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MP 2.01.61 Measurement of Exhaled Nitric Oxide and Exhaled Breath Condensate in the Diagnosis and Management of Asthma and Other Respiratory Disorders

Medical Policy    

Section

Medicine

Original Policy Date
10/9/03
Last Review Status/Date
Reviewed with literature search/1:2015
Issue
1:2015
  Return to Medical Policy Index

Disclaimer

Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract.  Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage.  Medical technology is constantly changing, and we reserve the right to review and update our policies periodically. 


Description

Asthma is characterized by airway inflammation that leads to airway obstruction and hyper-responsiveness, which in turn lead to characteristic clinical symptoms including wheezing, shortness of breath, cough, and chest tightness. 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 1 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. NO 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. While the role of NO in asthma pathogenesis is still under investigation, patients with asthma have been found to have high levels of exhaled NO, which decreases with treatment with corticosteroids. 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 NO-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 NO (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.(1) 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.

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, pulmonary hypertension, and primary ciliary dyskinesia.

Regulatory Status

In 2003, 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 antiinflammatory 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 handheld and portable and that it is not suitable for children younger than 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 FDA. FDA product code: MXA.

The RTube™ Exhaled Breath Condensate collection system (Respiratory Research Inc.) and the ECoScreen EBC collection system (CareFusion, Germany) are registered with FDA as a class I devices that collect expired gas. Respiratory Research has a proprietary gas-standardized pH assay, which, when performed by the company, is considered a laboratory-developed test.


Policy 

Measurement of exhaled nitric oxide is considered investigational in the diagnosis and management of asthma and other respiratory disorders including but not limited to chronic obstructive pulmonary disease and chronic cough.

Measurement of exhaled breath condensate is considered investigational in the diagnosis and management of asthma and other respiratory disorders including but not limited to chronic obstructive pulmonary disease and chronic cough.


Policy Guidelines

There is a CPT code specific to direct determination of exhaled nitric oxide (eg, using the NIOX system):

95012: Nitric oxide expired gas determination

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

A variety of substances has been analyzed in a collected sample of exhaled breath condensate, including but not limited to leukotrienes, cytokines, and other substances reflecting oxidative stress. The above CPT code would not apply to this expanded analysis of exhaled breath condensate. It is likely that specific CPT codes describing the underlying laboratory technique for analysis would be used.


Benefit Application
BlueCard/National Account Issues  

State or federal mandates (e.g., FEP) may dictate that all devices approved for marketing by the FDA may not be considered investigational, and thus these devices may be assessed only on the basis of their medical necessity.


Rationale

This policy was created in 2003 and updated regularly with a literature review using the MEDLINE database, most recently through November 25, 2014. Evaluation of diagnostic tests requires that the test findings are reproducible on test-retest and that the test is reasonably accurate compared with a validated reference standard. Fractional exhaled nitric oxide (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 (ICS) and other medications, and as a marker of nonadherence in patients managed with ICS. Assessment of the clinical role of FeNO and exhaled breath condensate (EBC) tests requires controlled studies of those managed conventionally compared with those whose management was additionally directed by test measurements.

Following is a summary of the key literature to date.

Fractional Exhaled Nitric Oxide

FeNO in Asthma Management

Reproducibility of fractional concentration of exhaled nitric oxide measurements

In 2010, Selby et al published a study from the UK that evaluated the reproducibility of exhaled NO measurements in young people.(2) The study included 494 teenagers, aged 16 to 18 years, from an unselected birth cohort and 65 asthma patients between the ages of 6 and 17 years. Paired readings were obtained from each participant. The mean within-participant difference in fractional concentration of exhaled NO (FeNO) (second reading minus the first reading) was 1.37 parts per billion (ppb) (95% confidence interval [CI], -7.61 to 10.34 ppb); this difference was statistically significant; p less than 0.001. When participants with high FeNO values (above 75 ppb) were excluded, there was a lower mean within-participant difference, 0.90 ppb (95% CI, -4.89 to 6.70 ppb). Among the 71 participants with asthma, the mean within-participant difference in FeNO in the 2 measurements was 2.37 ppb (95% CI, -11.38 to 16.12 ppb). When FeNO values were categorized as low, normal, intermediate, or high (using different values for participants younger than age 12 years and 12 years or older), the findings were reproducible. That is, there were no statistically significant differences in the categorization using the first and second measurement.

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 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).(3) 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.(4) 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) curve 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%).

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.(5) 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 cutoff 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%).

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.(6) 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 hyperreactivity 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.(7) Asthma was diagnosed based on assessment of a respiratory specialist and airway hyperresponsiveness 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 hyperresponsiveness (sensitivity, 86%; specificity, 84%).

In 2012, Malinovschi et al in Denmark evaluated 282 individuals with symptoms suggestive of asthma.(8) Study participants were part of a sample of 10,400 individuals aged 14 to 44 years randomly selected from the civil registration list in Denmark. Individuals were eligible for the study if they had at least 2 symptoms suggestive of asthma. FeNO was measured with the NIOX MINO device, and patients were examined by a respiratory specialist to determine the clinical diagnosis of asthma. Among the 282 participants, 112 were current smokers, 108 never smoked, and 62 were ex-smokers. According to clinical evaluation, 96 of 282 (34%) had asthma, 32 smokers, 45 never smokers, and 19 ex-smokers. The authors examined different cutoffs of FeNO to determine the value with the optimal sensitivity and specificity for diagnosing asthma. They proposed a cutoff of 17 ppb in current smokers (sensitivity, 56.3%; specificity, 82.5%), 15 ppb in never smokers (sensitivity, 77.8%; specificity, 63.5%), and 22 ppb in ex-smokers (sensitivity, 63.2%; specificity, 86.1%).

Another 2012 study, by Schleich et al in Belgium, prospectively evaluated 174 individuals with suspected asthma who were referred for a methacholine challenge and who were not currently receiving ICS.(9) FeNO was measured with a NIOX device set at a flow rate of 50 mL/s. According to the methacholine challenge test findings, 82 of 174 (47%) of participants were diagnosed with asthma (ie, provocative  concentration of methacholine [PC20M] was 16 mg/mL or lower). FeNO was significantly higher in patients with a positive methacholine challenge (19 ppb) than a negative challenge test (15 ppb) (p<0.05). ROC analysis found that a FeNO cutoff of 34 ppb best predicted the outcome of the methacholine challenge test (sensitivity 35.4%, specificity 95.4%).

Woo et al in Korea also published a study in 2012 using prospectively collected data on 245 consecutive steroid-naïve children with respiratory symptoms suggestive of asthma.(10) FeNO was measured using the NIOX MINO, and lung function tests were performed with spirometry. Asthma was diagnosed in 167 (68%) of participants. Using ROC analysis, the investigators found that the optimal cutoff for FeNO in diagnosing asthma was 22 ppb, which provided 56.9% sensitivity and 87.2% specificity. At a cutoff of 42 parts per trillion, the specificity was 100%, but the sensitivity was very low, 23.4%.

