. J Allergy Clin Immunol 2006; 118: 347–353. doi:10.1016/j.jaci.2006.04.010
    OpenUrlCrossRefPubMed
    1. Fritsch M,
    2. Uxa S,
    3. Horak FJ, et al.
    Exhaled nitric oxide in the management of childhood asthma: a prospective 6-months study. Pediatr Pulmonol 2006; 41: 855–862.doi:10.1002/ppul.20455
    OpenUrlCrossRefPubMed
    1. Peirsman EJ,
    2. Carvelli TJ,
    3. Hage PY, et al.
    Exhaled nitric oxide in childhood allergic asthma management: a randomised controlled trial. Pediatr Pulmonol 2014; 49: 624–631.doi:10.1002/ppul.22873
    OpenUrlCrossRefPubMed
    1. Petsky HL,
    2. Cates CJ,
    3. Lasserson TJ, et al.
    A systematic review and meta-analysis: tailoring asthma treatment on eosinophilic markers (exhaled nitric oxide or sputum eosinophils). Thorax 2012; 67: 199–208.doi:10.1136/thx.2010.135574
    OpenUrlAbstract/FREE Full Text
    1. Pijnenburg MW,
    2. Bakker EM,
    3. Hop WC, et al.
    Titrating steroids on exhaled nitric oxide in children with asthma: a randomized controlled trial. Am J Respir Crit Care Med 2005; 172: 831–836.doi:10.1164/rccm.200503-458OC
    OpenUrlCrossRefPubMed
    1. Pike K,
    2. Selby A,
    3. Price S, et al.
    Exhaled nitric oxide monitoring does not reduce exacerbation frequency or inhaled corticosteroid dose in paediatric asthma: a randomised controlled trial. Clin Respir J 2013; 7: 204–213.doi:10.1111/j.1752-699X.2012.00306.x
    OpenUrlCrossRefPubMed
    1. Szefler SJ,
    2. Mitchell H,
    3. Sorkness CA, et al.
    Management of asthma based on exhaled nitric oxide in addition to guideline-based treatment for inner-city adolescents and young adults: a randomised controlled trial. Lancet 2008; 372(9643): 1065–72.doi:10.1016/S0140-6736(08)61448-8
    OpenUrlCrossRefPubMed
    1. Verini M,
    2. Consilvio NP,
    3. Di Pillo S, et al.
    FeNO as a marker of airways inflammation: the possible implications in childhood asthma management. J Allergy (Cairo) 2010; 691425.doi:10.1155/2010/691425
    1. Voorend-van Bergen S,
    2. Vaessen-Verberne AA,
    3. Brackel HJ, et al.
    Monitoring strategies in children with asthma: a randomised controlled trial. Thorax 2015; 70: 543–550.doi:10.1136/thoraxjnl-2014-206161
    OpenUrlAbstract/FREE Full Text
  29. ↵
    1. Petsky HL,
    2. Kew KM,
    3. Chang AB
    . Exhaled nitric oxide levels to guide treatment for children with asthma. Cochrane Database Syst Rev 2016; 11: CD011439. DOI: 10.1002/14651858.CD011439.pub2.
    OpenUrl
  30. ↵
    1. Wu AC,
    2. Tantisira K,
    3. Li L, et al.
    Childhood Asthma Management Program Research Group. Predictors of symptoms are different from predictors of severe exacerbations from asthma in children. Chest 2011; 140: 100–107. doi:10.1378/chest.10-2794
    OpenUrlCrossRefPubMed
  31. ↵
    1. Wang Z,
    2. Pianosi PT,
    3. Keogh KA, et al.
    The Diagnostic accuracy of fractional exhaled nitric oxide testing in asthma: a systematic review and meta-analyses. Mayo Clin Proc 2018; 93: 191–198. doi:10.1016/j.mayocp.2017.11.012
    OpenUrl
  32. ↵
    1. Jeppegaard M,
    2. Veidal S,
    3. Sverrild A, et al.
    Validation of ATS clinical practice guideline cut-points for FeNO in asthma. Respir Med 2018; 144: 22–29. doi:10.1016/j.rmed.2018.09.014
    OpenUrl
  33. ↵
    1. Price DB,
    2. Buhl R,
    3. Chan A, et al.
    Fractional exhaled nitric oxide as a predictor of response to inhaled corticosteroids in patients with non-specific respiratory symptoms and insignificant bronchodilator reversibility: a randomised controlled trial. Lancet Respir Med 2018; 6: 29–39. doi:10.1016/S2213-2600(17)30424-1
    OpenUrl
  34. ↵
    1. Petsky HL,
    2. Kew KM,
    3. Turner C, et al.
    Exhaled nitric oxide levels to guide treatment for adults with asthma. Cochrane Database Syst Rev 2016; 9: CD011440.
