- Email: [email protected]
Update on Exhaled Nitric Oxide in Clinical Practice
Accepted Manuscript Topics in Practice Management: Update on Exhaled Nitric Oxide in Clinical Practice Srinivas R. Mummadi, MD, FCCP, Peter Y. Hahn, MD, MBA, FCCP PII:
S0012-3692(15)00289-5
DOI:
10.1016/j.chest.2015.11.020
Reference:
CHEST 185
To appear in:
CHEST
Received Date: 6 May 2015 Revised Date:
14 October 2015
Accepted Date: 19 November 2015
Please cite this article as: Mummadi SR, Hahn PY, Topics in Practice Management: Update on Exhaled Nitric Oxide in Clinical Practice, CHEST (2016), doi: 10.1016/j.chest.2015.11.020. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
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Topics in Practice Management:
SC
Update on Exhaled Nitric Oxide in Clinical Practice
Srinivas R. Mummadi, MD, FCCP and Peter Y. Hahn MD, MBA, FCCP
M AN U
Department of Pulmonary, Critical Care, and Sleep Medicine Tuality Healthcare Hillsboro, OR.
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Corresponding Author:
Peter Y. Hahn, MD, MBA, FCCP Tuality Healthcare
EP
364 SE 8th Ave. Suite 301 Hillsboro, OR 97123
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[email protected]
Conflicts of Interest: Dr. Mummadi reports no potential conflicts of interest. Dr. Hahn has served as a consultant for AstraZeneca and Covidien. Dr. Hahn has served on the Speaker’s Bureau for Aerocrine and AstraZeneca.
1
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ABSTRACT
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Asthma is characterized by chronic airway inflammation. Fractional exhaled nitric oxide (FeNO) has emerged as a marker of T-helper cell type 2 (Th2)-mediated allergic airway
inflammation. Recent studies suggest a role for FeNO as a point-of-care tool in the management
SC
of asthma patients.This Topics in Practice Management article reviews current FeNO coverage
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M AN U
and reimbursement issues and provides and overview of pertinent recent studies.
2
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INTRODUCTION
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Asthma is a heterogenous disease characterized by chronic airway inflammation, variable airflow limitation, and airway hyperresponsiveness. It is increasingly recognized that asthma is a complex syndrome made of up recognizable demographic, clinical, and pathophysiologic
SC
clusters often referred to as asthma phenotypes.1 In the era of personalized medicine, better recognition of these different phenotypes may help guide therapy for individual patients.
M AN U
Although the type of airway inflammation can differ between asthma patients, a Th2 driven allergic inflammation is present in up to 80% of children and 50% of adults.2 Allergic airway inflammation has been shown to increase with allergen exposure and is associated with worsened asthma control and increased exacerbations. Allergic airway inflammation has also been shown
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to be very sensitive to inhaled corticosteroids. Measurement of Exhaled Nitric Oxide (FeNO) is a non-invasive point-of-care test that accurately reflects allergic airway inflammation and may be helpful in identifying patient with corticosteroid responsive airway inflammation and in the
EP
management of asthma patients.3
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BACKGROUND
Exhaled Nitric Oxide (FeNO) increases during Th2 allergic inflammation and often
correlates with eosinophilic inflammation in the airways.3 Elevated FeNO levels can help identify patients with allergic airway inflammation likely to respond to inhaled corticosteroid therapy (ICS).4 In allergic airway inflammation, mast cells and antigen specific Th2 cells are activated resulting in the production of cytokines including IL-4, IL-5, and IL-13. IL-4 and IL3
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13 result in the up-regulation of inducible nitric oxide synthase (iNOS) via the signal transducer and activator of transcription (STAT-6). The up-regulation of iNOS results in the increased
RI PT
production of FeNO in airway epithelial cells.5-7 This process is corticosteroid sensitive.
