Coverage Policy Manual
Policy #: 2005020
Category: Medicine
Initiated: July 2005
Last Review: January 2019
  Measurement of Exhaled Nitric Oxide and Exhaled Breath Condensate the Diagnosis and Management of Asthma and Other Respiratory Disorders

Description:
Current techniques for diagnosing and monitoring asthma and predicting exacerbations are suboptimal. Two new strategies, evaluation of exhaled nitric oxide (NO) and exhaled breath condensate are proposed. These techniques are also potentially useful in the management of other conditions such as chronic obstructive pulmonary disease (COPD) and chronic cough. There are commercially available devices for measuring NO in expired breath and various laboratory techniques for evaluating components of exhaled breath condensate.
 
Background
Guidelines for the management of persistent asthma stress the importance of long-term suppression of inflammation using steroids, leukotriene inhibitors, or other anti-inflammatory drugs. Existing techniques for monitoring the status of underlying inflammation have focused on bronchoscopy, with lavage and biopsy, or analysis by induced sputum. Given the cumbersome nature of these techniques, the ongoing assessment of asthma focuses not on the status of the underlying chronic inflammation, but rather on regular assessments of respiratory parameters such as forced expiratory volume in one second (FEV1) and peak flow. Therefore, there has been interest in noninvasive techniques to assess the underlying pathogenic chronic inflammation as reflected by measurements of inflammatory mediators.
 
Two proposed strategies are the measurement of exhaled nitric oxide (NO) and the evaluation of exhaled breath condensate. Nitric oxide is an important endogenous messenger and inflammatory mediator that is widespread in the human body, functioning, for example, to regulate peripheral blood flow, platelet function, immune reactions, and neurotransmission and to mediate inflammation. In biologic tissues, NO is unstable, limiting measurement. However, in the gas phase, NO is fairly stable, permitting its measurement in exhaled air. Exhaled NO is typically measured during single breath exhalations. First, the subject inspires nitric oxide-free air via a mouthpiece until total lung capacity is achieved, followed immediately by exhalation through the mouthpiece into the measuring device. Several devices measuring exhaled NO are commercially available in the United States. According to a 2009 joint statement by the American Thoracic Society (ATS) and European Respiratory Society (ERS), there is a consensus that the fractional concentration of exhaled nitric oxide (FeNO) is best measured at an exhaled rate of 50 mL per second (FeNO 50 mL/s) maintained within 10% for more than 6 seconds at an oral pressure between 5 and 20 cm H2O (Reddel, 2009). Results are expressed as the NO concentration in parts per billion (ppb), based on the mean of 2 or 3 values.
 
Exhaled breath condensate (EBC) consists of exhaled air passed through a condensing or cooling apparatus, resulting in an accumulation of fluid. Although EBC is primarily derived from water vapor, it also contains aerosol particles or respiratory fluid droplets, which in turn contain various nonvolatile inflammatory mediators, such as cytokines, leukotrienes, oxidants, antioxidants, and various other markers of oxidative stress. There are a variety of laboratory techniques to measure the components of EBC, including such simple techniques as pH measurement, to the more sophisticated gas chromatography/mass spectrometry or high performance liquid chromatography, depending on the component of interest.
 
Clinical Uses of FeNO and EBC
Measurements of FeNO have particularly been associated with an eosinophilic asthma phenotype. Eosinophilic asthma is a subtype of severe asthma associated with sputum and serum eosinophilia, along with later-onset asthma (Chung, 2014). Until recently, most asthma management strategies did not depend on the recognition or diagnosis of a particular subtype. However, 2 anti-interleukin 5 inhibitors have been approved by the Food and Drug Administration (FDA) for the treatment of severe asthma with an eosinophilic phenotype, mepolizumab (NUCALA, 2017) and reslizumab (Cinquair, 2017). An anti-interleukin 4 and 13 monoclonal antibody has also been shown to improve uncontrolled asthma, with the greatest improvement observed in the subgroup of patients with the highest blood eosinophil count (Wenzel, 2016).
 
Measurement of NO and EBC has been investigated in the diagnosis and management of asthma. Potential uses in management of asthma include assessing response to anti-inflammatory treatment, monitoring compliance with treatment, and predicting exacerbations. Aside from asthma, they have also been proposed in the management of patients with chronic obstructive pulmonary disease (COPD), cystic fibrosis, allergic rhinitis, and primary ciliary dyskinesia.
 
Regulatory Status
In 2003, the U.S. Food and Drug Administration (FDA) cleared for marketing the Nitric Oxide Monitoring System (NIOX) (Aerocrine; Sweden) with the following indication: “[Measurements of the fractional nitric oxide (NO) concentration in expired breath (FE-NO)] provide the physician with means of evaluating an asthma patient's response to anti-inflammatory therapy, as an adjunct to established clinical and laboratory assessments in asthma. NIOX should only be used by trained physicians, nurses and laboratory technicians. NIOX cannot be used with infants or by children approximately under the age of 4, as measurement requires patient cooperation. NIOX should not be used in critical care, emergency care or in anesthesiology." In March 2008, the NIOX MINO was cleared for marketing. The main differences between this new device and the NIOX are that the NIOX MINO is hand-held and portable and that it is not suitable for children under age 7 years. In November 2014, the NIOX VERO, which differs from prior devices in terms of its battery and display format, was cleared for marketing by the FDA. FDA product code: MXA
 
 
The Breathmeter (Ekipstech) is another device used to measure exhaled nitric oxide using laser spectroscopy. As of November 2010, the Breathmeter is available for research only; it has not yet received FDA approval or clearance.
 
The RTube Exhaled Breath Condensate collection system (Respiratory Research, Inc) is registered with the FDA as a Class I device that collects expired gas. Respiratory Research has a proprietary gas-standardized pH assay, which, when performed by the company, is considered a laboratory-developed test.
 
In November 2014, the NIOX VERO, which differs from prior devices in terms of its battery and display format, was cleared for marketing by the FDA. FDA product code: MXA
 
 
Coding
There is a CPT code specific to direct determination of exhaled nitric oxide (e.g., using the NIOX system):
 
95012: Nitric oxide expired gas determination
 
0064T: Spectroscopy, expired gas analysis (e.g., nitric oxide/carbon dioxide test)
 
Effective in 2010, the CPT book instructs that the unlisted code 94799 should be used for services previously coded as 0064T.
 
Effective in 2010, there is a CPT code to describe the collection of exhaled breath condensate with measurement of the pH:
 
83987: pH; exhaled breath condensate
 

Policy/
Coverage:
Effective October 2013
Measurement of exhaled nitric oxide in the diagnosis and management of asthma and other respiratory disorders does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For contracts without primary coverage criteria, the measurement of exhaled nitric oxide for the diagnosis and management of asthma and other respiratory disorders is considered investigational.  Investigational services are specific contract exclusions in the most member benefit certificates of coverage.
 
Measurement of exhaled breath condensate in the diagnosis and management of asthma and other respiratory disorders including but not limited to chronic obstructive pulmonary disease and chronic cough does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For contracts without primary coverage criteria, the measurement of exhaled breath condensate in the diagnosis and management of asthma and other respiratory disorders including but not limited to chronic obstructive pulmonary disease and chronic cough is considered investigational.  Investigational services are specific contract exclusions in the most member benefit certificates of coverage.
 
Effective July 2005 to September 2013
Measurement of exhaled or nasal nitric oxide in the diagnosis and management of asthma and other respiratory disorders does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For contracts without primary coverage criteria, the measurement of exhaled or nasal nitric oxide for the diagnosis and management of asthma and other respiratory disorders is considered investigational.  Investigational services are an exclusion in the member benefit contract.

Rationale:
Due to the detail of the rationale, the complete document is not online. If you would like a hardcopy print, please email: codespecificinquiry@arkbluecross.com .
 
