mp-181 - mp-181 - Medical Policies
Measurement of Exhaled Nitric Oxide and Exhaled Breath Condensate in the Diagnosis and Management of Respiratory Disorders
Policy Number: MP-181
Latest Review Date: August 2019
Policy Grade: C
Effective for dates of service on or after January 24, 2014:
Measurement of exhaled or nasal nitric oxide is considered not medically necessary and investigational for 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 not medically necessary and investigational for the diagnosis and management of asthma and other respiratory disorders including but not limited to chronic obstructive pulmonary disease and chronic cough.
DESCRIPTION OF PROCEDURE OR SERVICE:
Evaluation of exhaled nitric oxide (NO) and exhaled breath condensate (EBC) are proposed as techniques to diagnose and monitor asthma and other respiratory conditions. There are commercially available devices for measuring nitric oxide in expired breath and various laboratory techniques for evaluating components of exhaled breath condensate.
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 one second (FEV-1) and peak flow. Therefore, there has been an interest in noninvasive techniques to assess the underlying pathogenic chronic inflammation as reflected by measurements of inflammatory mediators.
Fractional Exhaled Nitric Oxide and Exhaled Breath Condensate
Two proposed strategies are the measurement of FeNO and the evaluation of exhaled breath condensate (EBC). Nitric oxide (NO) is an important endogenous messenger and inflammatory mediator that is widespread in the human body, with functions including the regulation of peripheral blood flow, platelet function, immune reactions, neurotransmission, and the mediation of inflammation. While the role of NO in asthma pathogenesis is still under investigation, patients with asthma have been found to have high levels of FeNO, 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. FeNO 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 FeNO are commercially available in the U. S. According to a joint statement by the American Thoracic Society and European Respiratory Society (2009), there is a consensus that the fractional concentration of FeNO is best measured at an exhaled rate of 50 mL per second maintained within 10% for more than 6 seconds at an oral pressure between 5 and 20 cm H2O. Results are expressed as the NO concentration in parts per billion, based on the mean of 2 or 3 values.
Exhaled Breath Condensate
EBC consists of exhaled air passed through a condensing or cooling apparatus, resulting in an accumulation of fluid. Although EBC is primarily derived from water vapor, it also contains aerosol particles or respiratory fluid droplets, which in turn contain various nonvolatile inflammatory mediators, such as cytokines, leukotrienes, oxidants, antioxidants, and various other markers of oxidative stress. There are a variety of laboratory techniques to measure the components of EBC, including such simple techniques as pH measurement, to the more sophisticated gas chromatography/mass spectrometry or high performance liquid chromatography, depending on the component of interest.
Clinical Uses of FeNO and EBC
Measurements of FeNO have particularly been associated with an eosinophilic asthma phenotype. Eosinophilic asthma is a subtype of severe asthma associated with sputum and serum eosinophilia, along with later-onset asthma. Until recently, most asthma management strategies did not depend on the recognition or diagnosis of a particular subtype. However, anti-interleukin 5 inhibitors have been approved by the Food and Drug Administration (FDA) for the treatment of severe asthma with an eosinophilic phenotype. An anti-interleukin 4 and 13 monoclonal antibody has also been shown to improve uncontrolled asthma, with the greatest improvement observed in the subgroup of patients with the highest blood eosinophil count.
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.
This evidence review has been updated regularly with a literature review using the MEDLINE database, most recently through June 12, 2019.