Previously FeNO was thought to be a marker specifically of eosinophilic airway
SC
inflammation. This is reflected in the 2011 American Thoracic Society guidelines for the use of FeNO in clinical practice.8 Recent studies, however, suggest that FeNO more accurately is a
M AN U
broader marker of Th2 mediated allergic inflammation which includes airway eosinophilia rather than eosinophilic inflammation only.9,10 This finding was highlighted by studies investigating the use of anti-IL-5 (mepolizumab) and anti-IL-13 (lebrikizumab). In the mepolizumab study, FeNO levels were unaffected in asthma patients who received mepolizumab whereas blood and
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sputum eosinophil counts were significantly reduced.10 In the lebrikizumab or anti-IL-13 study, patients who received lebrikizumab had a significant reduction in FeNO levels whereas peripheral blood eosinophils were unaffected especially among patients with high baseline
EP
periostin levels.9 Although increases in airway eosinophils and increases in FeNO often do occur concurrently, these studies suggest that the cytokines that regulate the induction of iNOS
AC C
via STAT-6 are separate from those regulating eosinophil traffic through the airways. This may result in a disassociation between FeNO and eosinophilic inflammation. Recent evidence also suggest that levels of FeNO may also be influenced by ongoing
systemic consumption of nitric oxide by systemic inflammatory pathways. Subgroup analyses of severe asthmatics with evidence of systemic inflammation (e.g., metabolic syndrome, diabetes, hypertension) revealed concomitantly low FeNO levels but higher blood levels of the end
4
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products of nitric oxide consumption. It has been suggested that measured levels of FeNO could
RI PT
thus represent a balance between airway production and systemic consumption.11
SC
FeNO AND ICS RESPONSIVENESS
M AN U
FeNO, as a marker of Th2-mediated allergic airway inflammation, can be useful as an indicator of ICS-responsive airway inflammation and in identifying airway inflammation that may not respond to corticosteroids. Several studies have demonstrated the superiority of FeNO over spirometry, bronchodilator responsiveness, peak flow rates, and other conventional measures in predicting response to inhaled corticosteroids.12,13 Taylor recently summarized
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studies evaluating subjects with non-specific respiratory symptoms and a variety of airway diseases and found high PPV and NPV of FeNO in predicting response to ICS.4 FeNO may also
compliance.14
EP
have a role in distinguishing patients whose lack of asthma control is due to ICS non-
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The 2011 American Thoracic Society guidelines advocates the clinical use of FeNO in determining likelihood of steroid responsiveness in patients with non-specific respiratory symptoms. The ATS guidelines recommended the use of cut points rather than reference values when interpreting FeNO levels. A level of greater than 50 parts per billion (ppb) was felt to be a strong indicator that responsiveness to corticosteroids is likely, whereas response to ICS was felt to be unlikely with a value less than 25 ppb.8 FeNO levels in non-asthmatic adults and children have been recently determined using data from the National Health and Nutrition Examination 5
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Survey (NHANES). According to NHANES, the 95th percentile for FeNO was 39 ppb in adults and 36 ppb in children (<12 years). Values above these are considered indicative of allergic
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airway inflammation.15
FeNO AND ASTHMA MANAGEMENT
SC
A number of studies have compared FeNO based asthma management algorithms with standard asthma management algorithms in adults and children.16-18 These studies have yielded
M AN U
conflicting results on whether FeNO guided management resulted in reduced exacerbation rates. A Cochrane systematic review in 2009 and a meta-analysis by Petsky in 2012 reviewed these studies and concluded that the use of FeNO in clinical practice could not be recommended and that future studies were needed.19,20 The primary outcome of both the Cochrane review and the
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Petsky meta-analysis was the number of subjects who had asthma exacerbations during followup. It has been suggested, however, that the number of subjects having exacerbations is not the most appropriate endpoint for assessing exacerbations, since it does not take into account
EP
subjects who may have multiple exacerbations during the course of a study. Rather, the time to first asthma exacerbation and/or asthma exacerbation rates are considered by the NIH to be the
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most appropriate outcomes for assessing asthma exacerbations. Another criticism of the Petsky meta-analysis was that they did not include the algorithm study by Powell et al published in 2011.21 The Powell study22 was a randomized controlled trial of up to 6 months duration in which 220 pregnant women with asthma were randomly assigned to a FeNO-based management group or a clinical management group. This study showed a significantly lower exacerbation rate in the FeNO group compared with the group managed using clinical parameters alone.
6
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Donohue and Jain, recently published a meta-analysis which included the Powell study and used the number of exacerbations as the primary endpoint.21 They found that FeNO guided asthma management resulted in a 40% relative reduction in asthma exacerbation rates. Similarly in
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children, Mahr et al found in a meta-analysis of pediatric studies that the rate of asthma
exacerbations was significantly reduced in favor of a FeNO-based asthma management strategy in children compared to asthma management using clinical parameters (i.e. spirometry) alone.23
M AN U
treatment algorithms on asthma exacerbation rates.
SC
Certainly, further studies are needed to more conclusively determine the effect of FeNO based
In addition to the 2011 ATS guidelines, recently the British National Institute for Health and Clinical Excellence (NICE) issued guidelines recommending FeNO in the diagnosis of asthma in adults and children and in guiding asthma management.24 It is important to note, however, that the use of FeNO may have limited utility in patients with asthma phenotypes not
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characterized by allergic airway inflammation. Increases in FeNO are also seen in atopic patients without asthma. This and other limitations of FeNO need to be appreciated.25 Further
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FeNO values.
EP
studies are also needed to better determine the influence of systemic inflammation on measured
FeNO COVERAGE AND REIMBURSEMENT
7
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Aerocrine currently makes the only FDA approved FeNO measurement device in the United States. The Nioxx Mino, a handheld FeNO device, was replaced in January 2015 by the Nioxx Vero. The company provides the Vero free of charge when ordered with 300 or more
RI PT
tests with each test costing $8.50. Thereafter tests can be purchased in batches of 100 to 200. The Vero is meant to be used in the outpatient setting. In the typical office setting,
medical assistants instruct the patient on the performance of the test. The patient is instructed to
SC
inhale deeply and then exhale using the handheld device. The entire testing procedure takes
M AN U
approximately 5 minutes and can selectively be performed prior to the physician seeing the patient. The current device is FDA approved for use in patients 7 years and older. FeNO testing (CPT 95012) is currently covered by all Medicare and Medicare Advantage plans. Currently, Medicaid payers in 37 states and many private insurance companies, including
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UnitedHealthcare, WellPoint, Kaiser, and 28 of the BlueCross BlueShield plans cover FeNO testing. The national average Medicare reimbursement for 2015 is $19.69 with 0.55 relative value units assigned (no physician work RVUs). The average commercial reimbursement for
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FeNO testing is between $25 and $35. Major private payers that do not cover FeNO are Aetna, Cigna and Humana. States with a large Medicaid population that do not currently cover FeNO
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include California, Florida, and Pennsylvania.
