Pulmonary function test, bronchial challenge test, and FeNO.pdf

Pulmonary function test
Bronchial challenge test & FeNO
Yada Sirisa, MD
Division of Allergy, Immunology and Rheumatology Unit
Departement of Pediatrics, King Chulalongkorn Memorial Hospital

Outline
• Spirometry
• Lung volumes
• Diffusing capacity for carbon monoxide
• Peak expiratory flow rate
• Bronchial challenge test
• Fractional exhaled nitric oxide (FeNO)

Spirometry
Physiological test: measures the maximal volume of air that an individual
can inspire and expire with maximal effort
Indications for spirometry
• Diagnosis
• Monitoring
• Disability/impairment/dysfunction of respiratory systems evaluations
• Other
Graham BL, et al.Am J Respir Crit Care Med. 2019 Oct 15;200(8):e70-e88.

Indication for Spirometry
Diagnosis Monitoring
• Evaluate symptoms, signs, or abnormal
laboratory test results
• Measure the physiologic effect of disease
or disorder
• Screen individuals at risk of having
pulmonary disease
• Assess preoperative risk
• Assess prognosis
• Assess response to therapeutic
intervention
• Monitor disease progression
• Monitor patients for exacerbations of
disease and recovery from exacerbations
• Monitor people for adverse effects of
exposure to injurious agents
• Watch for adverse reactions to drugs with
known pulmonary toxicity

Indication for Spirometry
Disability/impairment evaluations Other
• Assess patients as part of a rehabilitation program
• Assess risks as part of an insurance evaluation
• Assess individuals for legal reasons
• Research and clinical trials
• Epidemiological surveys
• Derivation of reference equations
• Preemployment and lung health
monitoring for at-risk occupations
• Assess health status before beginning
at risk physical activities

Relative contraindications for spirometry
• Increases in myocardial demand or changes in blood pressure
• Increases in intracranial/intraocular pressure
• Increases in sinus and middle ear pressures
• Increases in intrathoracic and intraabdominal pressure
• Increases in intrathoracic and intraabdominal pressure

Increases in myocardial demand
Changes in blood pressure
Increases in intracranial
Intraocular pressure
• Acute myocardial infarction within 1 wk
• Systemic hypotension or severe hypertension
• Significant atrial/ventricular arrhythmia
• Non compensated heart failure
• Uncontrolled pulmonary hypertension
• Acute cor pulmonale
• Clinically unstable pulmonary embolism
• History of syncope related to forced expiration/cough
• Cerebral aneurysm
• Brain surgery within 4 wk
• Recent concussion with continuing
symptoms
• Eye surgery within 1 wk

Increases in sinus/ middle ear pressures Infection control issue
• Sinus, middle ear surgery or infection within 1 wk • Active or suspected transmissible
respiratory or systemic infection,
including tuberculosis
• Physical conditions predisposing to
transmission of infections, such as
hemoptysis
• Significant secretions, or oral lesions or
oral bleeding
Increases in intrathoracic
Intraabdominal pressure
• Presence of pneumothorax
• Thoracic surgery within 4 wk
• Abdominal surgery within 4 wk
• Late-term pregnancy

Equipment
Volume displacement spirometer
• Water seal spirometer
• Dry rolling seal spirometer
• Bellows-Type Spirometers
Flow-sensing spirometer
• Pneumotachometer or pressure differential type
• Thermistor, hot-wire anemometer
• Turbine flow sensor
• Ultrasonic flow sensor

Prepare the patient
Activities should be avoided
• Smoking and/or vaping and/or water pipe use within 1 hr
• Consuming intoxicants within 8 hr
• Performing vigorous exercise within 1 hr
• Wearing clothing that substantially restricts full chest and abdominal expansion
Age of test: at least 5-6 years and depend on
• Ability to perform maneuver follow command
• Able to take deep breaths, cough and blowout forcefully

