1. Single Breath Assessing Airway Inflammation with FeNO1
Applying Science With a
Single Breath
Assessing Airway Inflammation with FeNO
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2. IMPORTANT INFORMATION REGARDING NIOX VERO®
NIOX VERO is a portable system for the non-invasive, quantitative, simple and safe measurement of Nitric Oxide (NO) in human breath. Nitric Oxide is frequently increased in some inflammatory processes such as asthma. FeNO measurements provide the physician with means of evaluating an asthma patient’s response to anti-inflammatory therapy, as an adjunct to the established clinical and laboratory assessments in asthma. The NIOX VERO is intended for prescription use and should only be used as directed in the NIOX VERO User Manual by trained healthcare professionals. NIOX VERO is suitable for children, approximately 7–17 years, and adults 18 years and older. NIOX VERO cannot be used with infants or by children approximately under the age of 7, as measurement requires patient cooperation.
NIOX VERO should not be used in critical care, emergency care or in anesthesiology.
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3. Objectives This presentation is intended to show:
FeNO is a diagnostic marker of allergic (Th2) airway inflammation
FeNO is a predictor of inhaled corticosteroid (ICS) response
FeNO is helpful in determining adherence to therapy
FeNO helps to optimize ICS dose and reduces exacerbations by up to 50%
FeNO, fractional exhaled nitric oxide
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4. Pakhale et al. BMC Pulm Med. 2011;11:27.
Asthma Is A Complex Condition That Is Both Over- and Under-diagnosed
Asthma is a clinical diagnosis
Symptoms can be variable and misleading
Objective information should be, but is rarely, used in initial or ongoing assessment of asthma
Approximately 1/3 of patients with asthma do not have
asthma when objectively assessed
71%
$$$
Pakhale et al. BMC Pulm Med. 2011;11:27.
of misdiagnosed patients are on therapy
Pharmaceuticals represent the single largest
expenditure in asthma care
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5. Asthma Is A Condition That Can Be Difficult And Costly To Manage
Two ‘types’ of asthma exist:
“Typical” asthma
Relatively easy to diagnose and manage
Responsive to therapy
Relatively low cost
“Difficult” asthma
Difficult to diagnose and manage
Poorly responsive to traditional therapy (due to resistance,
non-adherence, etc.)
Very costly
Under- and over-diagnosis can result in significant cost, morbidity, and mortality
FeNO Can Assist in the Diagnosis and Management
of Typical and Difficult Asthma
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6. Asthma Heterogeneity Leads to Difficulty In Diagnosis And Management
Complex genetic disorder with heterogeneous phenotype1
Largely attributed to interactions among many genes and between these genes and the environment
Increasingly recognized as syndrome rather than specific
disease2,3
Variability in underlying inflammation, clinical symptoms, natural history, and response to treatment2,3
Variability contributes to suboptimal therapeutic control
1. Hakonarson et al. Am J Pharmacogenomics. 2002;2(3): Lötvall et al. J Allergy Clin Immunol. 2011;127(2): Dolovich et al. Thorax ;36(9):
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7. Phenotypes In Asthma
“A cluster of characteristics that define a disease and its subsets”1
Three ways to classify asthma phenotypes1
Trigger induced (eg., allergic vs. non allergic; exercise induced; viral induced)
Clinical presentation (eg., exacerbation-prone asthma; adult vs. childhood onset, steroid resistant)
Inflammatory markers / pattern of inflammation (eg., biomarkers, genotypes)
Phenotypes based on biomarkers (eg., FeNO, periostin, eosinophils)
Phenotypes based on genotypes (eg., possible genes associated aspirin-exacerbated respiratory disease; genes associated with FeNO)2,3