Summary of Evidence
For individuals who have suspected asthma who receive a measurement of fractional exhaled nitric oxide (FeNO), the evidence includes multiple retrospective and prospective studies of diagnostic accuracy, along with systematic reviews of those studies. The relevant outcomes are test accuracy and validity, symptoms, change in disease status, morbid events, and functional outcomes. There are multiple reports on the sensitivity and specificity of FeNO in asthma diagnosis; however, most studies are in the setting of patients with asthma symptoms without previous testing (or with unclear previous testing), which is unlikely to be how the test is used in a U.S. setting. The available evidence is limited by variability in FeNO cutoff levels used to diagnose asthma and lack of data on performance characteristics in diagnostic challenging settings, and lack of data on the incremental value of adding FeNO to existing diagnostic algorithms from studies with concurrent controls. Limitations of the published evidence preclude determining the effects of the technology on net health outcome. Evidence reported through clinical input suggests a possible adjunctive role when conventional testing may be limited, particularly where diagnosis with standard clinical diagnostic testing (e.g., routine spirometry) may be limited such as in pediatric patients. However, the published evidence does not show whether FeNO testing in such patients would be clinically practical and clinically valid to be clinically useful. The evidence is insufficient to determine the effect of the technology on health outcomes.
For individuals who have asthma who receive medication management directed by FeNO, the evidence includes diagnostic accuracy studies, multiple randomized controlled trials (RCTs), and systematic reviews of those trials. The relevant outcomes are symptoms, change in disease status, morbid events, and functional outcomes. The available randomized controlled trials evaluating the use of FeNO tests for the management of patients have not consistently found improvement in health outcomes. Two Cochrane reviews from 2016, one on adults and the other on children, found FeNO-guided asthma management reduced the number of individuals who had more than one exacerbation, but had no impact on day-to-day symptoms or hospitalizations. Limitations of the published evidence preclude determining the effects of the technology on net health outcome. For the use of FeNO to identify eosinophilic asthma for the purpose of selecting patients for therapy with anti-interleukin-5 therapy, using the criterion standard of sputum eosinophilia, the diagnostic accuracy of FeNO is moderate. Evidence reported through clinical input suggests a possible adjunctive role for FeNO testing particularly for individuals who may have limited awareness of worsening symptoms or when there is suspected noncompliance to medication. However, the published evidence does not study this subgroup to demonstrate that use of FeNO testing in such patients may be clinically useful to inform treatment decisions by reducing or avoiding unnecessary asthma therapy, or by indicating when step-up therapy is warranted. The evidence is insufficient to determine the effect of the technology on health outcomes.
For individuals who have suspected eosinophilic asthma who receive a measurement of FeNO to select a therapy, the evidence includes diagnostic accuracy studies and subgroup analyses of RCTs and observational studies. The relevant outcomes are symptoms, change in disease status, morbid events, and functional outcomes. For the use of FeNO to identify eosinophilic asthma for the purpose of selecting patients for therapy with anti-interleukin (IL)-5 therapy or an anti-IL-4 and -13 monoclonal antibody, subgroup analyses of RCTs are available. The evidence that points toward an interaction between baseline FeNO and treatment for the outcome of response suggests that there may be a quantitative but not necessarily a qualitative interaction between baseline FeNO and anti-IL-4 treatment (dupilumab), ie, it is unclear if baseline FeNO can identify a group for whom there is no benefit from dupilumab. Similarly, a 48-week multicenter prospective observational study with over 700 participants found that asthma exacerbations were reduced with omalizumab over a 12-month treatment period irrespective of baseline FeNO. Limitations of the published evidence preclude determining the effects of the technology on net health outcome. Evidence conveyed through clinical input suggests a possible adjunctive role for FeNO testing when it may be particularly difficult to confirm the presence of eosinophils using more invasive methods such as induced sputum or bronchiolar lavage. However, the published evidence does not show whether the adjunctive use of FeNO testing provides substantial improvement in net health outcome when conventional testing for the presence of eosinophils is limited or infeasible. The evidence is insufficient to determine the effect of the technology on health outcomes.
For individuals who have suspected or confirmed respiratory disorders other than asthma who receive a measurement of FeNO, the evidence includes a crossover trial and observational studies. The relevant outcomes are test accuracy and validity, symptoms, change in disease status, morbid events, and functional outcomes. The available evidence assessing the use of FeNO for respiratory disorders other than asthma is limited by heterogeneity in the conditions evaluated and uncertainty about how the test fits in defined clinical management pathways. The evidence provided by clinical input was not supportive of the use of FeNO testing for respiratory disorders other than asthma to improve the net health outcome. The evidence provided by clinical input was not supportive of the use of FeNO testing for respiratory disorders other than asthma to improve the net health outcome.The evidence is insufficient to determine the effect of the technology on health outcomes.