Other representative studies include one using the NIOX MINO device that was published in 2010 by Pedrosa et al in Spain.(11) The study included 114 individuals at least 14 years old who had symptoms consistent with asthma, with or without rhinitis symptoms, and had normal parameters on spirometry and a negative bronchodilator test. Definitive diagnosis was based on symptom assessment and a positive methacholine bronchial challenge test. Individuals underwent FeNO assessment (flow rate of 50 mL/s) just before the methacholine inhalation challenge test. According to challenge test findings, 35 patients (31%) were diagnosed with asthma. FeNO levels were significantly higher in individuals diagnosed with asthma (mean, 58 ppb) than in nonasthmatic patients (mean, 30 ppb; p<0.001). Using ROC analysis, the
cutoff point with maximum sensitivity (74.3%) and specificity (72.5%) for diagnosing asthma was a FeNO value of 40 ppb. A 2010 study conducted in Italy included 280 children with asthma, allergic rhinitis, or both.(12) The authors used ROC analysis and found that the optimal cutoff for discriminating between patients with bronchial hyperactivity from those with absent or borderline bronchial hyperactivity was 32
ppb of NO. In 2009, Schneider et al in Germany published data on 160 patients with symptoms suspicious of asthma.(13) All patients underwent measurement of exhaled NO. The reference standard was a stepwise series of tests, beginning with spirometry. Those with forced expiratory volume in 1 second (FEV1) less than 80% of predicted or FEV1/vital capacity ratio of 0.70 or less were referred to bronchodilator reversibility testing. Otherwise, patients 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 with baseline, and at least 200 mL, and lung volumes returned to predicted normal range; and (2) bronchial provocation found a 20% decrease in FEV1 from the baseline value after inhaling methacholine stepwise until the maximum concentration. FeNO test findings were compared with the final diagnosis status. According to standard testing, 75 (46.9%) of the patients had asthma. ROC analysis found the highest sum of sensitivity and specificity of FeNO at a cutoff of 46 ppb. Among patients with unsuspicious spirometry findings (n=101), 49 had asthma. The optimal cutoff of FeNO in this subgroup was also 46 ppb; the sensitivity of FeNO was 35%, and the specificity was 90%.

Arga et al published a retrospective cross-sectional evaluation of the role of FeNO in predicting bronchial hyperresponsiveness to adenosine 5'-monophosphate (AMP) among steroid-naive children with a diagnosis of asthma.(14) The authors considered bronchial hyperresponsiveness to AMP a more direct measure of airway inflammation than bronchial hyperresponsiveness 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 ICS 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 p, -0.466; p<0.001), but not between PC20
methacholine and FeNO (Spearman p, -0.115; p=0.220). FeNO levels were higher in atopic subjects (n=69 [59.5%]) compared with nonatopic subjects (44.53 vs 25.6 ppb; p<0.001). In ROC analysis, the best FeNO cutoff value to predict bronchial hyperresponsiveness 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.(15) Two hundred seventeen patients were identified, 141 of whom 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 hyperresponsiveness to mannitol. Thirty-six subjects (26%) had airway hyperresponsiveness to mannitol but a FeNO level below 25 ppb. The area under the ROC curve for FeNO as a predictor of airway hyperresponsiveness 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 hyperresponsiveness was predictive of asthma control. The authors hypothesize that the explanation for the large proportion of subjects with low FeNO but positive airway hyperresponsiveness 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.(16) 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 healthy 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 hyperreactivity 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, and 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.(17) The study included 116 infants and toddlers with eczema with no history of asthma or wheezing, 90 of whom 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.(18) One hundred seventyeight 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.(19) 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 an increased likelihood of asthma in logistic regression analysis (odds ratio [OR], 1.007; 95% CI, 1.003 to 1.011; p<0.001).

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.(20) 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 previously reported. 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.

Studies which report the sensitivity and specificity of FeNO in the diagnosis of asthma are summarized in Table 1.

Table 1: Studies Evaluating FeNO in Asthma Diagnosis

Author

Year

N

Population

Criterion Standard

Proposed Cutoff

Sens

Spec

Malinovschi et al(8)

2012

282

Aged 14-44 y with signs/symptoms suggestive of asthma

Clinical diagnosis by respiratory specialist

17 ppb (current smokers)

56.3%

82.5%

 

 

 

 

 

15 ppb (never smokers)

77.8%

63.5%

 

 

 

 

 

22 ppb (exsmokers)

63.2%

86.1%

Schleich et el(9)

2012

174

Individuals with suspected asthma referred for methacholine challenge

Positive methacholine challenge

34 ppb

35.4%

95.4%

Woo et al(10)

2012

245

Steroid-naive children with symptoms suggestive of asthma

Lung function testing

22 ppb

56.9%

87.2%

Pedrosa et al(11)

2010

114

Individuals aged 14+ y with symptoms consistent with asthma but normal spirometry and negative bronchodilator challenge

Positive methacholine challenge

40 ppb

74.3%

72.5%

Ciprandi et al(12)

2010

280

Children with asthma, allergic rhinitis, or both

Positive methacholine challenge

32 ppb

(predictive of

“bronchial

hyperreactivity”)

 

 

Schneider et al(13)

2009

160

Individuals with symptoms suggestive of asthma

Stepwise testing, including spirometry, bronchodilator challenge, and methacholine challenge

46 ppb

 

 

 

 

101

Subgroup with symptoms of asthma but normal spirometry

 

46 ppb

35%

90%

Schneider et al(4)

2013

393

Individuals with signs/symptoms of obstructive airway disease

Bronchial provocation or bronchodilator testing

25 ppb

35%

75%

 

 

109

Subgroup with symptoms but no neutrophilia on induced sputum

 

23 ppb

47%

85%

Katsoulis et al(6)

213

112

Individuals aged 25-37 y with asthma-like symptoms (based on 1 positive answer on 12-item questionnaire) and a

negative bronchodilation testing

Methacholine challenge

32 ppb

47%

85%

Sverrild et

al(7)

2013

180

Unselected individuals aged 14-24 y with no history of smoking or inhaled corticosteroid use

Mannitol challenge

25 ppb

86%

84%

Arga et al(14)

2014

116

Patients with a diagnosis of asthma on clinical history and evidence of reversible airway obstruction on spirometry

Hyperresponsiveness to AMP

33.3 ppb

78.36%

74.47%

Buslau et al(16)

2014

73

Subjects with allergic rhinitis and no history of asthma

Bronchial allergy provocation testing

18.05 ppb

74.4%

61.1%

Florentin et al(18)

2014

178

Adults in the bakery or hairdressing industries

Diagnosis of occupational asthma: clinical evaluation, peak-flow monitoring, spirometry and work-related specific IgE assays

25 ppb

42.1%

92.4%

 

 

 

 

 

50 ppb

21%

98.7%

Jerzynska et al(20)

2014

389

Children with atopy and allergic rhinitis

Physical exam and iimprovement in FEV1

23 ppb

90%

52%

AMP: adenosine 5'-monophosphate; FeNO: fractional exhaled nitric oxide; FEV1: forced expiratory volume in 1 second; sens: sensitivity; spec: specificity.