A literature search performed on the MEDLINE database identifies a large body of published data regarding exhaled nitric oxide in asthma and other respiratory diseases. However, these studies primarily focus on exhaled nitric oxide as a research tool exploring the underlying pathophysiology of asthma, establishment of the technical performance of the test, establishing cut off values for normal and abnormal values in different age groups. For example, studies have shown that asthma patients have nitric oxide measurements in the range of 25–85 ppb (part per billion) compared to control patients whose exhaled nitric oxide measurement is generally less than 20 ppb.  Other studies have shown that levels of exhaled nitric oxide correlate with levels of other known inflammatory markers, such as airway hyper-responsiveness and sputum eosinophils.  Pulmonary function tests represent the standard method for assessment asthma, but studies have found an inconsistent relationship between results of pulmonary function tests and exhaled nitric oxide, perhaps because changes in pulmonary function may lag behind changes in exhaled nitric oxide.  Several studies have confirmed the expected decrease in exhaled nitric oxide levels after administration of both corticosteroids  and anti-leukotriene drugs.
 
While the cited studies demonstrate the potential role of measurements of exhaled nitric oxide in the diagnosis and management of asthma, assessment of the clinical role of this test would require controlled studies of those diagnosed and managed conventionally and those whose diagnosis and management were additionally directed by measurements of exhaled nitric oxide. No such trials were identified. Compared to asthma, the data are more limited regarding other respiratory conditions, including chronic obstructive pulmonary disease (COPD), cystic fibrosis, and primary ciliary dyskinesia.
 
In 2002, the National Asthma Education and Prevention Program of the National Heart Lung and Blood Institute issued its second expert panel report on guidelines for the diagnosis and management of asthma.  Measurements of nitric oxide were not included among its recommendations.
 
2005 Update
A search of the literature was performed for the period of 2003 through June 2005. The literature search did reveal ongoing intense interest in exhaled nitric oxide as a biomarker for asthma. Studies continue to explore the potential clinical applications of exhaled nitric oxide. One randomized trial was identified in which 97 patients with asthma treated with inhaled corticosteroids (fluticasone) were randomized either to a group whose care was directed by results of exhaled nitric oxygen testing or to a conventional management group based on international guidelines.  In the first phase of the study, the lowest dose of fluticasone was established, based either on international guidelines or exhaled nitric oxide. In the second phase, patients were maintained on this baseline dose, monitored for exacerbations either conventionally or with results of exhaled nitric oxide, with the fluticasone dose adjusted accordingly. Patients were followed up for 12 months. The primary outcome was the frequency of asthma exacerbations, and the secondary outcome was the mean daily dose of corticosteroid. While there was no difference in the frequency of asthma exacerbations between the groups, the exhaled nitric oxygen group did report a significant 40% reduction in the dosage of inhaled corticosteroid.
 
The accompanying editorial by Deykin points out several limitations to this study.  For example, in the control group the mean dose of fluticasone after the initial titration period (567 mg/day) is nearly double the typical dose needed for asthma control. Therefore, the finding of lower fluticasone doses in patients managed with serial measurements of exhaled nitric oxide may reflect overtreatment in the control group rather than any effect of nitric oxide monitoring. The author also points out that it is unclear whether the reported results in these patients with moderate asthma can be extrapolated to those with milder or more severe asthma. Finally, Deykin questions the scientific basis of nitric oxide monitoring. For example, while corticosteroids may suppress the inflammatory activity of the airways, they also directly inhibit the enzymatic production of nitric oxide. Therefore, a reduction in exhaled nitric oxide may also reflect exposure to corticosteroids rather than simply a reduction in inflammation. Therefore, it is concluded that the results of this trial are inadequate to permit scientific conclusions regarding the clinical role of exhaled nitric oxide in the management of patients with asthma.
 
In October 2005, a Blue Cross Blue Shield Technology Evaluation Center Assessment on exhaled nitric oxide monitoring as a guide to treatment decisions in chronic asthma made the following conclusions:
    • The available evidence does not permit the conclusion that use of nitric oxide monitoring to guide treatment decisions in asthma leads to improved outcomes.
    • The two randomized controlled trials included in the assessment, reported by Smith  and Pijnenburg,  suggest possible benefits for nitric oxide monitoring but are not sufficient to conclude that outcomes are improved. Each study reported different benefits that have not been reproduced. Smith reported that equivalent outcomes were achieved in the nitric oxide group, with a lower overall dose of inhaled corticosteroids. Pijnenburg reported that bronchial hyper-reactivity was improved in the nitric oxide group. However, bronchial hyper-reactivity is an intermediate outcome that is not well benchmarked to true health outcomes.
    • Differences in the control management strategy raise questions about the optimal management strategy to which nitric oxide monitoring should be compared.
    • The 7 studies that evaluated the ability of nitric oxide to provide prognostic information that could lead to changes in management had considerable methodologic limitations and variability in study methodology that precluded synthesis of their results and definitive conclusions.
 
Exhaled Breath Condensate
Similar to exhaled nitric oxide, there is intense research interest in the analysis of exhaled breath condensate as a biomarker of inflammation. However, it appears from the published literature that exhaled breath condensate is at an earlier stage of development compared to exhaled nitric oxide. For example, several review articles note that before routine clinical use in the diagnosis and management of respiratory disorders can be considered the following issues must be resolved:
    • Standardization of collection and storage techniques
    • Effect of dilution of respiratory droplets by water vapor
    • Techniques of measuring concentrations of nonvolatile substances in EBC; in most cases these concentrations are very low, which may be at the lower limits of detection of conventional analytic techniques
    • Variability in exhaled breath condensate assays for certain substances
    • Further investigation of levels of compounds in health and disease
Ultimately controlled trials will be required to determine how evaluations of exhaled breath condensate can be used to direct patient management. The National Institute of Allergy and Infectious Disease is currently recruiting asthmatic children to a clinical trial evaluating the use of pH measurement of exhaled breath condensate in the management of asthma.  This trial will evaluate both asthmatic patients and normal controls with exhaled breath condensate pH, expired nitric oxide, pulmonary lung function tests, and peak flow meters over a period of a year. Neither exhaled nitric oxide or exhaled breath condensate pH are used in the management of the patient, but the study will determine whether these measures are correlated with known parameters of disease including number of hospitalizations, absenteeism from school, number of asthma exacerbations, lost work days (if applicable), and extent of rescue medication used.
 
2006 Update
No new studies were identified that would alter the conclusions of the policy statements above. No additional clinical trials were identified where use of these markers were used to adjust treatment decisions. While research efforts continue, the clinical utility of these measures is not currently known. In addition, studies also report factors that may influence the reliability of these results.  In a study of 17 patients with asthma, Belda and colleagues concluded that measure of nitric oxide was not helpful in predicting loss of asthma control during corticosteroid withdrawal.  A study of exhaled breath condensate concluded that the findings did not correlate with results from broncho-alveolar lavage.
 
2007 Update
The policy was updated with a literature search using MEDLINE from October 2006 through June 2007. Shaw and colleagues randomized 118 participants with asthma to a single-blind trial of corticosteroid therapy based on either exhaled nitric oxide measurements (n = 58) or British Thoracic Society guidelines (n = 60).  During the 12-month study, the primary outcome was the number of severe asthma exacerbations. The estimated mean exacerbation frequency was 0.33 per patient per year in the experimental group and 0.42 in the control group (p = 0.43). Overall the experimental group used 11% more inhaled corticosteroid, although the final daily dose of inhaled corticosteroid was lower in the nitric oxide directed group (557 vs. 895 mug, p = 0.028). The authors concluded that the asthma treatment strategy based on the measurement of exhaled nitric oxide did not result in a large reduction in asthma exacerbations or in the total amount of inhaled corticosteroid therapy used during the 12-month study when compared with current asthma care.
 
Fritsch and colleagues reported on a prospective, randomized, single-blind study to examine whether the inclusion of repeated exhaled NO (FeNO) measurements into asthma monitoring leads to an improvement in asthma outcome.  Forty-seven children with mild to moderate asthma were allocated to a NO group (n = 22) and to a control group (n = 25) for 5 visits performed at 6-week intervals. In the FeNO group, therapy was based on symptoms, beta-agonist use, lung function, and FeNO whereas in the control group, the FeNO results were not obtained. Frequency of respiratory symptoms, beta-agonist use, FEV-1-percent of predicted and the frequency of exacerbations were similar between groups. Patients in the FeNO group received higher doses of inhaled corticosteroids and had significantly higher mean expiratory flow (as a percent of predicted) was 68.5% in the control group and 83.2% in the FENO group. The authors concluded that a therapy regimen aimed at lowering FeNO in children with asthma showed improved parameters of small airway function, but was not able to improve clinical markers of asthma control.
 