8
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CONCLUSION
Despite advancements in asthma treatments, morbidity from asthma remains high. FeNO is a non-invasive point-of-care test which is an indicator of Th2-mediated allergic airway
SC
inflammation. FeNO can assist clinicians in identifying patients with airway inflammation
responsive to inhaled corticosteroids and incorporating FeNO in the management of asthma
M AN U
patients may result in reductions in exacerbation rates. Although coverage for FeNO testing is
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increasing, the limitations of the test need to be understood to prevent overuse.
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ABBREVIATIONS FeNO: Fractional Exhaled Nitric Oxide GERD: Gastroesophageal Reflux
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ICS: Inhaled Corticosteroids iNOS: Inducible Nitric Oxide Synthase Th2: T-helper cell type 2
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VCD: Vocal Cord Dysfunction
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REFERENCES
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1 Lötvall J, Akdis CA, Bacharier LB, et al. Asthma endotypes: A new approach to classification of disease entities within the asthma syndrome. Journal of Allergy and Clinical Immunology; 127:355-360 2 Pearce N, Pekkanen J, Beasley R. How much asthma is really attributable to atopy? Thorax 1999; 54:268-272 3 An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications. Am. J. Respir. Crit. Care Med. 2011; 184:602 4 Taylor DR. Advances in the clinical applications of exhaled nitric oxide measurements. Journal of Breath Research 2012; 6:047102 5 Durrant DM, Metzger DW. Emerging Roles of T Helper Subsets in the Pathogenesis of Asthma. Immunological Investigations 2010; 39:526-549 6 Alving K, Malinovschi A. Basic aspects of exhaled nitric oxide. Eur Respir Mon, 2010; 1-31 7 Alving K, Weitzberg E, Lundberg JM. Increased amount of nitric oxide in exhaled air of asthmatics. Eur Respir J 1993; 6:1368-1370 8 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; 184:602-615 9 Corren J, Lemanske RF, Hanania NA, et al. Lebrikizumab Treatment in Adults with Asthma. New England Journal of Medicine 2011; 365:1088-1098 10 Haldar P, Brightling CE, Hargadon B, et al. Mepolizumab and Exacerbations of Refractory Eosinophilic Asthma. New England Journal of Medicine 2009; 360:973-984 11 Dweik RA, Sorkness RL, Wenzel S, et al. Use of Exhaled Nitric Oxide Measurement to Identify a Reactive, at-Risk Phenotype among Patients with Asthma. American Journal of Respiratory and Critical Care Medicine 2010; 181:1033-1041 12 Smith AD, Cowan JO, Brassett KP, et al. Exhaled Nitric Oxide: A Predictor of Steroid Response
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10.1164/rccm.200411-1498OC. Am. J. Respir. Crit. Care Med. 2005; 172:453-459 13 Smith AD, Cowan JO, Filsell S, et al. Diagnosing Asthma: Comparisons between Exhaled Nitric Oxide Measurements and Conventional Tests. Am. J. Respir. Crit. Care Med. 2004; 169:473-478 14 Delgado-Corcoran C, Kissoon N, Murphy SP, et al. Exhaled nitric oxide reflects asthma severity and asthma control. Pediatric Critical Care Medicine 2004; 5:48-52 15 See KC, Christiani DC. Normal values and thresholds for the clinical interpretation of exhaled nitric oxide levels in the us general population: Results from the national health and nutrition examination survey 2007-2010. Chest 2013; 143:107-116 16 Calhoun WJ, Ameredes BT, King TS, et al. Comparison of physician-, biomarker-, and symptom-based strategies for adjustment of inhaled corticosteroid therapy in adults with asthma: The basalt randomized controlled trial. JAMA 2012; 308:987-997 17 Smith AD, Cowan JO, Brassett KP, et al. Use of Exhaled Nitric Oxide Measurements to Guide Treatment in Chronic Asthma. New England Journal of Medicine 2005; 352:2163-2173 18 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. The Lancet; 372:1065-1072
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19 Petsky Helen L, Cates Christopher J, Li A, et al. Tailored interventions based on exhaled nitric oxide versus clinical symptoms for asthma in children and adults. Cochrane Database of Systematic Reviews: John Wiley & Sons, Ltd, 2009 20 Petsky HL, Cates CJ, Lasserson TJ, et al. A systematic review and meta-analysis: tailoring asthma treatment on eosinophilic markers (exhaled nitric oxide or sputum eosinophils). Thorax 2012; 67:199-208 21 Donohue JF, Jain N. Exhaled nitric oxide to predict corticosteroid responsiveness and reduce asthma exacerbation rates. Respiratory Medicine; 107:943-952 22 Powell H, Murphy VE, Taylor DR, et al. Management of asthma in pregnancy guided by measurement of fraction of exhaled nitric oxide: a double-blind, randomised controlled trial. The Lancet; 378:983-990 23 Mahr TA, Malka J, Spahn JD. Inflammometry in pediatric asthma: A review of fractional exhaled nitric oxide in clinical practice. Allergy and Asthma Proceedings 2013; 34:210-219 24 British guideline on the management of asthma. Thorax 2014; 69 Suppl 1:1-192 25 Pavord ID, Bush A, Holgate S. Asthma diagnosis: addressing the challenges. The Lancet Respiratory Medicine; 3:339-341
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Fig 1. Factors which can increase or decrease FeNO levels6
Decrease
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Increase Smoking
