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Exhaled Nitric Oxide Here To Stay 2008

Steven Bencze MD FRCP(C) University of Ottawa Respiratory Medicine Ottawa Hospital

Conflict of Interest
Aerocrine AZ GSK Altana Actelion Abbott Novartis Scherring

Pfizer
Boehringer
cyberdoc2@ROGERS.COM

Objectives

Introduction
Measurement Technique

Normal values Diagnosis of asthma

Role in dx eosinophilic airway inflammation

Role in asthma treatment monitoring

eNO is Here To Stay

Annual publication rate

> 1000 Publications in 10 years 239 peer reviewed papers in 2007 82 peer reviewed papers in 2008
Courtesy of Professor Alvin - modified

Introduction to eNO
1. Symptom and spirometry based asthma management is no longer the state of the art. 2. Asthma syndrome 3. Diagnostic label vs predicting response to therapy
1. FeNO eosinophilc airway inflammation

Flow dependency of FENO

Silkoff et al., AJRCCM 1997

FENO levels in respiratory diseases

Asthma Respiratory infection Allergic rhinitis COPD - exacerbation

Steroid therapy PCD Cystic Fibrosis Smokers

ATS/ERS Guidelines re FeNO Measurment

Use of NO free air (< 5ppb) for inhalation

1999 ATS statement recommended a flow rate of 50 mL/second

ATS & ERS FeNO GUIDELINES

Exhalation against expiratory resistance

NPO x 2 hours before No caffeine Hold BDs x 6 hours

American Thoracic Society, European Respiratory Society. Am J Respir Crit Care Med. 2005;171(8):912-930.

eNO Measurement

success rate 1. 40% in children 4 years old 2. ~100% in children 10 years old
JACI VOLUME 115, NUMBER 6 2005

Agreement between NIOX and MINO measurements


125

MINO FENO (ppb)

100 75 50 25 0 0

r=0.98 P<.0001 n=110

25

50

75

100

NIOX FENO (ppb)


Khalili B et al. Allergy. 2007;62(10):1171-1174.

Take Home Points


FeNO values are airflow dependent Guideline based approach to FeNO measurment should be followed

Portable device is available and validated

Normal Values Adult Onset Asthma and Nitric Oxide N=3600 adults

FENO is associated to height and age FENO = e(-0.0057+ age*0.0088+ height *0.013)

Olin, Chest 2007 131:1852-1856

Normal values for eNO in children

Malmberg et al., Ped Pulmonol 2006;

Buchvald et al., JACI 2005

Influence of Gender on eNO


N= 204 healthy non-smoking adults
male

14 12
*

female

FENO ppb

10 8
6
**

*p<0.01 **p<0.001

4
2

**

50

100

150

200

Flow ml/s
Oliveri M et al. Respir Res. 2006;7:94.

Ethnic Differences of eNO levels


N=531 Chinese Children
200.0
P=.01

100.0 Exhaled nitric oxide (ppb) 50.0

P=.011

P=.037

50.4

20.0
17.0 11.6

10.0 5.0

10.8 9.1

2.0
ChMC (n=111) CauMC (n=111) ChFC (n=111) CauFC (n=111) ChCA (n=111)

Wong GW et al. Clin Exp Allergy. 2005;35:889-893.

***

Ethnic Differences of eNO levels


N=657 Canadian Children
Kovesi; Chest October 9 2007

Guide to interpretation of FENO values in patients with Airway Disease

FeNO
Eosinophilic inflammation

LOW Unlikely <5


Consider: - Smoker Children -PCD - CF

NORMAL Unlikely 5-25

INTERMEDIATE Present, but mild

HIGH Significant

25-50

>50

If symptomatic review diagnosis

If asymptomatic and on treatment -Patient compliant -Dose reduction?

Interpretation based on clinical presentation

Symptomatic patients likely to respond to antiinflammatory treatment If on ICS Check compliance Consider allergen load, imminent exacerbation
Thorax, 2006

Take Home Points


Normal values depend on :
age
sex height

ethnicity

Interpretation strategy requires clinical correlation

Association Between Exhaled NO and Eosinophilic Airway Inflammation


Sputum eosinophil count (%)
100 30

P<.001 R = 0.52

1.00

3 1 0.3 0.1

Sensitivity

10

0.75

8.3 ppb

0.50 Flow rate: 250 ml/s 0.25 0.00

0.1

0.3

10

30

100

0.0

0.25

0.5

0.75

1.0

Exhaled NO concentration (ppb)


Male Female

1-Specificity

Berry MA et al. Clin Exp Allergy. 2005;35(9):1175-1179.