Finally, Gelb reported on the use of combining FeNO and FEV-1 in predicting asthma exacerbations among 44 non-smoking adults (average age 51 years) with stable asthma during a subsequent 18-month period. This study reported that having FeNO below 28 ppb and FEV-1 above 76% predicted a probability of 0% among the 9 patients who met both criteria.  
 
These studies add to the existing literature, but the relationship between use of these assays and improvements in patient outcomes is uncertain. The policy statement(s) are unchanged.
 
None of the literature identified during the update adds important new information to the existing literature on the use of exhaled breath condensates.
 
2010 Update
A Cochrane review was published in 2008 that identified studies comparing outcomes in asthma patients managed with and without findings from exhaled nitric oxide tests (Petsky, 2008).  Four randomized controlled trials were identified, including the two that were previously included in the TEC Assessment (Smith et al. 2005; Pijnenburg et al. 2005) and two additional studies, Shaw et al. 2007 and Fritsch et al. 2006.  Two of the four studies were conducted with adults (Smith, 2005) (Shaw, 2007) and findings were pooled for selected outcomes; there were a total of 197 patients. Meta-analyses did not find a significant difference in the number of patients experiencing an exacerbation or the occurrence of any exacerbation. There was also no significant difference in symptom scores. Both studies did report a significant difference between groups for the outcome of final daily dose of inhaled corticosteroirds; however, this was a post-hoc analysis in the Shaw study. Results of the two pediatric trials, (Fritsch, 2006) and (Pijnenburg, 2005) could not be pooled. The Cochrane reviewers state that the data in the Pijenburg forest plot of cumulative dose shows no significant difference between groups. The authors of the Cochrane review concluded: “Tailoring the dose of inhaled corticosteroids based on exhaled nitric oxide in comparison to clinical symptoms was carried out in different ways in the four studies that were found, and the results show only modest differences. The role of utilizing exhaled nitric oxide to tailor the dose of inhaled corticosteroids is currently uncertain.”
 
A fifth randomized controlled trial (RCT) was identified.  Szefler and colleagues randomly assigned 546 eligible participants (inner-city adolescents and young adults) who adhered to treatment during a run-in period to 46 weeks of either standard treatment, based on the guidelines of the National Asthma Education and Prevention Program (NAEPP), or standard treatment modified on the basis of measurements of fraction of exhaled NO (Szefler, 2008). The primary outcome was the number of days with asthma symptoms. During the 46-week treatment period, the mean number of days with asthma symptoms did not differ between the treatment groups. Other symptoms, pulmonary function, and asthma exacerbations did not differ between groups. Patients in the NO monitoring group received higher doses of inhaled corticosteroids than controls. Adverse events did not differ between treatment groups. The authors concluded that conventional asthma management resulted in good control of symptoms in most participants and the addition of a fraction of exhaled NO as an indicator of control of asthma resulted in higher doses of inhaled corticosteroids without clinically important improvements in symptomatic control.
 
Several review articles were identified including one systematic review of published RCTs by Gibson that evaluated exhaled nitric oxide tests in the management of patients with asthma (Gibson, 2009). The review cited the 5 RCTs previously discussed in the policy; data were not pooled. The authors commented that the studies did not show a significant reduction in asthma exacerbation when patients are managed with exhaled NO tests and that treatment algorithms based on exhaled NO levels are less successful than treatment based on induced sputum eosinophils. Moreover, the review states that the published RCTs may have study design limitations that limit their ability to adequately test the utility of exhaled NO tests. For example, equipment failure has been a substantial issue and future studies should ensure back-up equipment is available. In addition, there is variation within individuals and an imperfect relationship between exhaled NO and eosinophilic inflammation; exhaled NO levels are also influenced by factors such as age, atopy, gender and smoking status. The review authors recommend that studies alter the cut-point for positive tests to reduce false positive findings, or use composite outcomes such as exhaled NO and FEV.
 
Two prospective studies on the diagnosis of asthma using exhaled nitric oxide measurements were identified.  Sivan and colleagues evaluated the diagnostic yield of exhaled NO test findings in 150 children age 18 years or less compared to sputum eosinophil count, the ‘gold standard” for assessment of eosinophilic inflammation of the airways (Sivan, 2009). Final assessment of asthma status was done by a pediatric pulmonologist after at least 18 months of follow-up. Receiver operating curves (ROC) were used to determine the optimal cutoff points for the exhaled NO test. A total of 150 children were included. Eligibility criteria included non-specific respiratory symptoms suggestive of asthma for at least 3 months and absence of other conditions that could affect exhaled NO or sputum eosinophil count. The authors concluded that exhaled NO measurement is useful in early diagnosis of pediatric asthma. The study was conducted in Israel and the device used to measure exhaled NO in the study, the CLD88 FeNO analyzer by Eco Medics (Switzerland), does not appear to be cleared by the FDA.
 
Schneider and colleagues evaluated a new portable NIOX MINO in a prospective study conducted in a primary care setting (Schneider, 2009). They recruited 160 patients with symptoms suspicious of obstructive airway disease from general practices in Germany. All patients underwent measurement of exhaled nitric oxide. The reference standard was a step-wise series of tests, beginning with spirometry. Those with FEV1 less than 80% of predicted or FEV1/vital capacity (VC) ratio of 0.70 or less were referred to bronchodilator reversibility testing. Otherwise, patients net received bronchial provocation with methacholine. Patients were classified as having asthma when: 1) Bronchodilation testing found a change in FEV1 was at least 12% compared to baseline, and at least 200 ml and lung volumes returned to predicted normal range; 2) Bronchial provocation found a 20% decrease in FEV1 from the baseline value after inhaling methacholine stepwise until the maximum concentration. Exhaled nitric oxide test findings were compared to the final diagnosis status. According to standard testing, 75 of the patients had asthma. ROC analysis found the highest sum of sensitivity and specificity of exhaled nitric oxide at a cutoff of 46 ppb. Among 101 patients with unsuspicious spirometry findings, 49 had asthma. The optimal cutoff of exhaled nitric oxide in this subgroup was 46 ppb; sensitivity of exhaled NO was 35% and specificity was 90%.
 
The two recent prospective studies on asthma diagnosis found different optimal cutoffs for exhaled nitric oxide, 18 ppb in the Sivan study conducted with children and 46 ppb in the Schneider study with adults. The cutoff level of exhaled nitric oxide also varied in earlier studies: Dupont evaluated 240 non-smoking steroid-naïve patients without age limitations and found the optimal cutoff was 16 ppb exhaled nitric oxide (Dupont, 2003).  Berkman studied 95 asthmatic and nonasthmatic patients without age limitation and found that a cutoff of exhaled nitric oxide over 7 ppb best differentiated between the two groups (Berkman, 2005). The manufacturer of the NIOX and NIOX MINO devices, Aerocrine, does not have a recommendation on their website for the cutoff of exhaled nitric oxide to use when diagnosing asthma. Thus, the studies on diagnosis of asthma using exhaled nitric oxide can be preliminary. Once there is an agreed-upon cutoff of exhaled NO levels for diagnosing asthma, there is a need for prospective validation studies using that cutoff to determine the diagnostic accuracy of exhaled NO measurement.
 
