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Using exhaled nitric oxide to guide

management in chronic asthma

Professor D Robin Taylor

Dunedin School of MedicineUniversity of Otago

New Zealand

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The performance characteristics of FENO

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100504030201054321.5.4.3.2.1

100

80

60

40

20

10

8

6

4

2

FENO

(ppb

)at250mL/s

r = 0.62,

p

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Predictive value of FENO

for eosinophilia

Berry et al. 2005

N = 566 adults

Stable asthma

Smokers excluded

20 ppb

Sensitivity 71%

Specificity 72%

Warke et al. 2002

N = 71 children

Asthma / non-asthma

9 taking ICS

Sensitivity 81%

Specificity 80%

SPUTUM EOS. >3% BAL EOS. >0.87%

17 ppb

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Reference Subjects Results ppb

Van der Lee,

2002

Non-atopic adults

(n=117)

2 SD above mean Females

Males

21.3

31.2

Kharitonov et

al. 2003

Mixed population

of adults andchildren (n=59)

Upper limit for All

95% C.I. AdultsChildren

31.4

33.134.0

Olin et al.

2004

Healthy adults

(n=230)

90th centile All

Atopy

Non-atopic

Healthy with rhinitis

32.5

40.2

30.5

31.8

Buchvald et

al. 2005

Healthy children

(n=405)

Upper limit for age 4

95% C.I. age 14-17

15.7

24.3

Normal values for FENO: healthy subjects

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Interpreting changes in FENO

Stat ist ically sign if icant changes FENO is highly reproducible [ICC 0.99]

CV ranges from 10% in healthy and to 26% in asthmaticsubjects

Ekroos et al Respir Med 2002; Kharitonov et al. ERJ 2003

Clin ical ly sign i f icant changes

Mean change with withdrawal or introduction of ICS:16 ppb

Beck-Ripp et al. ERJ 2002

Mean change from control to loss of control: +25 ppbbut ranging from -10 to 141 ppb

60% increase had best predictive values for imminentexacerbation

Jones et al. AJRCCM 2001

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Low FENO less than 25 ppb (adults),

(20ppb, children)

Eosinophilic airway inflammation unlikely

Steroid requirement unlikely

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Reference values for FENO

All Atopic (179) Non-atopic (67)

n Mean 95% C.I. Mean 95% C.I. Mean 95% C.I.

Without

rhinitis

or

asthma

170 19.3 17.5, 21.1 21.6 16.5, 26.7 18.7 16.8, 20.6

Rhinitis

only

27 24.6 17.4, 31.8 36.2 19.8, 52.6 17.8 14.0, 21.6

Asthma

only

49 33.1 22.6, 43.6 46.6 32.7, 60.5 20.2 16.3, 24.1

Anna Olin. Personal communication

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Predicting relapse of asthma after ICS

withdrawal: interpretation of low FENO

Sens. Spec. PPV NPV

BHR 63.6 59.5 31.8 84.6

Eosinophils

>0% 100 51.0 41.0 100

>3% 54.5 84.8 46.1 78.7

FENO

>22ppb 78.6 68.6 44.0 92.5>35ppb 71.4 82.4 52.6 91.3

n = 40 children

ICS dose: 200-

500g/dayDose reduced by 50%

every 8 weeks

30% weaned off ICS

38% lost control

Conclusion: low FENO (

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Smith et al.: subgroup analysisPatients with FENO less than 33ppb

throughout study

Convent ional strategy group

N = 35 / 49

Mean dose increaseof

231 g/day FLU

FENO strategy group

N = 14 / 48

Mean dose reduct ionof

289 g/day FLU

Conclusion: consistently low FENO enables steroid

unresponsive airways disease to be identified

Dose difference between groups = 520 g/day FLU

No difference between groups in exacerbation rates orPC20 methacholine

Smith et al., NEJM, 2005

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Smith et al. unpublished data

Relationship between dysfunctional

breathing and ICS dose requirements

N=45

p=0.04

FENO group Conventional group

0

10

20

30

40

50

100 250 500 10000 7500

10

20

30

40

50

100 250 500 10000 750

------------------------ -----------------------

N=46

p=0.31

Nijmegen

score

Nijmegen

score

N=45

p=0.04

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Low FENO

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Low FENO

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High FENO greater than 45ppb (adults),

(40ppb children)

Eosinophilic airway inflammation likely

Steroid response likely

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Reference values for FENO

All Atopic (179) Non-atopic (67)

n Mean 95% C.I. Mean 95% C.I. Mean 95% C.I.

