524 Form

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Medical Policy Measurement of Exhaled Nitric Oxide and Exhaled Breath Condensate in the Diagnosis and Management of Respiratory Disorders Table of Contents • Policy: Commercial • Coding Information
• Information Pertaining to All Policies
• Policy: Medicare • Description
• References
• Authorization Information • Policy History

Policy Number: 524

BCBSA Reference Number: 2.01.61 (For Plan internal use only) NCD/LCD: NA Related Policies
None Policy Commercial Members: Managed Care (HMO and POS), PPO, and Indemnity
Medicare HMO BlueSM and Medicare PPO BlueSM Members

Measurement of exhaled or nasal 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.

Prior Authorization Information Inpatient • For services described in this policy, precertification/preauthorization IS REQUIRED for all products if the procedure is performed inpatient.
Outpatient • For services described in this policy, see below for products where prior authorization might be required if the procedure is performed outpatient.

Outpatient Commercial Managed Care (HMO and POS) This is not a covered service. Commercial PPO and Indemnity This is not a covered service. Medicare HMO BlueSM This is not a covered service. Medicare PPO BlueSM This is not a covered service.

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CPT Codes / HCPCS Codes / ICD Codes Inclusion or exclusion of a code does not constitute or imply member coverage or provider reimbursement. Please refer to the member’s contract benefits in effect at the time of service to determine coverage or non-coverage as it applies to an individual member.

Providers should report all services using the most up-to-date industry-standard procedure, revenue, and diagnosis codes, including modifiers where applicable.

The following codes are included below for informational purposes only; this is not an all-inclusive list. The following CPT codes are considered investigational for Commercial Members: Managed Care (HMO and POS), PPO, Indemnity, Medicare HMO Blue and Medicare PPO Blue:

CPT Codes CPT codes:

Code Description 83987 pH; exhaled breath condensate
95012 Nitric oxide expired gas determination

Description 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 1 second and peak flow. Therefore, there has been an interest in noninvasive techniques to assess the underlying pathogenic chronic inflammation as reflected by measurements of inflammatory mediators. Fractional Exhaled Nitric Oxide One proposed strategy is the 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. Fractional exhaled NO 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

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measuring FeNO are commercially available in the U.S. According to a joint statement by the American Thoracic Society and European Respiratory Society (2009), 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.1, 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.2, Until recently, most asthma management strategies did not depend on the recognition or diagnosis of a particular subtype. However, anti-interleukin (IL)-5 agents have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of severe asthma with an eosinophilic phenotype. Anti-IL-4 receptor/anti-IL-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. Summary
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. Summary of Evidence For individuals who have suspected asthma who receive measurement of fractional exhaled nitric oxide (FeNO) for diagnosis, the evidence includes multiple retrospective and prospective studies of diagnostic accuracy, along with systematic reviews of those studies. Relevant outcomes are test validity, symptoms, change in disease status, morbid events, and functional outcomes. There are multiple reports on the sensitivity and specificity of FeNO in asthma diagnosis; however, most studies are in the setting of patients with asthma symptoms without previous testing (or with unclear previous testing), which is unlikely to be how the test is used in a U.S. setting. The available evidence is limited by variability in FeNO cutoff levels used to diagnose asthma, lack of data on performance characteristics in challenging diagnostic settings, and lack of data on the incremental value of adding FeNO to existing diagnostic algorithms from studies with concurrent controls. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. For individuals who have asthma who receive medication management directed by FeNO, the evidence includes diagnostic accuracy studies, multiple randomized controlled trials (RCTs), and systematic