A 2011 clinical practice guideline from ATS) (described in more detail and critically appraised in the section on Practice Guidelines and Position Statements) recommended FeNO cutoff values for predicting the presence of eosinophilic inflammation.(21) Many, but not all, patients with asthma will have eosinophilic inflammation. The guidelines recommended that FeNO less than 25 ppb (<20 ppb in children) be used to
indicate that eosinophilic inflammation is less likely and that FeNO greater than 50 ppb (>35 ppb in children) be used to indicate that eosinophilic inflammation is more likely. Based on their assessment of U.S. population-based normal ranges for FeNO, See and Christiani concluded that the ATS thresholds are reasonable to use for clinical decision making.(3) However, the sensitivity and specificity of these
recommended cutoffs have not been evaluated in published studies for the diagnosis of asthma.

In 2013, as part of the development of National Institute for Health and Care Excellence 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.(22) 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.”

FeNO for the Diagnosis of Asthma Subtypes

FeNO has also been studied as a way to identify particular subtypes of asthma or wheezing phenotypes, or for the identification of more severe asthma. Studies related to this indication are primarily crosssectional studies, which are summarized in Table 2.

Table 2: Studies of FeNO for the Diagnosis of Asthma/Wheezing Subtypes

Study

Overview

Population

FeNO Cutoff

Primary Results

Oh et al(2013)(23)

Characterize FeNO levels in different wheezing phenotypes in young children

372 children aged 4-6 y with and without a history of wheezing

  • 67 transient wheezers
  • 23 persistent wheezers
  • 282 nonwheezers

NA

  • Persistent wheezers had significantly higher FeNO than transient wheezers (14.4 ppb vs 11.5 ppb; p<0.005) and non-wheezers (14.4 ppb vs 10.1 ppb; p<0.005)
  • Persistent wheezers with airway hyper-responsiveness and atopy had significantly higher FeNO than wheezers without atopy (27.0 ppb vs 10.9 ppb; p<0.05) and wheezers without airway hyper-responsiveness (27.0 ppb vs 11.2 ppb; p<0.05)

Dweik et al(2010)(24)

Use FeNO levels to characterize asthma severity

446 adults with various degrees of asthma severity

  • 175 with severe asthma
  • 271 with nonsevere asthma
  • 49 healthy controls

35 ppb

  • Proportion of asthmatics with high FeNO did not differ between severe and nonsevere asthmatics (nonsevere 40% vs severe 40%)
  • Asthmatics with high FeNO more likely to be atopic based on positive skin prick tests, serum IgE, and blood eosinophils
  • Asthmatics with high FeNO more likely to have been in the ED (73% vs 66%; p=0.05) or admitted to ICU (25% vs 16%; p=0.02)

Perez-de-Llano et al (2010)(25)

Use FeNO levels to identify patients who may respond to highdose ICS or systemic steroids

102 patients with suboptimal asthma control treated with highdose fluticasone/salmeterol x1 mo, followed by systemic steroids if ongoing poor control

30 ppb

  • 53 patients (52%) gained asthma control
  • FeNO value ≥30 ppb had sensitivity of 87.5% (95% CI, 73.9 to 94.5) and specificity of 90.6% (95% CI, 79.7 to

95.9) in predicting those who gained control

Langley et al(2014)(26)

Use FeNO levels to identify acute asthma exacerbation severity

436 children aged 5-17 y presenting with acute asthma exacerbation

NA

FeNO was associated with percent predicted FEV1 in multivariable model: regression β coefficient -5.5% (95% CI,

-1.7 to -9.4; p<0.018)

CI: confidence interval; ED: emergency department; FeNO: fractional exhaled nitric oxide; FEV1: forced expiratory volume in 1 second; ICS: inhaled corticosteroids; ICU: intensive care unit; ppb: parts per billion.

Section Summary

Numerous studies have evaluated measurement of FeNO as a tool to aid in the diagnosis of asthma or particular asthma subtypes. The optimal cutoff of FeNO for diagnosing asthma has varied among studies. Available studies tend to report low to moderate sensitivity and moderate to high specificity, but with wide variability among studies that may be related to different cutoff levels used, different study populations, and different “criterion standards” for asthma diagnosis. ATS has issued consensus guidelines regarding optimal cutoffs to predict eosinophilic inflammation, although these specific cutoffs have not been evaluated in published studies for diagnosing asthma. No studies were identified that evaluated whether the use of FeNO improved the accuracy of asthma diagnosis compared with clinical diagnosis. Given these limitations, it is not possible to evaluate whether the use of FeNO levels in clinical practice improves the accuracy of diagnosing asthma.

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 ICS.

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.(21) Data from 3 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.(27) There was a higher rate of response to ICS (defined as an increase in FEV1 of at least 15%) in individuals with higher baseline FeNO (median, 17.6 ppb) compared with lower baseline FeNO (median, 11.1 ppb). In 2005, Smith et al conducted a single-blind placebo-controlled trial of inhaled fluticasone in 60 patients presenting with undiagnosed respiratory symptoms.(28) Steroid response was defined as an increase in FEV1 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. A baseline FeNO of over 47 ppb had a 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 an 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.(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 3 studies found significant associations between baseline FeNO and response to ICS.

Following the ATS clinical practice guideline publication, several studies have been published that address the association between FeNO and markers of airway inflammation and 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.(30) 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.

In 2014, Malinovschi et al conducted a retrospective observational study in 153 beclomethasone-treated asthmatic subjects to evaluate whether baseline FeNO measurements were associated with response to therapy.(31) Patients were previously steroid-naive and were treated with ICS according to Global Initiative for Asthma (GINA) guidelines. At follow-up, asthma control (response to therapy) was assessed with the French version of the Asthma Control Questionnaire (ACQ) and spirometry. Asthma inflammation was classified by FeNO based on ATS guidelines into normal (FeNO <25 ppb), intermediate (FeNO ≥25 but <50 ppb), or high (≥50 ppb). Compared with those in the low-inflammation group, a higher proportion of subjects in the groups with intermediate- and high-inflammation achieved an improvement of ACQ by at least 1 point (p=0.02 for high- vs low-inflammation group; p=0.004 for intermediate- vs low-inflammation group; proportions presented in graphical form but point estimates not provided). In multiple logistic regression analysis, having intermediate (vs low) and high (vs low) FeNO-estimated inflammation were significantly associated with likelihood of having an ACQ improvement of at least 1 point (adjusted odds
ratio [OR], 7.63 [95% CI, 1.65 to 35.3] for intermediate vs low; adjusted OR=4.10 [95% CI, 1.10 to 15.2] for high vs low).


Visitsunthorn et al conducted a cross-sectional study to assess the relationship between FeNO measurements and asthma control in 114 children with atopic asthma.(32) Enrolled subjects had a diagnosis of asthma based on clinical symptoms and a positive reaction to at least 1 aeroallergen on skin prick testing. Most of the patients had mild persistent asthma (79.8%) followed by moderate to severe persistent asthma (14.9%) and mild intermittent asthma (5.3%). Median FeNO levels were not statistically significantly different between patients with controlled, partially controlled, and uncontrolled asthma based on the Asthma Control Test (ACT). In a subgroup analysis of the 20 patients who were steroid-naive, patients with uncontrolled asthma had higher median FeNO level than those with controlled asthma (92 ppb vs 31.8 ppb; p=0.034) and partially-controlled asthma (92 ppb vs 34.1 ppb; p=0.027), although Cis around the FeNO estimates were wide.