    OpenUrl
  35. ↵
    1. Caminati M,
    2. Vianello A,
    3. Chieco Bianchi F, et al.
    Relevance of Th2 markers in the assessment and therapeutic management of severe allergic asthma: a real life perspective. J Investig Allergol Clin Immunol 2019; in press[https://doi.org/10.18176/jiaci.0379].
  36. ↵
    1. Hanania NA,
    2. Alpan O,
    3. Hamilos DL, et al.
    Omalizumab in severe allergic asthma inadequately controlled with standard therapy: a randomized trial. Ann Intern Med 2011; 154: 573–582. doi:10.7326/0003-4819-154-9-201105030-00002
    OpenUrlCrossRefPubMed
  37. ↵
    1. Hanania NA,
    2. Wenzel S,
    3. Rosen K, et al.
    Exploring the effects of omalizumab in allergic asthma: an analysis of biomarkers in the EXTRA study. Am J Respir Crit Care Med 2013; 187: 804–811. doi:10.1164/rccm.201208-1414OC
    OpenUrlCrossRefPubMed
  38. ↵
    1. Corren J,
    2. Lemanske RF,
    3. Hanania NA, et al.
    Lebrikizumab treatment in adults with asthma. N Engl J Med 2011; 365: 1088–1098. doi:10.1056/NEJMoa1106469
    OpenUrlCrossRefPubMed
  39. ↵
    1. Fricker M,
    2. Gibson PG,
    3. Powell H, et al.
    A sputum 6-gene signature predicts future exacerbations of poorly controlled asthma. J Allergy Clin Immunol 2019; 144: 51–60. doi:10.1016/j.jaci.2018.12.1020
    OpenUrl
  40. ↵
    1. Alcazar-Navarrete B,
    2. Ruiz Rodriguez O,
    3. Conde Baena P, et al.
    Persistently elevated exhaled nitric oxide fraction is associated with increased risk of exacerbation in COPD. Eur Respir J 2018; 51: 01. doi:10.1183/13993003.01457-2017
    OpenUrl
  41. ↵
    1. Gao J,
    2. Zhang M,
    3. Zhou L, et al.
    Correlation between fractional exhaled nitric oxide and sputum eosinophilia in exacerbations of COPD. Int J Chron Obstruct Pulmon Dis 2017; 12: 1287–1293. doi:10.2147/COPD.S134998
    OpenUrl
  42. ↵
    1. Rio Ramirez MT,
    2. Juretschke Moragues MA,
    3. Fernandez Gonzalez R, et al.
    Value of Exhaled Nitric Oxide (FeNO) And Eosinophilia During the Exacerbations of Chronic Obstructive Pulmonary Disease Requiring Hospital Admission. COPD 2018; 15: 369–376. doi:10.1080/15412555.2018.1482532
    OpenUrl
  43. ↵
    1. Lim C,
    2. Rani FA,
    3. Tan L
    . Response of exhaled nitric oxide to inhaled corticosteroids in patients with stable COPD: A systematic review and meta-analysis. Clin Respir J 2018; 12: 218–226. doi:10.1111/crj.12518
    OpenUrl
  44. ↵
    1. Wu Y,
    2. Su W,
    3. Huang C, et al.
    Treatment of chronic obstructive pulmonary disease in patients with different fractional exhaled nitric oxide levels. Medicine 2018; 97: e11922. doi:10.1097/MD.0000000000011922
    OpenUrl
  45. ↵
    1. Matthes S,
    2. Stadler J,
    3. Barton J, et al.
    Asthma features in severe COPD: Identifying treatable traits. Respir Med 2018; 145: 89–94. doi:10.1016/j.rmed.2018.10.027
    OpenUrl
  46. ↵
    1. Takayama Y,
    2. Ohnishi H,
    3. Ogasawara F, et al.
    Clinical utility of fractional exhaled nitric oxide and blood eosinophils counts in the diagnosis of asthma–COPD overlap. Int J Chron Obstruct Pulmon Dis 2018; 13: 2525–2532. doi:10.2147/COPD.S167600
    OpenUrl
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Clinical utility of exhaled nitric oxide fraction in the management of asthma and COPD
Steve W. Turner, Anne B. Chang, Ian A. Yang
Breathe Dec 2019, 15 (4) 306-316; DOI: 10.1183/20734735.0268-2019
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