Advancing Asthma
Management with
Exhaled Nitric Oxide
Table of Contents
                                                                                 Summary                ...
1. The Burden of Asthma                                                    considering the prevalence of asthma and the fr...
2. Exhaled Nitric Oxide (eNO)                                                            effective local vasodilator. It c...
Separate recommendations have also been developed for children.                                                           ...
Performing eNO Testing is Simple and                                       steadily through a disposable breath tube, and ...
oxide molecules from the breath sample flow into the sensor,                               •	 A carbon dioxide filter to r...
Twenty-four samples containing all of the above potential
     Parameter                    Analysis                   Res...
Case Study 1
 4. Case Studies

“Let’s go fishing dad!” – Maya, 10, Pensacola FL
Case Study 2

“I like to win.” – Scott, 23, Fresno CA
                                      Scott is a talented young race...
Case Study 3

“It feels good to be in control.” - Lynn, 36, Long Island NY
                                         Lynn w...
5. Exhaled Nitric Oxide Cost Model                                       6. Coding Information for Exhaled Nitric
This cos...
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Advancing Asthma Management with Exhaled Nitric Oxide


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Exhaled nitric oxide (eNO) is an established marker of airway inflammation that can be safely and accurately measured in people with asthma. This resource kit provides comprehensive information about the benefits and technology of eNO testing,
and highlights the medical necessity and the extent of acceptance of eNO testing.

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Advancing Asthma Management with Exhaled Nitric Oxide

  1. 1. Advancing Asthma Management with Exhaled Nitric Oxide RESOURCE KIT
  2. 2. Table of Contents Summary 2 1 The Burden of Asthma 3 2 Exhaled Nitric Oxide (eNO) 4 3 Insight™ eNO System 6 4 Case Studies 9 5 Exhaled Nitric Oxide Cost Model 12 6 Coding Information for Exhaled Nitric Oxide (eNO)-CPT 95012 12 Summary Clinical Utility of eNO Exhaled nitric oxide (eNO) is an established marker of airway Monitoring of eNO and adjusting medication accordingly could inflammation that can be safely and accurately measured in significantly improve disease management, resulting in reduction people with asthma. This resource kit provides comprehensive of the severity of symptoms, optimization of drug usage and information about the benefits and technology of eNO testing, improvement of compliance in individual patients, and fewer and highlights the medical necessity and the extent of acceptance exacerbations. The end result is optimal use of healthcare of eNO testing. resources and improved quality of life for asthma patients. The Asthma and Airway Inflammation Dilemma Reimbursement for eNO Testing It is estimated that 22 million+ people in the U.S. suffer from asthma, In 2007 the CPT editorial committee added a specific code to , making it one of the most common and costly of all diseases. One the CPT Coding Book for Nitric Oxide Expired Gas Determination quarter of all emergency room visits are asthma related and asthma (CPT Code 95012©). With this action, the procedure should be is the one of the leading chronic childhood diseases. recognized as a standard service provided to patients. Exhaled nitric oxide (eNO) determination is considered a service which is Controlling inflammation of the airways has become the central consistent with contemporary medical practice for the evaluation focus for managing asthma. Strong clinical evidence suggests of patients with respiratory complaints. that asthma management and control can be significantly improved by regularly monitoring airway inflammation. However, current methods used to monitor and manage asthma, such as Apieron and the Insight™ eNO System lung function tests, do not measure airway inflammation. Apieron, Inc. is a medical device company based in Menlo Park, California. The company was founded in 2001 to develop the Physicians have relied largely on correlating symptoms and disease first practical, office-based device for routine measurement of severity to assess their patients. Until now, the degree of airway exhaled nitric oxide. In March 2008, the company received FDA inflammation has not been measurable in a simple and practical way. 510(k) clearance for the Insight™ eNO System, which is now commercially available. Apieron’s goal is to offer a better way to The eNO Solution manage asthma and improve the standard of care for patients Exhaled nitric oxide has been established as a reliable marker of who live with the disease. airway inflammation in asthma for over 10 years. It has been the The Insight system is a highly accurate device, expressly central focus of studies, establishing its link to optimization of designed for the physician’s office to measure nitric oxide in medication and prediction of asthma exacerbations. expired human breath (eNO). It is non-invasive, safe, easy to Measurement of eNO in the physician’s office is a much awaited use, and provides results in less than a minute. Apieron’s unique breakthrough in medical technology that provides physicians with biosensor utilizes proprietary technology to detect trace amounts a reliable tool to measure airway inflammation as an adjunct to of nitric oxide in a single human breath. the current diagnostic measures, such as lung function. 2
