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

Policy Number: MP-181

Latest Review Date: June 2023

Category:  Medical                                        

POLICY:

Measurement of exhaled or nasal nitric oxide is considered not medically necessary for the diagnosis and management of asthma and other respiratory disorders including but not limited to chronic obstructive pulmonary disease and chronic cough.

Measurement of exhaled breath condensate is considered not medically necessary for the diagnosis and management of asthma and other respiratory disorders including but not limited to chronic obstructive pulmonary disease and chronic cough.

DESCRIPTION OF PROCEDURE OR SERVICE:

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 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. FeNOFractional 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 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. 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 FeNO and EBC

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 (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.

KEY POINTS:

This evidence review has been updated regularly with a literature review using the MEDLINE database, most recently through April 21, 2023.

Summary of Evidence

For individuals who have suspected asthma who receive measurement of fractional exhaled nitric oxide (FeNO), the evidence includes multiple retrospective and prospective studies of diagnostic accuracy, along with systematic reviews of those studies. The relevant outcomes are test accuracy and 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 and 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 reviews of those trials. The relevant outcomes are symptoms, change in disease status, morbid events, and functional outcomes. The available RCTs evaluating the use of FeNO tests for the management of 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 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-4 receptor (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. The relevant outcomes are test accuracy and 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 net health outcome.

Practice Guidelines and Position Statements

American Academy of Pediatrics

In 2017, the American Academy of Pediatrics issued a report on clinical tools to assess asthma control in children. The report stated the following on the use of FeNO: "The value of additional FeNO monitoring in children whose asthma is appropriately managed using guideline-based strategies is unproven."

American Thoracic Society

In 2021, the American Thoracic Society (ATS) published updated guidelines on the use of FeNO to guide the treatment of asthma. Previous guidelines on this topic were published by the ATS over a decade ago. The following question was the basis of the updated guideline: "Should patients with asthma in whom treatment is being contemplated undergo FENO testing?" Based on an overall low quality of available evidence, the panel made the following conditional recommendation for FeNO-based care:

"In patients with asthma in whom treatment is being considered, we suggest to use FENO testing in addition to usual care over usual care alone."

The authors go on to note that "..judgment is based on a balance of effects that probably favors the intervention; the moderate costs and availability of resources, which probably favors the intervention; and the perceived acceptability and feasibility of the intervention in daily practice."

European Respiratory Society/American Thoracic Society

In 2020, the European Respiratory Society and American Thoracic Society published a joint guideline on the management of severe asthma. The guideline addresses whether measurement of a specific biomarker should be used to guide initiation of treatment with an anti- interleukin (IL)-5 therapy or anti-immunoglobulin E (IgE) therapy for adults and children with severe asthma. For anti-IL-5 therapies, the guideline states that most studies focused on blood eosinophils and no data were available for FeNO. For adult and adolescent patients with severe asthma being considered for omalizumab, the guideline suggested "using a FeNO cut-off ≥19.5 ppb to identify adolescents (>12 years) and adults with severe allergic asthma more likely to benefit from anti-IgE treatment (conditional recommendation, low quality of evidence)."

Global Initiative for Asthma

In 2022, the Global Initiative for Asthma released its updated global strategy for asthma management and prevention.

The report made the following statement on FeNO for asthma diagnosis:

  • "FeNO has not been established as useful for ruling in or ruling out a diagnosis of asthma."

The report made the following statement on FeNO for decisions realted to initiation of inhaled corticosteroids:

  • "In studies mainly limited to non-smoking patients, FeNO >50 ppb [parts per billion] has been associated with a good short-term response to ICS. However, these studies did not examine the longer-term risk of exacerbations. Such evidence therefore does not mean that it is safe with regard to exacerbations to withhold ICS in patients with low initial FeNO. More recently, in two 12-month studies in mild asthma, severe exacerbations were reduced with as-needed ICS-formoterol versus as-needed SABA and versus maintenance ICS, independent of baseline inflammatory characteristics including FeNO."
  • "In patients with a diagnosis or suspected diagnosis of asthma, measurement of FeNO can support the decision to start ICS, but cannot be used to decide against treatment with ICS."

