Medical Policy
2.01.057 Exhaled Nitric Oxide Measurement for Treatment of Asthma
Original MPC Approval: 05/30/2007
Last Review: 07/20/2009
Last Revision: 07/20/2009 |
 Description
Asthma is characterized by inflammation of the respiratory tract, with periodic airway obstruction and symptoms of wheezing, coughing, and dyspnea. The chronic inflammatory process can lead to degenerative changes in the respiratory tissues and impaired pulmonary function. Exhaled gaseous nitric oxide (NO), which is normally produced in the airway mucosa, is known to be elevated in asthmatic patients, and is even higher during acute exacerbations than during remissions. The measurement of exhaled NO has therefore been proposed as a surrogate marker of airway inflammation for purposes of evaluating a patient's response to medications and perhaps reduce dosages of inhaled corticosteroids.
Policy
Measurement of exhaled nitric oxide is considered medically necessary in the management of asthma patients.
Measurement of exhaled nitric oxide is considered experimental / investigational for all other conditions as it does not meet TEC criteria # 2-5.
Policy Guidelines
Rationale (2007):
1. The technology must have final approval from the appropriate government regulatory bodies:
The NIOX Breath Nitric Oxide Test System® (Aerocrine, Inc.) received clearance for distribution from the FDA in April, 2003 under the 510(k) process. It is labeled as "intended to aid in evaluating an asthma patient's response to anti-inflammatory therapy by measuring changes in fractional exhaled nitric oxide concentration as an adjunct to established clinical and laboratory assessments of asthma."
2. The scientific evidence must permit conclusions concerning the effect on health outcomes:
There are a number of studies that have evaluated the use of exhaled NO (ENO) as a potential marker that could influence decisions regarding asthma management, few of them in the form of randomized, controlled trials. Smith et al (2005) randomized 97 asthmatic patients to an ENO group (n=46) or to a conventional treatment algorithm (n=48). (Three patients did not complete the study). The single-blind study was designed to adjust the dosage of corticosteroid without compromising asthma control. Frequency of exacerbation of symptoms was the primary outcome measure. At 12 months after dose adjustment, there was a nonsignificant reduction of exacerbation favoring the ENO group, and a significant reduction of the mean daily dose of inhaled steroid in the ENO group. There were no significant differences in other markers of asthma control between the two groups. The authors concluded that ENO could be used to reduce maintenance dosages of inhaled corticosteroids without compromising asthma control. The study was limited by its single blind design, meaning that physicians who made treatment decisions were aware of the patient's group assignment, and the monitoring strategy used may not reflect usual clinical practice. The significant increase in the use of corticosteroid by the control group may reflect over-treatment, as previous studies have shown that stable asthma patients can generally reduce their use of corticosteroids.
Pijnenburg et al (2005) reported on a randomized, double blind clinical trial (n=85) that measured whether titration of steroids based on ENO measurement improved asthma management of children. One group (n=39) had treatment decisions based on ENO measurement, and the control group (n=46) was treated based on symptoms. Over a one year period, changes in steroids from baseline did not differ between the two groups. The authors did report that in the ENO group, airway hyper-responsiveness was improved over the symptom group (p=0.04). This latter measure, however, is not considered a primary outcome in asthma management. The study is further weakened by the fact that a substantial number of patients did not complete baseline measurements, and so were excluded from the final analysis, thus making the reported p-value open to question.
Overall, the studies to date do not permit conclusions regarding the effect of the technology on health outcomes. It is unclear whether the use of ENO results in improved asthma control over time, or whether its use reduces exacerbations. Experts in the field have expressed opinions that although the preliminary evidence is promising, additional well designed studies are needed to define the clinical utility of ENO measurement.
3. The technology must improve the net health outcome:
4. The technology must be as effective as any established alternatives:
Exhaled nitric oxide measurement is intended as an adjunctive test in the management of asthma patients. At the present time, it is unclear that ENO improves the net health outcome or that it is at least as effective as traditional methods of managing treatment.
5. The improvement must be attainable outside the investigational settings:
The evidence does not establish an expected improvement outside the investigational settings.