  3. 3. 1. The Burden of Asthma considering the prevalence of asthma and the frequency of such visits, as outlined in the statistics below, the costs become Asthma Overview monumental. Asthma is a chronic disease characterized by inflammation of the • 34.1 million people have been diagnosed with asthma during airways caused by allergens and other triggers. When airways their lifetime.1 are inflamed, the inner walls of the airways swell making them • 22.8 million people have asthma.1 irregular. This causes the flow of air to become turbulent. • There were 14.1 million outpatient asthma visits to private The events that lead to obstruction of airflow and thus to asthma physician offices and hospital outpatient departments.2 symptoms are complex and usually involve the following events: • Children less than 18 years had 7 million physician office and • Bronchoconstriction, where the smooth muscle surrounding the outpatient visits.3 airways tightens in response to a trigger and narrows the airway. Morbidity • Inflammation, where inner walls of airways swell. • Asthma accounts for one quarter of all emergency room visits • Mucus formation within the airways that obstructs airflow. in the U.S. each year, with 2 million emergency room visits.4 Typical asthma symptoms include wheezing, coughing, chest • Each year, asthma accounts for more than 1 million outpatient tightness (dyspnea) and shortness of breath. visits4 and 500,000 hospitalizations.5 • The average length of stay (LOS) for asthma hospitalizations is The Role of Inflammation in Asthma 3 days.6 Asthma signs and symptoms evolve from three basic • Nearly half (41%) of asthma-related hospitalizations are for characteristics that underlie the disease and its exacerbations: children less than 19 years old.5 airway obstruction, airway hyperresponsiveness and airway • Respiratory illnesses like asthma are the leading cause of inflammation. Airway obstruction and hyperresponsiveness hospitalization for children. 6 represent the classic physiology of asthma, and their contribution to the disease process and symptomatology have been well Mortality recognized for some time. Appreciation of the role of airway • There are about 4,000 deaths due to asthma each year, many inflammation in asthma has evolved more recently. of which are avoidable with proper treatment and care.7 Today asthma experts consider airway inflammation a central Social and Economic Costs feature of asthma pathogenesis and its clinical manifestations. In fact, airway inflammation likely plays a critical role in airway • The annual cost of asthma is estimated to be nearly $18 billion. obstruction and hyperresponsiveness. In recent years, clinical • Direct costs accounted for nearly $10 billion (hospitalizations and scientific knowledge of asthma has evolved from a model the single largest portion of direct cost) and indirect costs of $8 of episodic constriction of bronchial smooth muscle to a model billion (lost earnings due to illness or death).8 which involves chronic airway inflammation. • For adults, asthma is one of the leading causes of work Airway inflammation precedes symptoms. Evidence of absenteeism and “presenteeism, resulting in nearly 13 million ” inflammation is present at the onset of symptoms in newly missed or lost (“less productive”) workdays each year.9 diagnosed patients with asthma. Accordingly, treatment • Among children ages 5 to 17 asthma is the leading cause , algorithms for asthma have emphasized treatment of the of school absences from a chronic illness. It accounts for an underlying inflammation, as well as the bronchoconstrictive annual loss of more than 13 million school days per year.3 It is symptoms. By acquiring a better understanding and appreciation estimated that children with asthma spend a nearly 8 million of the inflammatory process, physicians can employ treatments days per year restricted to bed.8 to inhibit specific steps in the process and improve control over asthma and its symptoms. The Cost of Asthma Asthma affects 22 million Americans. A principal clinical 1. “National Health Interview Survey, National Center for Health Statistics, CDC, 2006. ” consequence of both acute and chronic inflammation is the 2. CDC: - accessed on Sep 2, 2008. development of asthma exacerbations. Exacerbations of 3. “State of childhood asthma in the United States, CDC,1980-2005. ” asthma are not only an important clinical marker of inadequately 4. “National Hospital Ambulatory Medical Care Survey, CDC, 2001-2004. ” controlled or worsening asthma but are probably the most 5. “National Hospital Discharge Survey, National Center for Health Statistics, CDC, ” important outcomes from both a humanistic and health 2001-2004. economics viewpoint. Severe asthma exacerbations lead to about 6. “National Health Statistics Survey, National Center for Health Statistics, CDC, 2006. ” 4,000 deaths and nearly 500,000 hospitalizations per year. 7 “National Vital Statistics Reports, Vol 56, Number 10, CDC, 2005. . ” Healthcare costs for asthma include outpatient visits to physician 8. “The Costs of Asthma, Asthma and Allergy Foundation 1992 and 1998 Study, ” offices and hospital outpatient departments, visits to hospital 2000 Update. emergency departments (EDs) and hospitalizations. When 9. “Asthma Prevalence, Health Care Use and Mortality, CDC, 2003-2005. ” 3