The report made the following statements on FeNO for adjusting asthma treatment:

  • "In children, FeNO-guided treatment significantly reduces exacerbation rates compared to guideline-based treatment (Evidence A). However, further studies are needed to identify the populations most likely to benefit from sputum-guided or FeNO-guided treatment and the optimal frequency of FeNO monitoring."

Global Initiative for Asthma released a 'pocket guide for health professionals' in Nov 2018 with an update in Apr 2019 entitled "Difficult-to-Treat & Severe Asthma in Adolescent and Adult Patients – Diagnosis and Management.” The guide states the following regarding using FeNO to manage medications:

"The possibility of refractory type 2 inflammation should be considered if any of the following are found while the patient is taking high-dose ICS or daily OCS:

  • Blood eosinophils ≥150 µl, and/or
  • FeNO ≥20 ppb, and/or
  • Sputum eosinophils ≥2%, and/or
  • Asthma is clinically allergen-driven."

It continues to state that these criteria are suggested for initial assessment; those for blood eosinophils and FeNO are based on lowest levels associated with response to some biologics. They are not the criteria for eligibility for type 2-targeted biologic therapy, which may differ. Consider repeating blood eosinophils and FeNO up to 3 times (e.g., when asthma worsens, before giving OCS), before assuming asthma is non- type 2.

The guide also states that if the patient has had a good response to type 2 targeted therapy:

"For oral treatments, consider gradually decreased or stopping OCS first, because of their significant adverse effects. Tapering may be supported by internet-based monitoring of symptoms control and FeNO."

Another update of this guideline is due for release sometime in 2022.

National Heart Lung and Blood Institute

In 2007, the National Heart Lung and Blood Institute's expert panel guidelines on the diagnosis and management of asthma stated:

"Use of minimally invasive markers (‘biomarkers') to monitor asthma control and guide treatment decisions for therapy is of increasing interest. Some markers, such as spirometry measures, are currently and widely used in clinical care; others, such as sputum eosinophils and FeNO, may also be useful, but they require further evaluation in both children and adults before they can be recommended as clinical tools for routine asthma management (Evidence D)."

"The Expert Panel recommends some minimally invasive markers for monitoring asthma control, such as spirometry and airway hyper-responsiveness, that are appropriately used, currently and widely, in asthma care (Evidence B). Other markers, such as sputum eosinophils and FeNO, are increasingly used in clinical research and will require further evaluation in adults and children before they can be recommended as a clinical tool for routine asthma management (Evidence D)."

A focused update to the 2007 guidelines was published in 2020. The focused update included several updated recommendations on the role of FeNO in asthma diagnosis and management. For asthma diagnosis, the expert panel "conditionally recommends the addition of FeNO measurement as an adjunct to the evaluation process" in individuals 5 years of age or older "for whom the diagnosis of asthma is uncertain using history, clinical findings, clinical course, and spirometry, including bronchodilator responsiveness testing, or in whom spirometry cannot be performed" (conditional recommendation, moderate certainty of evidence). The guidelines mention that FeNO levels greater than 50 parts per billion (ppb) or greater than 35 ppb in children aged 5 to 12 years are consistent with elevated type 2 inflammation and support an asthma diagnosis.

With regard to the role of FeNO testing in asthma management, the expert panel "conditionally recommends the addition of FeNO measurement as part of an ongoing asthma monitoring and management strategy that includes frequent assessments" in "individuals ages 5 years and older with persistent allergic asthma, for whom there is uncertainty in choosing, monitoring, or adjusting anti-inflammatory therapies based on history, clinical findings, and spirometry" (conditional recommendation, low certainty of evidence). Of note, this recommendation does not apply to individuals taking biologic agents, with the exception of omalizumab. The expert panel "recommends against the use of FeNO measurements in isolation to assess asthma control, predict future exacerbations, or assess exacerbation severity" in individuals 5 years of age or older, stating that "FeNO should only be used as part of an ongoing monitoring and management strategy" (strong recommendation, low certainty of evidence). The expert panel also recommended "against FeNO measurement to predict the future development of asthma" in children aged 0 to 4 years with recurrent wheezing (strong recommendation, low certainty of evidence).