Other Respiratory Disorders
One RCT, a double-blind cross-over study by Dummer and colleagues, evaluated the ability of exhaled nitric oxide test results to predict corticosteroid response in chronic obstructive pulmonary disease (COPD) (Dummer, 2009). The study included 65 patients with COPD who were 45 years of older, were previous smokers with at least a 10 pack year history, had persistent symptoms of chronic airflow obstruction, had a post-bronchodilator forced expiratory volume in one second/forced vital capacity ratio (FEV1/FVC) of less than 70% and a FEV1 of 30-80% predicted. Patients with asthma or other co-morbidities, and those taking regular corticosteroids or had used oral corticosteroids for exacerbations more than twice during the past six months were excluded. Treatments, given in random order, were 30 mg/day of prednisone or placebo for three weeks; there was a four-week washout period before each treatment. Patients who withdrew during the first treatment period were excluded from the analysis. Those who withdrew between treatments or during the second treatment were assigned a net change of zero for the second treatment period. Fifty-five patients completed the study. Two of the three primary outcomes, six-minute walk distance (6MWD) and FEV1 increased significantly from baseline with prednisone compared to placebo. There was a non-significant decrease in the third primary outcome, score on the St. George’s Respiratory Questionnaire (SGRQ). The correlation between baseline fraction of exhaled nitric oxide was not significantly correlated with change in 6MWD or SGRQ  but was significantly related to change in FEV1 . At the optimal fraction exhaled nitric oxide cutoff of 50ppb, as determined by ROC analysis, there was a 29% sensitivity and 96% specificity for predicting a 0.2 liter increase in FEV1. (A 0.2 liter change was considered to be the minimal clinically important difference). The authors concluded that exhaled nitric oxide is a weak predictor of short-term response to oral corticosteroid treatment in patients with stable, moderately severe COPD and that a normal test result could help clinicians decide to avoid prescriptions that may be unnecessary; only about 20% of patients respond to corticosteroid treatments. Limitations of the study include that the response to treatment measured was short-term and this was not a trial of management decisions based on exhaled nitric oxide test results.
 
No controlled studies were identified that evaluated the role of exhaled nitric oxides tests in the management of respiratory conditions other than asthma and COPD. A prospective uncontrolled study by Prieto and colleagues assessed the utility of exhaled oxide measurement for predicting response to inhaled corticosteroids in patients with chronic cough (Prieto, 2009). The study included 43 patients with cough of at least 8 weeks’ duration who were non-smokers and did not have a history of other lung disease. Patients were evaluated at baseline and after 4 weeks of treatment with inhaled fluticasone propionate 100 ug twice daily. Nineteen patients (44%) had a positive response to the treatment defined as at least a 50% reduction in mean daily cough symptom scores. ROC analysis showed that, using 20 ppb as the exhaled nitric oxide cutoff, the sensitivity was 53% and the specificity was 63%. The authors concluded that exhaled NO was not an adequate predictor of treatment response.
 
Summary
Five randomized controlled studies have evaluated the use of exhaled nitric oxide tests for the management of patients with asthma and have not consistently found improvement in health outcomes. Several prospective studies on using exhaled nitric oxide to diagnose asthma have been published, but they differ in the optimal cutoff of exhaled nitric oxide for indicating that the patient has asthma; until this is standardized and validated, exhaled nitric oxide is not useful as a diagnostic test. There is less evidence on exhaled nitric oxide for the diagnosis and management of other respiratory disorders for the diagnosis and treatment of asthma and other conditions. Thus, the evidence is insufficient to determine the effect of exhaled nitric oxide tests on health outcomes.
 
2011 Update
A literature review was conducted using the MEDLINE database through November 2011. The majority of the literature focused on guiding treatment decisions in patients with asthma.
 
In 2011, Powell and colleagues in Australia published a double-blind RCT evaluating FeNO for guiding treatment decisions in pregnant non-smoking women with asthma (Powell, 2011). Eligiblity included being between 12 and 20 weeks’ of gestation and using inhaled therapy for asthma within the past year. Women were randomized to a FeNO algorithm to adjust therapy (n=111) or a clinical guideline algorithm that did not include FeNO measurement (n=109). The FeNO algorithm appeared to be devised by the study investigators. According to the algorithm, the cutoff for reducing the dose of inhaled corticosteroids was less than 16 ppb and the cutoff for dose increase was at least 30 ppb. Both treatment groups also had their symptoms assessed by the Asthma Control Questionnaire (ACQ) and ACQ scores were utilized in both medication adjustment algorithms. A total of 203 of 220 women (92%) completed the study; analysis was intention to treat. The primary study outcome was the total number of asthma exacerbations during pregnancy (and after study enrollment) for which the patient sought medical attention. The mean total exacerbation rate was significantly lower in the FeNO group (0.29 per pregnancy) compared to the control group (0.62 per pregnancy), p=0.01. Overall, 28 (25%) of women in the FeNO group and 45 (41%) in the control group had at least one exacerbation; the difference between groups was statistically significant, p=0.01. Among the secondary outcomes, there were significantly fewer unplanned doctors visits in the FeNO group (mean of 0.26 per patient) than the control group (mean of 0.56 per patient), p=0.002.
 
The Powell study demonstrates a potential benefit to using a treatment algorithm that incorporates FeNO levels. However, this trial is prone to many of the same limitations as previous trials of FeNO management algorithms. Most importantly, patients in each group end up on differing regimens of medications according to the algorithm followed. It is then difficult to isolate the effect of the algorithm from the efficacy of the medications themselves. For example, if a FeNO algorithm uses a lenient cut-off point for increasing inhaled corticosteroids, then the FeNO group will likely end up on higher doses of inhaled steroids. Improved outcomes are then more likely to be due to the efficacious effect of inhaled steroids, rather than the inclusion of FeNO in the algorithm. In the Powell study, the cut-off point for increasing inhaled steroids was lowered compared to previous algorithms, thus resulting in more patients being started on inhaled steroids. Together with this, the control group was treated by an algorithm that differed from current treatment guidelines in at least two important ways, both which resulted in less intensive treatment compared to treatment guidelines. The net effect of these algorithms was that more patients in the FeNO group received both long-acting beta-agonists and inhaled corticosteroids, although patients treated with inhaled steroids in the control group were treated at higher doses. Therefore, the differences in outcomes may be due to differences in treatment regimens that could have been achieved with or without the use of FeNO in the guidelines.
 
One study involved the use of FeNO in the diagnosis of respiratory disorders other than asthma. Rouhos and colleagues in Finland published a study in 2011 on repeatability of FeNO measurements in 20 patients with stable COPD and 20 healthy controls (Rouhos, 2011). FeNO was measured 3 times in each individual; a baseline measurement and measurements 10 minutes and 24 hours after baseline. In COPD patients, median FeNO values were 15.2 ppb at baseline, 17.4 ppb 10 minutes later and 14.5 ppb 24 hours later. In healthy controls, corresponding median FeNO values were 15.6 ppb, 19.6 ppb and 15.7 ppb. Differences between the baseline and 24 hour measurements in both groups were not statistically significant. FeNO values 10 minutes after baseline were significantly higher than the 24 hour measurement in both groups; the authors attributed this difference to the fact that patients did not rinse their mouths with sodium bicarbonate between the baseline and 10-minute measurements.
 
The American Thoracic Society (ATS) published a clinical practice guideline on interpretation of FeNO levels (Dweik, 2011). The guideline was critically appraised using criteria developed by the Institute of Medicine (IOM) which includes 8 standards. The guideline was judged to not adequately meet the following standards: Standard 3: guideline development group composition; Standard 4: clinical practice guideline-systematic review intersection; Standard 5: Establishing evidence foundation for and rating strength of recommendations; and Standard 7: external review.
 