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reviews of those trials. Relevant outcomes are symptoms, change in disease status, morbid events, and functional outcomes. The available RCTs evaluating the use of FeNO tests to guide step-up/step-down therapy in patients have not consistently found improvement in health outcomes. Two Cochrane reviews from 2016, 1 on adults and the other on children, found that FeNO-guided asthma management to guide step-up/step-down therapy reduced the number of individuals who had more than 1 exacerbation in children but not in adults compared with guidelines-driven therapy. However, it had no impact on day-to- day symptoms or hospitalizations. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. For individuals who have severe asthma who receive measurement of FeNO to select treatment, the evidence includes diagnostic accuracy studies and subgroup analyses of RCTs and observational studies. Relevant outcomes are test validity, symptoms, change in disease status, morbid events, and functional outcomes. For the use of FeNO to identify eosinophilic asthma for the purpose of selecting patients for therapy with anti-interleukin (IL)-5 therapy or an anti-IL-4R/anti-IL-13 monoclonal antibody, subgroup analyses of RCTs are available. The evidence that points toward an interaction between baseline FeNO and treatment for the outcome of response suggests that there may be a quantitative but not necessarily a qualitative interaction between baseline FeNO and anti-IL-4R/anti-IL-13 treatment (dupilumab). Therefore, it is unclear if baseline FeNO can identify a group for whom there is no benefit from dupilumab. Similarly, a subgroup analysis for mepolizumab suggested a more pronounced effect compared to placebo in those with elevated levels of both blood eosinophils and FeNO. However, outcomes were not reported stratified based on FeNO alone, precluding insight into the utility of using FeNO to predict response to treatment. For use of FeNO to predict response to therapy for patients with other severe asthma phenotypes, such as the allergic subtype, where anti-immunoglobulin E therapy is used, a subgroup analysis of an RCT is available. Subgroup analysis of omalizumab showed an association with more favorable outcomes in patients with high FeNO levels, but as with dupilumab, a qualitative interaction has not been established. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. For individuals who have suspected or confirmed respiratory disorders other than asthma who receive measurement of FeNO, the evidence includes a crossover trial, an open-label trial, a pilot study, and observational studies. Relevant outcomes are test validity, symptoms, change in disease status, morbid events, and functional outcomes. The available evidence assessing the use of FeNO for respiratory disorders other than asthma is limited by heterogeneity in the conditions evaluated and uncertainty about how the test fits in defined clinical management pathways. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. For individuals who have suspected or confirmed respiratory disorders who receive measurement of exhaled breath condensate (EBC), the evidence includes observational studies reporting on the association between various EBC components and disease severity. Relevant outcomes are test validity, symptoms, change in disease status, morbid events, and functional outcomes. There is considerable variability in the particular EBC components measured and criteria for standardized measurements. Also, there is limited evidence on the use of EBC for determining asthma severity, diagnosing other respiratory conditions, or guiding treatment decisions for asthma or other respiratory conditions. The available published evidence does not support conclusions on the utility of EBC for any indication. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome Policy History
Date Action 12/2025 Annual policy review. Policy updated with literature review through May 1, 2025; references added. 8/2024 Annual policy review. References updated. Policy statements unchanged. 8/2023 Annual policy review. Description, summary, and references updated. Policy statements unchanged. 8/2022 Annual policy review. Description, summary, and references updated. Policy statements unchanged.

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10/2020 Annual policy review. Description, summary, and references updated. Policy statements unchanged. 10/2019 Annual policy review. Description, summary, and references updated. Policy statements unchanged. 2/2019 Annual policy review. Investigational indications clarified to indicate eosinophilic asthma. 7/2018 Annual policy review. Description, summary, and references updated. Policy statements unchanged. 10/2017 Annual policy review. New references added. 8/2016 Annual policy review. Policy statement unchanged. Title changed to “Measurement of Exhaled Nitric Oxide and Exhaled Breath Condensate in the Diagnosis and Management of Respiratory Disorders.
12/2015 Clarified coding information. 3/2015 Annual policy review. New references added. 7/2014 Updated Coding section with ICD10 procedure and diagnosis codes. Effective 10/2015. 3/2014 Annual policy review. New references added. 2/2013 Annual policy review. New references added. 11/2011-4/2012 Medical policy ICD 10 remediation: Formatting, editing and coding updates. No changes to policy statements.
4/2011 Reviewed - Medical Policy Group – Cardiology and Pulmonology. No changes to policy statements.
3/21/2011 New policy describing ongoing non-coverage. Information Pertaining to All Blue Cross Blue Shield Medical Policies Click on any of the following terms to access the relevant information: Medical Policy Terms of Use Managed Care Guidelines Indemnity/PPO Guidelines Clinical Exception Process Medical Technology Assessment Guidelines