Exhaled nitric oxide shows correlation with airway eosinophilia


Author Study Reference

Warke et al
N= 31 pts,

BAL EOS+ - eNO ++ correlation

Thorax 2002;57;383387

Payne et al.
N= 31

airway biopsy Eos score - eNO ARCCM Vol 164. pp


13761381, 2001

Berry et al
566 pts..

induced sputum -eNO BAL/EBx - EOS+ had elevated eNO Alveolar eNO correlates with BAL Eos+ but not sputum eos

Clin Exp Allergy 2005; 35:11751179

Silkoff et al
N= 41

JACI,2005;116:12

49-55. ERJ 2005; 25: 986991

Berry et al.
N=65

Exhaled nitric oxide shows correlation with airway eosinophilia (contd)


Author Study Reference

Jakatanon et al
N=35 stable

induced sputum - eNO ++ correlation SI eNO ++ correlation EBBx (MBP) eNO ++ correlation SI - eNO BAL eNO (segmental)

Thorax 1998;53;91-95

Piancentini et al N=25 Van Toorn et al


N=54

Eur Respir J 1999; 13: 13861390


AJRCCM 2001;Vol 164. pp 21072113, 2001

Andrew Smith et al N=47 Erpenbeck et al N=16

AJRCCM Vol 169. pp 473478, 2004

Nitric Oxide 13 (2005) 125133

Alveolar NO in Adults With Asthma: Evidence of Distal Lung Inflammation


1 0

Alveolar NO concentration ppb

20

***

BAL eosinophil count %

3 1

***

15

.03

10

NS

.01

0.03 0 1 2 3 4 5 6 Alveolar NO concentration ppb 7

0 Normal Mild-to-moderate asthma Refractory asthma

steroid naive Berry M et al. Eur. Respir J. 2005; 25: 986-991

inhaled steroid treated only

oral and inhaled steroid treated

***p,0.001; NS: Non-significant.

Correlation Between Exhaled NO and Airway Hyperresponsiveness


FENO reflects AHR in steroid-naive patients (N=104) with mild asthma

Exhaled NO (ppb)

100

r=-0.65 P<.001

10 0.01 0.1 1 10

PC20 histamine (mg/mL)


Dupont LJ et al. Am J Respir Crit Care Med. 1998;157(3)(pt 1):894-898.

FeNO Is Superior to Lung Function in pts with Probable Asthma


1
Flow rate = 50 mL/s
10 ppb

0.9 0.8

Sensitivity

0.7

0.6
0.5
FENO Rre5%pred Xre5%pred

0.4
FENO ROC properties: Sensitivity: 86% Specificity: 92% 0.3

0.2
0.1 0 0 0.2 0.4 0.6 0.8 1

Malmberg LP et al. Thorax. 2003;58(6):494-499.

1-specificity

Utility of Available Diagnostic Tests


Positive Specificity Predictive Value Negative Predictive Value

Sensitivity

(%)
Peak flow increase with steroid >15% FEV1 improvement with steroid >15% FEV1 <80% predicted FEV1/FVC <70% Sputum eosinophils >3% FENO50 >20 ppb 24 12 29 35 86 88

(%)
100 100 100 100 88 79

(%)
100 100 100 100 80 70

(%)
69 66 71 73 92 92

Adapted from: Smith AD et al. Am J Respir Crit Care Med. 2004;169(4):473-478.

Exhaled NO Levels Significantly Higher in Asthma than COPD


140 120

Exhaled nitric oxide (ppb)

60

40

20

*
16 ppb

COPD
Fabbri LM et al. Am J Respir Crit Care Med. 2003;167(3):418-424.

Asthma
**

Differential Assessment of Chronic Cough and FeNO


FENO significantly higher in asthmatics with chronic cough
150

Exhaled NO (ppb)

100

50 Flow rate = 45 mL/s 0


Healthy controls

Non-asthmatics with chronic cough

Asthmatics with chronic cough

Asthmatics with wheezing or dyspnea

Chatkin JM et al. Am J Respir Crit Care Med. 1999;159(6):1810-1813.

GERD vs Asthma
35 30 25 FENO (ppb) 20 15 10
P=.0001

5
0
Children with allergic asthma
Silvestri M et al. Respiration. 2004;71:329-335.

Children with GER and asthma like symptoms

Exhaled nitric oxide as a diagnostic test for asthma


Author Study design Reference

Deykin et al Dupont et al. Malmberg et al Berkman et al

Selected asthmatics and nonasthmatics, N=46 Prospective unselected adults N=240

AJRCCM 2002
(v165: 1597-1601)

Chest 2003
(v123: 751-5)

Prospective unselected children Thorax 2003 (v58: 494-9) and healthy controls n=96 Prospective unselected adults N=40 Prospective unselected adults N=47 Thorax 2005
(v60: 383-8)

Smith et al.

