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1 for the Diagnosis and Management of Asthma and Other Pulmonary Disorders IEHP Policy: Based on a review of the currently available literature, there is insufficient evidence to support the use of FE NO measurement in the diagnosis or management of asthma or other pulmonary disorders. Therefore, the IEHP UM Subcommittee concurred not to endorse FE NO as a covered benefit at this time. MEDICARE 1 : As of April 22, 2014, Medicare does not have a National Coverage Determination (NCD) or a Local Coverage Determination (LCD) for California for the measurement of FE NO (Fractional Exhaled Nitric Oxide Concentration) for the diagnosis or management of asthma or other pulmonary disorders. MEDI-CAL 2 : CPT code is the appropriate code describing Exhaled Nitric Oxide Measurement. According to the Medi-Cal Benefit Manual, this procedure is not a covered benefit. Additional searches of the Medi-Cal website failed to detect any documents regarding this test such as relevant guidelines, medical reviews or policy statements. APOLLO GUIDELINES : Exhaled nitrous oxide had not been demonstrated to be clinically useful in the management of asthma or other inflammatory airway disorders. It is considered to be experimental and therefore not covered. AETNA 4 : Aetna considers measurement of exhaled nitric oxide experimental and investigational for assessment of asthma, lung cancer, other pulmonary diseases (e.g., COPD, pulmonary tuberculosis, sino-nasal disease) and all other conditions because of insufficient evidence of its effectiveness Sixth St, Rancho Cucamonga, CA Tel (909) Fax (909) Visit our web site at: A Public Entity

2 Page 2 of 5 BLUE SHIELD OF CALIFORNIA 5 : there is insufficient evidence through lack of studies to determine the effect of exhaled nitric oxide and exhaled breath condensate tests on health outcomes, and require further investigation. These tests are therefore considered investigational. CIGNA 6 : Cigna does not cover the measurement of exhaled nitric oxide or exhaled breath condensate for any indication, including the management of asthma and/or other respiratory disorders, because it is considered experimental, investigational or unproven due to insufficient evidence of beneficial health outcomes. BACKGROUND: The Biochemistry of Nitric Oxide (NO) in Mammalian Systems 7, 8 : NO is a gaseous molecule present in virtually all mammalian organ systems. It is produced by the action of the enzyme Nitric Oxide Synthase (NOS) on the amino acid L-arginine. One isoform of this enzyme is inducible by inflammatory cytokines and inhibited by glucocorticoids. Thus, NO has been investigated as a surrogate biomarker of underlying inflammation in various diseases. The Biological Effects of NO in the Human Airway 7, 8 : In the lungs, NO is a bronchodilator; it causes relaxation of bronchial smooth muscles. It is also thought to have anti-inflammatory properties due to its action as an antioxidant. The Clinical Role of Measuring Exhaled Nitric Oxide 7, 8 : Patients with asthma and other inflammatory respiratory disorders including COPD have abnormally elevated levels of NO in their exhaled breath. The observation that FE NO levels in asthmatics decrease following treatment with inhaled corticosteroids has led to the theory that FE NO may be a useful biological marker of inflammation in patients with inflammatory respiratory conditions. As a surrogate marker of inflammation and oxidative stress, FE NO is suggested to have many useful clinical applications for diagnosing and monitoring asthma, COPD, cystic fibrosis, lung cancer, and other conditions. FE NO is currently being used to diagnose disease and identify patients who are likely responders to anti-inflammatory treatment. It is also believed to be useful for monitoring compliance with medications and permitting dose tailoring to avoid inaccurate dosing. Measurement of FE NO levels is less cumbersome and invasive than current techniques for monitoring the status of underlying inflammation such as bronchoscopy (with lavage and biopsy), or analysis by induced sputum. Therefore, there has been interest in noninvasive techniques such as FE NO to assess underlying pathogenic chronic inflammation. Interpretation of Exhaled NO in Asthma 7, 8 : Initial studies of FE NO in asthma used reference ranges to define normal and abnormal values. However, it has been difficult to determine appropriate reference ranges as healthy individuals

