Clinical Policy Title: Exhaled nitric oxide for diagnosis of lung disease

Clinical Policy Title: Exhaled nitric oxide for diagnosis of lung disease Clinical Policy Number: 07.01.04 Effective Date: June 1, 2014 Initial Review Date: February 19, 2014 Most Recent Review Date: November 16, 2016 Next Review Date: November 2017 Related policies: Policy contains: Asthma. Fractional exhaled nitric oxide (FeNO). None. ABOUT THIS POLICY: Keystone First has developed clinical policies to assist with making coverage determinations. Keystone First s clinical policies are based on guidelines from established industry sources, such as the Centers for Medicare & Medicaid Services (CMS), state regulatory agencies, the American Medical Association (AMA), medical specialty professional societies, and peer-reviewed professional literature. These clinical policies along with other sources, such as plan benefits and state and federal laws and regulatory requirements, including any state- or plan-specific definition of medically necessary, and the specific facts of the particular situation are considered by Keystone First when making coverage determinations. In the event of conflict between this clinical policy and plan benefits and/or state or federal laws and/or regulatory requirements, the plan benefits and/or state and federal laws and/or regulatory requirements shall control. Keystone First s clinical policies are for informational purposes only and not intended as medical advice or to direct treatment. Physicians and other health care providers are solely responsible for the treatment decisions for their patients. Keystone First s clinical policies are reflective of evidence-based medicine at the time of review. As medical science evolves, Keystone First will update its clinical policies as necessary. Keystone First s clinical policies are not guarantees of payment. Coverage policy Keystone First considers the measurement of fractional exhaled nitric oxide (FeNO) in the diagnosis and management of asthma and chronic lung disease to be investigational and, therefore, not medically necessary. Limitations: All other uses of FeNO testing are not medically necessary. Alternative covered services: Standard pulmonary function testing including, but not limited to, peak expiratory flows rate and spirometry. Background 1

Nitric oxide (NO) is an important cellular signaling molecule involved in many physiological and pathological processes. Physiologically, NO causes vasodilatation and relaxation of smooth muscles. NO is synthesized from arginine by the actions of NO synthase (NOS). NOS activates cytosolic guanylate cyclase, which elevates intracellular levels of cyclic-guanosine 3, 5 -monophosphate yielding NO and water. Three isoenzymes of NOS exist with a similar final common pathway. The inducible isoform, inos, is involved in immune response and produces NO as an immune defense mechanism. More NO is produced in the face of inflammatory processes and is reduced in the face of glucocorticosteroids. Exhaled nitric oxide: Because of its active role in pulmonary physiology, NO is present in exhaled breath in concentrations much higher than in the atmosphere. Higher levels of NO in exhaled air have been associated with a more exacerbation-prone phenotype in severe asthma. Since the diagnosis of asthma and other chronic lung disease is often not straightforward, diagnostic modalities that can strengthen the rationale for diagnosing asthma, chronic lung disease or other inflammatory conditions of the pulmonary system have been sought. The measurement of FeNO has been proposed as a biomarker of assessing inflammatory airways disease, including asthma. Searches Keystone First searched PubMed and the databases of: UK National Health Services Centre for Reviews and Dissemination. Agency for Healthcare Research and Quality s National Guideline Clearinghouse and other evidence-based practice centers. The Centers for Medicare & Medicaid Services (CMS). We conducted searches on October 7, 2016. Search terms were: exhaled nitric oxide,"lung diseases/diagnosis"[mesh] and "nitric oxide"[mesh]. We included: Systematic reviews, which pool results from multiple studies to achieve larger sample sizes and greater precision of effect estimation than in smaller primary studies. Systematic reviews use predetermined transparent methods to minimize bias, effectively treating the review as a scientific endeavor, and are thus rated highest in evidence-grading hierarchies. Guidelines based on systematic reviews. Economic analyses, such as cost-effectiveness, and benefit or utility studies (but not simple cost studies), reporting both costs and outcomes sometimes referred to as efficiency studies which also rank near the top of evidence hierarchies. Findings 2