For individuals who have suspected or confirmed respiratory disorders who receive a measurement of EBC, the evidence includes observational studies reporting on the association between various EBC components and disease severity. The relevant outcomes are test accuracy and validity, symptoms, change in disease status, morbid events, and functional outcomes. There is considerable variability in the particular EBC components measured and criteria for standardized measurements. Also, there is limited evidence on the use of EBC for determining asthma severity, diagnosing other respiratory conditions, or guiding treatment decisions for asthma or other respiratory conditions. The available published evidence does not support conclusions on the utility of EBC for any indication. The evidence provided by clinical input was not supportive of the use of EBC as a test to improve the net health outcome. The evidence is insufficient to determine the effect of the technology on health outcomes.
PRACTICE GUIDELINES AND POSITION STATEMENTS
National Institute for Health and Care Excellence
In 2017, the National Institute for Health and Care Excellence issued guidance on asthma diagnosis and monitoring. The guidance recommended the following for diagnosis:
- “Offer a FeNO [fractional exhaled nitric oxide] test to adults (aged 17 and over) if a diagnosis of asthma is being considered.
- Consider a FeNO test in children and young people (aged 5 to 16) if there is diagnostic uncertainty after initial assessment
- Diagnose asthma in children and young people (aged 5 to 16) if they have symptoms suggestive of asthma and:
- a FeNO level of 35 ppb or more and positive peak flow variability or
- obstructive spirometry and positive bronchodilator reversibility.
- Diagnose asthma in adults (aged 17 and over) if they have symptoms suggestive of asthma and:
- a FeNO level of 40 ppb or more with either positive bronchodilator reversibility or positive peak flow variability, or bronchial hyperreactivity, or
- a FeNO level between 25 and 39 ppb and a positive bronchial challenge test, or
- positive bronchodilator reversibility and positive peak flow variability irrespective of FeNO level.”
The guidance recommended the following for monitoring asthma control:
- “Do not routinely use FeNO to monitor asthma control.
- Consider FeNO measurement as an option to support asthma management in people who are symptomatic despite using inhaled corticosteroids.”
American Thoracic Society
In 2011, the American Thoracic Society (ATS) published a clinical practice guideline on the interpretation of FeNO levels. The guideline was critically appraised using criteria developed by the Institute of Medicine (IOM) which includes eight standards. The guideline was judged to not adequately meet the following standards: Standard 3: guideline development group composition; Standard 4: clinical practice guideline-systematic review intersection; Standard 5: Establishing evidence foundation for and rating strength of recommendations; and Standard 7: an external review.
Table 12 lists American Thoracic Society guideline recommendations on management of patients with asthma.
Table 12. Guidelines on Management of Patients with Asthma
“We recommend the use of FENO in the diagnosis of eosinophilic airway inflammation”
“We recommend the use of FENO in determining the likelihood of steroid responsiveness in individuals with chronic respiratory symptoms possibly due to airway inflammation”
“We recommend accounting for age as a factor affecting FENO in children younger than 12 years of age”
“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”
“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”
“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”
“We recommend accounting for persistent and/or high allergen exposure as a factor associated with higher levels of FENO”
“We recommend the use of FENO in monitoring airway inflammation in patients with asthma”
FENO: fractional exhaled nitric oxide; ppb:part per billion; QOE: quality of evidence; SOR: strength of recommendation.
National Heart Lung and Blood Institute (NHLBI):
NHLBI’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).”
American Academy of Pediatrics
The American Academy of Pediatrics issued a report on clinical tools to assess asthma control in children in 2017. The report stated the following on the use of FeNO: “The value of additional FENO monitoring in children whose asthma is appropriately managed using guideline-based strategies is unproven.”