Airway Infection
ICS Therapy
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Bronchodilator
Allergic Rhinitis
Exercise
Nitrate-rich Diet
Spirometric Maneuvers Alcohol Consumption
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Height
Brochoconstriction Ciliary Dyskinesia Pulmonary Hypertension Cystic Fibrosis
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Response to Inhaled Corticosteroids
<25
Unlikely
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FeNO (ppb)
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Fig 2. FeNO Interpretation in Patients with Asthma-Like Symptoms Not Treated with ICS Adapted from Dweik et al8 and Taylor et al24
Consider:
Non-eosinophilic Asthma
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<20, children under 12 years
VCD
Rhinosinusitis GERD
>35*, children under 12 years
Likely
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20-35, children under 12 years >50*
Possible, Cautious Interpretation
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25-50
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Anxiety
Cardiac disease Consider: High levels of allergen exposure Infection Consider: Atopic Asthma High-levels of Allergen Exposure Infection COPD with mixed inflammatory phenotype Eosinophilic Bronchitis
*Based
on NHANES, cutoff points of 39 ppb in adults and 36 ppb in children could be considered.15 VCD: Vocal Cord Dysfunction; GERD: Gastroesophageal Reflux
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FeNO (ppb)
Allergic Airway Inflammation
<25
Unlikely
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Fig 3. FeNO Interpretation in Patients with Established Asthma, Adapted from Dweik et al8 and Taylor et al24
If symptomatic on ICS – review diagnosis
Consider alternative diagnoses (i.e., noneosinophilic asthma, VCD, Rhinosinusitis, GERD, Anxiety, Cardiac disease)
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<20, children under 12 years
If asymptomatic and taking ICS:
Consider dose reduction of ICS If symptomatic on ICS - Consider :
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25-50
Possible, Cautious Interpretation
Adding LABA
20-35, children under 12 years
Increasing ICS dose
Infection as reason for worsening
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High level allergen exposure If asymptomatic
Likely
Inadequate ICS treatment – Increase ICS dose
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>35*, children under 12 years
No change in ICS dose if patient is stable If symptomatic – Consider :
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>50*
Check inhaler technique Check compliance Imminent exacerbation or relapse Continuous high level allergen exposure Steroid resistance If asymptomatic No change in ICS dose if FeNO level stable over time
*Based
on NHANES, cutoff points of 39 ppb in adults and 36 ppb in children could be considered.15 ICS: Inhaled Corticosteroids; LABA: Long-acting Bronchodilators; VCD: Vocal Cord Dysfunction; GERD: Gastroesophageal Reflux
Advantage Health Solutions (IN)
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Anthem Blue Cross Blue Shield in 14 states CA, CO, CT, GA, IN, KT, ME, MO, NV, NH, OH, VA, WI, NY AvMed Health Plans (FL) Bluegrass Family Health (KY) Blue Cross Blue Shield of Florida Blue Cross Blue Shield of Louisiana Blue Cross Blue Shield of Minnesota Blue Cross Blue Shield of Nebraska Blue Shield in 5 states IL, MT, NM, OK, TX CareFirst Blue Cross Blue Shield (DC, MD, VA) Dean Health Insurance (WI) Group Health Cooperative (ID, WA) Harvard Pilgrim Health Care (MA, ME, NH)
Health Net (AZ, CA, OR, WA) HealthPartners (MN, WI) Horizon Blue Cross Blue Shield of New Jersey Intermountain Healthcare / Select Health (UT) Kaiser Permanente (CA, CO, GA, OH, OR) Medical Mutual of Ohio (GA, IN, MI, OH) Medica Health Plans (MN, ND, SD, WI) Moda Health/ ODS Health (AK, OR, WA) MVP Health Care (NH, NY, VT) Network Health Plan (WI) New West Health Services elathH(MT) PacificSource Health Plans (ID, MT, OR) Physicians Plus Insurance (WI) Preferred One (MN) Premera Blue Cross (AK, OR, WA) Presbyterian Health Plan (NM) Priority Health / Spectrum Health Group (MI) QualCare (NJ) Scott & White Health Plan (TX) Texas Children’s Health Plan (TX) UnitedHealthcare Unity Health Insurance (WI) UPMC Health Plan (PA)
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Medicare & Medicare Advantage Plans (50 states and District of Columbia) Medicaid (37 states and District of Columbia)
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Health Care Service Corporation/ Blue Cross Health Alliance Plan of Michigan/Henry Ford Health System
S0012-3692(15)00289-5
DOI:
10.1016/j.chest.2015.11.020
Reference:
CHEST 185
To appear in:
CHEST
Received Date: 6 May 2015 Revised Date:
14 October 2015
Accepted Date: 19 November 2015
Please cite this article as: Mummadi SR, Hahn PY, Topics in Practice Management: Update on Exhaled Nitric Oxide in Clinical Practice, CHEST (2016), doi: 10.1016/j.chest.2015.11.020. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
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Topics in Practice Management:
SC
Update on Exhaled Nitric Oxide in Clinical Practice
Srinivas R. Mummadi, MD, FCCP and Peter Y. Hahn MD, MBA, FCCP
M AN U
Department of Pulmonary, Critical Care, and Sleep Medicine Tuality Healthcare Hillsboro, OR.