Wilson et al investigated whether FeNO predicted loss of symptom control after the reduction of ICS dose in a cohort of 191 well-controlled asthmatic patients.(33) Following 50% reduction in ICS dose, 128 participants (67%) had no loss of asthma control (defined as an Asthma Control Questionnaire-5 [ACQ-5] score >0.5) or exacerbation, while 63 participants (33%) had either a loss of asthma control (n=32 [17%]) or an asthma exacerbation (n=31 [16%]). There was no significant difference in baseline FeNO level between those who successfully reduced their ICS dose and those who had loss of control or an exacerbation with a reduced ICD dose: geometric mean FeNO level 18.9 ppb in the stable group compared with 19.7 ppb in the unstable group (p=0.76).

FeNO and Response to Other Medications

While most studies on the predictive value of FeNO measurements relates to its use in predicting response to ICS, there has been some interest in evaluating the relationship between FeNO and other medications that target steps in the Th2-inflammation cascade. In 2013, Hanania et al evaluated the association between FeNO, along with peripheral blood eosinophil count and periostin level, in the prediction of response to omalizumab, and anti-IgE monoclonal antibody, in the management of patients with uncontrolled severe persistent asthma.(34)
The study included 850 individuals aged 12 to 75 who were randomized to treatment with omalizumab or control, of whom 394 (46.4%) had available FeNO measurements. The study predefined the median of FeNO levels as the cutoff for determining high and low subgroups: 19.5 ppb or less versus greater than 19.5 ppb. Patients with high FeNO levels (>19.5 ppb) treated with omalizumab demonstrated a 53% reduction (95% CI, 37% to 70%; p=0.001) in exacerbations compared with those treated with placebo, whereas those with low FeNO levels (≤19.5 ppb) treated with omalizumab demonstrated a nonsignificant 16% reduction (95% CI, -32 to 46; p=0.45). Similar results were obtained in a post hoc analysis that used the ATS-recommended FeNO cutoffs to determine high and low FeNO groups.

Section Summary

Several studies have evaluated the association between FeNO level and response to ICS or loss of asthma control with reduction of steroid dose. These studies have been mixed in demonstrating a significant association between FeNO level and ICS response.

Does Measurement of FeNO to Guide Treatment Decisions in Patients With Asthma Improve Health Outcomes?

Systematic Reviews

In 2005, a TEC Assessment was published on exhaled NO monitoring for guiding treatment decisions in patients with chronic asthma.(35) The assessment identified 2 RCTs; both were published in 2005. Smith et al reported that equivalent outcomes (eg, exacerbations, pulmonary function) were achieved in the group managed using exhaled NO measurements compared with the group managed using conventional guidelines.(36) The FeNO group, however, used lower doses of ICS at the end of the study. Pijnenburg et al found similar changes in steroid dose and FEV1 in groups managed with and without FeNO measurements.(37) Bronchial hyperreactivity, an intermediate outcome, improved more in the FeNO group. The TEC Assessment concluded that the available evidence did not permit the conclusion that use of NO monitoring to guide treatment decisions in asthma leads to improved outcomes.

In 2012, Petsky et al published a meta-analysis of RCTs evaluating the use of tailoring asthma treatment based on levels of eosinophilic markers (FeNO or sputum eosinophils) compared with clinical symptoms (with or without spirometry/peak flow).(38) The study combined 2 Cochrane reviews including a 2009 review on FeNO.(39) Updated literature searches were not performed. As in the 2009 Cochrane review, the 2012 review identified a total 6 RCTs on FeNO. In addition to the 2 RCTs previously described in the section on the TEC Assessment, the studies were Shaw et al (2007),(40) Fritsch et al (2006),(41) Szefler et al (2008),(42) and de Jongste et al (2009).(43) Four of the studies included children or adolescents, one included only adults and the sixth included both adolescents and adults. Two studies were double-blind and the other 4 were single-blind. Five studies used hospital-based FeNO measurements, and one used a portable athome NO analyzer. Four studies measured FeNO at a flow rate of 50 mL/s.

The primary outcome of the meta-analysis was the difference in the number of patients in each group who had asthma exacerbations during follow-up. When findings for the 2 FeNO studies that included adults and/or adolescents were pooled (Shaw et al [2007] and Smith et al [2005]), there was not a significant difference in the number of patients experiencing an exacerbation (OR, 0.85; 95% CI, 0.30 to 2.43). There was also no significant difference in symptom scores (mean difference, -0.10 [95% CI, -0.33 to 0.12]). Findings from 3 of the 4 pediatric trials were pooled, Pijnenburg et al (2005),(37) Szefler et al (2008),(42) and de Jongste et al (2009).(43) As with the adult studies, there was not a significant difference in the number of patients experiencing an exacerbation (OR=0.75; 95% CI, 0.55 to 1.01). A pooled analysis of 2 of the pediatric studies (Pijnenburg et al [2005] and Szefler et al [2008]) did not find a significant difference in symptom scores between patients managed with and without FeNO measurement (mean difference, 0.13; 95% CI, -0.32-0.57).

There were, however, statistically significant differences between groups in the final dose of ICS, although the direction of this relationship was different in adults and children. In adults, patients who had their medication doses adjusted based on FeNO levels had a significantly lower final dose of ICS than those in the control group (pooled analysis of 2 studies: mean difference, -450 g budesonide equivalent; 95% CI, -677 to -223). In contrast, children in the FeNO group had a significantly higher dose of ICS compared with the control group (pooled analysis of 3 studies; mean difference, 140 g; 95% CI, 29 to 251).

In the 2013 Harnan et al health technology assessment to assess the clinical and cost-effectiveness of FeNO measurements in people with asthma (previously described), the authors conducted a systematic review of the efficacy of FeNO-guided management of asthma based on RCTs published since the previous systematic reviews.(22) The authors identified 4 studies in adults. In pooled analysis, there was no significant difference between subjects managed with FeNO and control subjects in terms of major/severe exacerbation rates (pooled rate ratio [RR], 0.87 [favors FeNO]; 95% CI, 0.64 to 1.19). However, for the composite outcome of all exacerbations, FeNO-based management was associated with reduced exacerbation rates (pooled RR=0.58 [favors FeNO]; 95% CI, 0.43 to 0.77). For pooled analysis of ICS use, the authors noted high heterogeneity among studies, but reported no statistically significant differences in mean ICS (standardized mean difference, -0.24 [favors FeNO]; 95% CI, -0.56 to 0.07).Results were heterogeneous.

The authors identified 5 studies in children. Among the 4 studies that reported on asthma exacerbations or treatment failures, all reported fewer exacerbations or treatment failures in the FeNO-managed groups, although the differences were statistically significant in only 1 study. While most studies provided some information about ICS use, the authors concluded, “The effects on ICS use were heterogeneous, with two studies showing a statistically significant increase in ICS use, one showing no difference, one being difficult to interpret and one further study not reporting this outcome.”