Global Initiative for Asthma
The Global Initiative for Asthma released its updated global strategy for asthma management and prevention in 2018. The report made the following statements on use of FeNO for diagnosis:
“FeNO has not been established as useful for ruling in or ruling out a diagnosis of asthma.”
- “In adult steroid-naïve patients with non-specific respiratory symptoms, a finding of FeNO > 50 ppb was associated with a good short-term response to ICS [inhaled corticosteroid]. However, there are no long-term studies examining the safety (with regard to risk of exacerbations) of withholding ICS in patients with low initial FeNO. Consequently, in patients with a diagnosis or suspected diagnosis of asthma, FeNO cannot be recommended at present for deciding against treatment with ICS.”
The report made the following statements on FeNO for adjusting asthma treatment:
- “At present, neither sputum- nor FeNO-guided treatment is recommended for the general asthma population.”
- “FeNO-guided treatment significantly reduces exacerbation rates compared to guideline-based treatment, at least in children (Evidence A). However, further studies are needed to identify the populations most likely to benefit from sputum-guided or FeNO-guided treatment and the optimal frequency of FeNO monitoring.”
- “…in patients with a diagnosis or suspected diagnosis of asthma, FeNO can support the decision to start ICS, but cannot safely be recommended at present for deciding against treatment with ICS.”
Global Initiative for Asthma released a 'pocket guide for health professionals' in Nov 2018 with an update in Apr 2019 entitled 'Difficult-to-Treat &
Severe Asthma in Adolescent and Adult Patients – Diagnosis and Management.” The guide states the following regarding using FeNO to
'The possibility of refractory Type 2 inflammation should be considered if any of the following are found while the patient is taking high-dose ICS
or daily OCS:
- Blood eosinophils >= 150 mul, and/or
- FeNO >= 20 ppb, and/or
- Sputum eosinophils >= 2%, and/or
- Asthma is clinically allergen-driven.'
It continues to state that these criteria 'are suggested for initial assessment; those for blood eosinophils and FeNO are based on lowest levels
associated with response to some biologics. They are not the criteria for eligibility for Type 2-targeted biologic therapy, which may differ. Consider
repeating blood eosinophils and FeNO up to 3 times (e.g., when asthma worsens, before giving OCS), before assuming asthma is non-Type 2.'
The guide also states that if the patient has had a good response to Type 2 targeted therapy:
"For oral treatments, consider gradually decreased or stopping OCS first, because of their significant adverse effects. Tapering may be supported
by internet-based monitoring of symptoms control and FeNO."
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.
Asthma, nitric oxide, NIOX, Breathmeter, exhaled breath condensate pH, exhaled breath condensate, EBC, NIOX MINO, FeNO, NIOX VERO®, RTube™, ECoScreen EBC
APPROVED BY GOVERNING BODIES:
The devices in Table 1 are cleared by the FDA for measuring FeNO with FDA product code MXA.
Table 1. FeNO Devices Cleared by FDA
Nitric Oxide Monitoring System (NIOX®)
Aerocrine; acquired by Circassia
"[Measurements …FE-NO provide the physician with means of evaluating an asthma patient's response to anti-inflammatory therapy, as an adjunct to established clinical and laboratory assessments in asthma. NIOX should only be used by trained physicians, nurses and laboratory technicians. NIOX cannot be used with infants or by children approximately under the age of 4, as measurement requires patient cooperation. NIOX should not be used in critical care, emergency care or in anesthesiology."
De novo DEN030001
Aerocrine; acquired by Circassia
Same as above except used for ages 7 and older. Handheld and portable.
Aerocrine; acquired by Circassia
Same as MINO®. Differs from predicate devices in terms of its battery and display format
Fenom Pro™ Nitric Oxide Test
Measurement of FeNO by Fenom Pro™ is a method to measure the decrease in FeNO concentration in asthma patients that often occurs after treatment with anti-inflammatory pharmacological therapy as an indication of therapeutic effect in patients with elevated FeNO levels. FeNO measurements are to be used as an adjunct to established clinical assessments. Fenom Pro™ is suitable for children, approximately 7-17 years, and adults 18 years and older. Testing using the Fenom Pro™ should only be done in a point-ofcare healthcare setting under professional supervision. Fenom Pro™ should not be used in critical care, emergency care or in anesthesiology.