Results of a number of observational studies have suggested higher levels of FeNO in patients with bronchospasm and atopy or eosinophilia, but the clinical use of FeNO testing remains controversial. There is an absence of a consistent, clinically validated protocol for interpretation of test results, and results of randomized controlled trials (RCTs) have not demonstrated the impact of FeNO testing on outcomes. The American Thoracic Society (ATS) guidelines issued a strong recommendation for using FeNO testing to help identify the eosinophilic asthma phenotype in persons with mild-to-moderate asthma based on moderate quality of evidence, as this group is more likely to be steroid responsive than asthmatic patients who are neutrophilic, mixed or paucigranulocytic phenotypes (Dweik, 2011). The Society issued weak recommendations for FeNO testing to determine steroid responsiveness or establish an asthma diagnosis in situations where objective evidence is needed. The ATS did not indicate how FeNO testing would assist in patient management, since there are no recommendations for monitoring drug use or clinical patterns, nor did they recommend its use in critical care or for diagnosing other pulmonary conditions. The Global Initiative for Asthma (GINA) made no mention of the use of FeNO in the diagnosis or management of asthma in their guidance (GINA, 2012). In persons with mild-to-moderate asthma, the ATS recommended specific cut points rather than reference values for interpreting FeNO levels, because multiple confounding factors and overlapping values found in subjects with and without asthma precluded the routine application of reference values in the clinical setting. These proposed cut points are based on low-to-moderate quality evidence (see Table 1; Dweik, 2011). Table 1. ATS-defined cut points for FeNO levels by age and responsiveness Level of FeNO Adults Children Recommendations Low FeNO < 25 PPB* < 20 PPB Less likely to be steroid responsive. Moderate FeNO 25 50 PPB 20 35 PPB Interpret cautiously. High FeNO > 50 PPB > 35 PPB Probably steroid responsive. *PPB, parts per billion In persons with severe asthma, FeNO testing remains controversial. A joint task force supported by the European Respiratory Society (ERS) and ATS issued a conditional recommendation suggesting clinicians not use FeNO testing to guide therapy in adults or children with severe asthma based on very low quality evidence available (Chung, 2014). Policy update: A 2014 practice guideline from the National Institute for Health and Care Excellence (NICE) recommends fractional exhaled nitric oxide as an option to help diagnose asthma in adults and children, but cautions that FeNO testing be done in combination with other options (NICE, 2014). 3