Withholding some medication

1. Have patient assume the correct posture
2. Attach nose clip, place mouthpiece in mouth, and close lips around the mouthpiece
3. Breathe normally
4. Inspire completely and rapidly with a pause of ≤ 2 sec at TLC
5. Expire with maximal effort until no more air can be expelled
6. Inspire with maximal effort until completely full
7. Repeat instructions as necessary, coaching vigorously
8. Repeat for a minimum of three maneuvers, usually no more than eight for adults
9. Check FEV1 and FVC repeatability and perform more maneuvers as necessary
Procedures for spirometry

• Acceptability and Repeatability of test
• Flow volume loop
• Parameter
• FVC
• FEV1
• FEV1/FVC ratio
• FEF25-75%
• Airway reactivity test
Interpretation

Acceptability and Repeatability of test

Acceptability: Good start of test
UAO or NMD are often unable to
initiate a rapid increase in flow, and
the BEV limit may be exceeded
BEV <5% of FVC or 0.100 L

Acceptability: No unsatisfied flow-volume curve

Repeatability
Age > 6 years
• The difference between
the two largest FEV1, FVC
values must be ≤ 0.150 L
Age ≤ 6 years
•The difference between the
two largest FEV1, FVC
values must be ≤ 0.100 L or
≤ 10% of the highest value,
whichever is greater

Parameter
FVC Disease with low FVC
• Maximal volume of air exhaled with maximally
forced effort from a maximal inspiration
• Depend on effort and adequate exhalation
• Restrictive lung disease from chest wall,
respiratory muscle, lung parenchyma
• Severe airflow obstruction with air trapping
• Inadequate exhalation

Parameter
FEV1 Disease with low FEV1
• Maximal volume of air exhaled in the 1st second of a
forced expiration from a position of full inspiration
• Good correlation with PEFR
• Good for diagnosis, follow up and evaluate reversibility
• Obstructive lung disease
• Restrictive lung disease from chest wall,
lung parenchyma, respiratory muscle
• Increase age, poor effort

Parameter
FEV1/FVC ratio
• More sensitive than FEV1 for detecting mild airway obstruction
• Advantage for diagnose obstructive lung disease

Parameter
FEF 25-75%
• Mean forced expiratory flow between 25% and 75% of the FVC
• Indicative of the status of the medium to small airway
• Reduced mid-expiratory flow = nonspecific to small airway
o Variable even in normal patients
o Perform the FVC maneuver inadequately often show widely varying FEF 25-75%
Calculated by
determining the slope of
the line drawn connecting
points on the spirogram
at 25% to 75% of
expiratory vital capacity

Parameter
Normal Dysfunction
Parameter Predicted value Obstructive Restrictive
FVC ≥80% Normal or ↓ ↓
FEV1 ≥80% ↓ Normal or ↓
FEV1/FVC ≥80% ↓ Normal or ↑
FEF25-75% ≥70% ↓ Normal , ↑, ↓
PEFR ≥80% ↓

Parameter
Severity
Parameter Obstructive (FEV1)
Normal ≥ 80%
Mild 60-79%
Moderate 40-59%
Severe < 40%

Bronchodilator responsiveness testing
Eur J Med Res, 2009: 170-176
• Determination of the degree of improvement of airflow in response to
bronchodilator administration: changes in FEV1 and FVC

Eur Resp J 2005
• Three acceptable tests of FEV1, FVC and PEF recorded
• The drug is administered in the dose and by the method indicated for the test
• Three additional acceptable tests are recorded ≥10 min and up to 15 min later for short-
acting B2-agonists, and 30 min later for short- acting anticholinergic agents

Eur Resp J 2005
Parameters
Minimum significant changes
From baseline (%)
FVC +10
FEV1 +12
FEF25-75% +25
PEFR +12

Lung Volume
• Body plethysmography (Body Box)
• Gas dilution or wash out technique
- Closed circuit helium dilution
- Opened circuit nitrogen washout
• Imaging techniques
- Conventional radiograph
- CT
- MRI
Wanger J, et al. Eur Respir J 2005 26: 511-522