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Corresponding Author:
Peter Y. Hahn, MD, MBA, FCCP Tuality Healthcare
EP
364 SE 8th Ave. Suite 301 Hillsboro, OR 97123
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[email protected]
Conflicts of Interest: Dr. Mummadi reports no potential conflicts of interest. Dr. Hahn has served as a consultant for AstraZeneca and Covidien. Dr. Hahn has served on the Speaker’s Bureau for Aerocrine and AstraZeneca.
1
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ABSTRACT
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Asthma is characterized by chronic airway inflammation. Fractional exhaled nitric oxide (FeNO) has emerged as a marker of T-helper cell type 2 (Th2)-mediated allergic airway
inflammation. Recent studies suggest a role for FeNO as a point-of-care tool in the management
SC
of asthma patients.This Topics in Practice Management article reviews current FeNO coverage
AC C
EP
TE D
M AN U
and reimbursement issues and provides and overview of pertinent recent studies.
2
ACCEPTED MANUSCRIPT
INTRODUCTION
RI PT
Asthma is a heterogenous disease characterized by chronic airway inflammation, variable airflow limitation, and airway hyperresponsiveness. It is increasingly recognized that asthma is a complex syndrome made of up recognizable demographic, clinical, and pathophysiologic
SC
clusters often referred to as asthma phenotypes.1 In the era of personalized medicine, better recognition of these different phenotypes may help guide therapy for individual patients.
M AN U
Although the type of airway inflammation can differ between asthma patients, a Th2 driven allergic inflammation is present in up to 80% of children and 50% of adults.2 Allergic airway inflammation has been shown to increase with allergen exposure and is associated with worsened asthma control and increased exacerbations. Allergic airway inflammation has also been shown
TE D
to be very sensitive to inhaled corticosteroids. Measurement of Exhaled Nitric Oxide (FeNO) is a non-invasive point-of-care test that accurately reflects allergic airway inflammation and may be helpful in identifying patient with corticosteroid responsive airway inflammation and in the
EP
management of asthma patients.3
AC C
BACKGROUND
Exhaled Nitric Oxide (FeNO) increases during Th2 allergic inflammation and often
correlates with eosinophilic inflammation in the airways.3 Elevated FeNO levels can help identify patients with allergic airway inflammation likely to respond to inhaled corticosteroid therapy (ICS).4 In allergic airway inflammation, mast cells and antigen specific Th2 cells are activated resulting in the production of cytokines including IL-4, IL-5, and IL-13. IL-4 and IL3
ACCEPTED MANUSCRIPT
13 result in the up-regulation of inducible nitric oxide synthase (iNOS) via the signal transducer and activator of transcription (STAT-6). The up-regulation of iNOS results in the increased
RI PT
production of FeNO in airway epithelial cells.5-7 This process is corticosteroid sensitive.
Previously FeNO was thought to be a marker specifically of eosinophilic airway
SC
inflammation. This is reflected in the 2011 American Thoracic Society guidelines for the use of FeNO in clinical practice.8 Recent studies, however, suggest that FeNO more accurately is a
M AN U
broader marker of Th2 mediated allergic inflammation which includes airway eosinophilia rather than eosinophilic inflammation only.9,10 This finding was highlighted by studies investigating the use of anti-IL-5 (mepolizumab) and anti-IL-13 (lebrikizumab). In the mepolizumab study, FeNO levels were unaffected in asthma patients who received mepolizumab whereas blood and
TE D
sputum eosinophil counts were significantly reduced.10 In the lebrikizumab or anti-IL-13 study, patients who received lebrikizumab had a significant reduction in FeNO levels whereas peripheral blood eosinophils were unaffected especially among patients with high baseline
EP
periostin levels.9 Although increases in airway eosinophils and increases in FeNO often do occur concurrently, these studies suggest that the cytokines that regulate the induction of iNOS
AC C
via STAT-6 are separate from those regulating eosinophil traffic through the airways. This may result in a disassociation between FeNO and eosinophilic inflammation. Recent evidence also suggest that levels of FeNO may also be influenced by ongoing
systemic consumption of nitric oxide by systemic inflammatory pathways. Subgroup analyses of severe asthmatics with evidence of systemic inflammation (e.g., metabolic syndrome, diabetes, hypertension) revealed concomitantly low FeNO levels but higher blood levels of the end
4
ACCEPTED MANUSCRIPT
products of nitric oxide consumption. It has been suggested that measured levels of FeNO could
RI PT
thus represent a balance between airway production and systemic consumption.11
SC
FeNO AND ICS RESPONSIVENESS
M AN U
FeNO, as a marker of Th2-mediated allergic airway inflammation, can be useful as an indicator of ICS-responsive airway inflammation and in identifying airway inflammation that may not respond to corticosteroids. Several studies have demonstrated the superiority of FeNO over spirometry, bronchodilator responsiveness, peak flow rates, and other conventional measures in predicting response to inhaled corticosteroids.12,13 Taylor recently summarized
TE D
studies evaluating subjects with non-specific respiratory symptoms and a variety of airway diseases and found high PPV and NPV of FeNO in predicting response to ICS.4 FeNO may also
compliance.14
EP
have a role in distinguishing patients whose lack of asthma control is due to ICS non-
AC C