  4. 4. 2. Exhaled Nitric Oxide (eNO) effective local vasodilator. It causes smooth muscle relaxation thereby matching regional airflow and blood flow. Nitric oxide is Current Methods for Assessing Airway also important for ciliary action. Numerous studies over the past decade have validated that exhaled nitric oxide (eNO) can serve as Inflammation a biomarker of airway inflammation in asthma. Airway inflammation is shown to be an appropriate target for In 1991, NO in exhaled breath was first reported.12 Studies have improving asthma control10, and while it is recognized as playing shown that eNO is correlated with other markers of inflammation. a key role in the pathophysiology of asthma, current methods to For example, exhaled nitric oxide correlates with eosonophilic evaluate a patient’s asthma status fall short because they do not airway inflammation measured in induced sputum13 and in directly measure the degree of airway inflammation. Physicians bronchoscopy (lavage and biopsy), most commonly seen in attempt to monitor asthma severity through clinical exam and asthma but also in any condition where eosonophils are present, pulmonary function testing using spirometry or peak flow meters. such as allergic rhinitis, eosonophilic bronchitis14 and chronic Unfortunately, these lung function tests do not directly measure obstructive pulmonary disease (COPD).15 airway inflammation. Other markers of inflammation such as bronchoalveolar lavage and induced sputum are invasive and It has also been shown that eNO levels are elevated in steroid- impractical to perform in a physician’s office. Therefore, when naive asthma,16 and eNO levels fall rapidly with anti-inflammatory prescribing and titrating medication, physicians have had to rely medication (e.g. inhaled corticosteroids)17, oral steroids, anti- on qualitative measures such as correlation of disease severity leukotrienes (e.g. montelukast)18 and anti-IgE (e.g. Xolair).19 Exhaled and symptoms. Adding to this challenge is the fact that patients nitric oxide also correlates with non-specific bronchial reactivity with severe asthma may have a compromised perception of to methacholine (typically assessed in methacholine challenge) in airflow obstruction and dyspnea compared to normal individuals11 steroid-naïve patients. Increased reactivity is reflected by higher and, thus, underestimate the severity of their symptoms. eNO levels and is an indirect marker of airway inflammation. Without a convenient means to accurately and regularly assess It is now well established that the concentration of nitric oxide inflammation, it is difficult for physicians to manage asthma. in exhaled breath (eNO) is a reliable indicator of the degree of Inhaled corticosteroids (ICS) are the mainstay of treatment for inflammation in the airways. Exhaled nitric oxide levels increase as chronic asthma, and dosing should be adequate to control asthma inflammation increases and decrease as inflammation decreases. symptoms but also be as low as possible to avoid side effects. Under-medication and over-medication are sub-optimal both Clinical Recommendations for eNO clinically and economically. If not managed properly, people with asthma could experience permanent and irreversible damage Clinical recommendations exist for use of eNO measurements in to their airways. Since the dose of medication required is highly asthma management, and such recommendations are currently variable, both among patients and within individual patients, being reviewed and updated: physicians need an easy, effective and safe method to assist • The American Thoracic Society and European Respiratory them with titrating medication precisely. Society (ATS/ERS) have published recommendations for the The lack of knowing a patient’s degree of airway inflammation standardized measurement of eNO.20 creates a significant gap in asthma management today. With 12. Gustafsson LE, Leone AM, Persson MG, Wiklund NP Moncada S. Endogenous , direct markers of inflammation, this gap can be closed to improve nitric oxide is present in the exhaled air of rabbits, guinea pigs and humans. Biochem Biophys Res Commun. 1991;181(2):852-857 . the overall treatment and management of asthma. Insight into a patient’s airway inflammation could enable physicians to make 13. Jatakanon A, Lim S, Kharitonov SA, Chung KF Barnes PJ. Correlation between , exhaled nitric oxide, sputum eosinophils, and methacholine responsiveness in earlier interventions with appropriate levels of therapy, thereby patients with mild asthma. Thorax 1998;53:91-95. preventing emergency room visits and hospitalizations. 14. Berlyne GS, Parameswaran K, Kamada D, Efthimiadis A, Hargreave FE. A comparison of exhaled nitric oxide and induced sputum as markers of airway Exhaled Nitric Oxide (eNO) as a Biomarker of inflammation. J Allergy Clin Immunol 2000;106:638-644. Airway Inflammation 15. Fabbri LM, Romagnoli M, Corbetta L, et al. Differences in airway inflammation in patients with fixed airflow obstruction due to asthma or chronic obstructive Nitric oxide (NO), a free radical, is produced by the body as part pulmonary disease. Am J Respir Crit Care Med 2003;167:418-424. of the inflammatory response and can be detected as exhaled 16. Alving K, Weitzberg E, and Lundberg JM. Increased amount of nitric oxide in nitric oxide in expired human breath. Nitric oxide is produced exhaled air of asthmatics. Eur Respir J. 1993;6(9):1368-1370. in the airway epithelial cells by a family of NO synthases called 17 Yates DH, Kharitonov SA, Robbins RA, Thomas PS, Barnes PJ. Effect of a nitric . inducible nitric oxide synthase. Inducible NO synthase expression oxide synthase inhibitor and a glucocorticosteroid on exhaled nitric oxide. Am J is sensitive to steroids and therefore shows a change in response Respir Crit Care Med. 1995;152(3):892-896. to treatment with anti-inflammatory medication like inhaled 18. Bratton DL, Lanz MJ, Miyazawa N, White CW, Silkoff PE. Exhaled nitric oxide steroids. Nitric oxide is a mediator of inflammation and it is an before and after montelukast sodium therapy in school-age children with chronic asthma: A preliminary study. Pediatr Pulmonol 1999;28:402-407 . 10. Green RH, Brightling CE, McKenna S, Hargadon B, Parker D, Bradding P, 19. Silkoff PE, Romero FA, Gupta N, Townley RG, Milgrom H. Exhaled nitric oxide Wardlaw AJ, Pavord ID. Asthma exacerbations and sputum eosinophil counts: A in children with asthma receiving xolair (omalizumab), a monoclonal anti- randomised controlled trial. Lancet 2002;360:1715-1721. immunoglobulin e antibody. Pediatrics 2004;113:e308-312. 11. Kikuchi Y, Okabe S, Tamura G, Hida W, Homma M, Shirato K, Takishima T. 20 Recommendations for standardization procedures for the online and offline Chemosensitivity and perception of dyspnea in patients with a history of near- measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide in fatal asthma. N Engl J Med. 1994;330(19):1329–1334. adults and in children. Am J Respir Crit Care Med. 2005;171:913-930. 4