Lung Volume
Gas dilution or wash out technique
• Measure lung volumes only communicating airway
• Underestimated lung volume in the presence of moderate or severe obstruction
- Nitrogen trapped in alveoli supplied by closed airways cannot be washed out
- Helium cannot enter alveoli supplied by closed airways
• Overestimated lung volume in case leak in breathing circuit

Closed circuit helium dilution
Inert, insoluble gas
Not present in the human body
Not cross alveolar capillary membrane
• A spirometer is filled with a mixture of 10% He in air
• The patient breathes for 30-60 secs on mouthpiece
• Starting precisely at the end-normal tidal expiration
• Patient begin to breath from the closed spirometer system
• Regular rebreathing pattern
• Rebreathing until equilibrium (rarely exceeds 10 min)
Helium

Opened circuit nitrogen washout
• The patient breathes for 30-60 s on mouthpiece
• Starting precisely at the end-normal tidal expiration (at FRC)
• Switched into the circuit so that 100% O2
• The N2 concentration is monitored during the washout
• Complete when the N2 concentration is < 1.5% for at least three successive breaths
• A change in inspired N2 of >1% or sudden large increases in expiratory N2
concentrations indicate a leak
• The test should be stopped and repeated after a 15 min period of breathing room air
• Washout time should be report(appropriate < 7 min)
• If more than one measurement of FRC N2 acceptable results that agree within 10%

Imaging Technique
Conventional radiographs
• Required PA and lateral
• Must be breath hold to TLC
• Not accurate in the presence of diffuse,
space-occupying disease
Computed tomography
• Radiation exposure
• Cost
• Must be breath hold to TLC
• Underestimate in airway obstruction
Magnetic resonance imaging
• No radiation exposure
• Very costly
• Research only

Lung volumes
Ruppel's Manual of Pulmonary Function Testing, 11th Edition

Interpretation
• Obstructive lung disease: FEV1/FVC < 5th percentile of predicted (spirometry)
• Restrictive lung disease: TLC < 5th percentile of predicted (lung volume)
• Mixed: FEV1/FVC and TLC < 5th percentile of predicted
Severity of dysfunction
Severity
Obstructive
(FEV1) (%)
Restrictive
(TLC) (%)
Normal ≥ 80 ≥ 80
Mild 60-79 70-79
Moderate 40-59 50-69
Severe < 40 < 50

Fick’s law of diffusion
West’s Respiratory Physiology The Essentials 10th Edition
Rate of diffusion
• Proportional to area (A)
• Inverse proportion to thickness (T)
• Diffusion constant (D)
• Partial pressure difference (P1-P2)
Diffusion constant
•Proportional to solubility of gas
•Inverse proportional to square root of molecular weight

Diffusion capacity of lungs for CO (DLCO)
Pulmonary physiology-Michael G. Levitzky 2017
Diffusion capacity of lungs for CO
• Measure of gas transfer across the alveolar-
capillary membrane
• CO: high affinity for hemoglobin, 210 times of O2
• CO: not contribute to the partial pressure of carbon
• Monoxide in the blood > diffusion-limited
DLCO varies with
• Age, sex, and height
• Normal value = 20-30 ml/min/mmHg

Acceptable DLCO maneuvers
ERS/ATS standards for single-breath carbon monoxide uptake in the lung 2017

Measurement of diffusing capacity
• Normal DLCO 80-120% of predicted
• Diffusion defect: grades of severity in DLCO reduction
Grading DLCO (%predicted)
Normal 80-120
Mild 60-80
Moderate 40-60
Severe < 40

Slide courtesy from Natchaya Thaiyanon

Peak expiratory flow rate
Dobra R, et al. Arch Dis Child Educ Pract Ed. 2018 Jun;103(3):158-162
• PEFR is the maximum rate of flow in forced expiration starting from full inspiration
• Occurs within the first 200 ms of expiration
• Measured in liters per minute
• PEFR not only reflects airway caliber but also muscle strength and voluntary effort

Peak flow meter
• Peak flow is technique and cooperation dependent
• Most children over 5 years old
• Not suitable for children who lack coordination, are unable to understand the
instructions or have poor muscle strength