Randomized Controlled Trials

Following the Petsky systematic review, 7 additional RCTs evaluating the use of FeNO as part of an asthma management strategy have been identified.

In 2014, Honkoop et al reported results of a cluster-randomized RCT comparing a FeNO-based asthma management strategy with 1 of 2 asthma-control strategies based on ACQ score: partial control (PCa;ACQ <1.5) and control (Ca; ACQ <0.75).(44) and were managed in primary care offices, who were randomized based on general practice site to each of the 3 strategies: n=219 in PCa; n=203 in Ca; and n=189 in the FeNO-directed group (FCa). Subjects were followed every 3 months for a year, and at each visit were classified based on ACQ score as
controlled (ACQ, ≤0.75), partially controlled (ACQ, >0.75 but ≤1.5), or uncontrolled (ACQ, >1.5). FCa subjects were classified based on FeNO level: low/no inflammation for FeNO 25 ppb or less; intermediate at 26 to 50 ppb; and high/presence of airway inflammation at greater than 50 ppb. Treatment decisions were made based on a prespecified algorithm for ICS dose increase or decrease, which was implemented with an online decision support tool. Asthma control at follow-up was significantly better in the FCa group than in the PCa group (change in ACQ score, -0.12; 95% CI, -0.23 to -0.02; p=0.02), although no significant differences were found in change in ACQ score between the PCa and Ca
strategies or between the FCa and Ca strategies. There were no significant differences across the groups in number of severe exacerbations (0.29 exacerbations/ patient/year for PCa vs 0.29 exacerbations/patient/year for Ca vs 0.19 exacerbations/patient/year for FCa). ICS dose did not significantly differ among the groups at the study’s conclusion, although FCa subjects had a lower montelukast dose compared with Ca subjects (mean difference, -0.38; 95% CI, -0.74 to -0.03; p=0.04). Cost analyses are also presented, with significantly lower asthma medication cost for the PCa and FCa strategies compared with the Ca strategy (medication costs: PCa=$452; Ca=$4551; FCa=$456; p≤0.04).

Also in 2014, Petsky et al reported results of a smaller RCT to evaluate whether an asthma management strategy based on atopy-adjusted FeNO levels reduced asthma exacerbation rates in ICS-requiring asthmatic children.(45) Sixty-three children were randomized to a FeNO-based management group (n=31) or a control group (n=32) in which patients were managed based on asthma-related symptoms recorded on a symptom diary card. In the FeNO group, asthma therapy was stepped up if FeNO was elevated; an elevated FeNO level was defied as 10 ppb or more in children with no positive skin prick test (SPT), 12 ppb or more in children with 1 positive SPT, and 20 ppb or more in children with 2 or more positive SPTs. The elevated FeNO levels were determined based on a 1999 cohort study, before the development of the ATS guidelines. For the study’s primary outcome of exacerbation frequency, fewer children in the FeNO group had at least 1 exacerbation over the study period (6 vs 15; p=0.017). The asthma exacerbation rate, asthma quality of life scores, and spirometry results did not differ significantly between groups. The final daily ICS dose was higher in the FeNO group compared with the control group (median 400 µg vs 200 µg; p=0.037), although the difference between final and baseline dose did not differ significantly between the groups (median change, -175 in the FeNO group vs -200 in the control group; p=0.139). The authors note that their study was limited by slow enrollment, which prevented them from reaching their planned sample size.

In 2013, Syk et al in Sweden published 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.(46) 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 change in the mini Asthma Quality of Life Questionnaire (mAQLQ), with secondary outcomes of change in 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 mAQLQ score (0.23; [interquartile range (IQR), 0.07-0.73] in the FeNO-guided group vs 0.07 [IQR, -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 [IQR, -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 The study included 611 asthmatic adults who required ICS 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, and a clearly outlined algorithm for how asthma therapy was adjusted.

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.(47) 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 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 µg vs +100 µg, p=0.016).

In 2012, an RCT by Pike et al in the U.K. included 90 children with severe asthma.(48) Medication management decisions were based on clinical symptoms (ie, 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 FeNO group, when symptoms were poorly controlled and FeNO was less than 25 ppb, long-acting β-agonist therapy 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 followup period, 37 (84.1%) of patients in the FeNO group and 38 (82.6%) of patients in the standard care group experienced at least 1 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 g in the FeNO group and 500 g in the standard management group.

Also in 2012, Calhoun et al 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.(49) 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 FeNO 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 β-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 predefined 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 FeNO 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 FeNO-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 physiciandirected medication adjustment group (1610 µg) and the FeNO-based medication adjustment group (1617 µg) compared with the patient-based symptom medication adjustment groups (832 µg, p=0.01 for both comparisons). An editorial accompanying the publication of the BASALT trial noted that, given the trial findings, it is difficult to recommend routine monitoring of FeNO in adults with mild to moderate asthma.(50)


An additional RCT, conducted by Powell et al, found improved outcomes in pregnant women with asthma managed with an algorithm including FeNO.(51) Eligibility included being between 12 and 20 weeks of gestation a nonsmoker 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 ICS 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 ACQ, and ACQ scores were used 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 with 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 1 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, 0.26 per patient) than the control group (mean, 0.56 per patient; p=0.002).

In a follow-up study to their primary analysis, the authors of the Powell et al RCT reported respiratory outcomes for infants of the mothers enrolled in the trial.(52) Of the 220 women who completed the original trial, 174 consented to participate in a follow-up birth cohort. Among 146 (82%) infants with follow-up at 1 year of age, there were no significant differences between infants of mothers in the clinically managed
group compared with infants of mothers in the FeNO group in prevalence of “wheeze ever.” However, infants of mothers in the FeNO group were less likely to have recurrent episodes of bronchiolitis: 16% in the clinically-managed group versus 1.5% in the FeNO group (OR=0.08; 95% CI, 0.01 to 0.62; p=0.016).

Noncomparative Studies

In an industry-sponsored study published in 2014, LaForce et al reported results of an observational study of 50 patients with asthma whose treatment was guided by FeNO measurements.(53) Subjects were established patients at an allergy clinic with a previous diagnosis of asthma but no prior FeNO measurements. Subjects were evaluated with spirometry, the Asthma Control Test (ACT), and physical exam, along with FeNO measurements. FeNO was used to categorize airway inflammation as “low,” “intermediate,” or “high,” based on ATS thresholds. FeNO measurements were initially concealed from treating clinicians. Clinicians were asked to estimate the degree of airway inflammation and document a treatment plan both blinded and unblinded to the FeNO measurements. Clinicians tended to underestimate the FeNO-classified airway inflammation levels: on clinician appraisal, 68%, 28%, and 4% of subjects were estimated to have low, intermediate, or high airway inflammation, respectively, whereas based on FeNO levels, 58%, 20%, and 22% of subjects were classified as having low, intermediate, or
high airway inflammation. Statistical comparisons are not presented. After clinicians were unblinded to FeNO levels, the amount of anti-inflammatory medication prescribed was increased in 20% of patients.