We identified two new systematic reviews (Lu, 2015; Bain, 2014), one update of a previously included review (Hayes, 2015) and one new guideline for this policy update (GINA, 2015). The new evidence is insufficient to support using FeNO as either an adjunct to, or as a replacement for, current testing. Results suggest moderate ability of FeNO to diagnose asthma, but the cutoff values used to interpret FeNO results vary widely. FeNO-guided treatment is associated with a reduction in the number of asthma exacerbations, but its effect on resource use and clinical outcomes has not been established. A uniform protocol for its interpretation such as that developed by the ATS should be evaluated in clinical trials to show that it provides useful information. New guidance from GINA does not recommend FeNO testing for deciding whether to treat patients with possible asthma with inhaled corticosteroids (ICS) (GINA, 2015). FeNO has not been established for making a diagnosis of asthma, as it is increased in both eosinophilic asthma and non-asthma conditions (e.g., eosinophilic bronchitis, atopy and allergic rhinitis). FeNO is decreased in smokers and during bronchoconstriction, and may be increased or decreased during viral respiratory infections. In patients (mainly nonsmokers) with non-specific respiratory symptoms, a finding of FeNO greater than 50 PPB was associated with a good short-term response to ICS. However, there are no long-term studies examining the safety of withholding ICS in patients with low initial FeNO. Therefore, the clinical utility of FeNO remains controversial. A systematic review of seven studies concluded that FeNO testing was effective in helping reduce adult asthma exacerbations, but had no impact on day-to-day clinical symptoms, end-of-study FeNO levels, or inhaled corticosteroid dose; the authors could not advocate FeNO to guide therapy (Petsky, 2016). In various systematic reviews, FeNO was also found to have only a moderate or equivocal ability, at best, to diagnose or predict management of asthma in children (Gomersal, 2016; Li 2015; and Tang, 2016). A review of five studies showed FeNO, while able to assess airway inflammation, is not a good predictor of responsiveness to inhaled corticosteroids in patients with chronic cough (Song, 2016). Results from different types of hand-held electrochemical devices did not always agree (Harnan, 2015). The most recent (2016) update added four new meta-analyses and systemic reviews in the Summary of clinical evidence section. Three new guidelines have been added, along with nine peer-reviewed reports, mostly published in the past year. Summary of clinical evidence: Citation Guo (2016) Diagnostic accuracy of FeNO in asthma Petsky (2016) Content, Methods, Recommendations Meta-analysis of 25 studies (n=3983) patients testing accuracy of exhaled nitric oxide for diagnosing asthma. Sensitivity and specificity were 72% and 78% for all patients Report concludes that exhaled nitric oxide is accurate for diagnosing asthma in steroid-naïve or non-smoking patients, especially those with chronic cough. 4

Citation Ability of FeNO to guide treatment of adult asthma Song (2016) Ability of FeNO to predict corticosteroid response in chronic cough Lu (2015) FeNO and asthma treatment in children Bain (2014) Cochrane review Managing asthma in pregnancy Donohue (2013) Measuring asthma exacerbations Hayes (2013, updated 2015) Content, Methods, Recommendations Systematic review of seven studies, 1,546 adult asthma patients. Patients who had FeNO had fewer exacerbations versus controls. No differences between FeNO and control groups in day-to-day clinical symptoms, end-of-study FeNO levels, inhaled corticosteroid dose. Authors conclude FeNO not helpful in guiding therapy in adults with asthma Systematic review, five studies, patients with chronic cough. Study design heterogeneous, difficult to combine study results. Sensitivity range from 44 59%, specificity range from 63 97%. FeNO testing not a good predictor of corticosteroid response. Meta-analysis of six RCTs with 506 total subjects managed with FeNO-based treatment regimen and 511 total subjects managed using conventional markers. No between-group differences in FeNO value (95% confidence interval [CI]: -0.31, 0.1), change from baseline in forced expired volume in one second (FEV1) (95% CI: -0.07 to 0.20), or steroid use (95% CI: -0.67 to 1.80). FeNO group was associated with a lower frequency of greater than one asthma exacerbation (95% CI: 0.532 to 0.895). Little clinical benefit of a FeNO-guided treatment regimen, although it may decrease asthma exacerbations. Findings support guideline-based asthma management and diagnosis. Systematic review included one RCT (220 nonsmoking, pregnant women) of FeNO-based algorithm vs. a clinical guideline-based algorithm to adjust inhaled corticosteroid therapy. Overall quality: high with low risk of bias. FeNO-based algorithm significantly reduced asthma exacerbations (RR 0.61; 95% CI 0.41 to 0.90); trended towards fewer neonatal hospitalizations (RR 0.46; 95% CI 0.21 to 1.02; 214 infants); may improve some quality of life scores, use of inhaled corticosteroids and long-acting beta-agonists; may lower use of short-acting betaagonists; may be associated with fewer infants with recurrent episodes of bronchiolitis in their first year of life, and trended towards fewer episodes of croup in infants. While a FeNO-based algorithm reduced exacerbations, the effects on perinatal outcomes were less certain, and thus widespread implementation is not yet appropriate. Future trials must be sufficiently powered, and well-designed, to allow differences in important outcomes for mothers and babies to be detected. The impact on health services requires evaluation. Meta-analysis of three RCTs, comparing FeNO-based and clinically-based adult asthma management programs. Rate of exacerbations measured using both types of algorithms. Asthma exacerbation rate significantly reduced using FeNO-based algorithm. 5