Update 2009:
1. In March, 2008, the FDA granted marketing clearance for the NIOX MINO® system, a compact, portable ENO measurement device. The system could be used in the home setting by the patient, but it is unclear whether promotion of home ENO testing can improve disease management.
2. Evidence from studies have established that the NIOX® system demonstrates moderate to good sensitivity and specificity (71% to 88%, and 69% to 93% respectively), but a variable negative predictive value due to differences in threshold values. Randomized, controlled studies have been undertaken to test whether ENO measurement improved asthma control. Shaw and colleagues (2007) randomized 118 asthma patients to corticosteroid therapy based on ENO measurements (n=58) or British Thoracic Society guidelines using lung function tests and symptom assessment (n=60). The number of severe exacerbations was the primary outcome measure. After one year, the authors concluded that a treatment strategy based on ENO did not result in a large reduction in asthma exacerbations or steroid use. Szefler et al (2008) studied a cohort of 546 inner-city adolescents and young adults in ten centers in the U.S. They were randomized to 46 weeks of treatment either based on guidelines of the National Asthma Education and Prevention Program (NAEPP) or standard treatment modified with the addition of ENO measurements. The authors observed that use of standard guidelines resulted in good asthma symptom control in most patients. The addition of ENO resulted in higher inhaled steroid use without significant improvement in symptom control. Kwok and associates (2009) assessed the feasibility of ENO measurement in the pediatric emergency setting during an acute exacerbation of asthma (n=133). The authors observed that most subjects showed no change in ENO concentrations from the beginning to the end of treatment, and the median initial value was the same among the subjects regardless of the severity of the attack. They concluded that ENO measurement has limited utility in the emergency department management of acute asthma in children. The evidence from randomized, controlled studies for ENO as a marker to guide inhaled steroid dosages and predict steroid response and exacerbations is limited. No studies have been published that have reported on patient outcomes over time or on quality of life improvements.
According to a comprehensive review by Lim and Mottram (2008), there is now international consensus regarding testing methodology, and normative reference values have been established.
3. Asthma involves airway inflammation, which if uncontrolled may lead to tissue destruction. Exhaled nitric oxide is a marker of airway inflammation, which previously could only be assessed indirectly. No test-related adverse events or complications have been reported. ENO measurement is meant to be adjunctive to well-established parameters of asthma management. Net health outcomes would be improved if evidence were to show that ENO testing led to a reduction in the number and severity of exacerbations or more accurately guided medication dosages. According to Lim and Mottram, ENO can be used effectively in predicting relapse, maintaining asthma control, and monitoring compliance with medication. Another review by Bush and Eber (2008) corroborates these conclusions and adds that a low ENO value in the setting of supposedly poor asthma control may cast doubt on the diagnosis. Elevated ENO can also indicate possible environmental influences affecting the patient. There is limited evidence from randomized, blinded, controlled studies of the usefulness of ENO testing.
4. According to Lim, ENO measurement is the only routine clinical test for airway inflammation that can be performed conveniently in the office setting.
5. At the present time it appears that ENO testing is mainly being used to better manage patients with moderate to severe asthma by pulmonary specialists. Additional well-designed studies should be able to confirm a benefit to disease management in the broader community setting.
Additional uses have been proposed for measuring exhaled nitric oxide, including assessment of chronic cough, emphysema, cystic fibrosis, allergic rhinitis, and primary ciliary dyskinesia. The evidence is comparatively scarce for these conditions and does not permit conclusions regarding health outcomes.
References
The following were among the resources reviewed and considered in developing this policy. By reviewing and considering the resources, CareFirst does not in any way endorse the contents thereof nor assume any liability or responsibility in connection therewith. The opinions and conclusions of the authors of these resources are their own, and may or may not be in agreement with those of CareFirst.
American Thoracic Society (2005). ATS/ERS Recommendations for Standardized Procedures for the Online and Offline Measurement of Exhaled Lower Respiratory Nitric Oxide and Nasal Nitric Oxide. [On-Line]. Accessed May 23, 2007. Available at: http://www.thoracic.org/sections/publications/statements/pages/respiratory-disease-adults/nitric1-19.html
Hayes, Inc. Hayes Alert. Nitric Oxide Breath Test for Asthma. Lansdale, PA: Hayes, Inc. May 2006.