The ATS guideline included the following strong recommendations  (if not otherwise stated, the recommendations apply to asthma patients):
    • We recommend the use of FENO in the diagnosis of eosinophilic airway inflammation (strong recommendation, moderate quality of evidence).
    • We recommend the use of FENO in determining the likelihood of steroid responsiveness in individuals with chronic respiratory symptoms possibly due to airway inflammation (strong recommendation, low quality of evidence).
    • We recommend accounting for age as a factor affecting FENO in children younger than 12 years of age (strong recommendation, high quality of evidence).
    • We recommend that low FENO less than 25 ppb (<20 ppb in children) be used to indicate that eosinophilic inflammation and responsiveness to corticosteroids are less likely (strong recommendation, moderate quality of evidence).
    • We recommend that FENO greater than 50 ppb (>35 ppb in children) be used to indicate that eosinophilic inflammation and, in symptomatic patients, responsiveness to corticosteroids are likely (strong recommendation, moderate quality of evidence).
    • We recommend that FENO values between 25 ppb and 50 ppb (20–35 ppb in children) should be interpreted cautiously and with reference to the clinical context. (strong recommendation, low quality of evidence).
    • We recommend accounting for persistent and/or high allergen exposure as a factor associated with higher levels of FENO (strong recommendation, moderate quality of evidence).
    • We recommend the use of FENO in monitoring airway inflammation in patients with asthma (strong recommendation, low quality of evidence).
 
It is important to note that only one of the above “strong recommendations” was based on high quality evidence.
 
Summary
Evaluation of exhaled nitric oxide and exhaled breath condensate are proposed as techniques to diagnose and monitor asthma and other respiratory conditions. Several prospective studies have addressed FeNO measurement; however, there is still no standardized and validated cut-off to use for diagnosing asthma. Multiple randomized controlled studies have evaluated the use of FeNO tests for the management of patients and have not consistently found improvement in health outcomes. Moreover, a 2009 Cochrane review pooling results of studies evaluating FeNO in the management of patients with asthma found a high degree of variability among studies and did not recommend routine use of FeNO in clinical practice. A 2011 RCT with pregnant women who had asthma found better outcomes in the group managed using a FeNO algorithm than standard care.. In this study, as in many others, there are concerns that differences in treatment regimens that arise as a result of different algorithms may confound the outcomes, particularly in cases where the control algorithm may lead to undertreatment.
 
There is less evidence on the utility of FeNO for the diagnosis and management of other respiratory disorders. There are also few studies on exhaled breath condensate evaluation for the diagnosis and treatment of asthma and other conditions. Thus, the evidence is insufficient to determine the effect of exhaled nitric oxide and exhaled breath condensate tests on health outcomes.
 
2012 Update
A search of the MEDLINE database through September 2012 and clinicaltrials.gov was conducted.  There was no published literature identified that would prompt a change in the coverage statement.
 
Yoon and colleagues (2012) studied  148 children with asthma (age, 8 to 16 years) who had maintained asthma control and normal forced expiratory volume in the first second (FEV(1)) without control medication for ≥3 months.  Patients with fractionated exhaled nitric oxide (FeNO) levels >25 ppb were allocated to one of two groups: 1) treated group (inhaled corticosteroid-treated (FeNO-based management) or  2) untreated group (guideline-based management).   Changes in FeNO levels and spirometric values  from baseline were evaluated after 6 weeks.  After 6 weeks, the geometric mean (GM) FeNO level in the inhaled corticosteroid-treated group was 45% lower than the baseline value, and the mean percent increase in forced expiratory flow (FEF) was 18.% which was greater than that in other spirometric values. There was a negative correlation between percent changes in FEF (25-75) and FeNO (r=-0.368, P=0.001).   In contrast, the GM FeNO and spirometric values were not significantly different from the baseline values in the untreated group.  The anti-inflammatory treatment simultaneously improved the FeNO levels and FEF(25-75) in CA patients when their FeNO levels were >25 ppb.
2013 Update
 
Measurement of Exhaled Nitric Oxide
In 2012, an RCT by Pike and colleagues in the U.K. included 90 children with severe asthma (Pike, 2012). Medication management decisions were based on clinical symptoms (i.e., standard management) (n=46) or clinical symptoms and FeNO levels (n=44). In the standard management group, therapy was increased if symptoms were poorly controlled or decreased if symptoms were well-controlled for 3 months. Medications were given according to a stepped care algorithm consistent with British clinical guidelines. In the exhaled NO group, when symptoms were poorly controlled and FeNO was less than 25 ppb, long-acting beta-agonist therapy (LABA) was maximized before ICS was increased. If FeNO was at least 25 ppb or doubled from baseline, ICS was increased. ICS was decreased if symptoms were well-controlled for 3 months (as in the standard care group) or if FeNo was 15 ppb or lower and symptoms were controlled. Seventy-seven of 90 (86%) of participants completed the 12-month study; analysis was intention to treat. During the follow-up period, 37 (84.1%) of patients in the FeNO group and 38 (82.6%) of patients in the standard care group experienced at least one asthma exacerbation. The proportion of children with exacerbations did not differ significantly between groups, p=0.85. Five (11.4%) children in the FeNO group and 3 (6.5%) in the standard care group experienced a severe exacerbation; the difference between groups was not statistically significant, p=0.42. In addition, there was not a significant difference between groups in the initial ICS dose, the final ICS dose, and the change in ICS during the study. Median final dose of ICS was 800 mcg in the FeNO group and 500 mcg in the standard management group.
 
Also in 2012, Calhoun and colleagues published a multicenter trial funded by the National Institutes of Health (NIH) known as the Best Adjustment Strategy for Asthma in the Long Term (BASALT) trial (Calhoun, 2012). The study included 342 adults with mild to moderate persistent asthma that was well or partially controlled by low-dose ICS. Participants were randomized to one of 2 strategies for medication adjustment: 1) adjusted by physicians at clinic visits (every 6 weeks) according to NIH clinical guidelines; 2) adjusted according to levels of exhaled NO at clinic visits (every 6 weeks); or 3) adjusted by patients on a day-to-day basis based on their symptoms. The third strategy involved patients using an inhaler that contained corticosteroids whenever they used an inhaler containing a short-term beta-agonist for symptom relief. No details were provided in the article or supplemental material regarding how steroid dose was adjusted according to FeNO level. A total of 290 of 342 randomized patients completed the 9-month study; analysis was intention to treat. The primary study outcome was time to first treatment failure according to pre-defined criteria. The 9-month Kaplan-Meier first treatment failure rate did not differ significantly among the 3 groups. The rates were 22% (97.5% CI: 14% to 33%) in the physician-directed medication adjustment group, 20% (97.5% CI: 13% to 30%) in the exhaled NO medication adjustment group, and 15% (97.5% CI: 9% to 25%) in the symptom-based medication adjustment group. The failure rate in the physician-based and exhaled NO-based medication adjustment groups were not significantly different (hazard ratio: 1.2, 95.5% CI: 0.6 to 2.3). Secondary outcomes, including measures of lung function and asthma symptoms, also did not differ significantly among groups. The mean monthly dose of ICS was significantly higher in both the physician-directed medication adjustment group (1610 ug) and the exhaled NO-based medication adjustment group (1617 ug) compared to the patient-based symptom medication adjustment groups (832 ug, p=0.01 for both comparisons). An editorial accompanying the publication of the BASALT trial noted that, given the trials findings, it is difficult to recommend routine monitoring of exhaled NO in adults with mild to moderate asthma (O’Connor, 2012).
 
Measurement of Exhaled Breath Condensate
In general, it appears from the published literature that exhaled breath condensate (EBC) is at an earlier stage of development compared to exhaled NO. A 2012 review by Davis and colleagues noted that this is due, in part, to the fact that FeNO is a single biomarker and EBC is a matrix that contains so many potential biomarkers that research efforts have thus far been spread among numerous of these markers.
 
EBC used as markers of asthma severity
 
Several studies have been published on components of exhaled breath condensate (EBC) and their relationship with asthma severity. A 2011 study by Liu and colleagues, the Severe Asthma Research Program, was a multicenter study funded by the National Institutes of Health. This study had the largest sample size with 572 patients (Liu, 2011). Study participants consisted of 250 patients with severe asthma, 291 patients with non-severe asthma, and 51 healthy controls. Samples of EBC were collected at baseline and were analyzed for pH levels. Overall, the median pH of asthma patients (2 groups combined), 7.94, did not differ significantly from the median pH of controls, 7.90, p=0.80. However, the median pH of patients with non-severe asthma, 7.90, was significantly lower than patients with severe asthma, 8.02 (p value not reported).
 