Section Summary

The most direct evidence related to the use of FeNO in the management of asthma comes from numerous RCTs comparing management of asthma with and without FeNO. These studies are heterogeneous in terms of the patient populations, FeNO cutoff levels, and the protocol for management of patients in the control group. A 2012 meta-analysis of 6 RCTs did not find significantly improved outcomes (eg, a lower rate of asthma exacerbations, lower symptom scores) when medication dose was tailored to FeNO level. In contrast, a subsequent meta-analysis found statistically significant reductions in asthma exacerbations in patients managed with FeNO measurements. RCTs in various populations
published since 2012 have had mixed findings. Two RCTs, including a large multicenter NIH-funded trial, had findings of no benefit to a FeNO-based management strategy. Four RCTs, 1 in adults, 2 in children, and 1 in pregnant women, found a lower rate of asthma exacerbations in subjects managed with an algorithm that included FeNO measurement compared with an algorithm without FeNO. An additional RCT demonstrated improvements in asthma control with a FeNO-based management approach compared with clinical management targeting “partial control,” although not compared with a clinical management approach targeting complete control. Most of the RCTs use a relatively low cutoff value for FeNO; in these cases, this might be expected to lead to an overall increase in ICS use among patients managed with a FeNO-based algorithm. However, it does not appear than a FeNO-based management strategy (even using relatively low FeNO cutoffs) systematically leads to an increase in ICS doses.

Respiratory Conditions Other Than Asthma

Does FeNO Aid in the Diagnosis of Respiratory Disorders Other Than Asthma?

Rouhos et al in Finland published a study in 2011 on repeatability of FeNO measurements in 20 patients with stable chronic obstructive pulmonary disease (COPD) and 20 healthy controls.(54) 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.

In 2014, Chou et al reported results of study to evaluate the use of FeNO measurements in predicting sputum eosinophilia in patients with COPD.(55) The study included 90 subjects with COPD but no known history of asthma or allergic diseases. Compared with patients without sputum eosinophilia, those with sputum eosinophilia had higher FeNO levels (29 vs 18 ppb; p=0.01). In ROC analysis, a FeNO cutoff of 23.5 ppb had the highest sum of sensitivity (62.1%) and specificity (70.5%) in predicting sputum eosinophilia. After adjusting for age, sex, smoking status, serum IgE, and allergy test results, a FeNO value greater than 23.5 ppb was significantly associated with the presence of sputum eosinophilia: adjusted OR 4.329 (95% CI, 1.306 to 14.356; p=0.017). The authors hypothesize that individuals with COPD with sputum eosinophilia may be likely to respond well to inhaled or oral corticosteroids.

Boon et al evaluated the role of FeNO in the diagnosis of primary ciliary dyskinesia (PCD) in a population of 226 patients, 38 individuals with PCD, 49 healthy controls, and 139 individuals with other respiratory diseases.(56) A definitive diagnosis of PCD was made via structural and functional evaluation of the cilia on a nasal or bronchial biopsy. Using a FeNO cutoff of 10 ppb, with lower values predictive of PCD, the sensitivity for PCD diagnosis was 89.5%, with a specificity of 58.3%.

Does FeNO Level Predict Response to Medication Therapy in Patients With Respiratory Conditions Other Than Asthma?

A double-blind crossover trial by Dummer et al evaluated the ability of FeNO test results to predict corticosteroid response in COPD.(57) The study included 65 patients with COPD who were 45 years or older, were previous smokers with at least a 10-pack a year history, had persistent symptoms of chronic airflow obstruction, had a postbronchodilator FEV1/FVC of less than 70% and a FEV1 of 30% to 80% predicted. Patients with asthma or other comorbidities and those taking regular corticosteroids or had used oral corticosteroids for exacerbations more than twice during the past 6 months were excluded. Treatments, given in random order, were 30 mg/d of prednisone or placebo for 3 weeks; there was a 4-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 3 primary outcomes, 6-minute walk distance (6MWD) and FEV1 increased significantly from baseline with prednisone compared with placebo. There was a nonsignificant decrease in the third primary outcome, score on the St. George’s Respiratory Questionnaire (SGRQ). The correlation between baseline fraction of FeNO was not significantly correlated with change in 6MWD (r=0.10, p=0.45) or SGRQ (r=0.12, p=0.36) but was significantly related to change in FEV1 (r=0.32, p=0.01). At the optimal fraction of FeNO cutoff of 50 ppb, 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 FeNO 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 FeNO test results.

A prospective uncontrolled study by Prieto et al assessed the utility of FeNO measurement for predicting response to ICS in patients with chronic cough.(58) The study included 43 patients with cough of at least 8 weeks in duration who were nonsmokers 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 µg 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 FeNO cutoff, the sensitivity was 53% and the specificity was 63%. The authors concluded that FeNO is not an adequate predictor of treatment response.

Does Measurement of FeNO Improve Health Outcomes When Used to Guide Treatment Decisions in Patients With Respiratory Disorders Other Than Asthma?

No controlled studies were identified that compared health outcomes in patients with COPD or other respiratory diseases whose treatment was managed with and without FeNO measurement.

Exhaled Breath Condensate

In general, it appears from the published literature that EBC is at an earlier stage of development compared with FeNO. A 2012 review by Davis et al 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.(59) In addition, 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(59-63):

  • Standardization of collection and storage techniques
  • Effect of dilution of respiratory droplets by water vapor
  • Effect of contamination from oral and retropharyngeal mucosa
  • Variability in EBC assays for certain substances, including assay kits for the same biomarker and kit lot numbers from the same manufacturer.
  • Lack of criterion standard for determining absolute concentrations of airway lining fluid nonvolatile constituents to compare with EBC.
  • Lack of normative values specific to each potential EBC biomarker.

Are Components of EBC Useful as Markers of Asthma Severity or Control?

Similar to FeNO, EBC has been associated with asthma severity. In 2013, Thomas et al conducted a systematic review of studies assessing the association components of EBC with pediatric asthma.(64) The authors identified 46 papers that measured at least 1 EBC marker in asthma, allergy, and atopy in children up to age 18 years. Most studies were cross-sectional, but there was wide variation in the definitions used to identify children with asthma and the collection devices and assays for EBC components. Studies reviewed evaluated multiple specific EBC components, including hydrogen ions, NO, glutathione and aldehydes, hydrogen peroxide, eicosanoids (including prostaglandins and leukotrienes), and cytokines (including interleukins in the TH2 pathway and interferon gamma). The authors note that hydrogen ions and markers of oxidative stress, including hydrogen peroxide and oxides of nitrogen, were most consistently associated with asthma severity. Eicosanoids and cytokines demonstrated more variable results, but were frequently elevated in the EBC of patients with asthma. Overall, the authors conclude that while EBC has the potential to aid diagnosis of asthma and evaluate inflammation in pediatric asthma, further studies on EBC collection and interpretation techniques are needed.

Among adults, a number of studies have been published on components of EBC and their relationship with asthma severity. A 2011 study by Liu et al, the Severe Asthma Research Program, was a multicenter study funded by NIH. This study had the largest sample size with 572 patients.(65) Study participants consisted of 250 patients with severe asthma, 291 patients with nonsevere 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 nonsevere asthma, 7.90, was significantly lower than patients with severe asthma, 8.02 (p not reported).