The 2011 American Thoracic Society guidelines advocates the clinical use of FeNO in determining likelihood of steroid responsiveness in patients with non-specific respiratory symptoms. The ATS guidelines recommended the use of cut points rather than reference values when interpreting FeNO levels. A level of greater than 50 parts per billion (ppb) was felt to be a strong indicator that responsiveness to corticosteroids is likely, whereas response to ICS was felt to be unlikely with a value less than 25 ppb.8 FeNO levels in non-asthmatic adults and children have been recently determined using data from the National Health and Nutrition Examination 5
ACCEPTED MANUSCRIPT
Survey (NHANES). According to NHANES, the 95th percentile for FeNO was 39 ppb in adults and 36 ppb in children (<12 years). Values above these are considered indicative of allergic
RI PT
airway inflammation.15
FeNO AND ASTHMA MANAGEMENT
SC
A number of studies have compared FeNO based asthma management algorithms with standard asthma management algorithms in adults and children.16-18 These studies have yielded
M AN U
conflicting results on whether FeNO guided management resulted in reduced exacerbation rates. A Cochrane systematic review in 2009 and a meta-analysis by Petsky in 2012 reviewed these studies and concluded that the use of FeNO in clinical practice could not be recommended and that future studies were needed.19,20 The primary outcome of both the Cochrane review and the
TE D
Petsky meta-analysis was the number of subjects who had asthma exacerbations during followup. It has been suggested, however, that the number of subjects having exacerbations is not the most appropriate endpoint for assessing exacerbations, since it does not take into account
EP
subjects who may have multiple exacerbations during the course of a study. Rather, the time to first asthma exacerbation and/or asthma exacerbation rates are considered by the NIH to be the
AC C
most appropriate outcomes for assessing asthma exacerbations. Another criticism of the Petsky meta-analysis was that they did not include the algorithm study by Powell et al published in 2011.21 The Powell study22 was a randomized controlled trial of up to 6 months duration in which 220 pregnant women with asthma were randomly assigned to a FeNO-based management group or a clinical management group. This study showed a significantly lower exacerbation rate in the FeNO group compared with the group managed using clinical parameters alone.
6
ACCEPTED MANUSCRIPT
Donohue and Jain, recently published a meta-analysis which included the Powell study and used the number of exacerbations as the primary endpoint.21 They found that FeNO guided asthma management resulted in a 40% relative reduction in asthma exacerbation rates. Similarly in
RI PT
children, Mahr et al found in a meta-analysis of pediatric studies that the rate of asthma
exacerbations was significantly reduced in favor of a FeNO-based asthma management strategy in children compared to asthma management using clinical parameters (i.e. spirometry) alone.23
M AN U
treatment algorithms on asthma exacerbation rates.
SC
Certainly, further studies are needed to more conclusively determine the effect of FeNO based
In addition to the 2011 ATS guidelines, recently the British National Institute for Health and Clinical Excellence (NICE) issued guidelines recommending FeNO in the diagnosis of asthma in adults and children and in guiding asthma management.24 It is important to note, however, that the use of FeNO may have limited utility in patients with asthma phenotypes not
TE D
characterized by allergic airway inflammation. Increases in FeNO are also seen in atopic patients without asthma. This and other limitations of FeNO need to be appreciated.25 Further
AC C
FeNO values.
EP
studies are also needed to better determine the influence of systemic inflammation on measured
FeNO COVERAGE AND REIMBURSEMENT
7
ACCEPTED MANUSCRIPT
Aerocrine currently makes the only FDA approved FeNO measurement device in the United States. The Nioxx Mino, a handheld FeNO device, was replaced in January 2015 by the Nioxx Vero. The company provides the Vero free of charge when ordered with 300 or more
RI PT
tests with each test costing $8.50. Thereafter tests can be purchased in batches of 100 to 200. The Vero is meant to be used in the outpatient setting. In the typical office setting,
medical assistants instruct the patient on the performance of the test. The patient is instructed to
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inhale deeply and then exhale using the handheld device. The entire testing procedure takes
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approximately 5 minutes and can selectively be performed prior to the physician seeing the patient. The current device is FDA approved for use in patients 7 years and older. FeNO testing (CPT 95012) is currently covered by all Medicare and Medicare Advantage plans. Currently, Medicaid payers in 37 states and many private insurance companies, including
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UnitedHealthcare, WellPoint, Kaiser, and 28 of the BlueCross BlueShield plans cover FeNO testing. The national average Medicare reimbursement for 2015 is $19.69 with 0.55 relative value units assigned (no physician work RVUs). The average commercial reimbursement for
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FeNO testing is between $25 and $35. Major private payers that do not cover FeNO are Aetna, Cigna and Humana. States with a large Medicaid population that do not currently cover FeNO
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include California, Florida, and Pennsylvania.