A 2012 cross-sectional study by Karakoc and colleagues in Turkey evaluated 42 children; 20 with persistent asthma (group 1); 10 with intermittent asthma (group 2), and 12 healthy controls (group 3) (Karakoc, 2012). EBC was collected from all participants and levels of matrix metalloprotease (MMP-9) and tissue inhibitors of metalloproteinases (TIMP-1) levels were analyzed. Mean MMP-9 of EBC levels was 57.7 ng/mL, 35.4 ng/mL, and 30.6 ng/mL in groups 1, 2 and 3, respectively. Levels were significantly higher in children with persistent asthma and intermittent asthma compared to controls. There were no significant differences among groups in levels of TIMP-1 of EBC.
 
In 2011, Piotrowski and colleagues in Poland prospectively studied adult patients with asthma (Piotrowski, 2012). The study included 27 patients with severe asthma who were receiving treatment (group 1), 16 newly diagnosed and never-treated asthma patients (group 2), and 11 health controls (group 3). At baseline and at weeks 4 and 8, EBC was collected and patients underwent spirometry and other tests of asthma severity. Patients were able to take all medications needed to control symptoms throughout the study. Levels of 8-isoprostane (8-IP) in breath condensate were analyzed. At baseline, the median level of 8-IP was 4.67 pg/mL, 6.93 pg/mL, and 3.80 pg/mL in groups 1, 2 and 3, respectively. There were no statistically significant differences among groups in 8-IP levels. In addition, 8-IP levels did not significantly correlate with asthma severity measures, including the number of symptom-free days, FEV1 reversibility, and scores on the asthma control test (ACT). In this study, 8-IP in EBC was not found to be a useful marker of asthma severity.
 
There is limited evidence on the use of EBC for determining asthma severity. The available evidence is insufficient to form conclusions on the utility of EBC for this purpose.
 
EBC used as markers of respiratory disorders other than asthma?
 
There is little published literature on EBC levels in patients with respiratory disorders other than asthma. A 2010 study by Antus and colleagues evaluated EBC in 58 hospitalized patients (20 with asthma and 38 with COPD) and 36 healthy controls (18 smokers and 18 non-smokers) (Antus, 2010). The EBC pH was significantly lower in patients with asthma exacerbations (all non-smokers) at hospital admission compared to non-smoking controls (6.2 vs. 6.4, respectively, p<0.001). The pH of EBC in asthma patients increased during the hospital stay and was similar to that of non-smoking controls at discharge. Contrary to investigators’ expectations, EBC pH values in ex-smoking COPD patients (n=17) did not differ significantly from non-smoking controls, either at hospital admission or discharge. Similarly, pH values in EBC samples from smoking COPD patients (n=21) at admission and discharge did not differ significantly from smoking controls.
 
EBC measurement used in guiding treatment decisions for patients with asthma or other respiratory disorders
 
No controlled studies were identified that evaluated the role of EBC tests in the management of asthma or other respiratory disorders. Uncontrolled studies include a 2009 case series investigating whether components of EBC could predict response to steroid treatment in patients with asthma (Matsunaga, 2009). Eighteen steroid-naive asthma patients were included; EBC collection, spirometry, and methacholine challenge were performed before and 12 weeks after inhaled steroid therapy (equivalent dose of 400 µg fluticasone propionate/d). Among the molecules in EBC examined, higher IL-4 and RANTES levels and lower IP-10 levels at baseline were correlated with an improvement in FEV1. The study had a small sample size, was uncontrolled, and did not address whether EBC measurement could improve patient management or health outcomes.
 
2014 Update
A literature search conducted through September 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
In 2013, See and Christiani published an evaluation of reference ranges for FeNO evaluated with the NIOX MINO for a representative sample of the U.S. population aged 6 through 80 years that was derived from the National Health and Nutrition Examination Survey (NHANES, 2007-2010) (See, 2010). They report that the range of FeNO values (5th-95th percentile) was 3.5 to 36.5 ppb for children younger than age 12 years and 3.5 to 39 ppb for individuals from 12 to 80 years of age and conclude that a reasonable upper limit of “normal” values for FeNO, as represented by 95% of the general population is 36 ppb for children younger than age 12 years and 39 for older individuals.
 
In 2013, Schneider et al in Germany reported findings from a prospective diagnostic study of 393 patients presenting to a pulmonology practice with signs/symptoms suggestive of obstructive airway disease (Schneider, 2013). FeNO was measured with the NIOX MINO device at a flow rate of 50 mL/s. Asthma was diagnosed based on bronchial provocation or bronchodilator testing. Among all 393 participants, receiver operating characteristic (ROC) analysis found that a FeNO cutoff of 25 ppb had the highest sum of sensitivity/specificity (sensitivity, 49%; specificity, 75%). The authors also evaluated the influence of inflammatory cell predominance in first morning sputum on the accuracy of FeNO in diagnosing asthma. Among the subset of 128 patients who provided sputum, when patients with a neutrophilic predominance on Giemsa-stained sputum smear slides were excluded, the highest sum of sensitivity and specificity was reached at a FeNO cutoff of 23 ppb (sensitivity, 67%; specificity, 77%).
 
Also in 2013, Katsoulis et al in Greece reported findings from an evaluation of 112 individuals aged 22 to 37 years recruited from an outpatient clinic setting who endorsed at least 1 symptom of asthma and had a negative bronchodilator test (Katsoulis, 2013). FeNO was measured with the NIOX MINO device at a flow rate of 50 mL/s. Asthma was diagnosed based on methacholine challenge. ROC analysis found that a FeNO cutoff of 32 best predicted bronchial hyper-reactivity on methacholine challenge (sensitivity, 47%; specificity, 85%).
 
Sverrild et al in Denmark reported results from a post hoc analysis of a random-sample population study of 238 individuals aged 14 to 24 years who underwent mannitol challenge and FeNO measurement using the NIOX (Sverrild, 2013).) Asthma was diagnosed based on assessment of a respiratory specialist and airway hyper-responsiveness was defined as a positive result on a mannitol challenge. Among 180 subjects who were not active smokers or on an inhaled corticosteroid, ROC analysis found that a FeNO cutoff of 25 ppb best predicted airway hyper-responsiveness (sensitivity, 86%; specificity, 84%).
 
Several trials have been published that addressed the association between FeNO and subsequent response to ICS. Anderson et al conducted a randomized crossover trial in 21 patients with persistent asthma and elevated FeNO levels (>30 ppb) receiving ICS at baseline (Anderson,  2012).) Following an ICS washout period, subjects were randomized to either low- or high-dose inhaled fluticasone, with a 2-week ICS washout period followed by crossover to the other arm. The primary outcome was diurnal household FeNO level measured by the NIOX MINO device. Analysis was performed on a per protocol basis. The authors reported significant improvements in FeNO compared with baseline for both morning and evening values, with a dose-dependent effect: morning FeNO decreased from baseline 71 ppb to 34 ppb for those receiving the lower dose ICS and to 27 ppb for those receiving the higher dose ICS; evening FeNO decreased from baseline 67 ppb to 31 ppb for those receiving the lower dose ICS and to 22 ppb for those receiving the higher dose ICS. While this study suggests that ICS dose is associated with FeNO levels, it is limited by its small size; furthermore, it does not address the question of FeNO’s role in predicting ICS response ex ante.
 