  5. 5. Separate recommendations have also been developed for children. • Monitoring patient compliance An elevated eNO level is suggestive of an inadequate anti- Clinical Utility of eNO inflammatory regimen, which may be due to poor compliance Exhaled nitric oxide measurement offers new benefits for or under-medication.24 A study by Beck-Ripp and his colleagues asthma management. showed that there was a strong correlation between reduction in eNO values and patient compliance (measured as percentage • Predicting steroid response of prescribed medication taken). In this study, the researchers An elevated eNO level is highly predictive of a positive response followed 54 patients between the ages of 6 and 16 over 16 to ICS.21 Smith et al showed that eNO levels are very good weeks. The results showed that there was a 50% reduction in indicators of response to steroid in people with undiagnosed eNO values with higher compliance. respiratory symptoms. Exhaled nitric oxide was shown to be • Predicting exacerbations more accurate than spirometry, peak flow meters, bronchodilator response and airway hyper-responsiveness (AHR). This study An elevated eNO level at a clinic visit has been shown to be followed 52 subjects in a single-blind, fixed sequence, placebo- associated with an increased risk for an exacerbation in the controlled trial of inhaled fluticasone over 4 weeks. Similar results following two weeks.25 In this study, moderate and severe- were found in another study 22 (Figure 1.1 below) involving 73 persistent asthma patients were evaluated during a routine clinic steroid-naïve subjects with uncontrolled asthma which showed visit and then noted whether they had an exacerbation within about 50% reduction in eNO levels following ICS therapy over 2 weeks of the initial appointment. Those with an exacerbation 2 weeks. The study also showed that eNO was a significantly had a higher mean eNO (29.67 ppb ± 14.48) compared to those better predictor of response to steroid therapy than conventional who did not (12.92 ppb ± 5.17), p = 0.002. A nominal logistic lung function tests. Additionally, a 35% improvement in asthma regression model to determine those variables that predict symptom scores were seen following the 2-week therapy. asthma exacerbation found that eNO was the only significant predictor, p = 0.03. TAS = Total Asthma In another study26 with 31 subjects (19 adults and 12 children) Normalized measure of ability to predict steroid use. eNO is a more reliable Score predictor of steroid eNO = Exhaled Nitric using the Insight system, it was shown that by regularly response than lung Oxide monitoring the diurnal changes in eNO levels, it is possible to function FEV1 = Forced predict asthma exacerbations up to 1 week in advance. In this Expiratory Volume in study, spirometry measurements showed no indication of an 1 Second impending exacerbation. During this study, subjects measured Rev = FEV1 and recorded eNO levels and peak flow values twice daily Reversibility (morning and evening). Once a week they also performed a 4-Var = Regression Model Using spirometry measurement at the study site. The subjects also All 4 Variables maintained a diary of asthma symptoms. The analysis showed 4-var TAS eNO Rev FEV that a change in the week-to-week pattern of diurnal change in eNO values predicted an exacerbation. It was also clear that morning eNO values are better predictors than evening eNO Figure 1.1 values. See Figure 2.1. • Improving titration of medication Study Day Relative Smith et al showed that using eNO to guide ICS dose in addition 80 eNO (ppb), PEF ( % of Personal Best) to Exacerbation to clinical management compared with clinical management alone 70 Evening eNO significantly reduced the dose of inhaled steroid while showing a 60 Morning eNO numerical reduction in exacerbations.23 In a single-blind, placebo- 50 Overnight controlled trial, the researchers randomly assigned 97 patients 40 Change Evening PEF with asthma who had been regularly receiving treatment with 30 Morning PEF inhaled corticosteroids, to have their corticosteroid dose adjusted, 20 No. of subjects in a stepwise fashion, on the basis of either eNO measurements 10 observed or an algorithm based on conventional guidelines. After the 0 -14 -7 0 7 optimal dose was determined (phase 1), patients were followed up for 12 months (phase 2). They found that a 40% reduction in the dose of ICS can be achieved without loss of asthma control. Figure 2.1 21 Smith AD, Cowan JO, Brassett KP et al. Exhaled nitric oxide: a predictor of steroid , 24 Beck-Ripp J, Griese M, Arenz S, Koring C, Pasqualoni B, Bufler P Changes of . response. Am J Respir Crit Care Med. 2005;172(4):453-459. exhaled nitric oxide during steroid treatment of childhood asthma. Eur Respir J 2002;19(6):1015-1019. 22 Dreon DM, Berger WE, Hutchins EE, and Parikh BR. Exhaled Nitric Oxide Predicts Use of Controller Medication. J Allergy Clin Immunol 2008;121(2):S157 Scientific 25 Harkins MS, Fiato KL, Iwamoto GK. Exhaled nitric oxide predicts asthma poster at AAAAI 2008 (NOT PUBLISHED). exacerbation. J Asthma. 2004;41(4):471-476. 23 Smith AD, Cowan JO, Brassett KP Herbison GP Taylor DR. Use of exhaled nitric , , 26 Wolfe JD, Dreon DM, Hutchins EE, and Parikh BR. Relationship of Exhaled oxide measurements to guide treatment in chronic asthma. N Engl J Med. Nitric Oxide and Peak Expiratory Flow to Loss of Asthma Control. J Allergy Clin 2005.;352(21):2163-2173. Immunol 2008;121(2):S159 Scientific poster at AAAAI 2008 (NOT PUBLISHED). 5
