NONO

NONO

NONO

NO

Oh, mama mia, mama mia, mama mia, let me go

Freddy Mercury, 1975

Analysis of Exhaled Nitric Oxide for Patients with

Asthma

Paul Enright, MDThe University of Arizona

LungGuy@AOL.com

Outline

Background Indications Methods Interpretation Summary References

Background

1991 – eNO first measured by Gustafsson 1993 – eNO found elevated in asthmatics

Kjell Alving – Karolinska Institute

Guidelines 1997 ERS 1999 ATS 2005 ATS+ERS

>1200 eNO publications

eNO is an index of eosinophilic airway inflammation.

eNO is not increased with bronchospasm.

eNO = FENO *

* The abbreviation for ivory tower physiologistsFraction of exhaled nitric oxide at a flow of 50mL/sec

0.05

Indications

Confirm asthma Differentiate asthma from COPD Guide inhaled corticosteroid therapy

Predict ICS response (& non-response)

Monitor ICS compliance Titrate ICS daily dose (step-up, step-down)

A high eNO confirms asthma in children with recurrent wheeze

Normal range5-30 ppb

Saito J, JACI 2005

Asthma vs. COPD

A few COPD patients also have eosinophilic inflammation.A few asthma patients have no eosinophilic inflammation.

Fabbri, AJRCCM 2003

eNO remains normal during COPD exacerbations

0

10

20

p<0.001

p<0.01

Smokers COPD

Exh

aled

NO

(p

pb

)

stable unstable

Normal range5-30 ppb

Maziak, AJRCCM 1998

eNO >50ppb predicts ICS response

much better than does spirometry

Hi

ROC curve from Smith, AJRCCM 2005

OptimaleNO

cut-point

FEV1 BDResponse

ICSs suppress airway inflammation,so eNO falls rapidly with ICS therapy.

100 µg/day

400 µg/day

placebo

Kharitonov, ERJ 2000

7 days on ICS 7 days off ICS

Good asthma controlGreen zone

Poor asthma controlYellow-orange zone

ICS dose : eNO response

Silkoff, Chest 2001

BeclomethasoneQVAR DPI

low – med – highdaily ICS dose

ICSnaive

A reduction in eNO suggests good compliance with ICS therapy

eNO fell in half

Beck-Ripp, ERJ 2002

Good %Poor

ICS Compliance

eNO to titrate ICS dosewhile maintaining good asthma

control

Smith, NEJM 2005

A high daily ICS

dosewhilst

following NAEP

guidelines

Future Indications

Guide prednisone tapers Determine Singulair efficacy ? Determine chronic cough cause Epidemiological surveys Occupational asthma

surveillance

Singulair pills lower eNO in some patients with asthma

Sandrini, Chest 2003

one week

Singulair vs.ICS responses

Szefler AJRCCM 2005. CARE, a multi-center, NIH-funded study

• 55% no response• 17% respond to both• 23% respond only to ICS (predicted by higher eNO)• 5% respond only to Singulair 126 children with mild to moderate asthma, crossover, 8 wk study

Correlates

Bronchial responsiveness Methacholine PC-20

Eosinophils (count and %) Induced Sputum Blood BAL and lung biopsy

Lung function (FEV1)

eNO correlates with airway biopsy indices of inflammation

Van den Toorn AJRCCM 2001

Symptomatic

no symptoms

MBP = major basic protein

ppb

21 ICS-naive adolescentswith asthma

Good correlations with blood IgE

Saito J, JACI 2005

An epi study of 278 Japanese school children

Poor correlation with FEV1

Saito J, JACI 2005

Advantages of eNO

Immediate results A painless and easy maneuver Effort independent Entirely safe No sample processing Predicts and measures ICS

response

Disadvantages

Expensive instrument No reimbursement (yet)

Doesn’t measure bronchospasm

Methods

On-line Single, slow exhalations Multiple exhalations

with 5 different flows (MEFT) central versus peripheral

5 minute tidal breathing

Off-line Nasal NO (+ humming for sinusitis)

Online eNO sampling assembly

mouthpiece

Ambient air inspired

Exhalation resistor

Sample to NO analyzer

to pressure gauge for feedback

Filter removesAmbient NO

eNO signals during testing

5-20cmH2O

50 mL/sec

Ignore the peak

Report the plateau value

Offline eNO sampling

Tedlar or Mylarbacteria-freeballoon

It’s okay to include dead space exhalate

Measure samples within 12 hours.