Traditional measures do not allow phenotyping by pattern of
inflammation
1. Lockey RF, Haley JA. Asthma Phenotypes Taskforce.
Available from:
Accessed 2 June Ledford DK, et al. J Allergy Clin Immunol Pract 2014;2: Modena BD, et al. Am J Respir Crit Care Med 2014;190:
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8. Problems With The Current Approach to Evaluate / Manage Asthma
Available tools:
Symptom / History Assessment
Inconsistent reporting by patients
Correlates more with bronchial hyper-responsiveness than
with inflammation
Pulmonary Function Testing
Identifies obstruction which is not necessarily correlated with inflammation
Heavily dependent upon patient effort
Medications
Only patients with T2 inflammation seem to respond to most anti-inflammatory therapies available
Dependent upon adherence which is difficult to assess
FeNO is an adjunct tool that can help to fill gaps left by other measures
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9. Cluster Phenotyping By Degree Of Th2 Inflammation
Two distinct molecular phenotypes:
Therapy targeting Th2 cytokines only benefits Th2-driven phenotypes
Non-Th2-driven asthma does not respond well to current
therapies including ICS
Woodruff PG, et al. Am J Respir Crit Care Med. 2009;180(5):
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10. Asthma Phenotypes: Not All Asthma Is Th2 Inflammation
Wenzel SE. Nat Med. 2012;18(5):
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11. Tools To Assess Inflammation
BAL, bronchoalveolar lavage; NO, nitric oxide.
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12. Nitric Oxide (NO) Production1,2 – Exhaled NO Is A Direct Signal Of Th2 / Allergic Airway Inflammation
NO — endogenous regulatory molecule
Synthesis regulated by family of enzymes — NO synthases (NOS)
Inducible NOS-derived NO is predominantly
produced in bronchial wall epithelial cells
Exhaled NO levels increase during
Th-2 (allergic) inflammation—often correlate with eosinophilic inflammation
AP, activator protein; iNOS, inducible nitric oxide synthase; IL, interleukin; IFN-, interferon-gamma; STAT, signal transducer and activator of transcription.
1. Yates. Immunol Cell Biol. 2001;79(2): Alving and Malinovschi. Eur Respir Mon. 2010;49:1-31.
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13. A Framework For Utilizing FeNO In Asthma
“Typical” Asthma
Identifies Th2 phenotype and likelihood of response to ICS therapy
Identifies adherence / non-adherence
Identifies ongoing allergen exposure
Can be used to monitor and titrate dose of ICS to
reduce exacerbations and optimize therapy
Differentiates symptoms (cough, wheeze, short of breath) related to Th2 inflammation from symptoms related to other causes (GERD, VCD, AR/Sinusitis, etc.)
Severe / Difficult-to-manage Asthma
Identifies persistence (or absence) of Th2 inflammation despite therapy
Identifies non-adherence as possible cause of difficulty with asthma control
May help to predict / identify patients in whom
therapy with biologics should be considered
Omalizumab
Mepolizumab
Dupilumab
Hankin CS et al. J Allergy Clin Immunol 2013; 131s: AB126.
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14. FEV1 bronchodilator response
Significantly Better Than FEV1 – FeNO Measurement Predicts ICS Responsiveness
1.00
In patients with nonspecific symptoms, a FeNO value of > 47 ppb is highy indicative
of corticosteriod
responsiveness
FeNO measurement was significantly better than FEV1, bronchodilator for predicting response to
inhaled fluticasone
propionate (P < 0.01)
0.75
Sensitivity
0.50
0.25
FeNO
52 patients referred by their family practitioners to the hospital with persistent, previously undiagnosed respiratory symptoms
FEV1 bronchodilator response
1-Specificity
1.00
1. Smith et al. Am J Respir Crit Care Med. 2005;172(4):
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15. Exhaled NO Identifies Steroid Responsiveness
Unlikely to respond to inhaled steroids
(negative predictive value – NPV)
Likely to respond to inhaled steroids
(positive predictive value – PPV)
47 ppb Nonspecific respiratory symptoms
91% NPV
82% PPV
91% NPV
25 ppb
35 ppb Cough
