Exhaled Nitric Oxide Today s Asthma Biomarker Richard F. Lavi, MD FAAAAI FAAP
Objectives Describe exhaled nitric oxide physiology and pathophysiology Review the current literature regarding exhaled nitric oxide testing Explore potential applications of exhaled nitric oxide measurement in clinical care
Disclosure Member of Aerocrine Speakers Bureau. ENO medical device manufacturer. No other relevant financial disclosures.
Biomarker? A characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. Biomarkers Definitions Working Group. Clin Pharmacol Ther. 2001;69(3):89-95.
The Search for Biomarkers Asthma: complex, heterogeneous disease Endotypes are key Allergic and eosinophilic asthma endotypes are well-recognized How do we endotype asthmatics to provide the most appropriate and effective tailored therapies? Here, try this. This will be effective. Lötvall J, Akdis CA, Bacharier LB, Bjermer L, Casale TB, Custovic A, Lemanske RF Jr, Wardlaw AJ, Wenzel SE, Greenberger PA. Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome. J Allergy Clin Immunol. 2011 Feb;127(2):355-60.
Biomarkers In Asthma Reduce risk of misdiagnosis Better define asthma endotype Evaluate response to therapy Improve disease management
Inflammation In Asthma From: Durrant & Metzger (2010) Immunol Invest 39: 526-49
Asthma Biomarker Candidates Total eosinophil count Sputum eosinophils Difficult to collect clinically Urinary leukotrienes Airway imaging Dynamic CT Szefler SJ, Wenzel S, Brown R, Erzurum SC, Fahy JV, Hamilton RG, Hunt JF, Kita H, Liu AH, Panettieri RA Jr, Schleimer RP, Minnicozzi M. Asthma outcomes: biomarkers. J Allergy Clin Immunol. 2012 Mar;129(3 Suppl):S9-23.
When in Rome
Airway Inflammation Markers Bronchoscopy Bronchial wash BAL Biopsy AHR Sputum investigation Breath condensates NO in exhaled air
Physiology of ENO HEALTHY NO Soluble mediator inos STAT-1 Corticosteroidresistant mechanism IFN-γ (homeostatic, source unknown) Kjell Alving & Andrei Malinovschi (2010). Eur Respir Monograph 49: 1-31.
Pathophysiology in Allergic Asthma ASTHMA NO NO NO Air pollution (oxidative stress) Allergen exposure inos AP-1 inos STAT-6 Mucus, AHR Corticosteroidsensitive mechanism IL-4/ IL-13 (Th2 cells, mast cells, eosinophils) Kjell Alving & Andrei Malinovschi (2010). Eur Respir Monograph 49: 1-31.
inos in the Lower Airways Control Asthma (- steroid) Asthma (+ steroid) Redington et al. (2001) Thorax 56: 351-7
ENO Standardization ERS 1997 ATS 1999 ERS 2001 ATS/ERS 2005
THE 2011 AMERICAN THORACIC SOCIETY GUIDELINES DEFINED HOW ENO SHOULD BE USED IN CLINICAL PRACTICE Diagnosis Treatment Monitoring Adherence Dweik et al. Am J Respir Crit Care Med. 2011;184(5):602-615. EMD/000585/00
ENO TESTING Diagnosis Diagnose eosinophilic airway inflammation Support asthma diagnosis when objective evidence is needed Assist in assessing etiology of respiratory symptoms Help identify eosinophilic asthma phenotype Dweik et al. Am J Respir Crit Care Med. 2011;184(5):602-615.