Hayes Medical Technology Directory (2007). Nitric Oxide Breath Analysis for the Diagnosis and Management of Asthma. August 28, 2007. Lansdale, PA: Hayes, Inc.
Komakula, S., Khatri, S., Mermis, J. et al (2007). Body mass index is associated with reduced exhaled nitric oxide and higher exhaled 8-isoprostanes in asthmatics. Respiratory Research 16, 32.
Kwok, M.Y, Walsh-Kelly, C.M., Gorelick, M.H. (2009). The role of exhaled nitric oxide in evaluation 9of acute asthma in a pediatric emergency department. Academic Emergency Medicine 16, 21-8.
Lemiere, C. (2007). Induced sputum and exhaled nitric oxide as noninvasive markers of airway inflammation from work exposures. Current Opinion in Allergy and Clinical Immunology 7, 133-7.
Lim, K.G., Mottram, C. (2008). The Use of Fraction of Exhaled Nitric Oxide in Pulmonary Practice. Chest 133, 1232-42.
National Heart, Lung, and Blood Institute. National Asthma Education and Prevention Program (2007). Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. August 28, 2007. Bethesda, MD: Author.
Nickmilder, M., de Burbare, C., Sylviane, C. et al (2007). Increase of exhaled nitric oxide in children exposed to low levels of ambient ozone. Journal of Toxicology and Environmental Health A 70, 270-4.
Petsky, H.L., Cates, C.J., Li, A. et al (2008). Tailored interventionsa based on exhaled nitric oxide versus clinical symptoms for asthma in children and adults. Cochrane Database of Systematic Reviews, 2008, Issue 2, Art. No. CD006340.
Pijnenburg, M.W., Bakker, E.M., Hop, W.C., DeJongst J.C. (2005). Titrating steroids on exhaled nitric oxide in children with asthma: a randomized controlled trial. American Journal of Respiratory and Critical Care Medicine 172, 831-6.
Rosias, P.P., Dompeling, E., Dentener, M.A., et al (2004). Childhood asthma: exhaled markers of airway inflammation, asthma control score, and lung function tests. Pediatric Pulmonology 38, 107-14.
Shaw, D.E., Berry, M.A., Thomas, M., et al (2007). The use of exhaled nitric oxide to guide asthma management: a randomized controlled trial. American Journal of Respiratory and Critical Care Medicine 176, 231-7.
Silkoff, P.E., Carlson, M., Bourke, T. et al (2004). The Aerocrine exhaled nitric oxide monitoring system NIOX is cleared by the US Food and Drug Administration for monitoring therapy in asthma. Journal of Allergy and Clinical Immunology 114, 1241-56.
Smith, A.D., Cowan, J.O., Brassett, K.P. et al (2005). Exhaled nitric oxide: a predictor of steroid response. American Journal of Respiratory and Critical Care Medicine 172, 453-9.
Smith, A.D., Cowan, J.O., Brassett, K.P. et al (2005). Use of exhaled nitric oxide measurements to guide treatments in chronic asthma. New England Journal of Medicine 352, 2163-73.
Smith, A.D., Taylor, D.R. (2005). Is exhaled nitric oxide a useful clinical test in asthma? Current Opinion in Allergy and Clinical Immunology5, 49-56.
Szefler, S.J., Mitchell, H., Sorkness, C.A. et al (2008). Management of asthma based on exhaled nitric oxide in addition to guideline based treatment for inner city adolescents and young adults: a randomised controlled trial. Lancet 372, 1065-72.
Taylor, D.R., Pijnenburg, M.W., Smith, A.D., De Jongste, J.C. (2006). Exhaled nitric oxide measurements: clinical application and interpretation. Thorax 61, 817-27.
Tsujino, I., Nishimura, M., Kamachi, A. et al (2000). Exhaled nitric oxide--is it really a good marker of airway inflammation in bronchial asthma? Respiration 67, 645-51.
Zeidler, M.R., Kleerup, E.C., Tashkin, D.P. (2004). Exhaled nitric oxide in the assessment of asthma. Current Opinion in Pulmonary Medicine 10, 31-36
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