Citation FeNO measurement for diagnosis of asthma Dweik (2011) Content, Methods, Recommendations Systematic review evaluating FeNO as an adjunct indicator (seven RCTs) or replacement indicator (three RCTs). FeNO testing is noninvasive and poses no direct risk to patient safety. FeNO may have moderate or moderately high sensitivity and specificity for the diagnosis of asthma. However, cutoff values used for interpretation of FeNO measurements vary widely. FeNO test cannot be considered suitable for routine clinical use until a uniform protocol for its interpretation has been established and evaluated in clinical trials demonstrating clinical benefit. ATS guideline Consensus panel from ATS that reviewed the literature using evidence weighting. Recommended the use of FeNO in diagnosis of eosinophilic airway inflammation (strong recommendation, moderate quality of evidence). Recommended use of FeNO in determining the likelihood of steroid responsiveness (strong recommendation, low quality of evidence). Suggests FeNO be used to support the diagnosis of asthma in situationswhere objective evidence is needed (weak recommendation, moderate quality of evidence). Glossary Bronchodilation Relaxation of the muscles around the bronchial tubes, causing the airways to open further. Fractional exhaled nitric oxide (FeNO) A test measuring the fraction of exhaled nitric oxide in the exhaled air of the patient. The test is purported to measure the degree of inflammatory response from the airway, as in eosinophilic asthma. Inhaled nitric oxide (ino) Use of nitric oxide as reported therapy for premature infants with respiratory failure, or other conditions. Nitric oxide A simple molecule with one atom each of nitrogen and oxygen. It is produced in the body as a result of enzyme reactions and is a potent regulator of vasodilatation and bronchodilation. Vasodilatation Relaxation of the small muscles within the artery wall, causing the artery to open to a wider diameter. References Professional society guidelines/other: 6

Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. The European respiratory journal. 2014; 43(2): 343 373. Dweik RA, Boggs PB, Erzurum SC, et al. An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications. American journal of respiratory and critical care medicine. 2011; 184(5): 602 615. From the Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma (GINA) 2012. GINA website. http://www.ginasthma.org/documents/5/documents_variants/37. Accessed November 9, 2015. From the Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma (GINA) 2015. GINA website. http://www.ginasthma.org/documents/4. Accessed November 8, 2015. Hayes, Inc. Nitric Oxide Breath Analysis for the Diagnosis of Asthma. Medical Technology Directory. Lansdale PA: Hayes, Inc. October 6, 2016. Accessed October 10, 2016. Hayes, Inc. Nitric Oxide Breath Analysis for the Management of Asthma. Medical Technology Directory. Lansdale PA: Hayes, Inc. September 29, 2016. Accessed October 10, 2016. National Institute for Health and Care Excellence (NICE). Measuring fractional exhaled nitric oxide concentration in asthma: NIOX MINO, NIOX VERO and NObreath. April 2014. https://www.guideline.gov/summaries/summary/48533/measuring-fractional-exhaled-nitric-oxideconcentration-in-asthma-niox-mino-niox-vero?q=exhaled+nitric+oxide. Accessed October 10, 2016. Peer-reviewed references: Bain E, Pierides KL, Clifton VL, et al. Interventions for managing asthma in pregnancy. The Cochrane database of systematic reviews. 2014; 10: Cd010660. Donohue JF, Jain N. Exhaled nitric oxide to predict corticosteroid responsiveness and reduce asthma exacerbation rates. Respir Med. 2013;107(7): 943 52. Gomersal T, Harnan S, Essat M, et al. A systematic review of fractional exhaled nitric oxide in the routine management of childhood asthma. Pediatr Pulmonol. 2016;51(3):316 28. Guo Z, Wang Y, Xing G, Wang X. Diagnostic accuracy of fractional exhaled nitric oxide in asthma: a systematic review and meta-analysis of prospective studies. J Asthma. 2016;53(4):404 12. Harnan SE, Tappenden P, Essat M, et al. Measurement of exhaled nitric oxide concentration in asthma: a systematic review and economic evaluation of NIOX MINO, NIOX VERO and NObreath. Health Technol Assess. 2015;19(82):1 330. 7

