Measurement of Exhaled Nitric Oxide and Exhaled Breath Condensate in the Diagnosis and Management of Respiratory Disorders

POLICY NUMBER

A.2.01.61

DESCRIPTION

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

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. In the United States, the burden of asthma falls disproportionately on Black, Hispanic, and American Indian and Alaska Native populations. Asthma-related emergency department visits are nearly 5 times higher for Black patients when compared to White patients, and Black patients are nearly 3 times as likely to die from asthma when compared to White patients. Differences in life experiences (eg, family, social, and economic environment), lifestyle choices (smoking, obesity, leisure-time physical activities), and exposure to adverse indoor and outdoor environment factors (e.g., mold, pollens, house dust mites, cockroaches, rodents, animal allergens, and other air pollutants) may account for some of the racial and ethnic differences in asthma prevalence. A sex difference also exists in asthma prevalence – in children, asthma is more common in males, whereas among adults, females are more likely to have an asthma diagnosis.

Management

Guidelines for the management of persistent asthma stress the importance of long-term suppression of inflammation using inhaled corticosteroids as primary treatment. 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 an interest in non-invasive techniques to assess the underlying pathogenic chronic inflammation as reflected by measurements of inflammatory mediators.

Fractional Exhaled Nitric Oxide

One proposed strategy isthe measurement of fractional exhaled nitric oxide (FeNO). 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. 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. Devices measuring FeNO are commercially available in the United States. According to a 2009 joint statement by the American Thoracic Society and European Respiratory Society, there is a consensus that 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

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 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 Fractional Exhaled Nitric Oxide and Exhaled Breath Condensate

Measurement of FeNO has been associated with an eosinophilic asthma phenotype. Eosinophilic asthma is a subtype of 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 agents have been approved by the Food and Drug Administration (FDA) for the treatment of severe asthma with an eosinophilic phenotype. Anti-interleukin-4 receptor/anti-interleukin-13 monoclonal antibodies, anti-immunoglobulin E monoclonal antibodies, and thymic stromal lymphopoietin blocker monoclonal antibodies are also available to improve uncontrolled asthma that does not necessarily have an eosinophilic phenotype.

Measurement of NO and EBC has been investigated in the diagnosis and management of asthma. Potential management uses 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.

The devices in the table below are cleared by the FDA for measuring FeNO with FDA product code MXA.

FeNO Devices Cleared by the FDA

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.

POLICY

Measurement of exhaled nitric oxide is considered investigational in the diagnosis and management of asthma, eosinophilic 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 EXCEPTIONS

Federal 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.

POLICY GUIDELINES

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 HISTORY

3/25/2004: 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 A.2.01.61 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.

10/11/2017: Policy description updated regarding clinical uses of fractional exhaled nitric oxide and exhaled breath condensate. Policy statements unchanged.

06/28/2018: Policy reviewed; no changes.

01/11/2019: Policy description updated. Added eosinophilic asthma to investigational statement for measurement of exhaled nitric oxide.

09/04/2019: Policy description updated regarding devices. Policy statements unchanged.

09/21/2020: Policy description updated. Policy statements unchanged.

08/25/2021: Policy reviewed; no changes.

07/12/2022: Policy description updated regarding asthma and fractional exhaled nitric oxide devices. Policy statements unchanged.

07/31/2023: Policy description updated. Policy statements unchanged.

07/10/2024: Policy description updated regarding devices. Policy statements unchanged.

12/02/2025: Policy reviewed; no changes.

SOURCE(S)

Blue Cross Blue Shield Association policy # 2.01.61

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

Investigational Codes

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