National Institute for Health and Care Excellence

The National Institute for Health and Care Excellence (2017, last updated March 2021) issued guidance on asthma diagnosis and monitoring. The guidance recommended the following for diagnosis:

  • “Offer a FeNO [fractional exhaled nitric oxide] test to adults (aged 17 and over) if a diagnosis of asthma is being considered.
  • Consider a FeNO test in children and young people (aged 5 to 16) if there is diagnostic uncertainty after initial assessment
  • Diagnose asthma in children and young people (aged 5 to 16) if they have symptoms suggestive of asthma and:
    • a FeNO level of 35 ppb or more and positive peak flow variability or
    • obstructive spirometry and positive bronchodilator reversibility.
  • Diagnose asthma in adults (aged 17 and over) if they have symptoms suggestive of asthma and:
    • a FeNO level of 40 ppb or more with either positive bronchodilator reversibility or positive peak flow variability, or bronchial hyperreactivity, or
    • a FeNO level between 25 and 39 ppb and a positive bronchial challenge test, or
    • positive bronchodilator reversibility and positive peak flow variability irrespective of FeNO level.”

The guidance recommended the following for monitoring asthma control:

  • “Do not routinely use FeNO to monitor asthma control.
  • Consider FeNO measurement as an option to support asthma management in people who are symptomatic despite using inhaled corticosteroids.”

U.S. Preventive Services Task Force Recommendations

No U.S. Preventive Services Task Force recommendations for asthma screening or the use of NO measurements or EBC have been identified.

KEY WORDS:

Asthma, nitric oxide, NIOX, Breathmeter, exhaled breath condensate pH, exhaled breath condensate, EBC, NIOX MINO, FeNO, NIOX VERO®, RTube™,  ECoScreen EBC, Fenom Pro™ Nitric Oxide Test, NObreath®

APPROVED BY GOVERNING BODIES:

The devices in Table 1 are cleared by the FDA for measuring FeNO with FDA product code MXA.

Table 1. FeNO Devices Cleared by FDA

Device

Manufacturer

Indication/Comments

Date Cleared

510(k)

Nitric Oxide Monitoring System (NIOX®)

Aerocrine; acquired by Circassia

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

2003

De novo DEN030001

 

K021133

NIOX MINO®

Aerocrine; acquired by Circassia

Same as above except used for ages 7 and older. Handheld and portable.

2008

K072816/KI101034

NIOX VERO®

Aerocrine; acquired by Circassia

Same as MINO®. Differs from predicate devices in terms of its battery and display format

2014

K133898

Fenom Pro™ Nitric Oxide Test

Spirosure

Measurement of FeNO by Fenom Pro™ is a method to measure the decrease in FeNO concentration in asthma patients that often occurs after treatment with anti-inflammatory pharmacological therapy as an indication of therapeutic effect in patients with elevated FeNO levels. FeNO measurements are to be used as an adjunct to established clinical assessments. Fenom Pro™ is suitable for children, approximately 7-17 years, and adults 18 years and older. Testing using the Fenom Pro™ should only be done in a point-ofcare healthcare setting under professional supervision. Fenom Pro™ should not be used in critical care, emergency care or in anesthesiology.

2019

K182874

NObreath®

Bedfont Scientific Ltd

Measurement of FeNO by NObreath is a method to measure the decrease in FeNO concentration in asthma patients that often occurs after treatment with anti-inflammatory pharmacological therapy, as an indication of the therapeutic effect in patients with elevated FeNO levels. NObreath is intended for children who are 7-17 years and adults. NObreath 12-second test mode is for ages 7 and up. NObreath 10-second test mode is for ages 7-10, only if successful completion of a 12-second test is not possible. The NObreath cannot be used with infants or by children under the age of 7 as measurement requires patient cooperation. NObreath should not be used in critical care, emergency care, or in anesthesiology.

2021

K203695

FDA: Food and Drug Administration; FeNO: fractional exhaled nitric oxide.