References

1. Reddel HK, Taylor DR, Bateman ED, et al. An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice. Am J Respir Crit Care Med. Jul 01 2009; 180(1): 59-99. PMID 19535666
2. Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. Feb 2014; 43(2): 343-73. PMID 24337046
3. National Heart Lung and Blood Institute. Guidelines for the Diagnosis and Management of Asthma (EPR-3) 2007; https://www.nhlbi.nih.gov/health-topics/guidelines-for-diagnosis-management-of- asthma. Accessed April 29, 2025.
4. Bossuyt PM, Irwig L, Craig J, et al. Comparative accuracy: assessing new tests against existing diagnostic pathways. BMJ. May 06 2006; 332(7549): 1089-92. PMID 16675820
5. National Institute for Health and Care Excellence (NICE). Asthma: diagnosis, monitoring and chronic asthma management [NG80]. 2017. Updated 2021; https://www.nice.org.uk/guidance/ng80. Accessed April 30, 2025.
6. Antony J, Vandersluis S, Thomas S, et al. Fractional Exhaled Nitric Oxide Testing for the Diagnosis and Management of Asthma: a Health Technology Assessment. Ont Health Technol Assess Ser. 2024; 24(5): 1-225. PMID 39329005
7. Harnan SE, Essat M, Gomersall T, et al. Exhaled nitric oxide in the diagnosis of asthma in adults: a systematic review. Clin Exp Allergy. Mar 2017; 47(3): 410-429. PMID 27906490
8. Karrasch S, Linde K, Rücker G, et al. Accuracy of FENO for diagnosing asthma: a systematic review. Thorax. Feb 2017; 72(2): 109-116. PMID 27388487

