Medicine Section - Measurement of Exhaled Nitric Oxide and Exhaled Breath Condensate in the Diagnosis and Management of Asthma and Other Respiratory Disorders

IMPORTANT REMINDER

This Medical Policy has been developed through consideration of medical necessity, generally accepted standards of medical practice, and review of medical literature and government approval status.

Benefit determinations should be based in all cases on the applicable contract language. To the extent there are any conflicts between these guidelines and the contract language, the contract language will control.

The purpose of medical policy is to provide a guide to coverage. Medical Policy is not intended to dictate to providers how to practice medicine. Providers are expected to exercise their medical judgment in providing the most appropriate care.

Description

Clinical Background

The National Heart, Lung, and Blood Institute, in its clinical guidelines regarding the management of asthma, offers the following definition of asthma: (2)

"Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role, in particular: mast cells, eosinophils, T lymphocytes, macrophages, neutrophils and epithelial cells. In susceptible individuals, this inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning. These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment. The inflammation also causes an associated increase in the existing bronchial hyper responsiveness to a variety of stimuli."

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 FEV-1 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 new strategies have been investigated, the measurement of exhaled nitric oxide and the evaluation of exhaled breath condensate.  Nitric oxide (NO) is an important endogenous messenger that is widespread in the human body, functioning for example, to regulate peripheral blood flow, platelet function, immune reactions, and neurotransmission, and also to mediate inflammation. In biologic tissues, nitric oxide is unstable, limiting measurement. However, in the gas phase nitric oxide is fairly stable, permitting its measurement in exhaled air.  While nitric oxide is a volatile mediator that can be measured in exhaled air, most inflammatory mediators are not volatile and thus cannot be detected in the gas phase. 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. The pH of EBC can also be measured. Various studies have focused on different components of EBC as inflammatory markers in respiratory disease.  The following clinical roles for measurement of NO and EBC have been investigataed in the diagnosis and management of asthma:

• Diagnosis of asthma

  The current method of asthma diagnosis focuses on the clinical history and the demonstration of reversible airflow limitation. For example, spirometry measurements may be performed before and after the administration of a short-acting bronchodilator to demonstrate the presence of reversible airflow limitation. Measurement of exhaled nitric oxide levels has been suggested as either an alternative or adjunct to spirometry.

• Response to anti-inflammatory treatment

  Declining levels of exhaled nitric oxide suggest declining inflammation.

• Monitoring compliance of anti-inflammatory treatment

  Persistent elevation of exhaled nitric oxide may suggest poor compliance with long-term therapy.

• Detection of steroid resistance

  Steroid resistance may be reflected by persistently high nitric oxide levels despite corticosteroid treatment. Steroid resistance may be related to poor inhalation technique, inadequate dosage, overwhelming anti-inflammatory technique, or poor compliance.

• Prediction of exacerbation of asthma
  

  Currently, prediction of exacerbation of asthma is based on self-assessment of peak flow meter measurements. Increasing levels of exhaled nitric oxide may be able to predict exacerbations before the onset of clinical symptoms or changes in peak flow values.

• Dose Optimization

  There has been interest in using measurements of exhaled nitric oxide to guide dosing of anti-inflammatory medications.

In addition to asthma, the following clinical applications of NO measurement have been proposed:

• Assessment of chronic cough

  Chronic cough may be related to smoking, postnasal drip, gastroesophageal reflux, COPD, or asthma. Elevation of exhaled nitric oxide may point to asthma as the etiology.

• Assessment of cystic fibrosis

  Exhaled nitric oxide appears to be decreased in patients with cystic fibrosis

• Rhinitis

  Nasal nitric oxide (as opposed to exhaled nitric oxide) may be increased in patients with allergic rhinitis.

• Primary ciliary dyskinesia

  Nasal nitric oxide may be decreased in patients with primary ciliary dyskinesia.

Measurement of Nitric Oxide

The most commonly used technique for measurement of exhaled nitric oxide is chemiluminescence after reaction with ozone. Exhaled nitric oxide 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. The early studies of exhaled nitric oxide showed various levels of nitric oxide in health and disease, attributed to the lack of a standardized technique of measurement. In 2005, the American Thoracic Society published updated recommendations for the standardized measurement of exhaled nitric oxide. (3)

In 2003, the U.S. Food and Drug Administration (FDA) approved for marketing the NIOX® Breath Nitric Oxide Test System for the following indication (4):

"[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 ages of 4, as measurement requires patient cooperation. NIOX should not be used in critical care, emergency care or in anesthesiology."

The Breathmeter is another device used to measure exhaled nitric oxide using laser spectroscopy. The Breathmeter has not yet received FDA approval for marketing.

Collection and Measurement of Exhaled Breath Condensate (EBC)

The basic technique of collecting EBC consists of a technique to cool exhaled air and collect EBC droplets. One commercially available system, the RTube consists of a disposable polypropylene condensation chamber that is cooled by an overlying aluminum cooling sleeve. 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.

