Steven Bencze MD FRCPC

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Exhaled Nitric Oxide Here To Stay2008

• Steven Bencze MD FRCP(C)
• University of Ottawa
• Respiratory Medicine
• Ottawa Hospital
• cyberdoc2_at_rogers.com

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Conflict of Interest

• Aerocrine
• AZ
• GSK
• Altana
• Pfizer
• Boehringer

• Actelion
• Abbott
• Novartis
• Scherring

cyberdoc2_at_ROGERS.COM
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Objectives

• Introduction
• Measurement Technique
• Normal values
• Role in dx eosinophilic airway inflammation
• Diagnosis of asthma
• Role in asthma treatment monitoring

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eNO is Here To Stay
gt 1000 Publications in 10 years 239 peer reviewed
papers in 2007 82 peer reviewed papers in 2008
Annual publication rate
Courtesy of Professor Alvin - modified
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Introduction to eNO

• Symptom and spirometry based asthma management is
  no longer the state of the art.
• Asthma syndrome
• Diagnostic label vs predicting response to
  therapy
• FeNO eosinophilc airway inflammation

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Flow dependency of FENO
Silkoff et al., AJRCCM 1997
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FENO levels in respiratory diseases

• Asthma
• Respiratory infection
• Allergic rhinitis
• COPD - exacerbation

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ATS/ERS Guidelines re FeNO Measurment
ATS ERS FeNO GUIDELINES
American Thoracic Society, European Respiratory
Society. Am J Respir Crit Care Med.
2005171(8)912-930.
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eNO Measurement

• success rate
• 40 in children 4 years old
• 100 in children 10 years old
• JACI VOLUME 115, NUMBER 6 2005

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(No Transcript)
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Agreement between NIOX and MINO measurements

Khalili B et al. Allergy. 200762(10)1171-1174.
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Take Home Points

• FeNO values are airflow dependent
• Guideline based approach to FeNO measurment
  should be followed
• Portable device is available and validated

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Normal Values Adult Onset Asthma and Nitric
Oxide N3600 adults
FENO is associated to height and age FENO
e(-0.0057 age0.0088 height 0.013)
Olin, Chest 2007 1311852-1856
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Normal values for eNO in children
Malmberg et al., Ped Pulmonol 2006
Buchvald et al., JACI 2005
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Influence of Gender on eNON 204 healthy
non-smoking adults

Oliveri M et al. Respir Res. 2006794.
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Ethnic Differences of eNO levelsN531 Chinese
Children

Wong GW et al. Clin Exp Allergy.
200535889-893.
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Ethnic Differences of eNO levelsN657 Canadian
ChildrenKovesi Chest October 9 2007

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Guide to interpretation of FENO values in
patients with Airway Disease
NORMAL Unlikely 5-25
LOW Unlikely lt5
FeNO Eosinophilic inflammation
INTERMEDIATE Present, but mild 25-50
HIGH Significant gt50

• Consider
• Smoker
• Children
• -PCD
• CF

• If symptomatic review diagnosis
• If asymptomatic and on treatment
• Patient compliant
• Dose reduction?

Symptomatic patients likely to respond to
anti-inflammatory treatment If on ICS Check
compliance Consider allergen load, imminent
exacerbation
Interpretation based on clinical presentation
Thorax, 2006
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Take Home Points

• Normal values depend on
• age
• sex
• height
• ethnicity
• Interpretation strategy requires clinical
  correlation

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Association Between Exhaled NO and Eosinophilic
Airway Inflammation
1.00
8.3 ppb
0.75
Sputum eosinophil count ()
0.50
Sensitivity
Flow rate 250 ml/s
0.25
0.00
0.0
0.25
0.75
1.0
0.5
100
1-Specificity

Berry MA et al. Clin Exp Allergy.
200535(9)1175-1179.
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Exhaled nitric oxide shows correlation with
airway eosinophilia
Reference
Study
Author
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Exhaled nitric oxide shows correlation with
airway eosinophilia (contd)
Reference
Study
Author

• Thorax 19985391-95

induced sputum - eNO
Jakatanon et al
N35 stable
Piancentini et al N25
Eur Respir J 1999 13 13861390
correlation SI eNO

• AJRCCM 2001Vol 164. pp 21072113, 2001

Van Toorn et al N54
correlation EBBx (MBP) eNO
AJRCCM Vol 169. pp 473478, 2004
correlation SI - eNO
Andrew Smith et al N47
Nitric Oxide 13 (2005) 125133
BAL eNO (segmental)
Erpenbeck et al N16
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Alveolar NO in Adults With Asthma Evidence of
Distal Lung Inflammation
steroid naive inhaled steroid treated only
oral and inhaled steroid treated

Berry M et al. Eur. Respir J. 2005 25 986-991
p,0.001 NS Non-significant.
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Correlation Between Exhaled NO and Airway
Hyperresponsiveness
FENO reflects AHR in steroid-naive patients
(N104) with mild asthma
100
r-0.65Plt.001
Exhaled NO (ppb)
10
0.01
0.1
1
10
PC20 histamine (mg/mL)