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.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits. Group-specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply

FEP contracts: Special benefit consideration may apply. Refer to member’s benefit plan.

CURRENT CODING: 

CPT codes:

83987

pH; exhaled breath condensate

 

94799

Unlisted pulmonary service or procedure

 

95012

Nitric oxide expired gas determination

 

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  49. 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.
  50. 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):514-520.
  51. 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.
  52. 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).
  53. Honkoop PJ, Loijmans RJ, Termeer EH, et al. Symptom- and fraction of exhaled nitric oxide-driven strategies for asthma control: A cluster-randomized trial in primary care. J Allergy Clin Immunol. Mar 2015; 135(3):682-688.e611.
  54. Inoue, YY, Sato, SS, Manabe, TT, Makita, EE, Chiyotanda, MM, Takahashi, KK, Yamamoto, HH, Yanagida, NN, Ebisawa, MM. Measurement of Exhaled Nitric Oxide in Children: A Comparison Between NObreath® and NIOX VERO® Analyzers.. Allergy Asthma Immunol Res, 2018 Aug 9;10(5).
  55. Institute of Medicine. Clinical Practice Guidelines We Can Trust. March 2011. iom.edu/Reports/2011/Clinical-Practice-Guidelines-We-Can-Trust.aspx.
  56. IOM (Institute of Medicine). 2011. Clinical Practice Guidelines We Can Trust. Washington, DC: The National Academies Press.
  57. Jacinto, TT, Amaral, RR, Malinovschi, AA, Janson, CC, Fonseca, JJ, Alving, KK. Exhaled NO reference limits in a large population-based sample using the Lambda-Mu-Sigma method.. NA.
  58. Jeppegaard, MM, Veidal, SS, Sverrild, AA, Backer, VV, Porsbjerg, CC. Validation of ATS clinical practice guideline cut-points for FeNO in asthma.. Respir Med, 2018 Oct 28;144:22-29.
  59. Jerzynska J, Majak P, Janas A, et al. Predictive value of fractional nitric oxide in asthma diagnosis-subgroup analyses. Nitric Oxide. Aug 31 2014; 40:87-91.
  60. Karakoc GB, Yukselen A, Yilmaz M et al. Exhaled breath condensate MMP-9 level and its relationship with asthma severity and interleukin-4/10 levels in children. Ann Allergy Asthma Immunol 2012; 108(5):300-304.
  61. Karrasch S, Linde K, Rucker G, et al. Accuracy of FENO for diagnosing asthma: a systematic review. Thorax. Feb 2017; 72(2):109-116.
  62. Katoh, SS, Ikeda, MM, Shirai, RR, Abe, MM, Ohue, YY, Kobashi, YY, Oka, MM. Biomarkers for differentiation of patients with asthma and chronic obstructive pulmonary disease.. J Asthma, 2017 Oct 17;55(10).
  63. Katsoulis K, Ganavias L, Michailopoulos P et al. Exhaled nitric oxide as screening tool in subjects with suspected asthma without reversibility. Int Arch Allergy Immunol 2013; 162(1):58-64.
  64. Keskin O, Balaban S, Keskin M, et al. Relationship between exhaled leukotriene and 8-isoprostane levels and asthma severity, asthma control level, and asthma control test score. Allergol Immunopathol (Madr). May-Jun 2014; 42(3):191-197.
  65. Kessler A, Kragl U, Glass A, et al. Exhaled nitric oxide can't replace the methacholine challenge in suspected pediatric asthma. Respir Med. Oct 2019; 157: 21-25. Kroes JA, Zielhuis SW, van Roon EN, et al. Prediction of response to biological treatment with monoclonal antibodies in severe asthma. Biochem Pharmacol. Apr 17 2020: 113978.
  66. 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.
  67. 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.
  68. 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.
  69. Kroll, JJ, Werchan, CC, Rosenfield, DD, Ritz, TT. Acute ingestion of beetroot juice increases exhaled nitric oxide in healthy individuals.. NA
  70. LaForce C, Brooks E, Herje N, et al. Impact of exhaled nitric oxide measurements on treatment decisions in an asthma specialty clinic. Ann Allergy Asthma Immunol. Jul 22 2014.