In 2013, Syk et al in Sweden published the results from an RCT of FeNO-based asthma management in a primary care setting among 187 nonsmoking patients aged 18 to 64 with asthma requiring regular ICS use (Syk, 2013). Subjects were randomized to a FeNO-guided management group or a control group and followed for 1 year. In the control group, treatment with an algorithm of escalating doses of inhaled corticosteroid (budesonide, fluticasone, or mometasone), with the addition of a leukotriene receptor antagonist (LTRA) at higher doses, was based on the discretion of the treating physician. In the FeNO-guided group, ICS and LTRA therapies were adjusted according to the same stepwise treatment plan as the control group, but with treatment decisions based on FeNO level. The algorithm for women was as follows: 1 step down for FeNO less than 19 ppb; no change for FeNO from 19 to 23 ppb; 1 step up for FeNO of 24 ppb or higher; and 2 steps up for FeNO of 30 ppb or higher. The algorithm for men was: 1 step down for FeNO less than 21 ppb; no change for FeNO from 21 to 25 ppb; 1 step up for FeNO of 26 ppb or higher; and 2 steps up for FeNO of 32 ppb or higher. The study’s primary outcome was changes in the mini Asthma Quality of Life Questionnaire (mAQLQ), with secondary outcomes of change in Asthma Control Questionnaire (ACQ) score, exacerbation frequency, lung function, quality-of-life score, and medication use. For the primary study outcome, there was no significant difference between groups on the change in the mAQLQ score (0.23 [interquartile range, 0.07-0.73] in the FeNO-guided group vs 0.07 [interquartile range, -0.20 to 0.80] in the control group, p=0.197). On secondary outcomes, the frequency of exacerbations was significantly lower in the FeNO-guided group than in the control group (0.22 vs 0.41 exacerbations/patient/year, p=0.024). The change in ACQ score was significantly higher in the FeNO-guided group than in the control group (-0.17 [interquartile range, -0.67 to 0.17] in the FeNO-guided group vs 0 [-0.33 to 0.50] in the control group, p=0.045). Other secondary outcomes did not show any significant differences. (The authors state that the mean ICS dose did not differ between the 2 groups, but statistics are not provided. Strengths of this study include a primary care-based setting, allowing results to be generalized to the setting in which most asthmatics are treated, a relatively large sample size, and a clearly outlined algorithm for how asthma therapy was adjusted. Limitations include the fact that the analysis was not intention-to-treat and the article does not provide details about the statistical comparisons to support several of its conclusions.
 
Also in 2013, Peirsman et al in Belgium reported results from an industry-sponsored single-blind RCT of a FeNO-based asthma management strategy among 99 children aged 5 to 14 years with persistent allergic asthma (Peirsman, 2013). Similar to the Syk study, subjects were randomized to a FeNO-guided management group or a control group and followed for 1 year. In the control group, treatment was guided by the Global Initiative for Asthma (GINA) guidelines on the basis of symptom reporting every 3 months. Details about who made decisions about treatment were not provided. In the FeNO-guided management group, FeNO measurements and the degree of symptom control were used to guide therapy based on a treatment algorithm. Using a classification of controlled asthma (FENO of ≤20 ppb and no symptoms), partly controlled asthma (FENO of ≤20 ppb with symptoms), or uncontrolled asthma (FENO of >20 ppb), ICS, LTRA, and long-acting beta-2 agonist therapies were stepped up or down on each visit. The primary outcome was symptom-free days; secondary outcomes were exacerbations, unscheduled asthma-related contact, hospital or emergency department admissions, and nonattendance at school. The authors found no significant differences between the treatment and control group on the primary outcome of symptom-free days, as recorded by symptom diary; the ability to detect a difference in this outcome may have been limited by a considerable amount of missing data, with 10 children failing to provide data for more than 85% of days. On secondary outcomes, the FeNO-guided group had significantly fewer asthma exacerbations (18 vs 35 exacerbations/year, p=0.02) but no differences on emergency department visits, hospital admissions, or time missed from school. While there was no difference between the median cumulative daily ICS doses between the groups, the FeNO group demonstrated a greater change in ICS dose from the beginning to the end of the study compared with the control group (0 mg vs +100 mg, p=0.016).
 
In 2011, Piotrowski et al in Poland prospectively studied adult patients with asthma (Piotrowski, 2012). The study included 27 patients with severe asthma who were receiving treatment (group 1), 16 newly diagnosed and never-treated asthma patients (group 2), and 11 health controls (group 3). At baseline and at weeks 4 and 8, EBC was collected and patients underwent spirometry and other tests of asthma severity. Patients were able to take all medications needed to control symptoms throughout the study. Levels of 8-isoprostane (8-IP) in breath condensate were analyzed. At baseline, the median level of 8-IP was 4.67 pg/mL, 6.93 pg/mL, and 3.80 pg/mL in groups 1, 2 and 3, respectively. There were no statistically significant differences among groups in 8-IP levels. In addition, 8-IP levels did not significantly correlate with asthma severity measures, including the number of symptom-free days, FEV1 reversibility, and scores on the asthma control test. In this study, 8-IP in EBC was not found to be a useful marker of asthma severity.
 
2015 Update
 
A literature search conducted through December 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
FeNO has been evaluated in a variety of contexts, including (but not limited to) the diagnosis of asthma, as a predictor of eosinophilic inflammation, as a predictor of response to inhaled corticosteroids and other medications, and as a marker of non-adherence in patients managed with inhaled corticosteroids.
 
Does FeNO Aid in the Diagnosis of Asthma in Individuals With Signs or Symptoms of Asthma?
A large number of studies have been conducted that correlate the presence of asthma with higher FeNO levels; a complete review is beyond the scope of this policy. The sensitivity and specificity of FeNO for the diagnosis of asthma is dependent on the cutoff point that is used. To date, the optimal cutoff point remains undefined; studies that report the sensitivity, specificity, and/or the positive and negative predictive value or positive and negative likelihood ratios for FeNO with various cutoffs in the diagnosis of asthma are outlined here.
 
In a follow up study published in 2014, Schneider et al compared the prognostic value of bronchoprovocation testing with FeNO in combination with clinical history in the assessment of asthma using the same population as described in the 2013 Schneider et al study (Schneider, 2014). Follow up data from subjects and their treating physicians were available for 302 subjects (76.8%). At 1 year follow-up, 83 subjects were considered to have asthma by their treating physicians (27.5% of the 302 subjects with available data). In ROC analysis, the area under the curve (AUC) for enrollment FeNO level predicting asthma at 1 year follow up was 0.603 (95% CI 0.528 to 0.677). The highest sum of sensitivity/specificity occurred with a FeNO cut-off point of 26 ppb, which was associated with a sensitivity of 47.0% (95% CI 36.6 to 57.6%) and a specificity of 73.1% (95% CI 66.8% to 78.5%).
 
Arga et al published a retrospective cross-sectional evaluation of the role of FeNO in predicting bronchial hyper-responsiveness to adenosine 5’-monophosphate (AMP) among steroid-naïve children with a diagnosis of asthma (Arga, 2014).The authors considered bronchial hyper-responsiveness to AMP a more direct measure of airway inflammation than bronchial hyper-responsiveness to methacholine. The study included 116 patients with a diagnosis of asthma based on clinical history with evidence of reversible airflow limitation on spirometry or a favorable response to inhaled corticosteroids and/or bronchodilators. The authors reported significant correlation between PC20 (provocative concentration of AMP or methacholine causing a 20% decrease in FEV1) for AMP and FeNO (Spearman’s rho: -0.466; P<0.001), but not between PC20 methacholine and FeNO (Spearman’s rho: -0.115; P=0.220). FeNO levels were higher in atopic subjects (N=69; 59.5%) compared with non-atopic subjects (44.53 vs 25.6 ppb; P<0.001). In receiver operator curve (ROC) analysis, the best FeNO cutoff value to predict bronchial hyper-responsiveness to AMP was 33.3 ppb among atopic subjects, with a sensitivity of 78.36% and specific of 74.47%.
 
Backer et al retrospectively evaluated the role of FeNO in the diagnosis of asthma among a population of adults presenting to an asthma clinic with suspected asthma (Backer, 2014). Two hundred seventeen patients were identified, of whom 141 underwent testing with both FeNO testing with the NIOX Mino device and mannitol challenge. For patients who had both tests, 32 (23%) had FeNO greater than 25 ppb, while 58 (41%) had airway hyper-responsiveness to mannitol. Thirty-six subjects (26%) had airway hyper-responsiveness to mannitol but a FeNO level below 25 ppb. The area under the ROC curve for FeNO as a predictor of airway hyper-responsiveness was 0.66 (95% CI 0.6 to 0.8), and for mannitol for having a high FeNO was 0.72 (95% CI 0.6 to 0.9). Neither FeNO level nor airway hyper-responsiveness was predictive of asthma control. The authors hypothesize that the explanation for the large proportion of subjects with low FeNO but positive airway hyper-responsiveness was related to the inclusion of subjects on ICS (44% of entire population of 217) and smokers (5% of entire population of 217.)
 