Hayes Inc., Hayes Medical Technology Report. Nitric Oxide Breath Analysis for the Diagnosis and Management of Asthma. Lansdale, Pa. Hayes Inc.; April 23, 2013. Updated March 10, 2015. Li Z, Qin W, LiL, WuQ, Wang Y. Diagnostic accuracy of exhaled nitric oxide in asthma: a meta-analysis of 4,691 participants. Int J Clin Exp Med. 2015;8(6):8516 24. Lu M, Wu B, Che D, Qiao R, Gu H. FeNO and asthma treatment in children: a systematic review and meta-analysis. Medicine. 2015; 94(4): e347. Ludviksdottir D, Diamant Z, Alving K, Bjermer L, Malinovschi A. Clinical aspects of using exhaled NO in asthma diagnosis and management. Clin Respir J. 2012; 6(4): 193 207. Mahr TA, Malka J, Spahn JD. Inflammometry in pediatric asthma: a review of fractional exhaled nitric oxide in clinical practice. Allergy Asthma Proc. 2013; 34(3): 210 19. McNicholl DM, Stevenson M, McGarvey LP, Heaney LG. The utility of fractional exhaled nitric oxide suppression in the identification of nonadherence in difficult asthma. American journal of respiratory and critical care medicine. 2012; 186(11): 1102 08. Petsky HL, Cates CJ, Lasserson TJ, et al. A systematic review and meta-anslysis: tailoring asthma treatment on eosinophilic markers (exhaled nitric oxide or sputum eosinophils. Thorax. 2012;67(3):199 208. Petsky HL, Kew KM, Turner C, Chang AB. Exhaled nitric oxide levels to guide treatment for adults with asthma. Cochrane Database Syst Rev. September 1, 2016; 9:CD011440 (Epub ahead of print) Smith AD, Cowan JO, Brassett KP, Herbison GP, Taylor DR. Use of exhaled nitric oxide measurements to guide treatment in chronic asthma. N Engl J Med. 2005; 352(21): 2163 73. Smith AD, Cowan JO, Filsell S, et al. Diagnosing asthma: comparisons between exhaled nitric oxide measurements and conventional tests. American journal of respiratory and critical care medicine. 2004; 169(4): 473 78. Song WJ, Won HK, Moon SD, et al. Could fractional exhaled nitric oxide test be useful in predicting inhaled corticosteroid responsibeness in chronic couth? A systematic review. J Allergy Clin Immunol Pract. 2016; doi: 10.1016/j.jaip.2016.07.017. Tang S, Xie Y, Yuan C, Sun X, Cui Y. Fractional exhaled nitric oxide for the diagnosis of childhood asthma: a systematic review and meta-analysis. Clin Rev Allergy Imunol. July 21, 2016 (Epub ahead of print). CMS National Coverage Determinations (NCDs): 8

No NCDs identified as of the writing of this policy. Local Coverage Determinations (LCDs): No LCDs identified as of the writing of this policy. Commonly submitted codes Below are the most commonly submitted codes for the service(s)/item(s) subject to this policy. This is not an exhaustive list of codes. Providers are expected to consult the appropriate coding manuals and bill accordingly. CPT Code Description Comment 95012 Nitric oxide expired gas determination. ICD-10 Code Description Comment J45.20-J45.998 Asthma HCPCS Level II Description Comment N/A 9