In 2011, Piotrowski et al in Poland prospectively studied adult patients with asthma.(66) 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.

In 2014, Keskin et al evaluated the relationship between two EBC components, cysteinyl leukotrienes (Cys-LTs) and 8-isoprostane, in asthma control among 30 children with asthma.(67) Included patients had a diagnosis of asthma and had been in a stable condition, free from acute exacerbations and respiratory tract infections for the 2 months prior to the EBC evaluation. Asthma control was evaluated with the childhood ACT and by assessment by pediatric allergists. Of the entire group, 19 subjects had mild persistent asthma, while 11 had moderate persistent asthma. EBC isoprostane-8 levels were higher in those with moderate persistent asthma compared with those with mild persistent asthma (114.0 pg/mL vs 52 pg/mL; p=0.05), and higher in those with greater than 4 exacerbations per year compared with those who had 1 to 4 exacerbations per year (114 pg/mL vs 52 pg/mL; p<0.05). Cys-LTs levels were not significantly associated with asthma exacerbation frequency or asthma severity.

Also in 2014, Navratil et al evaluated the relationship between EBC and asthma control in a crosssectional study of 103 children (age, 6-18 years) with asthma.(68) Subjects were enrolled from a single clinic, had an established asthma diagnosis, and were on stable dosage of their asthma treatment. Patients were considered to have controlled (n=50 [48.5%]) or uncontrolled asthma (n=53 [52.5%]) based on GINA guidelines. Controlled and uncontrolled asthmatics differed significantly in EBC urates (uncontrolled median EBC urate 10 µmol/L vs controlled median EBC urate 45 µmol/L; p<0.001); EBC pH (uncontrolled mean pH 7.2 vs controlled mean pH 7.33; p=0.002; and EBC temperature (EBT: uncontrolled mean EBT 34.26°C vs 33.9 °C; p=0.014). In addition, EBC urate concentration was significantly associated with time from last exacerbation (p<0.001), ACT results (p<0.001), and shortacting bronchodilator use (p<0.001) within the entire cohort.

Are Components of EBC Useful 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 et al evaluated EBC in 58 hospitalized patients (20 with asthma and 38 with COPD) and 36 healthy controls (18 smokers, 18 nonsmokers).(69) The EBC pH was significantly lower in patients with asthma exacerbations (all nonsmokers) at hospital admission compared with 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 nonsmoking controls at discharge. Contrary to investigators’ expectations, EBC pH values in ex-smoking COPD patients (n=17) did not differ significantly from nonsmoking 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.

Other small studies have reported on the feasibility of using EBC in the diagnosis or recognition of other respiratory conditions, including radiation pneumonitis after stereotactic ablative radiotherapy (N=26).(70)

Are Components of EBC Useful 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.(71) 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.

Section Summary

There is limited evidence on the use of EBC for determining asthma severity or diagnosing other respiratory conditions or guiding treatment decisions for asthma or other respiratory conditions. The available evidence is insufficient to form conclusions on the utility of EBC for any indication.

Ongoing and Unpublished Clinical Trials

A search of ClinicalTrials.gov in December 2014 identified the following ongoing randomized trials of FeNO-guided therapy:

  • Optimization of Inhaled Corticosteroid Treatment in Adult Patients With Asthma Guided by Exhaled NO Measurement at Home (OCTAGEN) (NCT01783132): This is a randomized, openlabel trial to compare outcomes for asthmatic patients with ICS dose managed via an algorithm
    directed by home FeNO measurements with those managed with standard of care. Enrollment is planned for 200 subjects; the estimated study completion date is December 2014.
  • Fractional Concentration of Exhaled NO (FENO) to Direct Montelukast Treatment of Sub-acute Cough (NCT02303600): This is a randomized, open-label trial to compare FeNO-directed montelukast treatment with routine montelukast treatment (montelukast given to all subjects in
    control group) for patients presenting with subacute cough. Enrollment is planned for 200 subjects; the estimated study completion date is August 2015.
  • The Evaluation of FeNO for Predicting Response to ICS in Subjects With Non-specific Respiratory Symptoms (NSRS) (NCT02294279): This is a randomized, double-blind trial to evaluate the association between FeNO levels and response to ICS treatment in patients with
    nonspecific respiratory symptoms defined as cough and/or wheeze and/or dyspnea. Enrollment is planned for 264 subjects; the estimated study completion date is August 2015.
  • Assessment of Utility of Exhaled Nitric Oxide Measurement for Treatment Monitoring in Children With Asthma (NCT00500253): This is a randomized, single-blinded trial to compare asthmarelated outcomes between group of children with asthma managed with FeNO-monitored
    treatment and those managed with standard clinical follow-up. Enrollment is planned for 120 subjects; the planned study completion date was December 2013, but no published results were identified.
  • Usefulness of Exhaled Breath Condensate for Evaluation of Markers of Airway Inflammation in Children With Asthma (NCT00961155): This is a randomized, double-blind, crossover trial to evaluate the association between EBC components and response to treatment with cyklezonid,
    montelukast, formoterol, or placebo in the management of children with mild-to-moderate asthma. Enrollment is planned for 200 subjects; the planned study completion date was June 2014, but no published results were identified.


Clinical Input Received From Physician Specialty Societies and Academic Medical Centers

While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

In response to requests, input was received through 3 physician specialty societies (1 specialty society submitted 2 reviews) and 5 academic medical centers when this policy was under review in 2012 Input was mixed on whether measurement of FeNO is considered investigational in the diagnosis and management of asthma and other respiratory disorders. There was consensus that measurement of EBC is considered investigational in the diagnosis and management of asthma and other respiratory disorders. Input was mixed on additional questions posed to reviewers including whether there is a well-accepted cutoff for FeNO, whether FeNO levels would affect their decision making regarding prescribing ICS, whether there is published evidence that using FeNO measurements to guide treatment improves health outcomes, and whether recommendations in ATS guidelines are supported by evidence.

Summary of Evidence

For use of fractional exhaled nitric oxide (FeNO) measurements in the diagnosis of asthma or particular asthma subtypes, the available evidence is limited by the use of wide variability in FeNO cutoff levels used to diagnose asthma, and wide variability in sensitivity and specificity for asthma diagnosis. The accuracy of the cutoffs recommended by the American Thoracic Society (ATS) guidelines has not been
evaluated in the diagnosis of asthma. In addition, no studies were identified that evaluated whether the use of FeNO improved the accuracy of asthma diagnosis compared with clinical diagnosis. Given these limitations, it is not possible to evaluate whether the use of FeNO levels in clinical practice improves the accuracy of diagnosing asthma, and FeNO is considered investigational for the diagnosis of asthma or other respiratory conditions.