  6. 6. Performing eNO Testing is Simple and steadily through a disposable breath tube, and the results appear Straightforward on the display within one minute. Patient data can be stored and maintained in patient cards for trend analysis or downloaded to a Exhaled nitric oxide testing is an accurate and reliable measure of printer for patients’ files. airway inflammation that is: With an accurate measure of their patients’ airway inflammation • Non-invasive and customized reports for each patient, physicians can • Patient-friendly significantly improve the precision of prescribed therapy. • Fast and suitable for routine clinical analysis The eNO test is simple to administer compared to some of the conventional lung function testing methods or breath analyses. The patient has to be seated and is required to exhale steadily for 11 seconds after taking in a deep breath. The device measures the eNO level and displays a number on the screen. The interpretation is based on this single numerical value rather than on a complex tracing or profile. Historical values of eNO can be added to gain better understanding of the patient’s disease progression. Important aspects of any system that measures exhaled nitric oxide include: Figure 3.1. Insight Monitor • Detection of trace amounts of the gas in parts per billion (ppb) • Constant expiratory flow rate due to flow dependence of Insight Sensor Technology exhaled nitric oxide Apieron is the first company to successfully implement a • Exclusion of nasal nitric oxide technique utilizing sol-gel technology to make a commercial biosensor for the detection of exhaled nitric oxide. The Insight 3. Insight™ eNO System sensor is a disposable, plastic cartridge that contains a path for exhaled breath to flow through and a sol-gel based biosensor for Indications for Use detecting nitric oxide. The gas flow path contains desiccant to The intended use of the Apieron Insight™ eNO System is to control the environment and condition the gas inside the sensor. quantitatively measure exhaled nitric oxide (eNO) in expired The biosensor consists of a sol-gel matrix (a glass-based three- human breath as a marker of inflammation in persons with dimensional matrix) with a porous structure that envelopes asthma. Measurement of eNO in expired human breath by protein molecules which are sensitive to nitric oxide. The the Apieron Insight eNO System is a non-invasive, simple and biosensor matrix changes its light absorption characteristics when safe method to measure a decrease in eNO in asthma patients exposed to nitric oxide (NO). This optical change can be measured that often occurs after treatment with anti-inflammatory and correlated to the concentration of nitric oxide. pharmacological therapy as an indication of the therapeutic effects in patients with elevated eNO levels. The Apieron Insight eNO System is suitable for use in children 8 to 17 years of age, and in adults 18 years of age and older. As an adjunct to established clinical assessments, such as spirometry and physical examination, eNO measurements give the physician an objective marker to evaluate the patient’s response to anti-inflammatory therapy. The Apieron Insight eNO System can be used by trained operators in a physician’s office or laboratory setting. The Apieron Insight eNO System should not be used in critical care, emergency care or in anesthesiology. Prescription device: Federal law restricts this device to sale by or on the order of a physician. A Convenient Way to Measure eNO Levels The Insight eNO System was developed to provide a practical Figure 3.2. Insight Sensor and accurate means for measuring eNO levels via a simple breath test. Designed for routine use in physician offices and clinics, the How Is eNO Measured? Insight system enables physicians to monitor and manage asthma The biosensor encapsulates a heme protein that has a high on a regular basis. The system includes a small desktop monitor affinity for nitric oxide. The heme protein has a metal active with a large color display. It employs an eNO sensor to measure site that is specific to nitric oxide (Figure 3.3). As exhaled nitric nitric oxide from the breath sample. The patient breathes out 6
  7. 7. oxide molecules from the breath sample flow into the sensor, • A carbon dioxide filter to remove CO2 from the breath sample. they diffuse into the porous matrix and react with the protein • A preconditioned desiccant to control the concentration of molecules. This results in a change in the optical transmission water vapor surrounding the biosensor and to condition the properties of the matrix in a consistent and measurable way incoming breath sample. when light of a certain wavelength (412 nm) is passed through the matrix (see Figure 3.4). • Temperature controllers to control the temperature of the sensor and gas and to prevent temperature-induced shifts in The optical signal generated is proportional to the concentration of optical absorbance. nitric oxide and enables the Insight system to accurately detect trace amounts of nitric oxide molecules in a single breath sample. Nitric Insight Monitor Technology oxide measurement results are reported in parts per billion (ppb). The Insight monitor consists of three subsystems controlled by a central microprocessor: an eNO measurement system, a pneumatic system and an user interface. Optically transparent porous glass matrix • Measurement system—contains the hardware required to stabilize the Insight sensor to