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CONCLUSION
Despite advancements in asthma treatments, morbidity from asthma remains high. FeNO is a non-invasive point-of-care test which is an indicator of Th2-mediated allergic airway
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inflammation. FeNO can assist clinicians in identifying patients with airway inflammation
responsive to inhaled corticosteroids and incorporating FeNO in the management of asthma
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patients may result in reductions in exacerbation rates. Although coverage for FeNO testing is
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increasing, the limitations of the test need to be understood to prevent overuse.
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ABBREVIATIONS FeNO: Fractional Exhaled Nitric Oxide GERD: Gastroesophageal Reflux
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ICS: Inhaled Corticosteroids iNOS: Inducible Nitric Oxide Synthase Th2: T-helper cell type 2
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VCD: Vocal Cord Dysfunction
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REFERENCES
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1 Lötvall J, Akdis CA, Bacharier LB, et al. Asthma endotypes: A new approach to classification of disease entities within the asthma syndrome. Journal of Allergy and Clinical Immunology; 127:355-360 2 Pearce N, Pekkanen J, Beasley R. How much asthma is really attributable to atopy? Thorax 1999; 54:268-272 3 An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications. Am. J. Respir. Crit. Care Med. 2011; 184:602 4 Taylor DR. Advances in the clinical applications of exhaled nitric oxide measurements. Journal of Breath Research 2012; 6:047102 5 Durrant DM, Metzger DW. Emerging Roles of T Helper Subsets in the Pathogenesis of Asthma. Immunological Investigations 2010; 39:526-549 6 Alving K, Malinovschi A. Basic aspects of exhaled nitric oxide. Eur Respir Mon, 2010; 1-31 7 Alving K, Weitzberg E, Lundberg JM. Increased amount of nitric oxide in exhaled air of asthmatics. Eur Respir J 1993; 6:1368-1370 8 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; 184:602-615 9 Corren J, Lemanske RF, Hanania NA, et al. Lebrikizumab Treatment in Adults with Asthma. New England Journal of Medicine 2011; 365:1088-1098 10 Haldar P, Brightling CE, Hargadon B, et al. Mepolizumab and Exacerbations of Refractory Eosinophilic Asthma. New England Journal of Medicine 2009; 360:973-984 11 Dweik RA, Sorkness RL, Wenzel S, et al. Use of Exhaled Nitric Oxide Measurement to Identify a Reactive, at-Risk Phenotype among Patients with Asthma. American Journal of Respiratory and Critical Care Medicine 2010; 181:1033-1041 12 Smith AD, Cowan JO, Brassett KP, et al. Exhaled Nitric Oxide: A Predictor of Steroid Response
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10.1164/rccm.200411-1498OC. Am. J. Respir. Crit. Care Med. 2005; 172:453-459 13 Smith AD, Cowan JO, Filsell S, et al. Diagnosing Asthma: Comparisons between Exhaled Nitric Oxide Measurements and Conventional Tests. Am. J. Respir. Crit. Care Med. 2004; 169:473-478 14 Delgado-Corcoran C, Kissoon N, Murphy SP, et al. Exhaled nitric oxide reflects asthma severity and asthma control. Pediatric Critical Care Medicine 2004; 5:48-52 15 See KC, Christiani DC. Normal values and thresholds for the clinical interpretation of exhaled nitric oxide levels in the us general population: Results from the national health and nutrition examination survey 2007-2010. Chest 2013; 143:107-116 16 Calhoun WJ, Ameredes BT, King TS, et al. Comparison of physician-, biomarker-, and symptom-based strategies for adjustment of inhaled corticosteroid therapy in adults with asthma: The basalt randomized controlled trial. JAMA 2012; 308:987-997 17 Smith AD, Cowan JO, Brassett KP, et al. Use of Exhaled Nitric Oxide Measurements to Guide Treatment in Chronic Asthma. New England Journal of Medicine 2005; 352:2163-2173 18 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. The Lancet; 372:1065-1072
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19 Petsky Helen L, Cates Christopher J, Li A, et al. Tailored interventions based on exhaled nitric oxide versus clinical symptoms for asthma in children and adults. Cochrane Database of Systematic Reviews: John Wiley & Sons, Ltd, 2009 20 Petsky HL, Cates CJ, Lasserson TJ, et al. A systematic review and meta-analysis: tailoring asthma treatment on eosinophilic markers (exhaled nitric oxide or sputum eosinophils). Thorax 2012; 67:199-208 21 Donohue JF, Jain N. Exhaled nitric oxide to predict corticosteroid responsiveness and reduce asthma exacerbation rates. Respiratory Medicine; 107:943-952 22 Powell H, Murphy VE, Taylor DR, et al. Management of asthma in pregnancy guided by measurement of fraction of exhaled nitric oxide: a double-blind, randomised controlled trial. The Lancet; 378:983-990 23 Mahr TA, Malka J, Spahn JD. Inflammometry in pediatric asthma: A review of fractional exhaled nitric oxide in clinical practice. Allergy and Asthma Proceedings 2013; 34:210-219 24 British guideline on the management of asthma. Thorax 2014; 69 Suppl 1:1-192 25 Pavord ID, Bush A, Holgate S. Asthma diagnosis: addressing the challenges. The Lancet Respiratory Medicine; 3:339-341