ENO TESTING IN THE INITIAL ASSESSMENT OF ASTHMA Parameter* Sensitivity, % Specificity, % PPV, % NPV, % Peak flow improvement with steroid >15% 24 100 100 69 FEV 1 improvement with steroid >15% 12 100 100 66 FEV 1 <80% predicted 29 100 100 71 FEV 1 /FVC <70% 35 100 100 73 Sputum eosinophils >3% 86 88 80 92 FeNO >20 ppb 88 79 70 92 Bronchodilator reversibility and AHR used to establish asthma diagnosis in study Both FeNO and sputum eosinophils had significantly higher accuracy than lung function tests FeNO testing provides added advantage of being noninvasive and easy to perform FEV 1, forced expiratory volume at 1 second; FVC, forced vital capacity; NPV, negative predictive value; Ppb, parts per billion; PPV, positive predictive value. *47 patients with symptoms suggestive of asthma, with 17 subsequently diagnosed with asthma. Smith et al. Am J Respir Crit Care Med. 2004;169(4):473-478. EMD/000585/00
ENO SIGNIFICANTLY P=0.0001 ELEVATED IN ASTHMA FeNO, ppb 160 140 120 100 80 60 40 20 0 Allergic asthma n=56 P=0.0001 Nonallergic asthma n=45 P=0.0001 Healthy volunteers n=39 FeNO levels significantly increased in both asthma groups FeNO levels significantly higher in patients with allergic asthma versus patients with nonallergic asthma Figure from Zietkowski et al. With permission. Zietkowski et al. J Investig Allergol Clin Immunol. 2006;16(4):239-246.
ENO LEVELS SIGNIFICANTLY HIGHER IN ASTHMA COMPARED WITH COPD 140 120 60 FeNO, ppb 40 P<0.01 38 20 16 ppb considered 11 cut point 0 COPD (n=27) Asthma (n=19) Figure reprinted from Fabbri et al with permission of the American Thoracic Society. Copyright 2011 American Thoracic Society. Patients aged >50 yrs with postbronchodilator FEV 1 /FVC <70% and history of asthma or chronic obstructive pulmonary disease (COPD). Horizontal bar represents median value. Fabbri et al. Am J Respir Crit Care Med. 2003;167(3):418-424.
ENO TESTING Treatment Determine likelihood of individual patient response to antiinflammatory agents, including ICS Guide changes in dosing of anti-inflammatory medications Step-down or step-up dosing or discontinuation of anti-inflammatory medications Dweik et al. Am J Respir Crit Care Med. 2011;184(5):602-615.
"FeNO has been shown to predict the likelihood of steroid responsiveness more consistently than spirometry, bronchodilator response, peak flow variation, or AHR to methacholine." Dweik et al. Am J Respir Crit Care Med. 2011;184(5):602-615.
ENO MONITORING VERSUS CONVENTIONAL MANAGEMENT FOR ICS DOSE TITRATION 40 Control group (n=48) Exacerbations, n 35 30 25 20 15 10 5 0 P=0.27 ENO group (n=46) 0 1 2 3 4 5 6 7 8 9 10 11 12 Months 46% reduction 0.5 and 0.9 exacerbations per patient per year in ENO and control groups, respectively Did not meet superiority statistical threshold of 60% reduction Figure from Smith et al. With permission from Massachusetts Medical Society. Smith et al. N Engl J Med. 2005;352(21):2163-2173. 22 EMD/000585/00
DOSE DISTRIBUTION OF INHALED FLUTICASONE AT STUDY COMPLETION 50 40 ENO group (n=46) Control group (n=48) P=0.008 for distribution Patients, % 30 20 10 0 0 100 250 500 750 1000 Fluticasone, µg/d Figure from Smith et al. With permission from Massachusetts Medical Society. Smith et al. N Engl J Med. 2005;352(21):2163-2173. 23 EMD/000585/00
ENO-GUIDED ASTHMA MANAGEMENT DURING PREGNANCY 75 Control group (n=109) ENO group (n=111) 900 Control group (n=109) ENO group (n=111) Exacerbations, n 50 15 Mean ICS dose, µg/d 800 700 600 P=0.043 0 0 5 10 15 20 25 Time, weeks 25% females in ENO group had an exacerbation versus 41% of patients in control group (P=0.011) NNT= 6; for every 6 receiving treatment adjustment by ENO-based algorithm, 1 was prevented from having an exacerbation Significant reduction in neonatal hospitalizations in ENO group (8%) vs control group (17%; P=0.046) Figures reprinted from The Lancet, 378, Powell et al, Management of asthma in pregnancy guided by measurement of fraction of exhaled nitric oxide: a double-blind, randomised controlled trial, 983-990, Copyright 2011, with permission from Elsevier. NNT, number needed to treat. Powell et al. Lancet. 2011;378(9795):983-990. 500 1 2 3 4 5 6 Visit 24 EMD/000585/00