  71. Langley EW, Gebretsadik T, Hartert TV, et al. Exhaled nitric oxide is associated with severity of pediatric acute asthma exacerbations. J Allergy Clin Immunol Pract. Sep-Oct 2014; 2(5):618-620 e611.
  72. Li, LL, Wang, RR, Cui, LL, Guan, KK. Efficacy of montelukast as prophylactic treatment for seasonal allergic rhinitis.. NA.
  73. Licari, AA, Castagnoli, RR, Brambilla, II, Marseglia, AA, Tosca, MM, Marseglia, GG, Ciprandi, GG. Asthma Endotyping and Biomarkers in Childhood Asthma.. NA
  74. 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.
  75. Liu, LL, Liu, WW, Liu, CC, Wang, DD, Zhao, JJ, Wang, JJ, Wu, JJ, Liu, TT, Zhang, YY, Liu, YY, Cao, LL, Dong, LL. Study on small airway function in asthmatics with fractional exhaled nitric oxide and impulse oscillometry.. NA.
  76. Lluncor, MM, Barranco, PP, Amaya, EE, Domínguez-Ortega, JJ, López-Carrasco, VV, Coman, II, Quirce, SS. Relationship between upper airway diseases, exhaled nitric oxide, and bronchial hyperresponsiveness to methacholine.. J Asthma, 2018 Feb 13;56(1).
  77. Lu, ZZ, Huang, WW, Wang, LL, Xu, NN, Ding, QQ, Cao, CC. Exhaled nitric oxide in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis.. Int J Chron Obstruct Pulmon Dis, 2018 Sep 15;13:2695-2705.
  78. MacBean, VV, Pooranampillai, DD, Howard, CC, Lunt, AA, Greenough, AA. The influence of dilution on the offline measurement of exhaled nitric oxide.. NA.
  79. Malinovschi A, Backer V, Harving H et al. The value of exhaled nitric oxide to identify asthma in smoking patients with asthma-like symptoms. Respir Med 2012; 106(6):794-801.
  80. Malinovschi A, Van Muylem A, Michiels S, et al. FeNO as a predictor of asthma control improvement after starting inhaled steroid treatment. Nitric Oxide. Aug 31 2014; 40:110-116.
  81. Matsunaga K, Hirano T, Oka A, et al. Persistently high exhaled nitric oxide and loss of lung function in controlled asthma. Allergol Int. Jul 2016; 65(3):266-271.
  82. Mattes J, Murphy VE, Powell H, et al. Prenatal origins of bronchiolitis: protective effect of optimised asthma management during pregnancy. Thorax. Apr 2014; 69(4):383-384.
  83. Molino, AA, Fuschillo, SS, Mosella, MM, Accardo, MM, Guida, PP, Motta, AA, Maniscalco, MM. Comparison of three different exhaled nitric oxide analyzers in chronic respiratory disorders.. J Breath Res, 2019 Jan 24;13(2).
  84. More JM, Eclov NC, Chung MP, et al. Feasibility and potential utility of multicomponent exhaled breath analysis for predicting development of radiation pneumonitis after stereotactic ablative radiotherapy. J Thorac Oncol. Jul 2014; 9(7):957-964.
  85. Morten M, Collison A, Murphy VE, et al. Managing Asthma in Pregnancy (MAP) trial: FENO levels and childhood asthma. J Allergy Clin Immunol. Mar 8 2018.
  86. Mostafavi-Pour-Manshadi, SS, Naderi, NN, Barrecheguren, MM, Dehghan, AA, Bourbeau, JJ. Investigating Fractional Exhaled Nitric Oxide in Chronic Obstructive Pulmonary Disease (COPD) and Asthma-COPD Overlap (ACO): A Scoping Review.. COPD, 2018 Aug 2;15(4).
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  88. National Institute for Health and Care Excellence (NICE). Asthma: diagnosis, monitoring and chronic asthma management [NG80]. 2017; https://www.nice.org.uk/guidance/ng80. Accessed April 18, 2021.
  89. National Institute for Health and Care Excellence (NICE). Measuring fractional exhaled nitric oxide concentration in asthma: NIOX MINO, NIOX VERO, and NObreath. 2014; www.nice.org.uk/guidance/dg12/chapter/1-recommendations.
  90. Navratil M, Plavec D, Bulat Lokas S, et al. Urates in exhaled breath condensate as a biomarker of control in childhood asthma. J Asthma. Nov 11 2014:1-37.
  91. NUCALA: Highlights of Prescribing Information. 2015; www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Nucala/pdf/NUCALA-PI-PIL.PDF.
  92. O'Connor GT, Reibman J. Inhaled corticosteroid dose adjustment in mild persistent asthma. JAMA. Sep 12 2012; 308(10):1036-1037.
  93. Oh MA, Shim JY, Jung YH, et al. Fraction of exhaled nitric oxide and wheezing phenotypes in preschool children. Pediatr Pulmonol. Jun 2013; 48(6):563-570.