AJRCCM 2004
(v169: 473-8)

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

Objectives
Introduction Measurement Technique

Normal values Diagnosis of asthma

Role in dx eosinophilic airway inflammation

Role in asthma treatment monitoring

Adjusting ICS dose Predicting relapse Monitoring for compliance Asthma control

FENO Measurements Provide a Method of Adjusting ICS Dose


85 children (6-18 years age) allocated to FENO group (n=39) or symptom group (n=46)

1 year of steroid titration on FENO improved AHR and inflammation and did not result in higher steroid doses
1050 42 40 38 1000 900 800 700 600 500 400 300 200 36

950

Mean PD20 methacholine (g)

2000

ICS dose (micrograms)

FENO (ppb)

34 32 30 28 26 24 22 20

850

750

650

100

Start 3 mo 6 mo 9 mo 12 mo

Start

12 mo

Start

12 mo

Start 3 mo 6 mo 9 mo 12 mo

Visit Symptom group

Visit FENO group

Visit

Pijnenburg M et al. Am J Respir Crit Care Med. 2005;172(7):831-836.

FENO Measurements Provide a Method of Adjusting ICS Dose

P=.27 Rate of exacerbations (no. of patients/y) 1.2 1.0 0.8 0.6 0.4 0.2 0.0 Total

P=.24

P=.91 750 Fluticasone dose (mcg/day) 500

P=.36

P=.003

P=.003

250 0.0

Minor

Major FENO group

Study entry

End of phase 1 End of phase 2 (final visit) (optimal dose)

Exacerbations
Control group
Smith AD et al. N Eng J Med. 2005;352(21):2163-2173.

Flow rate = 250 mL/s

FENO Predicts Asthma Relapse After Discontinuation of ICS


FENO levels > 49 ppb 4 weeks after steroid removal were highly indicative of asthma relapse

1.00 49 ppb 0.75


FENO 24 FENO 49 FENO 7

Sensitivity

0.50
FENO 58

Sensitivity: 71% Specificity: 93%

0.25

0.00 0.00

0.25

0.50

0.75

1.00

Flow rate = 50 mL/s

1-Specificity
Pijnenburg MW et al. Thorax. 2005;60(3):215-218.

FENO Facilitates Early Identification of Noncompliance

Reduction in exhaled NO (%)

100 P=.0003 R=0.77

50

-50 25
50

75

100

Compliance with BUD (% of prescribed)


Beck-Ripp J et al. Eur Respir J. 2002;19(6):1015-1019.

Exhaled nitric oxide and asthma control: a longitudinal study N=347


BDP< 500 mcg

BDP> 500 mcg

cut-off value of 40% change in FENO

Michils ERJ December 5, 2007

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 2006;129:1492-1499

ROC curve for FEV1 percentage of predicted for first asthma exacerbation

Flow rate 100 ml/sec

Gelb, Chest 2006;129:1492-1499

Use of Exhaled Nitric Oxide to Guide Asthma Management


N=118 asthmatics
30
No. of Exacerbations

19 patients, 26 exacerbations
12 patients, 18 exacerbations

20

10
P=0.43

0
0 3 6 9 Time elapsed (months) 12
Control group FENO group

Shaw DE et al. Am J Respir Crit Care Med. 2007;176(3):231-237.

**

Use of Exhaled Nitric Oxide to Guide Asthma Management


N=47 mild to moderate asthma FENO group (n=22) control group (n=25)
1.0 0.9 0.8 0.7 0.6

22.9 ppb

Sensitivity

0.5 0.4 0.3 0.2 0.1 0.0


0.1 0.2 0.3

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
0.4 0.5 0.6 0.7 0.8 0.9 1.0

1 - Specificity
Fritsch M et al. Pediatr Pulmonol. 2006;41(9):855-862

PCD nasal NO
Wodehouse, ERJ 2003; 21: 4347

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 30.0 30

FENO (ppb)

FENO (ppb)
130 150 170 190

25.0 20.0 15.0 10.0 5.0 0.0

25 20 15 10 5 0

110

10

12

14

16

18

Height (cm)

Age (years) Predicted FENO 95% prediction intervals


*

Malmberg LP et al. Pediatr Pulmonol. 2006;41(7):635-642. Buchvald F et al. J Allergy Clin Immunol. 2005;115(6):1130-1136.

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
NOPLAT % lowest flow ( s.e.m)
100.0 80.0 60.0

40.0 20.0
0.0 1.0 10.0 100.0 1000.0 10000.0

Flow mL/sec
Silkoff PE et al. Am J Crit Care Med. 1997;155:260-267.