AN INVESTIGATION OF ASTHMA CARE BEST PRACTICE IN A COMMUNITY HEALTH CENTER Journal of Health Care for the Poor and Underserved. 2012;23:255-264. 25 EMD/000585/00
UHP ASTHMA PREVALENCE RATES 1. Lester et al. J Health Care Poor Underserved. 2012;23:255-264. 2. Akinbami LJ et al. Asthma Prevalence, Health Care Use, and Mortality: United States, 2005 2009. January 12, 2011. DHHS Publication No. (PHS) 2011-1250. National Health Statistics Reports No. 32. 3. Centers for Disease Control and Prevention. Behavioral Risk Factor Surveillance System Survey Data. http://apps.nccd.cdc.gov/brfss/list.asp?cat=as&yr= 2009&qkey=4416&state=All. Accessed August 15, 2012. 26 EMD/000585/00
THE UHP PLAN Key elements of the plan Screen for symptoms, ER visits, hospitalizations, and intubations ACT Review medication use Develop an asthma action plan Set self-management goals ENO to help identify exacerbation risk and adherence to controller medications (ages 6 and older) Biannual spirometry Lester et al. J Health Care Poor Underserved. 2012;23:255-264. 27 EMD/000585/00
ER/URGENT CARE VISITS PRE- AND POST- PROGRAM IMPLEMENTATION Lester et al. J Health Care Poor Underserved. 2012;23:255-264. 28 EMD/000585/00
UHP COST COMPARISON Lester et al. J Health Care Poor Underserved. 2012;23:255-264. 29 EMD/000585/00
ASTHMA MANAGEMENT USING ENO AND GUIDELINE- BASED TREATMENT FOR INNER-CITY ADOLESCENTS Control group (n=270) ENO monitoring group (n=276) 40 Maximum days with symptoms, n 6 4 2 0 Run-in Mean ENO, ppb 30 20 10 0 Run-in 0 3 9 17 25 33 41 49 0 3 9 17 25 33 41 49 Week Week Figures reprinted from The Lancet, 372, Szefler 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, 1065-1072, Copyright 2008, with permission from Elsevier. Szefler et al. Lancet. 2008;372(9643):1065-1072. 30 EMD/000585/00
STUDY CONSIDERATIONS Significant (P<0.0001) differences in 3-week run-in period versus pre-study levels Mean ICS dose of 219 µg/d 12.9-ppb in mean ENO levels (31.7 18.8 ppb) 3.4-day in mean maximum symptomatic days (from 5.6 2.2 days) 3.0-point in ACT score (18.2 [poor] 21.2 [good control]) 3.3% in FEV 1 % predicted (92% 95%) Protocol issues Patients excluded if <25% adherence during run-in period If symptoms present, protocol mandated ICS dose increase even if low ENO levels; protocol did not permit ICS dose decrease if ENO levels low Primary endpoint, number of days with asthma symptoms, not reflective of ENO measurement utility - ENO levels poorly correlated with symptoms Fewer patients in ENO group (32%) required 1 prednisone course versus control (42%; P=0.01). Szefler et al. Lancet. 2008;372(9643):1065-1072. 31 EMD/000585/00
ENO TESTING: MONITORING AND ADHERENCE Monitoring and adherence Establish baseline ENO level during clinical stability for subsequent monitoring of chronic, persistent asthma Monitor airway inflammation levels in patients with asthma Account for persistent and/or high allergen exposure as a factor associated with elevated ENO levels Assist in evaluation of adherence to ICS treatment Assess whether airway inflammation is contributing to poor asthma control Dweik et al. Am J Respir Crit Care Med. 2011;184(5):602-615. 32 EMD/000585/00