Buslau et al conducted a study to determine predictors of bronchial allergen-induced asthma among individuals with allergic rhinitis which included FeNO as a predictor (Buslau, 2014). The authors identified 100 subjects with allergic rhinitis and 20 healthy control subjects; 23 subjects with physician-diagnosed asthma and 4 subjects with negative skin-prick testing were excluded, leaving a final sample of 73 allergic rhinitis subjects and 20 health control subjects. Thirty-nine of 73 allergic rhinitis patients had significant early asthmatic response on bronchial allergy provocation testing. Patients with allergic rhinitis and bronchial hyper-reactivity had a significantly higher FeNO value compared with control subjects (29.3 ppb vs 18.1 ppb; P<0.05). On ROC analysis, for FeNO as a predictor of positive bronchial allergy provocation testing, the area under the ROC curve was 0.64 (P<0.05) with a FeNO cutoff of 18.05, with a sensitivity of 74.4% (95% CI 57.9 to 87.0%) and a specificity of 61.1% (95% CI 46.9 to 74.1%).
 
Chang et al conducted a longitudinal study to relate levels of FeNO in early childhood to the development of asthma at age 5 (Chang, 2014). The study included 116 infants and toddlers with eczema with no history of asthma or wheezing, of whom 90 were evaluated at 5 years of age. At age 5, 61 subjects (68%) had a diagnosis of asthma. Subjects with asthma at age 5 years had significantly higher FeNO values at study entry before any wheezing (FeNO difference: 3.5 ppb; 95% CI 0.12 to 6.84 ppb; P=0.035), along with a significantly higher FeNO at age 5 compared with subjects without asthma (FeNO difference: 10.8 ppb; 95% CI 1.52 to 19.99; P=0.023).
 
Florentin et al conducted a nested case-control to assess the use of FeNO in the diagnosis of occupational asthma among workers in the bakery and hairdressing industries (Florentin, 2014). One hundred seventy-eight workers were included, 19 of whom were diagnosed with confirmed or probable occupational asthma based on clinical evaluation, 3 weeks of peak-flow monitoring, spirometry with bronchodilator challenge, and work-related specific IgE assays, when available. FeNO values were significantly higher in cases with occupational asthma than in controls without asthma (N=159 controls; 25.0 ppb vs 9.0 ppb). In ROC analysis for the use of FeNO in the diagnosis of occupational asthma, the AUC was significantly different than the reference line (AUC 0.717; 95% CI 0.574 to 0.860; P=0.002). FeNO cutoffs of 25 ppb and 50 ppb were associated with low sensitivity for the diagnosis of asthma: for 25 ppb, sensitivity 42.1% and specificity 92.4%; for 50 ppb, sensitivity 21% and specificity 98.7%.
 
Grzelewski et al evaluated the role of FeNO in the diagnosis of asthma among schoolchildren in a large, retrospective cross-sectional study (Grzelewski, 2014). The study included 3612 children evaluated for asthma in a single-center outpatient clinic from 2005 to 2012 who had at least 2 years of follow up, of whom 2178 (60%) were diagnosed with asthma based on physical exam and an improvement in FEV1 after salbutamol. In ROC analysis, the optimal cut point for FeNO for the diagnosis of asthma was 15.8 ppb; FeNO levels above 15.8 were associated with a an increased likelihood of asthma in logistic regression analysis (odds ratio [OR] 1.007; 95% CI 1.003 to 1.011; P<0.0001).
 
In a retrospective, cross-sectional study, Jerzynska et al evaluated the role of FeNO in the diagnosis of asthma in patients with and without atopy and allergic rhinitis (Jerzynska, 2014). The study included 1767 children evaluated for symptoms of allergic disease, including asthma and/or allergic rhinitis seen at a single outpatient clinic from 2005 to 2012. It appears that this study was conducted in the same center as the Grzelewski et al study reported above. For the present study, included children had a minimum of 3 years of prospective clinical observation after the first FeNO measurement until a final determination about presence or absences of asthma or allergic disease was made. Asthma diagnosis criteria were the same as for the Grzelewski et al study. An asthma diagnosis was made in 1054 children (59.6%). In a subgroup analysis of 389 patients with atopy and allergic rhinitis, based on ROC analysis, the optimal cut point for FeNO for asthma diagnosis in patients with atopy and allergic rhinitis was 23 ppb. A FeNO cutoff of 23 ppb was associated with a sensitivity of 90% (95% CI 68% to 98%) and specificity of 52% (95% CI 42% to 61%) for the diagnosis of asthma in subjects with atopy and allergic rhinitis
 
In 2013, as part of the development of National Institute for Health and Care Excellence (NICE) guidelines on the use of FeNO in the management of asthma (see “Practice Guidelines and Position Statements” section), Harnan et al. conducted a health technology assessment to assess the clinical and cost-effectiveness of FeNO measurements in people with asthma (Harnan, 2013). The authors identified 24 studies that met their inclusion criteria and addressed the use of FeNO in the diagnosis of asthma. The authors concluded, “Given the wide ranging estimates of sensitivity and specificity, together with heterogeneous cut-off points, it is difficult to draw any firm conclusions as to the diagnostic accuracy of FeNO in any situation and at any given cut-off point.”
 
Does FeNO Level Predict Response to Medication Therapy in Patients With Asthma?
 
FeNO and Response to Inhaled Corticosteroids. The largest body of evidence related to the use of FeNO in the management of asthma is in identifying eosinophilic airway inflammation and predicting response to inhaled corticosteroids.
 
The 2011 clinical practice guideline from the ATS recommended the use of FeNO to determine the likelihood of response to steroids in individuals with chronic respiratory symptoms that are possibly due to airway inflammation (Dweik, 2011). Data from three randomized controlled trials (RCTs) were cited in the guideline in support of this recommendation  In a 2002 open-label trial, Szefler et al randomized 30 asthma patients to 1 of 2 types of ICS (Szefler, 2002)...There was a higher rate of response to ICS (defined as an increase in FEV of at least 15%) baseline FeNO (median, 17.6 ppb) compared to lower baseline FeNO (median, 11.1 ppb). 28 Steroid response was defined as an increase in FEVIn 2005, Smith et al conducted a single-blind placebo-controlled trial of inhaled fluticasone in 60 patients presenting with undiagnosed respiratory symptoms.1 of at least 12% or an increase in peak morning flow (over the previous 7 days) of 15% or greater. In the 52 (87%) patients who completed the study, steroid response was significantly higher in patients with the highest FeNO quartile at baseline (>47 ppb) for both of the study end points.  29 The study was a planned post hoc analysis of data from an RCT comparing different treatment regimens in children with asthma. The authors evaluated predictors of long-term response to treatment in 191 children who received either fluticasone or montelukast. In a multivariate analysis, statistically significant predictors of a better asthma control days response to fluticasone over montelukast were a baseline FeNO of at least 25 ppb (p=0.01) and a parental history of asthma (p=0.02). All of these 3 studies found significant associations between baseline FeNO and response to inhaled corticosteroids. A baseline FeNO of over 47 ppb had 67% sensitivity and 78% specificity for predicting response to steroids, when response was defined as an increase in FEV1. When response to steroids was defined as an increase in peak morning flow, there was 82% sensitivity and 81% specificity for predicting response. The third study cited in the ATS guideline in support of FeNO for predicting response to corticosteroids was published by Knuffman et al in 2009.
 
2016 Update
A literature search conducted through December 2015 identified numerous published studies since the last policy update. A review of these studies does not prompt a change in the coverage statement.
 
2017 Update and later
Due to the detail, the entire rationale is not online. If you would like a hardcopy print, please email : codespecificinquiry@arkbluecross.com

CPT/HCPCS:
83987pH; exhaled breath condensate
94799Unlisted pulmonary service or procedure
95012Nitric oxide expired gas determination

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