Dupont LJ et al. Am J Respir Crit Care Med.
1998157(3)(pt 1)894-898.
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FeNO Is Superior to Lung Function in pts with
Probable Asthma

Malmberg LP et al. Thorax. 200358(6)494-499.
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Utility of Available Diagnostic Tests

Adapted from Smith AD et al. Am J Respir Crit
Care Med. 2004169(4)473-478.
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Exhaled NO Levels Significantly Higher in Asthma
than COPD
COPD
Asthma

Fabbri LM et al. Am J Respir Crit Care Med.
2003167(3)418-424.
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Differential Assessment of Chronic Cough and FeNO
FENO significantly higher in asthmatics with
chronic cough
150
100
Exhaled NO (ppb)
50
Flow rate 45 mL/s
0
Healthy controls
Asthmatics with wheezing or dyspnea
Asthmatics with chronic cough
Non-asthmatics with chronic cough

Chatkin JM et al. Am J Respir Crit Care Med.
1999159(6)1810-1813.
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GERD vs Asthma
Silvestri M et al. Respiration. 200471329-335.
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Exhaled nitric oxide as a diagnostic test for
asthma
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Take Home Messages

• Good correlation with eosinophilic airway
  inflammation - 10 studies
• As good as nonspecific airway challenge test in
  the diagnosis of asthma
• Validated tool to sort out pts with chronic
  cough

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Objectives

• Introduction
• Measurement Technique
• Normal values
• Role in dx eosinophilic airway inflammation
• Diagnosis of asthma
• Role in asthma treatment monitoring
• Adjusting ICS dose
• Predicting relapse
• Monitoring for compliance
• Asthma control

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FENO Measurements Provide a Method of Adjusting
ICS Dose

• 85 children (6-18 years age) allocated to FENO
  group (n39) or symptom group (n46)
• 1 year of steroid titration on FENO improved AHR
  and inflammation and did not result in higher
  steroid doses

Symptom group
FENO group

Pijnenburg M et al. Am J Respir Crit Care Med.
2005172(7)831-836.
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FENO Measurements Provide a Method of Adjusting
ICS Dose
Flow rate 250 mL/s

Smith AD et al. N Eng J Med. 2005352(21)2163-217
3.
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FENO Predicts Asthma Relapse After
Discontinuation of ICSFENO levels gt 49 ppb 4
weeks after steroid removal were highly
indicative of asthma relapse
Sensitivity 71 Specificity 93
Flow rate 50 mL/s

Pijnenburg MW et al. Thorax. 200560(3)215-218.
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FENO Facilitates Early Identification of
Noncompliance
100
P.0003 R0.77
50
Reduction in exhaled NO ()
0
-50
100
75
25
50
Compliance with BUD ( of prescribed)

Beck-Ripp J et al. Eur Respir J.
200219(6)1015-1019.
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Exhaled nitric oxide and asthma control a
longitudinal study N347
BDPlt 500 mcg
BDPgt 500 mcg
cut-off value of 40 change in FENO

• Michils ERJ December 5, 2007

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Distribution of clinical exacerbations in 22 of
44 asthmatics stratified by baseline FEV1
percentage of predicted (pred) and FENO of 100
mL/s
Flow rate 100 ml/sec
Gelb, A. F. et al. Chest 20061291492-1499
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ROC curve for FEV1 percentage of predicted for
first asthma exacerbation
Flow rate 100 ml/sec
Gelb, Chest 20061291492-1499
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Use of Exhaled Nitric Oxide to Guide Asthma
Management

• N118 asthmatics

19 patients, 26 exacerbations
30
20
12 patients, 18 exacerbations
No. of Exacerbations
10
P0.43
0
0
3
6
9
12
Control group
Time elapsed (months)
FENO group

Shaw DE et al. Am J Respir Crit Care Med.
2007176(3)231-237.
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Use of Exhaled Nitric Oxide to Guide Asthma
Management

• N47 mild to moderate asthma FENO group (n22)
  control group (n25)

• FENO predicts exacerbations with 80 sensitivity
  and 60 specificity
• A therapy regimen aimed at lowering FENO in
  children with asthma improved parameters of
  airway function

Fritsch M et al. Pediatr Pulmonol.
200641(9)855-862
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PCD nasal NO
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Determinants of FENO Reference Values in Children

• FENO positively associated with height and age
• The upper limit for normal FENO level in children
  at age 4 is 15 ppb and for adolescents is 25 ppb
  
• FENO increases from 7 to 14 ppb as height
  increases from 120 to 180 cm

Predicted FENO
95 prediction intervals
Malmberg LP et al. Pediatr Pulmonol.
200641(7)635-642.

Buchvald F et al. J Allergy Clin Immunol.
2005115(6)1130-1136.
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Relationship Between Exhalation Flow Rates and
Exhaled NO Concentration

• Concentration of NO varies with the flow of
  exhaled air
• More than 35 fold increase in mean NOPlat is
  observed for a 400 fold decrease in flow rate

100.0
80.0
60.0
NOPLAT lowest flow ( s.e.m)
40.0
20.0
0.0
10.0
1.0
100.0
1000.0
10000.0
Flow mL/sec
Silkoff PE et al. Am J Crit Care Med.
1997155260-267.