Medical Policy: 02.01.48
Original Effective Date: May 2012
Reviewed: February 2021
Revised: February 2021
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This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.
Current techniques for diagnosing and monitoring asthma and predicting exacerbations are peak flow measurement and spirometry. Two new strategies, evaluation of exhaled nitric oxide (NO) and exhaled breath condensate are proposed. These techniques are also potentially useful in the management of other conditions such as chronic obstructive pulmonary disease (COPD) and chronic cough. There are commercially available devices for measuring NO in expired breath and various laboratory techniques for evaluating components of exhaled breath condensate.
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. Current standards in the assessment of asthma focuses not on the status of the underlying chronic inflammation, but rather on regular assessments of respiratory parameters such as forced expiratory volume in one second (FEV1) and peak flow. There has been interest in noninvasive techniques to assess the underlying pathogenic chronic inflammation as reflected by measurements of inflammatory mediators. Two proposed strategies are the measurement of exhaled nitric oxide (NO) and the evaluation of exhaled breath condensate.
Nitric oxide is an important endogenous messenger and inflammatory mediator that is widespread in the human body, functioning, for example, to regulate peripheral blood flow, platelet function, immune reactions, and neurotransmission and to mediate inflammation. Exhaled NO can be measured online, while the subject exhales directly into the analyzer, or offline, by collection of exhaled air in an NO-impervious container and later measurement. Important technical factors include exclusion of nasal NO, use of proper procedures for online or offline measurement, adherence to optimal expiratory flow rates, and monitoring ambient NO levels. In biologic tissues, NO is unstable, limiting measurement. However, in the gas phase, NO is fairly stable, permitting its measurement in exhaled air. Exhaled NO is typically measured during single breath exhalations. First, the subject inspires nitric oxide-free air via a mouthpiece until total lung capacity is achieved, followed immediately by exhalation through the mouthpiece into the measuring device. Several devices measuring exhaled NO are commercially available in the United States.
According to a 2009 joint statement by the American Thoracic Society (ATS) and European Respiratory Society (ERS), there is a consensus that the fractional concentration of exhaled nitric oxide (FeNO) is best measured at an exhaled rate of 50 mL per second (FeNO 50 mL/s) maintained within 10% for more than 6 seconds at an oral pressure between 5 and 20 cm H2O. (1) Results are expressed as the NO concentration in parts per billion (ppb), based on the mean of 2 or 3 values.
While FeNO levels correlate with the presence of asthma and with eosinophilic airway inflammation and rise with exposure to asthma triggers, the exact role of FENO measurement in the diagnosis and characterization of asthma remain to be defined. The largest clinical trials and systematic reviews did not find sufficient evidence to support routine use of FeNO to guide asthma therapy.
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.
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:
Measurement of NO and EBC has been investigated in the diagnosis and management of asthma. Potential uses in management of asthma include assessing response to anti-inflammatory treatment, monitoring compliance with treatment, and predicting exacerbations. Aside from asthma, they have also been proposed in the management of patients with chronic obstructive pulmonary disease (COPD), cystic fibrosis, allergic rhinitis, and primary ciliary dyskinesia.
The following clinical roles for measurement of nitric oxide and EBC have been investigated in the diagnosis and management of asthma:
The ATS/ERS statement includes the following recommendations regarding use of biomarkers in clinical practice:
The authors acknowledge that more information is required on the utility of FeNO measurement as a tool for monitoring asthma control, and that there is a need for translational research to clarify the relationship between biomarkers and other parameters of asthma control, to establish the optimal frequency of monitoring, and to confirm the clinical and cost effectiveness of biomarker measurements in primary care and other settings.
Regarding exhaled breath condensate, the statement concludes that more work is needed on the validation of the various measures from EBC, and to describe the relationship between these measures and other markers of asthma control. The authors concluded that studies to address whether using EBC results in improved clinical decision-making or better asthma outcomes are required.
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.