ENO INTERPRETATION: PATIENTS WITH SUSPECTED ASTHMA LOW FeNO level <25 ppb in adults <20 ppb in children Eosinophilic inflammation less likely INTERMEDIATE/ INCREASING FeNO level* 25-50 ppb in adults 20-35 ppb in children HIGH FeNO level >50 ppb in adults >35 ppb in children Eosinophilic inflammation likely Symptomatic patients unlikely to benefit from trial of ICS therapy; consider other possible etiologies Symptomatic patients likely to benefit from trial of ICS therapy; investigate allergen exposure Cautious interpretation; based on clinical judgment, consider initiating trial of ICS therapy and monitor change in FeNO levels *Increasing defined as >40% increase from previous stable FeNO level. Chronic cough and/or wheeze and/or shortness of breath for >6 weeks. For example, rhinosinusitis, bronchiectasis, primary ciliary dyskinesia, anxiety-hyperventilation, cardiac disease, GERD, or vocal cord dysfunction. Dweik et al. Am J Respir Crit Care Med. 2011;184(5):602-615. 33 EMD/000585/00
SEVERAL FACTORS MAY INCREASE OR DECREASE ENO LEVELS Airway infection 1 Allergic rhinitis 2 Nitrate-rich diet 3 Bronchodilator 4 - Spirometric maneuvers 5 Exercise 6 Alcohol consumption 7 Bronchoconstriction 6, 8 Ciliary dyskinesia 9 Pulmonary hypertension 10 Cystic fibrosis 9 Smoking 11 ICS therapy 11,12 1. Sanders et al. J Allergy Clin Immunol. 2004;113(4):697-702. 2. Henriksen et al. Eur Respir J. 1999;13(2): 301-306. 3. Olin et al. Respir Med. 2001;95(2):153-158. 4. Papi et al. Am J Respir Crit Care Med. 2000;162(5): 1773-1777. 5. Silkoff et al. Am J Respir Crit Care Med. 1999;159:940-944. 6. Terada et al. Am J Respir Crit Care Med. 2001;164:1879-1884. 7. Yates et al. Eur Respir J. 1996;9(6):1130-1133. 8. Piacentini et al. Thorax. 2002;57:771-773. 9. Narang et al. Thorax. 2002;57(7):586-589. 10. Kaneko et al. Am J Respir Crit Care Med. 1998;158(3):917-923. 11. Verleden et al. Chest. 1999;116(1):59-64. 12. Silkoff et al. J Allergy Clin Immunol. 2004;114(5):1241-1256.
INTERPRETATION OF ENO MEASUREMENTS Use cut points rather than reference values Account for age as a factor in children <12 years old Clinical context in which ENO is obtained should be taken into account and reported* When monitoring patients, clinically significant increase determined as >20% change for levels >50 ppb >10-ppb change for levels <50 ppb Decrease of >20% in an elevated ENO level, which often occurs 2 to 6 weeks after initiation of anti-inflammatory therapy, supports that treatment was successful for reduction of inflammation *Includes date, time of day, age, sex, ethnicity, height, weight, smoking status, reasons for test, prior diagnosis if known, whether patient was using ICS or oral steroids at time of testing, and number of measurements made. Dweik et al. Am J Respir Crit Care Med. 2011;184(5):602-615.
Pearls? ENO as a personal best. ENO is a test of steroid responsive airway inflammation. ENO to test for and/or monitor successful steroid discontinuation? ENO to predict exacerbation. ENO to monitor adherence and possible ongoing allergen exposure.
4-STEP PROCEDURE 1. Empty lungs 2. Inhale deeply through disposable filter 3. Exhale through disposable filter 4. View results on screen
Case Study: Lauren Patient characteristics Female, 21 years old Reason for visit Increasingly severe asthma Patient history Asthma, atopic dermatitis, allergic rhinitis since early childhood Hospitalized >10 times in her lifetime; 2 times this year, including ICU visit 2 weeks ago Current medications High-dose ICS/LABA combination, LTRA once daily, SABA prn Intranasal steroids once daily Finished oral corticosteroid taper 3 days ago Present illness Symptoms of cough, wheeze, dyspnea requiring SABA 4 to 5 times/week Nighttime awakenings, 1 to 2 times/week Avoids exercise due to increased symptoms Asthma triggers: animal exposure, viral infections, changes in weather, and wind ICU, intensive care unit; LABA, long-acting beta-agonist; LTRA, leukotriene receptor antagonist; prn, as needed; SABA, short-acting beta-agonist.