Policy/Criteria

Measurement of exhaled or nasal nitric oxide or collection and analysis of exhaled breath condensate is considered investigational in the diagnosis and management of all respiratory disorders, including but not limited to asthma, chronic cough, cystic fibrosis, rhinitis, and primary ciliary dyskinesia.

Scientific Background

A search of the MEDLINE database through March 9, 2005 identified a large body of published data regarding exhaled nitric oxide in relation to asthma and other respiratory diseases. However, these studies primarily focused on exhaled nitric oxide as a research tool, exploring the underlying pathophysiology of asthma, establishing the technical performance of the test, and establishing cut off values for normal and abnormal values in different age groups. For example, studies have shown that asthma patients have nitric oxide measurements in the range of 25–85 parts per billion (ppb) compared to control patients whose exhaled nitric oxide measurement is generally less than 20 ppb. (5,6) Other studies have shown that levels of exhaled nitric oxide correlate with levels of other known inflammatory markers, such as airway hyper-responsiveness and sputum eosinophils. (7-10)

Pulmonary function tests represent the standard method for asthma assessment, but studies have found an inconsistent relationship between results of pulmonary function tests and exhaled nitric oxide, perhaps because changes in pulmonary function may lag behind changes in exhaled nitric oxide. (11,12) Several studies have confirmed the expected decrease in exhaled nitric oxide levels after administration of both corticosteroids (13-16) and anti-leukotriene drugs. (17,18,20)

While the cited studies demonstrate the potential role of exhaled nitric oxide measurement in the diagnosis and management of asthma, assessment of the clinical role of this test requires controlled studies comparing patients diagnosed and managed conventionally with patients whose diagnosis and management were additionally directed by measurements of exhaled nitric oxide. No such trials were identified. The more recent literature includes studies which continue to explore the potential clinical applications of exhaled nitric oxide (21-25), but there were no studies identified that actually demonstrated that the use of measurements of exhaled nitric oxide can improve the diagnosis and management of patients with asthma.

Compared to asthma, the data are more limited regarding the role of exhaled nitric oxide measurement in the diagnosis and management of other respiratory conditions, including chronic obstructive pulmonary disease (COPD), cystic fibrosis, and primary ciliary dyskinesia.

Additional Information

In 2002, the National Asthma Education and Prevention Program of the National Heart Lung and Blood Institute issued its second expert panel report on guidelines for the diagnosis and management of asthma. (19) Measurements of nitric oxide were not included among its recommendations.

An updated search of the literature was performed through March 2006.  The search revealed ongoing intense interest in exhaled nitric oxide as a biomarker for asthma.  Studies continue to explore the potential clinical applications of exhaled nitric oxide.  One randomized trial was identified in which 97 patients with asthma treated with inhaled corticosteroids (fluticasone) were randomized either to a group whose care was directed by results of exhaled nitric oxide testing, or to a conventional management group based on international guidelines. (26) In the first phase of the study, the lowest dose of fluticasone was established, based either on international guidelines or exhaled nitric oxide.  In the second phase, patients were maintained on this baseline dose, monitored for exacerbations either conventionally or with results of exhaled nitric oxide, with the fluticasone dose adjusted accordingly.  Patients were followed for twelve months.  The primary outcome was the frequency of asthma exacerbations, and the secondary outcome was the mean daily dose of corticosteroid.  While there was no difference in the frequency of asthma exacerbations between the two groups, the exhaled nitric oxide group did report a significant 40% reduction in the dosage of inhaled corticosteroid.

The accompanying editorial by Deykin points out several limitations to this study. (27) For example, in the control group the mean dose of fluticasone after the initial titration period (567 mg/day) is nearly double the typical dose needed for asthma control.  Therefore, the finding of lower fluticasone doses in patients managed with serial measurements of exhaled nitric oxide may reflect over treatment in the control group rather than any effect of nitric oxide monitoring.  Second, the author points out that it is unclear whether the reported results in these patients with moderate asthma can be extrapolated to those with milder or more severe asthma.  Finally, Deykin questions the scientific basis of nitric oxide monitoring.  For example, while corticosteroids may suppress the inflammatory activity of the airways, they also directly inhibit the enzymatic production of nitric oxide.  Therefore, a reduction in exhaled nitric oxide may also reflect exposure to corticosteroids, rather than simply a reduction in inflammation.  Therefore, it is concluded that the results of this trial are inadequate to permit conclusions regarding the clinical role of exhaled nitric oxide in the management of patients with asthma.