FDA: Food and Drug Administration; FeNO: fractional exhaled nitric oxide.
The RTube™ Exhaled Breath Condensate collection system (Respiratory Research) and the ECoScreen EBC collection system (CareFusion) are registered with the FDA as 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.
Coverage is subject to member’s specific benefits. Group specific policy will supersede this policy when applicable.
ITS: Home Policy provisions apply
FEP contracts: Special benefit consideration may apply. Refer to member’s benefit plan. FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.
pH; exhaled breath condensate
Unlisted pulmonary service or procedure
Nitric oxide expired gas determination
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Medical Policy Group, June 2004 (1)
Medical Policy Administration Committee, July 2004
Available for comment July 12-August 25, 2004
Medical Policy Group, June 2005 (1)
Medical Policy Group, June 2006 (1)
Medical Policy Administration Committee, June 2006
Available for comment July 5-August 18, 2006
Medical Policy Group, June 2007 (1)
Medical Policy Group, December 2009 (1)
Medical Policy Administration Committee, December 2009
Available for comment December 23, 2009-February 4, 2010
Medical Policy Group, December 2010 (1): Description updated, Key Points updated, Approved Governing Bodies, no policy statement change
Medical Policy Group, January 2012 (1): Policy retitled to include exhaled breath condensate; Update to Key Points and References related to MPP update; no change in policy statement
Medical Policy Panel, January 2013.
Medical Policy Group, January 2013 (3): 2013 Updates: Key Points, Summary and References. Policy statement remains unchanged.
Medical Policy Panel, January 2014
Medical Policy Group, January 2014 (3): Updates to Description, Policy Statement, Key Points, Governing Bodies, & References; policy statements updated to include the word “diagnosis”
Available for comment January 23 through March 7, 2014
Medical Policy panel, January 2015
Medical Policy Group, January 2015 (2): 2015 Updates to Description, Key Points, Summary, Approved by Governing Bodies, and References, no change to policy statement.
Medical Policy panel, July 2016
Medical Policy Group, July 2016 (7): 2016 Updates to Policy Title; Description, Key Points; Approved Governing Bodies, and References. Removed 2012 previous coding. No change to policy statement.
Medical Policy Panel, September 2017
Medical Policy Group, October 2017 (7): Updates to Description, Key Points, and References. No change to policy statement.
Medical Policy Panel, June 2018
Medical Policy Group, July 2018 (7): Updates to Description, Key Points, and References. Removed Policy Statement from 2014. No change in intent of policy statement.
Medical Policy Panel, November 2018
Medical Policy Group, December 2018 (3): Updated Description. No changes to policy statement or intent.
Medical Policy Panel, December 2018
Medical Policy Group, January 2019 (3): Updates to Key Points, References and Key Words: added: NIOX VERO®, RTube™ , and ECoScreen EBC. Medical Advisory Panel reviewed evidence for 3 indications related to FeNO for asthma in October 2018 and concluded evidence is insufficient for all 3 indications. Clinical input from 2017 was integrated with the evidence conclusions which remained insufficient and policy statements remained investigational for all indications.
Medical Policy Panel, August 2019
Medical Policy Group, August 2019 (5): Updates to Description, Key Points, and References. No changes to Policy Statement.
This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.
This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.
The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.
As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.
The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:
1. The technology must have final approval from the appropriate government regulatory bodies;
2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;
3. The technology must improve the net health outcome;
4. The technology must be as beneficial as any established alternatives;
5. The improvement must be attainable outside the investigational setting.
Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:
1. In accordance with generally accepted standards of medical practice; and
2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and
3. Not primarily for the convenience of the patient, physician or other health care provider; and
4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.