Without

rhinitis

or

asthma

170 19.3 17.5, 21.1 21.6 16.5, 26.7 18.7 16.8, 20.6

Rhinitis

only

27 24.6 17.4, 31.8 36.2 19.8, 52.6 17.8 14.0, 21.6

Asthma

only

49 33.1 22.6, 43.6 46.6 32.7, 60.5 20.2 16.3, 24.1

Anna Olin. Personal communication

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-5

0

5

10

15

20

25

-5

0

5

10

15

20

25

-3

-2

-1

0

1

2

-1

0

1

2

3

4

5

Peak flow (percent change)

PC20 AMP (d.d.shift)

Composite symptom score

FEV1 (percent change)

47

Baseline FENO (ppb)

47

Baseline FENO (ppb)

Relationship between FENO and steroid

responsiveness

Smith et al.AJRCCM, 2005

FLU minus

PLACEBO

PLACEBO

FLU

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Predicting steroid response:

increase in FEV1 > 12%

Predictor Cut-point Sens. Spec. PPV NPV

FENO >47ppb* 67 78 47 89

PD20MCh 20% 0 97 NA 76

FEV1%pred 12% 8 95 33 78

* Based on ROC curve analysis, not tertiles Smith et al. AJRCCM, 2005

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Predicting relapse of asthma after ICS

withdrawal: interpretation of high FENO

N = 40 children, clinically stable asthma

ICS discontinued: followed at -2, 0, 2, 4, 12 and 24weeks

Relapse, n = 9: median time to relapse 36 days Mean FENO increased from:

14.8ppbat baseline [10.5ppb]

to 35.3ppb @ 2 weeks [15.7ppb]

to 40.8ppb @ 4 weeks [15.9ppb]Figures in brackets = non-relapsers

Optimum FENO49ppb. PPV 71%; NPV 93%

Pijnenburg et al., 2005

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High FENO >45ppb or sputum eos. >2%

[or rising FENO: >60% change]

= uncontrolled eosinophilic airway

inflammation

In a symptomaticpatient

Poor compliance with ICSand/or ? poor inhaler technique

Inadequate ICS dose: likely to respond toincrease OR ?prednisone ?omalizumab

Rarely: truly steroid resistant asthma

Rarely: Churg Strauss syndrome

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High FENO >45ppb or sputum eos. >2%

[or rising FENO: >60% change]

= uncontrolled eosinophilic airway

inflammation

In an asymptomaticpatient

No change in ICS dose, but refer to

history of individual patient

Withdrawing ICS is likely to be followed by

relapse

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Intermediate FENO levels: 25 to 45 ppb

= cautious interpretation

IfSYMPTOMATIC, consider

? infection as reason for clinical deterioration

high levels of ongoing allergen exposure

adding in other therapy apart from ICS e.g.

LABA

ICS dose increase if receiving combination

therapy

IfASYMPTOMATIC

no change in ICS dose if patient is stable

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FENO in steroid dependent asthma

Sliding scale for oral prednisone dose -

based on two-weekly FE

NO measurements

Example only: individualized algorithm required

FENO less than 30 ppb reduce by 5 mg/day

FENO 30 to 50 ppb no change

FENO above 50 ppb increase to 40 mg/day

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Conclusions: interpretation

1. FENO may be used as a surrogate marker foreosinophilic airway inflammation, but it is not a perfecttest

2. In asthma, high (>45ppb) and low (

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Conclusions: application

1. Has a role in the management of difficult

asthma low levels indicate that adding or

increasing steroid therapy is unlikely to be

helpful

2. Role in routine ICS dose adjustment especially

mild asthma / primary care still to be defined

3. Results are almost useless in current smokers

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Acknowledgements

Research fellows

Andrew Smith

Stuart Jones

Bob Hancox

Statisticians

John Kittelson

Peter Herbison

Research technicians

Jan Cowan

Karen Brassett

Erin Flannery

Chest Clinic staff

Chris McLachlan,

Sue Filsell,

Gabrielle Monti-Sheehan,Pamela Jackson,

Carol Fitzgerald,Ruth Gardiner

Financial support

Glaxo Smith Kline

Health Research Council NZ

University of Otago (ORG),

Otago Medical ResearchFoundation

Lotteries Grants Board

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Otago Peninsula, South Island, New Zealand

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Effect of smoking on sp t m cell

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Asthmatic

Nonsmokers

Asthmatic

Smokers

n 36 31

Neutrophils,

106/mL

3.2

(0.87)

9.1

(6.917.8)***

Eosinophils,

106/mL

0.35

(0.050.76)

0.09

(00.26)*

Neutrophils, % 23 (1648) 47 (3463)**

Eosinophils, % 3.6 (0.86.3) 0.4 (01.0)***IL-8

pg/mL

660

(4861,045)

945

(7012,482)**

Chalmers et al. Chest, 2001

Effect of smoking on sputum cell

profiles in patients with asthma

* p

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ICS dose titration using FENO

measurements

0

10

20

30

40

50

0 100 250 500 750 1000

0

10

20

30

40

50

0 100 250 500 750 1000

FENO group, n=46 Conventional group, n=48

Fluticasone g/day Fluticasone g/day

Median: 100g/dayMean: 370g/day

Median: 750g/dayMean: 641g/day

p = 0.008 for between group comparisons

% patients

Smith et al. NEJM 2005

% patients

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Green et al.: subgroup analysisPat ients w ith sputum eos .