2005 TEC Assessment

In October 2005, a TEC Assessment (22) on exhaled nitric oxide monitoring as a guide to treatment decisions in chronic asthma made the following conclusions:

• The available evidence does not permit the conclusion that use of nitric oxide monitoring to guide treatment decisions in asthma leads to improved outcomes.
• The two RCTs included in the assessment, Smith (26) and Pijnenburg, (29) suggest possible benefits for nitric oxide monitoring but are not sufficient to conclude that outcomes are improved. Each study reported different benefits that have not been reproduced. Smith reported that equivalent outcomes were achieved in the nitric oxide group, with a lower overall dose of inhaled corticosteroids. Pijnenburg reported that bronchial hyper-reactivity was improved in the nitric oxide group. However, bronchial hyper-reactivity is an intermediate outcome that is not well benchmarked to true health outcomes.
• Differences in the control management strategy raise questions about the optimal management strategy to which nitric oxide monitoring should be compared.
• The 7 studies that evaluated the ability of nitric oxide to provide prognostic information that could lead to changes in management had considerable methodologic limitations and variability in study methodology that precluded synthesis of their results and definitive conclusions. (27, 30-35)

Exhaled Breath Condensate

Similar to exhaled nitric oxide, there is intense research interest in the analysis of exhaled breath condensate as a biomarker of inflammation. However, it appears from the published literature that exhaled breath condensate is at an earlier stage of development compared to exhaled nitric oxide. For example, 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 (36-39):

• Standardization of collection and storage techniques
• Effect of dilution of respiratory droplets by water vapor
• Techniques of measuring concentrations of nonvolatile substances in EBC; in most cases these concentrations are very low, which may be at the lower limits of detection of conventional analytic techniques
• Variability in exhaled breath condensate assays for certain substances
• Further investigation of levels of compounds in health and disease

Ultimately controlled trials will be required to determine how evaluations of exhaled breath condensate can be used to direct patient management. The National Institute of Allergy and Infectious Disease is currently recruiting asthmatic children to a clinical trial evaluating the use of pH measurement of exhaled breath condensate in the management of asthma. (40) This trial will evaluate both asthmatic patients and normal controls with exhaled breath condensate pH, expired nitric oxide, pulmonary lung function tests, and peak flow meters over a period of a year. Neither exhaled nitric oxide or exhaled breath condensate pH are used in the management of the patient, but the study will determine whether these measures are correlated with known parameters of disease including number of hospitalizations, absenteeism from school, number of asthma exacerbations, lost work days (if applicable), and extent of rescue medication used.

A literature search was performed through June 23, 2008. No new studies were identified that would alter the conclusions of the policy statements above. While research efforts continue, the clinical utility of these measures is not currently known. In addition, studies also report factors that may influence the reliability of these results. (41, 42) In a study of 17 patients with asthma, Belda and colleagues concluded that measure of nitric oxide was not helpful in predicting loss of asthma control during corticosteroid withdrawal. (43) A study of exhaled breath condensate concluded that the findings did not correlate with results from broncho-alveolar lavage. (44) Shaw and colleagues randomized 118 participants with asthma to a single-blind trial of corticosteroid therapy based on exhaled nitric oxide measurements. (45) During the 12-month study, the primary outcome was the number of severe asthma exacerbations. The authors concluded that the asthma treatment strategy based on the measurement of exhaled nitric oxide did not result in a large reduction in asthma exacerbations or in the total amount of inhaled corticosteroid therapy used during the 12-month study when compared with current asthma care.

References

1. BlueCross BlueShield Association Medical Policy Reference Manual, Policy No. 2.01.61
2. National Institutes of Health. National Heart, Lung and Blood Institute. Guidelines for the Diagnosis and Management of Asthma. NIH Publication 97-4051, 1997 and 2002 update. Available on the Web at: www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf (Verified 06/24/09)
3. American Thoracic Society. Recommendations for Standardized Procedures for the Online and Offline Measurement of Exhaled Lower Respiratory Nitric Oxide and Nasal Nitric Oxide in Adults and Children 2005. Available on the Web at:  www.thoracic.org/sections/publications/statements/pages/respiratory-disease-adults/nitric1-19.html (Verified 06/24/09)
4. FDA Approval Letter. NIOX® Breath Nitric Oxide Test System. Available on the Web at: www.fda.gov/cdrh/pdf2/k021133.pdf (Verified 06/24/09)
5. Baraldi E, Scollo M, Zaramella C et al. A simple flow-driven method for online measurement of exhaled NO starting at the age of 4 to 5 years. Am J Respir Crit Care Med 2000;162(5):1828-32
6. Kharitonov SA, Gonio F, Kelly C et al. Reproducibility of exhaled nitric oxide measurements in healthy and asthmatic adults and children. Eur Respir J 2003;21(3):433-48
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40. www.clinicaltrials.gov/ct/gui/show/NCT00078208  (Verified 06/24/08)
41. Gaston B, Kelly R, Urban P et al. Buffering airway acid decreases exhaled nitric oxide in asthma. J Allergy Clin Immunol 2006;118(4):817-22
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Cross References

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