its operating temperature and measure the optical absorbance of the biosensor material when exposed to the breath sample. • Pneumatic system—controls the exhalation flow rate as outlined in the American Thoracic Society 2005 recommendations. • User-friendly interface—guides the operator through the test sequence and guides the patient through the breath sampling maneuver. Embedded heme-protein Accuracy of the System A study was conducted on 82 non-randomized asthmatic subjects at a single site comparing eNO measurements taken with both Figure 3.3. Biosensor the Insight eNO System and the Aerocrine NIOX® System. The demographic data for this study is presented below. A total of 58 adults (ages ≥18 years) and 20 children (ages <18 years) completed the study resulting in 78 subjects eligible for analysis. Each subject 2.5 performed two breath maneuvers on each system, and the results ranged from 10 ppb to 197 ppb on the Insight eNO System. The testing was performed by three trained technicians. Results were 2 analyzed to evaluate the performance of the Insight eNO System as it compares to the NIOX System in a clinical setting. 1.5 Optical Absorbance measurement 1 band 200 Insight eNO System Result (ppb) 0.5 150 0 395 405 415 425 435 100 Wavelength (nm) NIOX Result ( ppb) eNO 50 Line of Identity Figure 3.4. Absorption Spectra (dotted line) Standard Regression 0 Overcoming Technical Challenges 0 50 100 150 200 NIOX Results (PPB) Although the heme protein is highly selective for NO, certain factors will affect the optical absorbance properties of the Figure 4.1. Correlation to reference biosensor. Detrimental factors include exposure to CO2 from the breath sample, changes in humidity and changes in temperature. The Insight system incorporates specific features to counteract these factors: 7
  8. 8. Twenty-four samples containing all of the above potential Parameter Analysis Results [95% CI] interferents (balance air) and 24 samples containing only air were Ordinary Least Squares Regression R2 = 0.95 prepared and tested on the Insight eNO System. The mean Agreement Slope 0.95 [0.90 to 1.00] difference in response was less than 0.05 ppb and was not Intercept 1.3 ppb [-1.9 to 4.5] statistically significant between the samples containing potential interferents and those containing only air. Bias Mean Difference -1.14 ppb [-3.08 to 0.80] Precision Mean Absolute Difference 5.86 ppb In the second set of experiments seven additional compounds (isoprene, ethanol, acetone, ammonia, acetaldehyde, Insight Within-Subject Standard Deviation 3.96 ppb (2.95 to 4.98) methanethiol and methane) were tested at physiologically Repeatability relevant concentrations by comparing the response of the Insight Clinical Agreement Positive Percent Agreement 100% eNO System to a test gas. The test gas contained 0 ppb NO @ 30 ppb Negative Percent Agreement 93% (nitric oxide). A compound was deemed non-interfering if, at the tested concentration, the response was within ±5 ppb NO Table 4.1. Performance of the Insight eNO System equivalent when compared to the nitrogen control. Agreement: Regression analysis performed on the first None of the tested compounds exhibited interference greater measurement from each system demonstrated agreement, than ±5 ppb equivalent NO when compared to a nitrogen control. with an R2 of 0.95, (y=0.95x+1.3 ppb) between the Insight eNO System and the NIOX System. Clinical interference testing (exogenous compounds): Bias: Mean difference between the Insight eNO System and The influence of mouthwash containing alcohol, alcohol- the NIOX System was -1.14 ppb, demonstrating that there is no free mouthwash, toothpaste, breath mints, throat lozenges, consistent bias between the two systems in clinical use. carbonated beverage with caffeine and caffeine-free carbonated beverage on eNO was assessed in a clinical study. Twelve Precision: The mean absolute difference between the Insight healthy adult subjects (9 males and 3 females; mean age 36 ± eNO System and the NIOX System was 5.86 ppb. 11.8 yrs; range 20-62 yrs) participated in the clinical study. The Repeatability: The first and second measurements taken on the eNO measurements for adults ranged from 5 ppb to 99 ppb. Insight eNO System were compared, and the average standard The endpoint was the difference in eNO before as compared to deviation between measurements was 3.96 ppb for the Insight one hour after exposure to each compound. None of the tested eNO System. exogenous compounds were found to interfere (at ± 5 ppb) with the eNO measurement at one hour post-exposure. Clinical Agreement: Using a clinically relevant decision point (30 ppb), an analysis was performed that compared the results In pediatric subjects, the influence of alcohol-free mouthwash, of measurements taken on the Insight eNO System as they toothpaste, breath mints, and caffeine-free carbonated beverage compared to the NIOX System results from the same subject. on eNO was assessed in a clinical study. Seven healthy children The 51 subjects identified as elevated by the NIOX System were (6 males and 1 female; ages 5-17 yrs) participated in the clinical also identified as elevated by the Insight eNO System (100% study. The eNO measurements for children ranged from 3 ppb positive agreement). Twenty-seven subjects were identified as to 27 ppb. The endpoint was the difference in eNO before as normal by the NIOX System and 25 of these were identified as compared to one hour after exposure to each compound. None of normal by the Insight eNO System (93% negative agreement). the exogenous compounds tested were found to interfere (at ± 5 This demonstrates that both the NIOX System and the Insight ppb) with the eNO measurement at one hour post-exposure. eNO System are highly consistent in detecting subjects with both These studies show that the Insight eNO System can normal and elevated eNO measurements. accurately and reliably measure exhaled nitric oxide Interference Two sets of endogenous interference experiments were conducted. In the first set of experiments, interference testing was performed on the Insight eNO System for the following common constituents of exhaled breath: • 200 ppm H2 (hydrogen) • 3 ppm CO (carbon monoxide) • 100% Relative Humidity (water vapor) • 0.5% CO2 (carbon dioxide) • 0 ppb NO (nitric oxide) 8