The Global Initiative for Asthma (GINA), in a report on the management and prevention of asthma (GINA, 2020), states the following:
The fractional concentration of exhaled nitric oxide (FENO) is modestly associated with levels of sputum and blood eosinophils. FENO has not been established as useful for ruling in or ruling out a diagnosis of asthma…FENO is higher in asthma that is characterized by Type 2 airway inflammation but it is also elevated in non-asthma conditions (e.g. eosinophilic bronchitis, atopy, allergic rhinitis, eczema), and it is not elevated in some asthma phenotypes (e.g. neutrophilic asthma). FENO is lower in smokers and during bronchoconstriction and the early phases of allergic response; it may be increased or decreased during viral respiratory infections.
Although in adult steroid-naïve patients (mainly non-smokers) with non-specific respiratory symptoms, a finding of FENO >50 parts per billion (ppb) was associated with a good short-term response to ICS. 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.
A statement by the American Academy of Pediatrics Section on Allergy and Immunology noted that some specialists may consider evaluation of airway inflammation by using FeNO to be useful, but concluded that the value of additional FeNO monitoring in children whose asthma is appropriately managed using guideline-based strategies is unproven.
While FeNO levels generally predict which patients will respond to inhaled glucocorticoid therapy,the largest trials and a systematic review did not find sufficient evidence to support routine use of FeNO to guide asthma therapy.
In a 2017 guidance on the management of chronic asthma, NICE includes FeNO levels as an indicator for initial treatment of acute symptoms and as an objective test to use for the diagnosis of asthma in an individual age ≥ 5 years. NICE recommended offering FeNO testing to adults if a diagnosis of asthma is being considered and that a FeNO level ≥ 40 parts per billion (ppb) is considered a positive test. In children aged 5–16, FeNO can be considered if there is diagnostic uncertainty with a normal spirometry or obstructive spirometry with a negative bronchodilator reversibility (BDR) test. NICE stated that a FeNO level ≥ 35 ppb is considered a positive test. The guidance provides FeNO levels based on age and FeNO levels when considering other testing (e.g., peak flow, direct bronchial challenge test). It was also noted that the results of spirometry and FeNO testing may be affected in patients who have been treated empirically with inhaled corticosteroids and in smokers. FeNO measurement may be an option to support asthma management in people who are symptomatic despite using inhaled corticosteroids. However, the routine use of FeNO is not recommended by NICE for monitoring asthma control.
Until recently, most asthma management strategies did not depend on the recognition or diagnosis of a particular subtype. However, medications recently have been approved by the Food and Drug Administration (FDA) for the treatment of severe asthma with an eosinophilic phenotype. The measurements of NO and EBC are also being investigated in the diagnosis pathway to determine eosinophilic status.
The following devices/systems have been cleared for marketing by the FDA:
Measurement of exhaled nitric oxide is considered investigational in the diagnosis and management of asthma and all other 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 all other disorders including but not limited to chronic obstructive pulmonary disease and chronic cough.
The evidence is insufficient to determine the effect of exhaled nitric oxide and exhaled breath condensate tests on health outcomes. The recent studies do prove that there is treatment change with the addition of FeNO measurements, but fail to examine the effect of the treatment changes on outcomes. There is still no validated standardized cutoff of FeNO to use for diagnosing asthma. As a result, it is not possible to determine the true sensitivity and specificity of the test for diagnosing asthma or any other disorder. Further investigation is recommended because a negative result does not exclude asthma. Inhaled steroids are a mainstay of treatment of asthma and have been associated with a variety of health outcome benefits. The change in management must be examined to determine net benefits on health outcomes. Recent systematic review concluded FeNO guided management showed no statistically significant benefit in terms of severe exacerbations or ICS use, but showed a statistically significant reduction in exacerbations of any severity. However, further research is warranted to clearly define which management protocols (including cut-off points) offer best efficacy and which patient groups would benefit the most. Additionally, ongoing research should provide guidance on whether characterization of asthma phenotypes by assessment of biomarkers improve asthma management.
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