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9. Wang Z, Pianosi PT, Keogh KA, et al. The Diagnostic Accuracy of Fractional Exhaled Nitric Oxide Testing in Asthma: A Systematic Review and Meta-analyses. Mayo Clin Proc. Feb 2018; 93(2): 191-
10. PMID 29275031
11. Wang Z, Pianosi P, Keogh K, et al. The Clinical Utility of Fractional Exhaled Nitric Oxide (FeNO) in Asthma Management (Comparative Effectiveness Review No. 197). Rockville, MD: Agency for Healthcare Research and Quality; 2017.
12. Tang W, Zhou J, Miao L, et al. Clinical features in patients of cough variant asthma with normal and high level of exhaled fractional nitric oxide. Clin Respir J. Feb 2018; 12(2): 595-600. PMID 27731932
13. Engel J, van Kampen V, Lotz A, et al. An increase of fractional exhaled nitric oxide after specific inhalation challenge is highly predictive of occupational asthma. Int Arch Occup Environ Health. Oct 2018; 91(7): 799-809. PMID 29850946
14. Kim K, Cho HJ, Yoon JW, et al. Exhaled nitric oxide and mannitol test to predict exercise-induced bronchoconstriction. Pediatr Int. Aug 2018; 60(8): 691-696. PMID 29786927
15. Guo Z, Wang Y, Xing G, et al. 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. PMID 26796787
16. Keßler A, Kragl U, Glass Ä, et al. Exhaled nitric oxide can't replace the methacholine challenge in suspected pediatric asthma. Respir Med. Oct 2019; 157: 21-25. PMID 31476569
17. Busse WW, Morgan WJ, Taggart V, et al. Asthma outcomes workshop: overview. J Allergy Clin Immunol. Mar 2012; 129(3 Suppl): S1-8. PMID 22386504
18. Fuhlbrigge A, Peden D, Apter AJ, et al. Asthma outcomes: exacerbations. J Allergy Clin Immunol. Mar 2012; 129(3 Suppl): S34-48. PMID 22386508
19. Cloutier MM, Schatz M, Castro M, et al. Asthma outcomes: composite scores of asthma control. J Allergy Clin Immunol. Mar 2012; 129(3 Suppl): S24-33. PMID 22386507
20. Juniper EF, Svensson K, Mörk AC, et al. Measurement properties and interpretation of three shortened versions of the asthma control questionnaire. Respir Med. May 2005; 99(5): 553-8. PMID 15823451
21. Schatz M, Zeiger RS, Zhang F, et al. Development and preliminary validation of the Asthma Intensity Manifestations Score (AIMS) derived from Asthma Control Test, FEV(1), fractional exhaled nitric oxide, and step therapy assessments. J Asthma. Mar 2012; 49(2): 172-7. PMID 22304003
22. Petsky HL, Kew KM, Turner C, et al. Exhaled nitric oxide levels to guide treatment for adults with asthma. Cochrane Database Syst Rev. Sep 01 2016; 9(9): CD011440. PMID 27580628
23. Korevaar DA, Damen JA, Heus P, et al. Effectiveness of FeNO-guided treatment in adult asthma patients: A systematic review and meta-analysis. Clin Exp Allergy. Aug 2023; 53(8): 798-808. PMID 37293870
24. Tsurumaki H, Abe Y, Oishi K, et al. Assessing the utility of fractional exhaled nitric oxide-guided management in adult patients with asthma: A systematic review and meta-analysis. Respir Investig. Jan 2025; 63(1): 118-126. PMID 39689589
25. Petsky HL, Kew KM, Chang AB. Exhaled nitric oxide levels to guide treatment for children with asthma. Cochrane Database Syst Rev. Nov 09 2016; 11(11): CD011439. PMID 27825189
26. Petsky HL, Cates CJ, Kew KM, et al. Tailoring asthma treatment on eosinophilic markers (exhaled nitric oxide or sputum eosinophils): a systematic review and meta-analysis. Thorax. Dec 2018; 73(12): 1110-
27. PMID 29858277
28. 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. Sep 20 2008; 372(9643): 1065-72. PMID 18805335
29. Turner S, Cotton S, Wood J, et al. Reducing asthma attacks in children using exhaled nitric oxide (RAACENO) as a biomarker to inform treatment strategy: a multicentre, parallel, randomised, controlled, phase 3 trial. Lancet Respir Med. Jun 2022; 10(6): 584-592. PMID 35101183
30. Heaney LG, Busby J, Hanratty CE, et al. Composite type-2 biomarker strategy versus a symptom-risk- based algorithm to adjust corticosteroid dose in patients with severe asthma: a multicentre, single-blind, parallel group, randomised controlled trial. Lancet Respir Med. Jan 2021; 9(1): 57-68. PMID 32916135
31. 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. Sep 12 2012; 308(10): 987-97. PMID 22968888
32. Hashimoto S, Brinke AT, Roldaan AC, et al. Internet-based tapering of oral corticosteroids in severe asthma: a pragmatic randomised controlled trial. Thorax. Jun 2011; 66(6): 514-20. PMID 21474498