Pre-test preparations

Avoid ETS exposure for 2 hours Avoid meals, drinks, smoking, exercise for 1

hr No spirometry or BD in prior 30 min Determine smoking status

Any cigarettes in last week? Consider exhaled CO confirmation

Determine asthma controller use Ask about recent viral URIs Ask ICS, Singulair, & prednisone last 2 weeks

ATS+ERS 2005

Step-by-step testing sequence

1. Don’t use nose-clips

2. Deep inhalation of NO-free air

3. Don’t pause at TLC

4. Slow exhalation for >6 seconds *

5. Discard dead space

6. Wait >30sec, repeat 2 or 3 times

* 3 sec okay for preschool kids

Quality Assurance

Verify analyzer accuracy daily 100-400ppb calibration gas

Exclude nasal and sinus NO Maintain back-pressure of 5-20cmH2O Display target pressure (display or gauge) Dynamic resistor preferred

Discard dead space gas if on-line Report mean value during flat plateau

Quality Assurance (continued)

Maintain target exhalation rate Standard: 50 mL/sec

Repeat maneuvers until eNOs match Goal: 3ppb or 5% match

Report the mean eNO and flow Rates of acceptable results

70% children ages 4-8 90% adults

ATS+ERS 2005

Effect of exhalation flow

eNO will be underestimated if the subject exhales too fast.

standardtarget

ATS+ERS 2005

Effect of recent smoking

eNO will be underestimated if the subject was smoking recently

Robbins, Chest 1995

3ppb short-term repeatability

Kharitonov, ERJ 2003

• No learning effect• No diurnal variation

Repeatability: children vs adults

The eNO coefficient of variability (CV%)is about 5% in healthy adults and about 10% in children.

Your name here

Instruments

Chemiluminescence Sievers (now GE Analytical, USA) Aerocrine NIOX (Sweden) * Eco Medics (Switzerland) Logan Research (UK)

Electrochemical (very new) Hand-held, no vacuum pump Can’t measure multiple rates

Enright’s conflict of interest statement:Aerocrine bought dinner for me 3 times

NIOX

Instrument Specifications

• Sensitivity: 1 ppb• Accuracy: better than 1 ppb• Repeatability: better than 1 ppb• Range: 1-500 ppb• Signal to noise: better than 3:1

ATS+ERS guidelines 2005

Instrument differences

Muller KC, Respir Med 2005

“Differences due to calibration procedures”

L, M, & H were 3 German biologic control subjects, tested once per day after a re-calibration

EcoMedics CLD88

Reimbursement

Aerocrine obtained FDA 510k pre-marketing approval for its NIOX model in 2003.

An AMA-CPT code for the test was awarded Dec 2005, with reimbursement expected 2007.

Meanwhile, you can charge patients directly for the test.

Interpretation

Consider the pre-test probability Consider the major confounders

Cigarette smoking Asthma controller medication use Nitrate-rich diet

High or low values may be abnormal >30ppb indicates out-of-control asthma <5ppb (very low) may indicate PCD Normal values increase with age in children

eNO in healthy children

Upper limit of the normal range

Mean values

Buchvald 2003

Response rates to ICS therapy

eNO begins to fall within 3-5 days

FEV1

Methacholine

Saito J, JACI 2004

Summary

eNO measures allergic airway inflammation

eNO is a fast, safe, & easy test eNO is standardized and highly repeatable eNO determines ICS need and response In asthma, eNO is complementary to FEV1

Nasal NO during humming detects sinus blockage

Maniscalso, ERJ 2003

Very high nasal NO from sinuses during humming

Low nasal NO with blocked sinus drainage

Recommended Reading

ATS+ERS guidelines, AJRCCM 2005; 171:912 Kharitonov SA, Swiss Med Wkly 2004; 134: 175 Smith AD, Curr Opin Allergy Clin Imm 2005; 5:49 Malmberg LP, J Asthma 2004; 41:511 Smith AD, NEJM 2005; 352(21):2163 Aerocrine, “Scientific Backgrounder” booklet, 2005