3 Page 3 of 5 sometimes fall outside the normal range and individuals with asthma occasionally fall within the range. Rather than develop reference ranges based on the varied combinations of these characteristics, a simpler method of using cut-points has been proposed in the American Thoracic Society (ATS) Clinical Practice Guideline for Interpretation of FE NO 11. Caution needs to be used in interpreting FE NO levels as several factors including age, sex, atopy and cigarette smoking can influence the level of exhaled nitric oxide. Use of Exhaled NO for the Diagnosis and Characterization of Asthma 8 : Patients with asthma have higher concentrations of NO in their exhaled air than do non-asthmatic subjects. Exhaled NO levels rise in association with acute airway inflammation, sputum eosinophilia, viral upper respiratory infections, and other clinical parameters associated with deteriorating asthma control. Intermediate of high FE NO levels are associated with asthma, wheeze and asthma exacerbations. Use of Exhaled NO as a Guide to Therapy 8 : While FE NO 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 FE NO to guide asthma therapy 12, 13, 14. The systematic review compared trials of asthma therapy guided by FE NO with those in which guidance was based on standard measures (symptoms with or without spirometry/peak flow) 8. This analysis was hampered by variations between studies in the definition of asthma exacerbations, algorithms for adjustment of medication, and cut-off values for increasing or decreasing therapy. In contrast, a subsequent meta-analysis that included an additional study found that the rate of exacerbations was significantly reduced in a FE NO -based asthma management algorithm compared with a clinicallybased algorithm 15. Research Review and Summary 7, 8 : According to the ECRI Institute s March 2014 Health Technology Assessment Information Service Hotline Response, which was based on an extensive search of numerous sources (including PubMed, the Cochrane Library, and selected web-based documents) and included a review of abstracts published between January 1, 2009 and March 25, 2014, a total of 141 documents relevant to this topic were found. Among these studies, there was a mixture of positive, negative and inconclusive results regarding the usefulness and effectiveness of FE NO as a tool to diagnose and monitor inflammatory airway disease 7. Similar results were obtained by a 2014 Up-to-Date review of the literature authored by Raed A. Dweik, MD, FACP, FCCP 8. According to this review, several studies found a benefit to using FE NO as a tool to guide asthma therapy while several others did not find such as benefit. Please refer to the bibliography in this document for references regarding both negative 12,13,16,17 and positive 18, 19, 20 studies. Concerns with the research studies regarding measurement of exhaled NO 21 : The overall strength of the available evidence is moderate due to: limitations in study design, heterogeneous patient populations, variable methodological and treatment protocols, different

4 Page 4 of 5 outcome measures, wide variations in threshold values of exhaled NO, and a lack of studies that evaluated whether exhaled NO resulted in improved long-term health outcomes including effects on long-term asthma control or improved quality of life. Additional studies are needed to clarify the role of exhaled NO breath testing in clinical practice. Effective Date: May 14, 2014 Reviewed Annually: November 9, 2016 Revised: Bibliography: 1. CMS.gov Centers for Medicaid and Medicare Services website: Medicare Coverage Database: Accessed 04/22/2014 at 2. CA.gov Department of Health Care Services: Medi-Cal Coverage Database: Accessed 04/22/2014 at 3. Apollo Guidelines 2013: Medical Review Criteria Guidelines for Managed Care: Exhaled Nitrous Oxide, p 841; Aetna Clinical Policy Bulletin: Breath Tests of Airway Inflammation: Exhaled Nitric Oxide and Exhaled Breath Condensate ph, Number Last reviewed: 11/15/2013. Accessed 04/22/2014 at 5. Blue Shield of California. Medical Policy: Exhaled Nitric Oxide and Exhaled Breath Condensate