NLHEP

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NO NO NO NO NO NO NO
Oh, mama mia, mama mia, mama mia, let me go
Freddy Mercury, 1975
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Analysis of Exhaled Nitric Oxide for Patients
with Asthma

• Paul Enright, MD
• The University of Arizona
• LungGuy_at_AOL.com

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Outline

• Background
• Indications
• Methods
• Interpretation
• Summary
• References

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Background

• 1991 eNO first measured by Gustafsson
• 1993 eNO found elevated in asthmatics
• Kjell Alving Karolinska Institute
• Guidelines
• 1997 ERS
• 1999 ATS
• 2005 ATSERS
• gt1200 eNO publications

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eNO FENO
0.05

• eNO is an index of eosinophilic airway
  inflammation.
• eNO is not increased with bronchospasm.

The abbreviation for ivory tower
physiologists Fraction of exhaled nitric oxide at
a flow of 50mL/sec
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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)

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A high eNO confirms asthma in children with
recurrent wheeze
Normal range 5-30 ppb
Saito J, JACI 2005
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Asthma vs. COPD
A few COPD patients also have eosinophilic
inflammation. A few asthma patients have no
eosinophilic inflammation.
Fabbri, AJRCCM 2003
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eNO remains normal during COPD exacerbations
Normal range 5-30 ppb
Maziak, AJRCCM 1998
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eNO gt50ppb predicts ICS responsemuch better than
does spirometry

• Hi

Optimal eNO cut-point
FEV1 BD Response
ROC curve from Smith, AJRCCM 2005
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ICSs suppress airway inflammation,so eNO falls
rapidly with ICS therapy.
Poor asthma control Yellow-orange zone
placebo
100 µg/day
Good asthma control Green zone
400 µg/day
7 days on ICS
7 days off ICS
Kharitonov, ERJ 2000
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ICS dose eNO response
Beclomethasone QVAR DPI
low med high daily ICS dose
ICS naive
Silkoff, Chest 2001
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A reduction in eNO suggests good compliance with
ICS therapy
eNO fell in half

Good
Poor
ICS Compliance
Beck-Ripp, ERJ 2002
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eNO to titrate ICS dosewhile maintaining good
asthma control
A high daily ICS dose whilst following NAEP
guidelines
Smith, NEJM 2005
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Future Indications

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

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Singulair pills lower eNO in some patients with
asthma
one week
Sandrini, Chest 2003
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Singulair vs.ICS responses

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

• Bronchial responsiveness
• Methacholine PC-20
• Eosinophils (count and )
• Induced Sputum
• Blood
• BAL and lung biopsy
• Lung function (FEV1)

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eNO correlates with airway biopsy indices of
inflammation
21 ICS-naive adolescents with asthma
Symptomatic
no symptoms
ppb
MBP major basic protein
Van den Toorn AJRCCM 2001
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Good correlations with blood IgE
An epi study of 278 Japanese school children
Saito J, JACI 2005
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Poor correlation with FEV1
Saito J, JACI 2005
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Advantages of eNO

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

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Disadvantages

• Expensive instrument
• No reimbursement (yet)
• Doesnt measure bronchospasm

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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)

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Online eNO sampling assembly
Filter removes Ambient NO
Exhalation resistor
Ambient air inspired
Sample to NO analyzer
to pressure gauge for feedback
mouthpiece
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eNO signals during testing
5-20cmH2O
50 mL/sec
Ignore the peak
Report the plateau value
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Offline eNO sampling
Tedlar or Mylar bacteria-free balloon
Measure samples within 12 hours.
Its okay to include dead space exhalate
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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

ATSERS 2005
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Step-by-step testing sequence

1. Dont use nose-clips
2. Deep inhalation of NO-free air
3. Dont pause at TLC
4. Slow exhalation for gt6 seconds
5. Discard dead space
6. Wait gt30sec, repeat 2 or 3 times

3 sec okay for preschool kids
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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

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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

ATSERS 2005
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Effect of exhalation flow
eNO will be underestimated if the subject exhales
too fast.
standard target
ATSERS 2005
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Effect of recent smoking
eNO will be underestimated if the subject was
smoking recently
Robbins, Chest 1995
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3ppb short-term repeatability

• No learning effect
• No diurnal variation

Kharitonov, ERJ 2003
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Repeatability children vs adults
The eNO coefficient of variability (CV) is about
5 in healthy adults and about 10 in children.
Your name here
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Instruments

• Chemiluminescence
• Sievers (now GE Analytical, USA)
• Aerocrine NIOX (Sweden)
• Eco Medics (Switzerland)
• Logan Research (UK)
• Electrochemical (very new)
• Hand-held, no vacuum pump
• Cant measure multiple rates

NIOX
Enrights conflict of interest statement Aerocrin
e bought dinner for me 3 times
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Instrument Specifications

• Sensitivity 1 ppb
• Accuracy better than 1 ppb
• Repeatability better than 1 ppb
• Range 1-500 ppb
• Signal to noise better than 31

ATSERS guidelines 2005
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Instrument differences
EcoMedics CLD88
L, M, H were 3 German biologic control
subjects, tested once per day after a
re-calibration
Differences due to calibration procedures
Muller KC, Respir Med 2005
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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.

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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
• gt30ppb indicates out-of-control asthma
• lt5ppb (very low) may indicate PCD
• Normal values increase with age in children

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eNO in healthy children
Upper limit of the normal range
Mean values
Buchvald 2003
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Response rates to ICS therapy
eNO begins to fall within 3-5 days
Methacholine
FEV1
Saito J, JACI 2004
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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

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Nasal NO during humming detects sinus blockage
Very high nasal NO from sinuses during humming
Low nasal NO with blocked sinus drainage
Maniscalso, ERJ 2003
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Recommended Reading

• ATSERS guidelines, AJRCCM 2005 171912
• Kharitonov SA, Swiss Med Wkly 2004 134 175
• Smith AD, Curr Opin Allergy Clin Imm 2005 549
• Malmberg LP, J Asthma 2004 41511
• Smith AD, NEJM 2005 352(21)2163
• Aerocrine, Scientific Backgrounder booklet, 2005