88% PPV
91% NPV
30 ppb
Patients with “difficult asthma” already on ICS
88% PPV
FeNO measurements provide the physician with means of evaluating asthma patients’ response to anti-inflammatory therapy, as an adjunct to the established clinical and laboratory assessments in asthma. Not all patients with asthma will have an elevated FeNO level. FeNO levels should be interpreted in the clinical context
1. Smith et al. Am J Respir Crit Care Med. 2005;172(4):
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16. Study Design of FeNO Guided Therapy
Asthma Control Questionnaire (ACQ), SABA, ICS use recorded at every visit
Total subjects 181 (93 FeNO, 88 Control) recruited from 17 primary care sites in Sweden, mild-to-moderate asthma
Average age: 40.9 FeNO, 41.1 Control
Baseline FEV1 (% predicted): 84.3 ± FeNO, 83.7 ±12.5; Baseline ICS dose μG/D
Syk et al. J Allergy Clin Immunol Pract. 2013;1(6):
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17. FeNO-directed Therapy Reduces Exacerbations
No significant difference between groups concerning
lung function
mean daily use of SABA
mean daily use of ICS
Syk et al. J Allergy Clin Immunol Pract. 2013;1(6):
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18. Cochrane: FeNO-based Management Reduces Exacerbation Rates
Population
Meta-Analysis Design
Odds Ratio for Reducing Exacerbations Using FeNO vs. Symptoms-based Approach
Adult1
7 Studies, 1700 Randomized Subjects,
1546 Completed Study
OR 0.60 (95% CI );
NNTB in one year = 12 (95% CI 8-32)
Pediatric2
9 Studies , 1426 Randomized Subjects,
1370 Completed Study
OR 0.63 (95% CI )
Conclusions: Tailoring asthma medications based on FeNO levels (compared with primarily on clinical symptoms) decreases the frequency of asthma exacerbations
1. Petsky HL et al. Cochrane Database of Systematic Reviews 2016; Petsky HL et al. Cochrane Database of Systematic Reviews 2016; abstract
submitted for publication
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19. FeNO Facilitates Early Detection of ICS Non-adherence
Good adherence (n=21)
Moderate adherence (n=9)
200
180
160
140
120
100 80 60 40 20
Poor adherence (n=11) No steroids (n=12)
Mean value ± SD
FEV , % predicted FeNO, ppb
Mean FeNO levels were significantly reduced in patients with good ICS adherence*
FEV1 levels were not substantially different among adherence groups
SD, standard deviation.
*Adherence determined by calculating number of doses taken per day/doses prescribed x 100. Good, moderate, and poor adherence defined as >75% adherence, 50% to 75% adherence, or <50% adherence to prescribed medication, respectively.
Delgado-Corcoran et al. Pediatr Crit Care Med. 2004;5(1):48-52
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20. Identifying Inflammation Without FeNO
Observational study of 50 previously diagnosed asthma patients (age 7-60) in a large allergy practice
CONSENT
Patient evaluation
Exam
Asthma Control test
Spirometry
FeNO (not revealed)
HCP assessment of airway inflammation:
High
Intermediate
Low
Treatment recommendation
FeNO score revealed
TREATMENT MODIFICATION, IF NEEDED
Laforce et al. Ann Allergy Asthma Immunol. 2014;113(6):
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21. Predicting Airway Inflammation Is a Coin Toss
FeNoO and Clinical evaluation inconsistent, n=25
FeNO and clinical evaluation agree, n=25
Standard clinical assessment of airway inflammation (history, symptom evaluation, spirometry) was inconsistent with underlying inflammation revealed by FeNO in 50% of patients (1/3 overestimate of inflammation, 2/3 underestimate of inflammation)
Laforce et al. Ann Allergy Asthma Immunol. 2014;113(6):
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22. A Framework For Utilizing FeNO In Asthma
“Typical” Asthma
Identifies Th2 phenotype and likelihood of response to ICS therapy
Identifies adherence / non-adherence
Identifies ongoing allergen exposure
Can be used to monitor and titrate dose of ICS to
reduce exacerbations and optimize therapy
Differentiates symptoms (cough, wheeze, short of breath) related to Th2 inflammation from symptoms related to other causes (GERD, VCD, AR/Sinusitis, etc.)
