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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 NO in expired breath and various laboratory techniques for evaluating components of EBC.
Asthma is characterized by airway inflammation that leads to airway obstruction and hyperresponsiveness, 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 and peak flow. Therefore, there has been interest in non-invasive 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 fractional exhaled nitric oxide (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, 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 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 United States. According to a 2009 joint statement by ATS and the European Respiratory Society, there is a consensus that the fractional concentration of 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. Results are expressed as the NO concentration in parts per billion (ppb), based on the mean of 2 or 3 values.
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 and 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, two anti-interleukin 5 inhibitors have been approved by the Food and Drug Administration (FDA) for the treatment of severe asthma with an eosinophilic phenotype, mepolizumab and reslizumab.
A 2015 Cochrane review compared the evidence for mepolizumab and placebo for asthma. The review included 8 studies (total N=1707 patients). One randomized controlled trial (RCT) used FeNO as one potential criterion for eosinophilic asthma. In another RCT, the criteria for eosinophilic asthma was a prior diagnosis of eosinophilic asthma or evidence of eosinophilic inflammation, but criteria for the diagnosis are not provided. Overall, the Cochrane review concluded: “It is not possible to draw firm conclusions from this review with respect to the role of mepolizumab in patients with asthma. Our confidence in the results of this review are limited by the fact that the intravenous route is not currently licensed for mepolizumab, and the evidence for the currently licensed subcutaneous route is limited to a single study in participants with severe eosinophilic asthma.”
Measurements 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, cystic fibrosis, allergic rhinitis, pulmonary hypertension, and primary ciliary dyskinesia.
In 2003, the Nitric Oxide Monitoring System (NIOX®; Aerocrine; Sweden; acquired by Circassia Pharmaceuticals, Oxford, U.K.) was cleared for marketing by the U.S. Food and Drug Administration (FDA) through the 510(k) process for the following indication:
“[Measurements of the fractional nitric oxide (NO) concentration in expired breath (FE-NO)] provide the physician with means of evaluating an asthma patient's response to anti-inflammatory therapy, as an adjunct to established clinical and laboratory assessments in asthma. NIOX should only be used by trained physicians, nurses and laboratory technicians. NIOX cannot be used with infants or by children approximately under the age of 4, as measurement requires patient cooperation. NIOX should not be used in critical care, emergency care or in anesthesiology."
In March 2008, the NIOX MINO® was cleared for marketing by FDA through the 510(k) process. The main differences between this new device and the NIOX® are that the NIOX MINO® is handheld, portable, and not suitable for children younger than age 7 years. In November 2014, the NIOX VERO®, which differs from predicate devices in terms of its battery and display format, was also cleared for marketing by FDA through the 510(k) process. FDA product code: MXA.
The RTube™ Exhaled Breath Condensate collection system (Respiratory Research) 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.
POLICYMeasurement 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 EXCEPTIONSFederal Employee Program (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.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.
POLICY HISTORY3/25/2004: Approved by Medical Policy Advisory Committee (MPAC)
4/29/2004: Code Reference section completed
3/22/2005: Code Reference section updated, CPT code 0064T added non-covered codes, CPT code 84999 Note: "To report services on or after 1/1/2005, see CPT code 0064T" added
12/22/2005: Collection and Measurement of Exhaled Breath Condensate and coding 0140T added to policy
1/3/2007: Code reference section updated per the 2007 CPT/HCPCS revisions
1/3/2007: Policy reviewed, no changes
12/17/2008: Policy reviewed, no changes
05/28/2010: Title updated with "Exhaled Breath Condensate"; Description section updated; Policy Statement section - existing policy statement was divided into two statements: one for exhaled nitric oxide and the other for exhaled breath condensate - both remain investigational; FEP verbiage was added to the Policy Exceptions section; and Code Reference section was updated to add new CPT Code 83987 and CPT Code 94799 to the Non-Covered Codes Table.
02/23/2011: Policy reviewed; no changes.
02/24/2012: The first policy statement was revised to change “exhaled or nasal nitric oxide” to “exhaled nitric oxide.” Intent unchanged. Deleted outdated references from the Sources section. Removed deleted CPT codes 0064T and 0140T from the Code Reference section.
04/04/2013: Policy reviewed; no changes.
03/11/2014: Policy reviewed; no changes.
07/20/2015: Policy title changed from "Exhaled Nitric Oxide and Exhaled Breath Condensate Measurements in the Diagnosis and Management of Asthma and Other Respiratory Disorders" to "Measurement of Exhaled Nitric Oxide and Exhaled Breath Condensate in the Diagnosis and Management of Asthma and Other Respiratory Disorders." Policy description revised and updated regarding devices. Policy statements unchanged. Policy guidelines updated to revise investigational definition. Code Reference section updated for ICD-10.
06/01/2016: Policy number added.
08/17/2016: Policy title changed from "Measurement of Exhaled Nitric Oxide and Exhaled Breath Condensate in the Diagnosis and Management of Asthma and Other Respiratory Disorders" to "Measurement of Exhaled Nitric Oxide and Exhaled Breath Condensate in the Diagnosis and Management of Respiratory Disorders." Policy description updated regarding clinical uses of fractional exhaled nitric oxide and exhaled breath condensate. Policy statements unchanged.
SOURCE(S)Blue Cross Blue Shield Association policy # 2.01.61
CODE REFERENCEThis may not be a comprehensive list of procedure codes applicable to this policy.