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Fig 1. Factors which can increase or decrease FeNO levels6
Decrease
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Increase Smoking
Airway Infection
ICS Therapy
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Bronchodilator
Allergic Rhinitis
Exercise
Nitrate-rich Diet
Spirometric Maneuvers Alcohol Consumption
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Height
Brochoconstriction Ciliary Dyskinesia Pulmonary Hypertension Cystic Fibrosis
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Response to Inhaled Corticosteroids
<25
Unlikely
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FeNO (ppb)
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Fig 2. FeNO Interpretation in Patients with Asthma-Like Symptoms Not Treated with ICS Adapted from Dweik et al8 and Taylor et al24
Consider:
Non-eosinophilic Asthma
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<20, children under 12 years
VCD
Rhinosinusitis GERD
>35*, children under 12 years
Likely
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20-35, children under 12 years >50*
Possible, Cautious Interpretation
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25-50
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Anxiety
Cardiac disease Consider: High levels of allergen exposure Infection Consider: Atopic Asthma High-levels of Allergen Exposure Infection COPD with mixed inflammatory phenotype Eosinophilic Bronchitis
*Based
on NHANES, cutoff points of 39 ppb in adults and 36 ppb in children could be considered.15 VCD: Vocal Cord Dysfunction; GERD: Gastroesophageal Reflux
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FeNO (ppb)
Allergic Airway Inflammation
<25
Unlikely
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Fig 3. FeNO Interpretation in Patients with Established Asthma, Adapted from Dweik et al8 and Taylor et al24
If symptomatic on ICS – review diagnosis
Consider alternative diagnoses (i.e., noneosinophilic asthma, VCD, Rhinosinusitis, GERD, Anxiety, Cardiac disease)
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<20, children under 12 years
If asymptomatic and taking ICS:
Consider dose reduction of ICS If symptomatic on ICS - Consider :
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25-50
Possible, Cautious Interpretation
Adding LABA
20-35, children under 12 years
Increasing ICS dose
Infection as reason for worsening
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High level allergen exposure If asymptomatic
Likely
Inadequate ICS treatment – Increase ICS dose
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>35*, children under 12 years
No change in ICS dose if patient is stable If symptomatic – Consider :
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>50*
Check inhaler technique Check compliance Imminent exacerbation or relapse Continuous high level allergen exposure Steroid resistance If asymptomatic No change in ICS dose if FeNO level stable over time
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on NHANES, cutoff points of 39 ppb in adults and 36 ppb in children could be considered.15 ICS: Inhaled Corticosteroids; LABA: Long-acting Bronchodilators; VCD: Vocal Cord Dysfunction; GERD: Gastroesophageal Reflux
Advantage Health Solutions (IN)
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Anthem Blue Cross Blue Shield in 14 states CA, CO, CT, GA, IN, KT, ME, MO, NV, NH, OH, VA, WI, NY AvMed Health Plans (FL) Bluegrass Family Health (KY) Blue Cross Blue Shield of Florida Blue Cross Blue Shield of Louisiana Blue Cross Blue Shield of Minnesota Blue Cross Blue Shield of Nebraska Blue Shield in 5 states IL, MT, NM, OK, TX CareFirst Blue Cross Blue Shield (DC, MD, VA) Dean Health Insurance (WI) Group Health Cooperative (ID, WA) Harvard Pilgrim Health Care (MA, ME, NH)
Health Net (AZ, CA, OR, WA) HealthPartners (MN, WI) Horizon Blue Cross Blue Shield of New Jersey Intermountain Healthcare / Select Health (UT) Kaiser Permanente (CA, CO, GA, OH, OR) Medical Mutual of Ohio (GA, IN, MI, OH) Medica Health Plans (MN, ND, SD, WI) Moda Health/ ODS Health (AK, OR, WA) MVP Health Care (NH, NY, VT) Network Health Plan (WI) New West Health Services elathH(MT) PacificSource Health Plans (ID, MT, OR) Physicians Plus Insurance (WI) Preferred One (MN) Premera Blue Cross (AK, OR, WA) Presbyterian Health Plan (NM) Priority Health / Spectrum Health Group (MI) QualCare (NJ) Scott & White Health Plan (TX) Texas Children’s Health Plan (TX) UnitedHealthcare Unity Health Insurance (WI) UPMC Health Plan (PA)
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Medicare & Medicare Advantage Plans (50 states and District of Columbia) Medicaid (37 states and District of Columbia)
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Health Care Service Corporation/ Blue Cross Health Alliance Plan of Michigan/Henry Ford Health System