Severe / Difficult-to-Manage Asthma
Identifies persistence (or absence) of Th2 inflammation despite therapy
Identifies non-adherence as possible cause of difficulty with asthma control
May help to predict / identify patients in whom
therapy with biologics should be considered
Omalizumab
Anti-IL-5 (mepolizumab, reslizumab)
Dupilumab (?)
Hankin CS et al. J Allergy Clin Immunol 2013; 131s: AB126.
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23. Severe Asthma: Increased Cost, Morbidity and Mortality
5 - 10% of 26 million Americans suffering from asthma experience severe disease
About 1/2 of patients with severe asthma have uncontrolled severe asthma
Approximately 1/2 of direct asthma costs related to care of patients with severe disease ($56 billion total, $28 billion for severe asthma)
Patients with uncontrolled severe asthma incur up to 3x cost compared to controlled severe asthma ($21 billion)
2.5% - 5% (650,000 – 1.3 million) with severe uncontrolled
disease account for 37.5% of asthma-related direct costs
Estimated per-patient direct asthma costs between
$16,154 - $32,308 per year
Pharmaceuticals represent the single largest expenditure for
asthma care
Hankin CS et al. J Allergy Clin Immunol 2013; 131s: AB126.
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24. FeNO Measurement May Help Guide Treatment Response To Other Therapies
FeNO measurements may be of value in predicting likelihood of response to treatments other than ICS:
Anti-IgE1, Omalizumab4
Drugs inhibiting the IL-4 and IL-13 pathway2,3
Anti-TSLP therapy5
Mepolizumab6
Oral Steroids7
FeNO, fractional exhaled nitric oxide; ICS, inhaled corticosteroid; IL, interleukin.
1. Hanania et al. Am J Respir Crit Care Med. 2013;187: Corren et al. N Engl J Med. 2011;365: Wenzel et al. N Engl J Med ;368: Hanania et al. Ann Intern Med. 2011;154: Gauvreau et al. N Engl J Med. 2014;370: Pavord ID et al. Lancet 2012;380: Kupczyk M, et al. Respiratory Medicine 2013;107:1521–1530.
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25. FeNO Measurement Identifies Oral Steroid Responsiveness In Severe Asthma
“Sputum eosinophils and FeNO represented the most promising options for predicting favorable outcome to oral steroid treatment”
Factor
Odds Ratio
95% CI RR
eNO > 50 ppb
6.94
1.13, 42.38
4.82
1.06, 21.78*
Blood eosinophils > 0.44 x 109/L
3.72
1.09, 12.68
2.891
1.08, 7.58**
*p=0.03; **p=0.029.
eNO/FeNO, exhaled nitric oxide.
1. Kupczyk M, et al. Respiratory Medicine 2013;107:1521–1530.
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26. Diagnostic Accuracy of FeNO, Blood Eosinophils, Total IgE And Their Combinations To Identify Sputum Eosinophils
ROC Characteristics for FeNO, Blood Eosinophils, IgE and combinations
Westerhof et al. Eur Respir J. 2015;46(3):
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27. FeNO May Predict Response To Omalizumab
FeNO identifies patients likely (and unlikely) to respond to Xolair® (omalizumab)
– $10,000 - $30,000 per year treatment for moderate-to-severe allergic asthma
CI = confidence interval.
Mean percent reduction (95% CI) in protocol-defined asthma exacerbation rate in the low- and high-biomarker subgroups (baseline fractional exhaled nitric oxide [FeNO], peripheral blood eosinophils, and serum periostin).
*Exacerbation reduction P values; omalizumab versus placebo in each biomarker subgroup. Hanania et al. Am J Respir Crit Care Med. 2013;187:
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28. FeNO Measures Response To A New α-IL4 Monoclonal Antibody
Note that FeNO changes also correlate well with lung function changes in this trial!