  9. 9. Case Study 1 4. Case Studies “Let’s go fishing dad!” – Maya, 10, Pensacola FL Maya is 10 years old and loves the Insight system, he incorporated exhaled nitric oxide (eNO) to go fishing with her dad on testing into her treatment plan. When he first measured Maya’s the weekends. She has eNO, it was 44 ppb. He felt it was a little high for her age, but moderate persistent asthma. he wanted to establish her usual eNO levels over time before She is very compliant and changing her medication. Over the next 8 weeks, he found that often corrects her dad when it her eNO values settled at around 30 ppb after initially fluctuating. comes to managing her He increased her Pulmicort dosage to 200 BID. Over the next 8 asthma. She gets on very well weeks, Maya’s eNO values decreased to the low 20’s. Her doctor with her doctor, who has been was very pleased with the results but the next time he measured seeing her for 3 years now. her, she was at 40 ppb. An almost two-fold increase in her eNO bothered him but further investigation with Maya and her father Maya has been on Pulmicort® revealed that she had missed taking her medication recently. DPI 200 mcg QD. Based Her eNO values dropped back down to around 20 ppb once she on her record of asthma resumed her treatment. By continuing to monitor Maya’s eNO control, her doctor wanted levels regularly, her doctor was confident that he could fine-tune to optimize Maya’s therapy. But he had no objective measure her medication. of her airway inflammation to monitor her response. Once he had access to exhaled nitric oxide (eNO) measurement with Maya’s history and medical information Titrate medication and monitor compliance with precise information • Age:10-year-old female • Classification:Moderate persistent 70 6 weeks 4 months • Medication:Pulmicort 60 • Dosage:200 mcg QD 50 Missed medication eNO in ppb shows up as abnormally • FEV1:80% high eNO values 40 • eNO:44 ppb • Other information: 30 - Non-allergic rhinitis 20 200 QD - Non-allergic conjunctivitis Pulmicort 200 BID Pulmicort 10 - Cold sores - Occasional headaches Time Benefits of eNO: Treatment gap revealed by eNO measurement with the Insight™ eNO System • Objective validation for a sound clinical decision • Insight into airway inflammation not manifesting as symptoms • Timely identification of suboptimal compliance to medication and therapy Patient benefits from the new treatment paradigm • Better titrated dosage enables patient to maintain control 9
  10. 10. Case Study 2 “I like to win.” – Scott, 23, Fresno CA Scott is a talented young racer Scott’s eNO was 32 ppb at his first visit, but Dr. Brewster who loves to drive his all-wheel planned to measure his eNO values over several visits and look drive car on wet and slippery for patterns before making any treatment changes. Consistent dirt roads. He competes in with Scott’s irregular compliance, his eNO values varied many local and regional events. widely. However, these variations did not coincide with Scott’s He has a keen eye for those symptoms. Most of the time, Scott’s symptoms were normal fast corners and usually leaves and he felt fine, but his eNO levels were high. Dr. Brewster then the rest of the racers in the shared the eNO values with Scott and explained the significance, dust. hoping to convince Scott to take his medications seriously and regularly. Scott liked having a number that showed him the status Scott spends a lot of time of the inflammation of his airways, and started to improve his outdoors and has complained compliance which resulted in a reduction and stability of his eNO about worsening asthma levels. Subsequently Dr. Brewster changed Scott’s medication symptoms with increased from Advair 500 BID (a combination of the 500 mcg of the inhaled activities. His doctor, Jim steroid fluticasone and salmeterol, a long acting bronchodilator) Brewster, knows him too well to ask him to reduce his need to fluticasone 220 BID alone. Scott’s eNO values are now in the for speed. Dr. Brewster decided to assess Scott’s airway low 20’s and do not fluctuate like before. Scott has not had any inflammation via exhaled nitric oxide (eNO) values as an aid to exacerbations since he started monitoring his eNO values, and titrating his controller medications. Scott was on Advair® 500 BID. Dr. Brewster has been able to reduce the daily dose of inhaled He suspected that Scott was not compliant and Dr. Brewster steroids by 50% and stop salmeterol. knew that Scott had some asthma attacks in the past that landed him in emergency care. Improve patient compliance and confidence Scott’s history and medical information Prednisone Prednisone & Augmentin • Age:23-year-old male 80 • Classification:Severe persistent Improved compliance 70 • Medication:Advair 60 • Dosage:500 BID Advair 500 BID to eNO in ppb • FEV1:117% 50 Flovent 220/2inh BID • eNO:32 ppb 40 • Other information 30 - Allergic rhinitis 20 - Severe asthma attacks Advair 500 BID 10 - Hospitalized /intubated in last 18 months - Occasional headaches 0 1 2 3 4 5 6 7 Time (months) Benefits of eNO testing Treatment gap revealed by eNO testing • Simple and compelling evidence to highlight to the patient the need to follow treatment plan and medication • Confirm suboptimal compliance with medication and treatment plan • Provide objective validation for clinical treatment decisions Patient benefits from the new treatment paradigm • More confidence from a precisely tailored therapy that fits lifestyle requirements • Greater awareness and motivation to improve compliance 10