  94. 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.
  95. 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):1198-1207.
  96. 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.
  97. 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. 
  98. 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):651-659.
  99. 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):624-631.
  100. 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(3):199-208.
  101. 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:Cd011439.
  102. 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:CD011440.
  103. Petsky HL, Li AM, Au CT, et al. Management based on exhaled nitric oxide levels adjusted for atopy reduces asthma exacerbations in children: A dual centre randomized controlled trial. Pediatr Pulmonol. June 2 2014.
  104. 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 1 2017;195(11):1439-1448.
  105. 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. Clin Respir J. Apr 2013; 7(2):204-213.
  106. Piotrowski WJ, Majewski S, Marczak J et al. Exhaled breath 8-isoprostane as a marker of asthma severity. Arch Med Sci. Jul 4 2012; 8(3):515-520.
  107. Powell H, Murphy V, Taylor DR et al. Management of asthma in pregnancy guided by measurement of fraction of exhaled nitric oxide: a double-blind randomized controlled trial. Lancet. Sep 10 2011; 376(9795):983-990.
  108. 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.
  109. 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.
  110. Rickard, KK, Jain, NN, MacDonald-Berko, MM. Measurement of FeNO with a portable, electrochemical analyzer using a 6-second exhalation time in 7-10-year-old children with asthma: comparison to a 10-second exhalation.. NA.
  111. Rouhos A, Kainu A, Piirla P et al. Repeatability of exhaled nitric oxide measurements in patients with COPD. Clin Physiol Funct Imaging. Jan 2011; 31(1):26-31.
  112. Sadeghi, MM, Wright, CC, Hart, SS, Crooks, MM, Morice, AA. Phenotyping patients with chronic cough: Evaluating the ability to predict the response to anti-inflammatory therapy.. NA.
  113. Sano, HH, Tomita, KK, Sano, AA, Saeki, SS, Nishikawa, YY, Nishiyama, OO, Iwanaga, TT, Tohda, YY. Accuracy of objective tests for diagnosing adult asthma in symptomatic patients: A systematic literature review and hierarchical Bayesian latent-class meta-analysis.. NA.
  114. 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):172-177.
  115. Schleich FN, Asandei R, Manise M et al. Is FENO50 useful diagnostic tool in suspected asthma? Int J Clin Pract 2012; 66(2):158-165.
  116. Schneider A, Faderl B, Schwarzbach J, et al. Prognostic value of bronchial provocation and FENO measurement for asthma diagnosis--results of a delayed type of diagnostic study. Respir Med. Jan 2014; 108(1):34-40.
  117. Schneider A, Schwarzbach J, Faderl B et al. FENO measurement and sputum analysis for diagnosing asthma in clinical practice. Respir Med 2013; 107(2):209-216.
  118. 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.
  119. Soma, TT, Iemura, HH, Naito, EE, Miyauchi, SS, Uchida, YY, Nakagome, KK, Nagata, MM. Implication of fraction of exhaled nitric oxide and blood eosinophil count in severe asthma.. NA
  120. Sverrild A, Malinovschi A, Porsbjerg C et al. Predicting airway hyperreactivity to mannitol using exhaled nitric oxide in an unselected sample of adolescents and young adults. Respir Med 2013; 107(1):150-152.
  121. Syk J, Malinovschi A, Johansson G et al. Anti-inflammatory Treatment of Atopic Asthma Guided by Exhaled Nitric Oxide: A Randomized, Controlled Trial. J Allergy Clin Immunol 2013; 1(6):639-648.e8.
  122. Takayama, YY, Ohnishi, HH, Ogasawara, FF, Oyama, KK, Kubota, TT, Yokoyama, AA. Clinical utility of fractional exhaled nitric oxide and blood eosinophils counts in the diagnosis of asthma-COPD overlap.. NA.
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POLICY HISTORY:

Medical Policy Group, June 2004 (1)

Medical Policy Administration Committee, July 2004

Available for comment July 12-August 25, 2004

Medical Policy Group, June 2005 (1)

Medical Policy Group, June 2006 (1)

Medical Policy Administration Committee, June 2006

Available for comment July 5-August 18, 2006

Medical Policy Group, June 2007 (1)

Medical Policy Group, December 2009 (1)

Medical Policy Administration Committee, December 2009

Available for comment December 23, 2009-February 4, 2010

Medical Policy Group, December 2010 (1): Description updated, Key Points updated, Approved Governing Bodies, no policy statement change

Medical Policy Group, January 2012 (1): Policy retitled to include exhaled breath condensate; Update to Key Points and References related to MPP update; no change in policy statement

Medical Policy Panel, January 2013.

Medical Policy Group, January 2013 (3): 2013 Updates:  Key Points, Summary and References.  Policy statement remains unchanged.

Medical Policy Panel, January 2014

Medical Policy Group, January 2014 (3):  Updates to Description, Policy Statement, Key Points, Governing Bodies, & References; policy statements updated to include the word “diagnosis”

Available for comment January 23 through March 7, 2014

Medical Policy panel, January 2015

Medical Policy Group, January 2015 (2): 2015 Updates to Description, Key Points, Summary, Approved by Governing Bodies, and References, no change to policy statement.

Medical Policy panel, July 2016

Medical Policy Group, July 2016 (7): 2016 Updates to Policy Title; Description, Key Points; Approved Governing Bodies, and References. Removed 2012 previous coding. No change to policy statement.

Medical Policy Panel, September 2017

Medical Policy Group, October 2017 (7): Updates to Description, Key Points, and References. No change to policy statement.

Medical Policy Panel, June 2018

Medical Policy Group, July 2018 (7): Updates to Description, Key Points, and References. Removed Policy Statement from 2014. No change in intent of policy statement.

Medical Policy Panel, November 2018

Medical Policy Group, December 2018 (3): Updated Description. No changes to policy statement or intent.

Medical Policy Panel, December 2018

Medical Policy Group, January 2019 (3): Updates to Key Points, References and Key Words: added: NIOX VERO®, RTube™  , and ECoScreen EBC. Medical Advisory Panel reviewed evidence for 3 indications related to FeNO for asthma in October 2018 and concluded evidence is insufficient for all 3 indications. Clinical input from 2017 was integrated with the evidence conclusions which remained insufficient and policy statements remained investigational for all indications.

Medical Policy Panel, August 2019

Medical Policy Group, August 2019 (5): Updates to Key Points, Practice Guidelines and Position Statements, and References. No changes to Policy Statement.

Medical Policy Group, June 2021 (5): Updates to Description, Key Points, Practice Guidelines and Position Statements, and References. Policy statement updated to remove “investigational,” no change to policy intent.

Medical Policy Panel, June 2022

Medical Policy Group, June 2022 (5): Updates to Description, Key Points, Key Words, Practice Guidelines and Position Statements, Approved by Governing Bodies, and References. No change to Policy Statement.

Medical Policy Panel, June 2023

Medical Policy Group, June 2023 (5): Updates to Description, Key Points, Benefit Application, and References. No change to Policy Statement.

 

 

This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

 

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

 

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.