Wenzel et al. N Engl J Med. 2013;368:
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29. Eosinophils And FeNO Predict Response To Mepolizumab
FeNO > 50 and blood eosinophil ≥300 predicted response to mepolizumab
Mepolizumab reduced sputum eosinophils in patients with eosinophilic asthma
Eosinophils were a better predictor than FeNO, but both identified patients likely to respond
Pavord ID et al. Lancet 2012;380:
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30. NIOX VERO® Only available point-of-care device to measure FeNO
Appropriate for patients ≥ 7 years of age
Easy-to-follow, on-screen guidance
10 seconds of active patient participation with a moderate
exhalation (50 ml/sec)
Results available in approximately 1 minute
Unlike PFTs, a result cannot be affected by patient effort
If the patient exhales outside of range (high / low), no result is
delivered, and test can quickly be restarted
PFT, pulmonary function test.
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31. Additional Factors Affecting FeNO Levels1-12
Airway infection (viral)
Allergic rhinitis
Atopy
Nitrate-rich diet
Effects generally not
clinically significant
Spirometric maneuvers that cause bronchospasm
Smoking
Alcohol consumption
Exercise
1. Sanders et al. J Allergy Clin Immunol. 2004;113(4): Henriksen et al. Eur Respir J. 1999;13(2): Olin et al. Respir Med ;95(2): Papi et al. Am J Respir Crit Care Med. 2000;162(5): Silkoff et al. Am J Respir Crit Care Med. 1999;159: Terada et al. Am J Respir Crit Care Med. 2001;164: Yates et al. Eur Respir J. 1996;9(6): Piacentini et al. Thorax. 2002;57: Narang et al. Thorax. 2002;57(7): Kaneko et al. Am J Respir Crit Care Med. 1998;158(3): Verleden et al. Chest ;116(1): Silkoff et al. J Allergy Clin Immunol. 2004;114(5):
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32. INCREASING FeNO level*
FeNO Interpretation
INTERMEDIATE/
INCREASING FeNO level*
LOW FeNO level
HIGH FeNO level
< 25 ppb in adults
< 20 ppb in children
ppb in adults
ppb in children
> 50 ppb in adults
> 35 ppb in children
Eosinophilic inflammation
less likely
Eosinophilic inflammation
likely
Symptomatic† patients unlikely to
benefit from trial of or additional ICS therapy; consider other possible etiologies‡
Symptomatic patients likely to benefit from trial or or increase in ICS/anti-Th2 therapy;
investigate allergen exposure
Cautious interpretation;
based on clinical judgment, consider initiating trial of or increasing ICS therapy / adherence 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):
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33. What Does A ‘Low’ FeNO Suggest?
That there is a low likelihood of Type-2 Inflammation
Also known as Th2 or allergic inflammation
That there is a low likelihood that the patient will respond to inhaled corticosteroids at the time of measurement
Or other anti-inflammatory therapy aimed at Type-2
inflammation, including biologics
It is important to note that a low FeNO does not mean a patient does not have asthma or that they may not develop Th2 inflammation at a later time
Asthma is a variable disease over time and disease activity can be affected by exposures, allergic sensitivity, and other factors
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34. American Thoracic Society (ATS) Guidelines1 For FeNO Use
In chronic inflammatory airway disease, including asthma, conventional tests such as FEV1 reversibility are only indirectly associated with airway inflammation.
FeNO offers advantages for patient care including:
Detecting allergic airway inflammation
Determining likelihood of inhaled corticosteroid (ICS) responsiveness
Monitoring airway inflammation to determine potential need for ICS
Unmasking otherwise unsuspected nonadherence to ICS
therapy
AAAAI and ACAAI have endorsed the ATS Clinical Practice Guideline on FeNO2
1. Dweik et al. Am J Respir Crit Care Med. 2011;184(5): AAAAI and ACAAI. Accessed November 12, 2015.
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35. Reveal if a patient will benefit from ICS treatment
Guide and optimize ICS therapy
FeNO
Reveal if a patient will benefit from ICS treatment
Detect and improve adherence
Reduce exacerbations by up to 50%
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36. NIOX VERO® and NIOX® are registered trademarks of Circassia AB
NIOX VERO® and NIOX® are registered trademarks of Circassia AB. CIRCASSIA is a registered trademark of
Circassia Limited.
© 2016 Circassia Pharmaceuticals Inc.. All rights reserved. October XXXXX-XX