  11. 11. Case Study 3 “It feels good to be in control.” - Lynn, 36, Long Island NY Lynn works in While on Advair® 250/50 BID and QVAR® 80mcg BID (i.e. emergency care at the 2 inhaled steroids), her doctor decided to monitor Lynn’s city hospital as a nurse inflammation using eNO testing. Her eNO levels were very high and loves her job. She (80-128 ppb where normal is about 20 ppb) and Lynn continued lives with her husband to have almost daily symptoms. Her doctor doubled her QVAR and two children. Her dosage to 160 BID. Over time, this brought her eNO down to the life is demanding to 45-50 ppb range but these levels were still elevated. Around that say the least. She has time, Lynn moved to a new house in Long Island (a surprise family been living with asthma inheritance) and after the move, there was a further drop in eNO for almost 14 years to around 20 ppb. Lynn also reported that her symptoms were now and feels that she getting much better. Lynn and her doctor figured that her older can’t quite get it under house, which had a moldy basement, might have triggered her control. Her health has symptoms. Her doctor then reduced her dosage of QVAR back been a big concern for to just 1 inhalation. He felt confident that he could further drop or her whole family. She even eliminate her dosage of QVAR and significantly reduce her has persistent asthma with symptoms most of the time. She has medication by following her eNO levels regularly. Lynn continues missed many days at work due to her asthma. to work in ER and is happy to be able to focus more on her work and family. Track disease progression and see impact of environment Lynn’s history and medical information • Age: 36-year-old female 140 • Classification:Severe persistent 120 • Medication: Advair, QVAR 100 • Dosage:Advair 250/50 BID and QVAR 80 BID QVAR 80 2inh BID eNO in ppb • FEV1:51% 80 • eNO: 85 ppb Moved to a 60 • Other information: new house 40 Decreased to - Asthma x 14 years QVAR 80 - Regularly symptomatic 1 inh BID 20 - Allergic Rhinitis 0 - Ragweed, mold, dander 1 2 3 4 5 6 7 8 - Intermittent psoriasis Time (months) Benefits of eNO testing Treatment gap revealed by eNO testing • Despite 2 controller medications, eNO indicated that airway inflammation was uncontrolled • Exhaled nitric oxide (eNO) showed that airway inflammation was decreasing after a change in environment. • Exhaled nitric oxide (eNO) allowed the tapering of medication in the better environment. Patient benefits from the new treatment paradigm • Titration of therapy to optimize asthma control • Improved quality of life 11
  12. 12. 5. Exhaled Nitric Oxide Cost Model 6. Coding Information for Exhaled Nitric This cost model provides an insurance payer with the Oxide (eNO)-CPT 95012 reimbursement costs of eNO patient testing with the Insight In 2007 the CPT editorial committee added a specific code to the , system and the expected savings in medical resources resulting CPT Coding Book for Nitric Oxide Expired Gas Determination. from improved asthma control.The cost model: With this action, the procedure should be recognized as a • Estimates the number of patients that are likely to undergo standard service provided to patients. The committee felt it eNO testing over a three year period. appropriate to add this code to the Category I codes instead of placing it in the Category III codes as a temporary or new • Estimates total eNO testing reimbursement costs to the services code. The Category I codes are considered consistent insurance payer. with contemporary medical practice and are performed by • Estimates the number of asthma exacerbation events likely to providers across the country. Determination of exhaled nitric be avoided by patients monitored with eNO. oxide (eNO) is considered a service which is consistent with • Estimates cost savings in medical resources (hospitalization, contemporary medical practice for the evaluation of patients with respiratory complaints. ER visits, office visits, drug use) due to avoidance of asthma exacerbation events. Centers for Medical Services (Medicare) also determined that • Estimates the net cost to the insurance payer of eNO testing the service should be recognized as a payable service for all reimbursement minus medical resource savings. Medicare beneficiaries. In doing this, the RUC committee (Relative Value Update Committee) assigned an RVU value of Please contact us at if you would like to see 0.50. This value does not have a physician work component RVU, how the model can be applied to your plan. only an overhead and malpractice RVU. RVU or relative value unit determines what the reimbursement will be for Medicare as well as many other carriers. Medicare has a conversion factor which may be higher or lower than the third party payers to determine the final reimbursement for the code. The code assigned for the Nitric Oxide Expired Gas Determination is 95012©. According to the CPT subsection heading for 2008, the interpretation and report for the test is included in the testing code. If a “significant and separately identifiable” evaluation and management service is provided in addition to the testing, then an evaluation and management code may be coded in addition to the testing code. The ‘25 modifier’ would need to be added to the evaluation and management code (E/M) in order for both the test, and the evaluation and management code to be appropriately reimbursed. © 2008 Apieron, Inc. Managing asthma is a breath away™ Insight™ is a trademark of Apieron, Inc. All other trademarks are properties of their respective owners. 12 ML00031.A