Randomized controlled trials (RCTs) evaluating the use of FeNO tests for the management of patients and have not consistently found improvement in health outcomes. A 2012 meta-analysis of 6 RCTs did not find significantly improved outcomes (eg, a lower rate of asthma exacerbations, lower symptom scores) when medication dose was tailored to FeNO level. In contrast, a subsequent meta-analysis found
statistically significant reductions in asthma exacerbations in patients managed with FeNO measurements. RCTs in various populations published since 2012 have had mixed findings. An additional RCT that demonstrated improvements in asthma control with a FeNO-based management approach compared clinical management targeting “partial control,” although not with clinical management approach targeting complete control. Most of the RCTs use a relatively low cutoff value for FeNO; in these cases, this might be expected to lead an overall increase in inhaled corticosteroid (ICS) use among patients managed with a FeNO-based algorithm. However, it does not appear than a FeNO-based management strategy (even using relatively low FeNO cutoffs) systematically leads to an increase in ICS dose. The available evidence suggests that a FeNO-based algorithm for adjusting ICS doses may be associated with modest improvements in asthma exacerbations; therefore, FeNO measurements may be considered medically necessary for tailoring ICS dose in patients with an asthma diagnosis.

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 (EBC) evaluation for the diagnosis and treatment of asthma and other conditions. Thus, the evidence is insufficient to determine the utility of FeNO for the management of conditions other than asthma EBC tests for the management of any respiratory condition, and these tests are therefore considered investigational.

Practice Guidelines and Position Statements

National Institute for Health and Care Excellence

In 2014, National Institute for Health and Care Excellence issued guidelines related to the use of FeNO in the management of asthma, based on the results of a health technology assessment.(72) The guidelines state:

  • Fractional exhaled nitric oxide (FeNO) testing is recommended as an option to help diagnose asthma in adults and children:
    • who, after initial clinical examination, are considered to have an intermediate probability of having asthma (as defined in the British guideline on the management of asthma 2012) and 
    • when FeNO testing is intended to be done in combination with other diagnostic options according to the British guideline on the management of asthma (2012).
      Further investigation is recommended for people whose FeNO test result is negative because a negative result does not exclude asthma.
  • FeNO measurement is recommended as an option to support asthma management (in conjunction with the British guideline on the management of asthma 2012) in people who are symptomatic despite using inhaled corticosteroids.

American Thoracic Society

In 2011, ATS published a clinical practice guideline on interpretation of FeNO levels.(21) The guideline was critically appraised using criteria developed by the Institute of Medicine which includes 8 standards.(73) 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).

ATS/European Respiratory Society

In 2014, the ATS/European Respiratory Society released guidelines on the management of severe asthma, which make the following recommendations about using FeNO in the management of severe asthma(74):

  • We suggest that clinicians do not use FeNO to guide therapy in adults or children with severe asthma (conditional recommendation, very low quality evidence).

A 2009 statement includes the following key points on exhaled NO:

“The clinical utility of FeNO-based management strategies has not been explored extensively. Currently available evidence suggests a role in identifying the phenotype in airways disease, particularly in the identification of corticosteroid responsiveness. Due to logistic and cost issues, FeNO is the only biomarker likely to have a role in primary care-based asthma studies, although it is possible that with technological improvements, other techniques including sputum induction could have a role in the medium term.”(1)

National Heart Lung and Blood Institute

The National Heart Lung and Blood Institute’s 2007 expert panel guidelines for the diagnosis and management of asthma state:

“Use of minimally invasive markers (“biomarkers”) to monitor asthma control and guide treatment decisions for therapy is of increasing interest. Some markers, such as spirometry measures, are currently and widely used in clinical care; others, such as sputum eosinophils and FeNO, may also be useful, but they require further evaluation in both children and adults before they can be recommended as clinical tools for routine asthma management (Evidence D).”

“The Expert Panel recommends some minimally invasive markers for monitoring asthma control, such as spirometry and airway hyper-responsiveness, that are appropriately used, currently and widely, in asthma care (Evidence B). Other markers, such as sputum eosinophils and FeNO, are increasingly used in clinical research and will require further evaluation in adults and children before they can be recommended as a clinical tool for routine asthma management (Evidence D).”(75).

U.S. Preventive Services Task Force Recommendations

No U.S. Preventive Services Task Force recommendations for asthma screening or the use of NO measurements or EBC have been identified.

Medicare National Coverage

There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers. 

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Codes

Number

Description

CPT 83987 pH; exhaled breath condensate
  94799 Unlisted pulmonary service or procedure
  95012 Nitric oxide expired gas determination
ICD-9 Diagnosis   Investigational for all relevant diagnoses
ICD-10-CM (effective 10/1/15)   Investigational for all relevant diagnoses
  J00-J99 Diseases of the respiratory system code range (including asthma and COPD)
ICD-10-PCS (effective 10/1/15)   Not applicable. ICD-10-PCS codes are only used for inpatient services. There are no ICD procedure codes for laboratory tests.

Index
Asthma, Nitric Oxide
Breath Condensate, Exhaled
Exhaled Breath Condensate
NIOX
Nitric Oxide

Policy History
Date Action Reason
10/9/03 Add policy to Medicine section New policy
04/1/05 Replace policy Policy updated with literature search; no change in policy statement. Reference numbers 16–19 added
08/17/05 Replace policy Policy updated with discussion of reference numbers 20 and 21. No change in policy statement
12/14/05 Replace policy Policy updated with October 2005 TEC Assessment. Policy revised to include discussion of exhaled breath condensate. Policy retitled, exhaled breath condensate added to policy statement (considered investigational), additional discussion added to Rationale section. Reference numbers 22–34 added
12/12/06 Replace policy Policy update with literature search through October 2005; policy statement unchanged. References 35-38 added. New CPT code added
09/18/07 Replace policy Policy updated with literature search through June 2007; no change in policy statement. Reference numbers 39 to 41 added. 
11/13/08 Replace policy  Policy updated with literature search through September 2008; no change in policy statement. Reference numbers 42 and 43 added.
12/10/09 Replace policy Policy updated with literature search through October 2009. Existing policy statement divided into two statements; one for exhaled nitric oxide, the other for exhaled breath condensate; examples of other respiratory disorders also added to policy statements. Both techniques remain investigational. Rationale extensively re-written; reference numbers 12-13, 15-22, 24, 27-30 added; other references renumbered/removed.
12/29/09 Coding update only add 83987
12/09/10 Replace policy Policy updated with literature search through October 2010. No change to policy statements. Background and Rationale re-written. References 3, 6, 9 13, 19 and 20 added; other references renumbered/removed.
12/08/11 Replace policy Policy updated with literature search through October 2011. In first policy statement, “exhaled or nasal nitric oxide” changed to “exhaled nitric oxide”; otherwise policy statements unchanged. References 9, 19, 25, 28 and 29 added; other references renumbered/removed.
1/10/13 Replace policy Policy updated with literature search through November 2012. Clinical input added. Need for policy affirmed. No change in policy statements. References 3-5, 10-12, 16, 22-24, 29 and 34-46 added; other references renumbered/removed.
1/09/14 Replace policy Policy updated with literature search through December 10, 2013. References 3-6, 17, 27, 28, and 44 added; other references renumbered/removed. No change in policy statement. Mention of the Breathmeter device removed from policy (no FDA clearance, no specific code).
1/15/15 Replace policy Policy updated with literature review through November 25, 2014. References 5, 14-20, 22-26, 31-35, 44-45, 52-26, 67-68, and 72 added. Policy statement unchanged.