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31. 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. Aug 01 2007; 176(3): 231-7. PMID 17496226
32. Smith AD, Cowan JO, Brassett KP, et al. Use of exhaled nitric oxide measurements to guide treatment in chronic asthma. N Engl J Med. May 26 2005; 352(21): 2163-73. PMID 15914548
33. Peirsman EJ, Carvelli TJ, Hage PY, et al. Exhaled nitric oxide in childhood allergic asthma management: a randomised controlled trial. Pediatr Pulmonol. Jul 2014; 49(7): 624-31. PMID 24039119
34. Pike K, Selby A, Price S, et al. Exhaled nitric oxide monitoring does not reduce exacerbation frequency or inhaled corticosteroid dose in paediatric asthma: a randomised controlled trial. Clin Respir J. Apr 2013; 7(2): 204-13. PMID 22747899
35. Verini M, Consilvio NP, Di Pillo S, et al. FeNO as a Marker of Airways Inflammation: The Possible Implications in Childhood Asthma Management. J Allergy (Cairo). 2010; 2010. PMID 20948878
36. Fritsch M, Uxa S, Horak F, et al. Exhaled nitric oxide in the management of childhood asthma: a prospective 6-months study. Pediatr Pulmonol. Sep 2006; 41(9): 855-62. PMID 16850457
37. Szefler SJ, Martin RJ, King TS, et al. Significant variability in response to inhaled corticosteroids for persistent asthma. J Allergy Clin Immunol. Mar 2002; 109(3): 410-8. PMID 11897984
38. Smith AD, Cowan JO, Brassett KP, et al. Exhaled nitric oxide: a predictor of steroid response. Am J Respir Crit Care Med. Aug 15 2005; 172(4): 453-9. PMID 15901605
39. Knuffman JE, Sorkness CA, Lemanske RF, et al. Phenotypic predictors of long-term response to inhaled corticosteroid and leukotriene modifier therapies in pediatric asthma. J Allergy Clin Immunol. Feb 2009; 123(2): 411-6. PMID 19121860
40. Anderson WJ, Short PM, Williamson PA, et al. Inhaled corticosteroid dose response using domiciliary exhaled nitric oxide in persistent asthma: the FENOtype trial. Chest. Dec 2012; 142(6): 1553-1561. PMID 23364390
41. Visitsunthorn N, Prottasan P, Jirapongsananuruk O, et al. Is fractional exhaled nitric oxide (FeNO) associated with asthma control in children?. Asian Pac J Allergy Immunol. Sep 2014; 32(3): 218-25. PMID 25268339
42. Wilson E, McKeever T, Hargadon B, et al. Exhaled nitric oxide and inhaled corticosteroid dose reduction in asthma: a cohort study. Eur Respir J. Dec 2014; 44(6): 1705-7. PMID 25142486
43. Phipatanakul W, Mauger DT, Sorkness RL, et al. Effects of Age and Disease Severity on Systemic Corticosteroid Responses in Asthma. Am J Respir Crit Care Med. Jun 01 2017; 195(11): 1439-1448. PMID 27967215
44. Price DB, Buhl R, Chan A, et al. Fractional exhaled nitric oxide as a predictor of response to inhaled corticosteroids in patients with non-specific respiratory symptoms and insignificant bronchodilator reversibility: a randomised controlled trial. Lancet Respir Med. Jan 2018; 6(1): 29-39. PMID 29108938
45. Korevaar DA, Westerhof GA, Wang J, et al. Diagnostic accuracy of minimally invasive markers for detection of airway eosinophilia in asthma: a systematic review and meta-analysis. Lancet Respir Med. Apr 2015; 3(4): 290-300. PMID 25801413
46. Gao J, Wu F. Association between fractional exhaled nitric oxide, sputum induction and peripheral blood eosinophil in uncontrolled asthma. Allergy Asthma Clin Immunol. 2018; 14: 21. PMID 29796021
47. Kroes JA, Zielhuis SW, van Roon EN, et al. Prediction of response to biological treatment with monoclonal antibodies in severe asthma. Biochem Pharmacol. Sep 2020; 179: 113978. PMID 32305434
48. Pavord ID, Korn S, Howarth P, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet. Aug 18 2012; 380(9842): 651-9. PMID 22901886
49. Ortega HG, Liu MC, Pavord ID, et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. Sep 25 2014; 371(13): 1198-207. PMID 25199059
50. Ortega HG, Yancey SW, Mayer B, et al. Severe eosinophilic asthma treated with mepolizumab stratified by baseline eosinophil thresholds: a secondary analysis of the DREAM and MENSA studies. Lancet Respir Med. Jul 2016; 4(7): 549-556. PMID 27177493
51. Shrimanker R, Keene O, Hynes G, et al. Prognostic and Predictive Value of Blood Eosinophil Count, Fractional Exhaled Nitric Oxide, and Their Combination in Severe Asthma: A Post Hoc Analysis. Am J Respir Crit Care Med. Nov 15 2019; 200(10): 1308-1312. PMID 31298922
52. Castro M, Corren J, Pavord ID, et al. Dupilumab Efficacy and Safety in Moderate-to-Severe Uncontrolled Asthma. N Engl J Med. Jun 28 2018; 378(26): 2486-2496. PMID 29782217