Case Study: Lauren Other information Hospital lab results: total IgE level, 653 ku/l; peripheral eosinophils, 6%; specific IgE positivity for cat, dog, Aspergillus, Alternaria, rye grass, dust mite, ragweed, and elm Assessment Pre-BD Post-BD % Change FVC, % predicted 94 99 5 FEV 1, % predicted 91 94 3 FEV 1 /FVC, % 83 84 1 FeNO, ppb 68 BD, bronchodilator.
Lauren: Control Assessment Impairment SABA use Activity limitations Daytime symptoms Nighttime symptoms Lung function FeNO Controlled Not controlled Risk Exacerbations FeNO Controlled Not controlleded
Lauren: Follow-up and Plan Plan Continue current medications encouraged improved adherence with all medications Allergen avoidance measures Follow up in 2 weeks Follow-up Reports regular use of medications Symptoms 2 days/week; SABA used 2 times/week; no nighttime awakenings; has not tried exercising Assessment Pre-BD Post-BD % Change FVC, % predicted 89 96 7 FEV 1, % predicted 84 91 8 FEV 1 /FVC, % 81 83 2 FeNO, ppb 134
Lauren: Control Assessment 2 Impairment Controlled Not controlled SABA use Activity limitations?? Daytime symptoms Nighttime symptoms Lung function FeNO Risk Exacerbations FeNO Controlled Not controlled
Lauren: Plan and Follow-up Plan Due to relatively normal lung function, good adherence, and limited symptom burden, decision made not to change therapy Asked to follow up in 1 to 2 months, sooner if having problems Contacted 5 days later by hospital after admission to ICU for continuous bronchodilator nebulization and IV steroids
Current medications Lauren: 2 days Post- Hospitalization Scheduled albuterol 2.5 mg neb every 8 hours Oral prednisone 20 mg twice daily, with tapering over 10 days High-dose ICS/LABA, LTRA, and intranasal steroids Present illness Reports slight ongoing dyspnea, frequent daytime and nighttime cough Continues to restrict activity Reports being scared of her asthma Assessment Pre-BD Post-BD % Change FVC, % predicted 84 83 1 FEV 1, % predicted 74 76 3 FEV 1 /FVC, % 77 78 1 FeNO, ppb 47
Lauren: 2 weeks post-hospitalization Current medications Last dose of prednisone 3 days ago (10 mg) Last used SABA 4 days ago Remains on high-dose ICS/LABA, LTRA, and intranasal steroids Present illness Daytime symptoms once in the last week No nighttime awakenings Has been avoiding work due to concern with possible virus exposure Reports good adherence with medications Assessment Pre-BD Post-BD % Change FVC, % predicted 81 83 2 FEV 1, % predicted 83 85 2 FEV 1 /FVC, % 82 82 0 FeNO, ppb 89
Lauren: Control Assessment 3 Impairment SABA use Controlled Not controlled Activity limitations?? Daytime symptoms Nighttime symptoms Lung function FeNO Risk Exacerbations FeNO Controlled Not controlled
Lauren: Post-hospital Plan Plan Based on significant increase in FeNO (47 to 89 ppb) decision made to add second inhaled steroid to current high-dose ICS/LABA and LTRA Given oral steroids to have on hand in case of any sudden increase in symptoms Omalizumab recommended approval process initiated Follow-up scheduled every 2 weeks
Lauren Key Points Spirometry and symptom measures do not provide information about the inflammatory status of the airway Following ENO longitudinally over time can aid the clinician in identifying a patient at risk for exacerbation, even in the absence of symptoms or abnormal lung function Patients with severe asthma and a persistently elevated ENO level are likely to have a high-risk phenotype Ongoing inflammation increases the risk of future exacerbations A significant increase in ENO should prompt adjustment to therapy, assessment of treatment adherence, or evaluation for ongoing allergen exposure
Conclusion Differentiate asthma from other conditions Predict loss of control and adherence FeNO levels Identify likelihood of response to ICS therapy Predict asthma relapse Guide and optimize ICS therapy