Measurement for Respiratory Disorders. Original Policy Date: 3/1/2006. Effective Date: 9/27/ Cigna Medical Coverage Policy. Exhaled Nitric Oxide and Exhaled Breath Condensate in the Management of Respiratory Disorders, Coverage Policy Number: Effective date: 2/15/ Fractional Exhaled Nitric Oxide (FENO) Measurement for Diagnosing and Monitoring Inflammatory Airway Diseases. ECRI Institute Health Technology Assessment Information Service Hotline Response. March Exhaled Nitric Oxide Analysis and Applications. Dweik, Raed A. UpToDate Accessed 04/22/2014 at 9. American Thoracic Society. Recommendations for standardized procedures for the on-line and off-line measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide in adults and children Am J Respir Crit Care Med 1999;160: American Thoracic Society/European Respiratory Society. ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, Am J Respir Crit Care Med 2005;171: An Official ATS Clinical Practice Guideline: Interpretation of Exhaled Nitric Oxide Levels (FE NO ) for Clinical Applications, Am J Respir Crit Care Med; 184; Calhoun WJ, Ameredes BT, King TS, et al. Comparison of physician-, biomarker-,and symptom-based strategies for adjustment of inhaled corticosteroid therapy in adults with asthma: the BASALT randomized controlled trial. JAMA 2012; 308: Szefler SJ, Mitchell H, Sorkness CA, et al. Management of asthma based on exhaled nitric oxide in addition to guideline-based treatment for inner-city adolescents and young adults: a randomised controlled trial. Lancet 2008; 372: Petsky HL, Cates CJ, Lasserson TJ, et al. A systematic review and meta-analysis: tailoring asthma treatment on eosinophilic markers (exhaled nitric oxide or sputum eosinophils). Thorax 2012; 67:199.

5 Page 5 of Donahue JF, Jain N. Exhaled nitric oxide to predict corticosteroid responsiveness and reduce asthma exacerbation rates. Respir Med 2013; 107: McCormack MC, Aloe C, Curtin-Brosnan J, et al. Guideline-recommended fractional exhaled nitric oxide is a poor predictor of health-care use among inner-city children and adolescents receiving usual asthma care. Chest 2013; 144: Shaw DE, Berry MA, Thomas M, et al. The use of exhaled nitric oxide to guide asthma management: a randomized controlled trial. AM J Respir Crit Care Med 2007; 176: Powell H, Murphy VE, Taylor DR, et al. Management of asthma in pregnancy guided by measurement of fraction of exhaled nitric oxide: a double-blind, randomised controlled trial. Lancet 2011; 378: Smith AD, Cowan JO, Filsell S, et al. Diagnosing asthma: comparisons between exhaled nitric oxide measurements and conventional tests. AM J Respir Crit Care Med 2004; 169: Sippel JM, Holden WE, Tilles SA, et al. Exhaled nitric oxide levels correlate with measures of disease control in asthma. J Allergy Clin Immunol 2000; 106: Nitric Oxide Breath Test & Exhaled Breath Condensate PH For Asthma. Healthcare Protocol: PUL006. Effective Date: May 6, Health Plan of Nevada/Sierra Health and Life: A UnitedHealthcare Company. 22. American Thoracic Society, European Respiratory Society. ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, Am J Respir Crit Care Med 2005; 171:912. Disclaimer IEHP Clinical Authorization Guidelines (CAG) are developed to assist in administering plan benefits, they do not constitute a description of plan benefits. The Clinical Authorization Guidelines (CAG) expresses IEHP's determination of whether certain services or supplies are medically necessary, experimental and investigational, or cosmetic. IEHP has reached these conclusions based upon a review of currently available clinical information (including clinical outcome studies in the peer-reviewed published medical literature, regulatory status of the technology, evidence-based guidelines of public health and health research agencies, evidence-based guidelines and positions of leading national health professional organizations, views of physicians practicing in relevant clinical areas, and other relevant factors). IEHP makes no representations and accepts no liability with respect to the content of any external information cited or relied upon in the Clinical Authorization Guidelines (CAG). IEHP expressly and solely reserves the right to revise the Clinical Authorization Guidelines (CAG), as clinical information changes.