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53. Rabe KF, Nair P, Brusselle G, et al. Efficacy and Safety of Dupilumab in Glucocorticoid-Dependent Severe Asthma. N Engl J Med. Jun 28 2018; 378(26): 2475-2485. PMID 29782224
54. Pavord ID, Deniz Y, Corren J, et al. Baseline FeNO Independently Predicts the Dupilumab Response in Patients With Moderate-to-Severe Asthma. J Allergy Clin Immunol Pract. Apr 2023; 11(4): 1213- 1220.e2. PMID 36535524
55. Global Strategy for Asthma Management and Prevention (GINA). 2025; https://ginasthma.org/reports/. Accessed May 7, 2025.
56. Hanania NA, Alpan O, Hamilos DL, et al. Omalizumab in severe allergic asthma inadequately controlled with standard therapy: a randomized trial. Ann Intern Med. May 03 2011; 154(9): 573-82. PMID 21536936
57. Hanania NA, Wenzel S, Rosén K, et al. Exploring the effects of omalizumab in allergic asthma: an analysis of biomarkers in the EXTRA study. Am J Respir Crit Care Med. Apr 15 2013; 187(8): 804-11. PMID 23471469
58. Casale TB, Luskin AT, Busse W, et al. Omalizumab Effectiveness by Biomarker Status in Patients with Asthma: Evidence From PROSPERO, A Prospective Real-World Study. J Allergy Clin Immunol Pract. Jan 2019; 7(1): 156-164.e1. PMID 29800752
59. Vincken S, Sylvia V, Daniel S, et al. The role of FeNO in stable COPD patients with eosinophilic airway inflammation. Respir Med. May 2021; 181: 106377. PMID 33838525
60. Tang B, Huang D, Wang J, et al. Relationship of Blood Eosinophils with Fractional Exhaled Nitric Oxide and Pulmonary Function Parameters in Chronic Obstructive Pulmonary Disease (COPD) Exacerbation. Med Sci Monit. Mar 12 2020; 26: e921182. PMID 32161254
61. Gao J, Zhang M, Zhou L, et al. Correlation between fractional exhaled nitric oxide and sputum eosinophilia in exacerbations of COPD. Int J Chron Obstruct Pulmon Dis. 2017; 12: 1287-1293. PMID 28490872
62. Chou KT, Su KC, Huang SF, et al. Exhaled nitric oxide predicts eosinophilic airway inflammation in COPD. Lung. Aug 2014; 192(4): 499-504. PMID 24816967
63. Oishi K, Hirano T, Suetake R, et al. Exhaled nitric oxide measurements in patients with acute-onset interstitial lung disease. J Breath Res. Jun 29 2017; 11(3): 036001. PMID 28660859
64. Guilleminault L, Saint-Hilaire A, Favelle O, et al. Can exhaled nitric oxide differentiate causes of pulmonary fibrosis?. Respir Med. Nov 2013; 107(11): 1789-96. PMID 24011803
65. Boon M, Meyts I, Proesmans M, et al. Diagnostic accuracy of nitric oxide measurements to detect primary ciliary dyskinesia. Eur J Clin Invest. May 2014; 44(5): 477-85. PMID 24597492
66. Su KC, Ko HK, Hsiao YH, et al. Fractional Exhaled Nitric Oxide Guided-Therapy in Chronic Obstructive Pulmonary Disease: A Stratified, Randomized, Controlled Trial. Arch Bronconeumol. Aug 2022; 58(8): 601-610. PMID 35312525
67. Dummer JF, Epton MJ, Cowan JO, et al. Predicting corticosteroid response in chronic obstructive pulmonary disease using exhaled nitric oxide. Am J Respir Crit Care Med. Nov 01 2009; 180(9): 846-
68. PMID 19661244
69. Prieto L, Bruno L, Gutiérrez V, et al. Airway responsiveness to adenosine 5'-monophosphate and exhaled nitric oxide measurements: predictive value as markers for reducing the dose of inhaled corticosteroids in asthmatic subjects. Chest. Oct 2003; 124(4): 1325-33. PMID 14555562
70. Kunisaki KM, Rice KL, Janoff EN, et al. Exhaled nitric oxide, systemic inflammation, and the spirometric response to inhaled fluticasone propionate in severe chronic obstructive pulmonary disease: a prospective study. Ther Adv Respir Dis. Apr 2008; 2(2): 55-64. PMID 19124359
71. Davis MD, Montpetit A, Hunt J. Exhaled breath condensate: an overview. Immunol Allergy Clin North Am. Aug 2012; 32(3): 363-75. PMID 22877615
72. Effros RM, Su J, Casaburi R, et al. Utility of exhaled breath condensates in chronic obstructive pulmonary disease: a critical review. Curr Opin Pulm Med. Mar 2005; 11(2): 135-9. PMID 15699785
73. Hunt J. Exhaled breath condensate: an overview. Immunol Allergy Clin North Am. Nov 2007; 27(4): 587-96; v. PMID 17996577
74. Kazani S, Israel E. Exhaled breath condensates in asthma: diagnostic and therapeutic implications. J Breath Res. Dec 2010; 4(4): 047001. PMID 21383487
75. Liu J, Thomas PS. Exhaled breath condensate as a method of sampling airway nitric oxide and other markers of inflammation. Med Sci Monit. Aug 2005; 11(8): MT53-62. PMID 16049390

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75. Thomas PS, Lowe AJ, Samarasinghe P, et al. Exhaled breath condensate in pediatric asthma: promising new advance or pouring cold water on a lot of hot air? a systematic review. Pediatr Pulmonol. May 2013; 48(5): 419-42. PMID 23401497
76. Aldakheel FM, Thomas PS, Bourke JE, et al. Relationships between adult asthma and oxidative stress markers and pH in exhaled breath condensate: a systematic review. Allergy. Jun 2016; 71(6): 741-57. PMID 26896172
77. Liu L, Teague WG, Erzurum S, et al. Determinants of exhaled breath condensate pH in a large population with asthma. Chest. Feb 2011; 139(2): 328-336. PMID 20966042
78. Navratil M, Plavec D, Erceg D, et al. Urates in exhaled breath condensate as a biomarker of control in childhood asthma. J Asthma. Jun 2015; 52(5): 437-46. PMID 25387148
79. Antus B, Barta I, Kullmann T, et al. Assessment of exhaled breath condensate pH in exacerbations of asthma and chronic obstructive pulmonary disease: A longitudinal study. Am J Respir Crit Care Med. Dec 15 2010; 182(12): 1492-7. PMID 20656939
80. Dinakar C, Chipps BE, Matsui EC, et al. Clinical Tools to Assess Asthma Control in Children. Pediatrics. Jan 2017; 139(1). PMID 28025241
81. Khatri SB, Iaccarino JM, Barochia A, et al. Use of Fractional Exhaled Nitric Oxide to Guide the Treatment of Asthma: An Official American Thoracic Society Clinical Practice Guideline. Am J Respir Crit Care Med. Nov 15 2021; 204(10): e97-e109. PMID 34779751
82. Dweik RA, Boggs PB, Erzurum SC, et al. An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications. Am J Respir Crit Care Med. Sep 01 2011; 184(5): 602-15. PMID 21885636
83. Holguin F, Cardet JC, Chung KF, et al. Management of severe asthma: a European Respiratory Society/American Thoracic Society guideline. Eur Respir J. Jan 2020; 55(1). PMID 31558662
84. Cloutier MM, Baptist AP, Blake KV, et al. 2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group. J Allergy Clin Immunol. Dec 2020; 146(6): 1217-1270. PMID 33280709
85. National Heart Lung and Blood Institute. 2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group 2020; https://www.nhlbi.nih.gov/health-topics/all-publications- and-resources/2020-focused-updates-asthma-management-guidelines. Accessed April 30, 2025.