Procedure
1. Ensure correctly fit mouthpiece is used
2. Make sure the indicator is at 0 (the bottom)
3. Stand or sit up straight
4. Take a deep breath in and hold it
5. Place the mouthpiece in your mouth and close your lips
around it to make a seal and make sure your tongue is
away from the opening of the mouthpiece
6. Blow out as hard and as fast as possible
7. Remove the meter and breathe normally
8. Note the number that appears on the meter

Serial measurements of PEFR: essential
• Monitoring, not diagnostic
• Single value is of very limited use
• Highly effort dependent
• Height variation
Asthma: age > 5yr, moderate to severe
>> Consider long-term daily peak flow monitoring:
• Moderate or severe persistent asthma
• History of severe exacerbations
• Patients who poorly perceive airflow
obstruction and worsening asthma
Polgar G, et al. Philadelphia, 1971

Diurnal variation of PEFR
Diurnal variability of > 20% for at least 3 days
in a week: marker of poor control

Airway Hyperresponsiveness
Middleton’s 9th Edition
• Airway hyperresponsivenss (AHR) to exogenous
stimuli: characteristic feature of asthma
• When assessed with non-selective direct acting stimuli
such as histamine or methacholine: defined as
increase in both magnitude and the ease of induced
brochoconstriction

• Increase in the magnitude of bronchoconstriction = progressive elevation of the plateau response
on the concentration reponse (or dose response) curve
• Increase in the ease of developing bronchocontriction = leftward shift of the concentration
response curve
• Left shift = reduced provocation concentration or dose producing 20% fall in forced expiratory
vlume in 1 second (FEV1) called PC20 or PD20
• Hyperresponsiveness measured by rhe PC20 or PD20 reflecting the leftward shift of the curve

Bronchoprovocation stimuli
Non-selective Selective
Direct Indirect Immunologic Non-immunologic
Histamine
Methacholine
Prostaglandins
Leukotrienes
Exercise
Cold air
Non-isotonic aerosols
Adenosine
monophosphate
Propranolol
Bradykinin
Mannitol
Allergen
- High molecular weight
protein containing
- IgE mediated
Occupational
- Low molecular weight
sensitizer
- Mechanism uncertain
ASA
NSAIDs
Food additives

Bronchial Challenge Testing
Coates AL, et al. Eur Respir J. 2017 May 1;49(5):1601526
Methacholine Indication
• Increasing dose from 0.0625 to 16 mg/mL
are given by nebulization
• Pulmonary function at baseline and after
each increasing dose of methacholine
• Result: dose concentration that produces
20% decline FEV1
• To exclude or confirm a suspected
diagnosis of asthma (when
inconclusive spirometry, esp. in
those with normal or near normal
lung function values)

Contraindications for bronchial challenge testing

Medications which may decrease airway hyperresponsiveness and withholding time

Direct Bronchial Challenge Testing
• Histamine and Methacholine most widely performed
2 Methods
• 2-minute tidal breathing method
• 5 total lung capacity (TLC) breath dosimeter method
Results expressed as the PC20 (or PD20)

Direct Bronchial Challenge Testing
• AHR increase: inflammatory stimuli and allergens, occupational sensitizers, viral infections
• AHR improve: environmental control, anti-inflammatory medication, spontaneously
• Pediatrics population: cut points as same as adults at age > 6 years
• 3 important points for interpretation of direct challenges
- Normal FEV1
- Requirement of clinical currency and exposures of suspicious symptoms
- Avoidance of deep inhalation during methacholine inhalation

Indirect Bronchial Challenge Testing
• Direct challenges more sensitive
• Indirect challenges more specific for asthma, probably
correlate better with asthma severity and activity

Exercise-induced bronchoconstriction
• Single, relative high dose challenge of near-maximal exercise for about 6 minutes
• Treadmill (> cycle ergometry)
• Dry and cool air (< 50% relative humidity, < 25 ◦c)
• Target HR =80-90% of predicted maximum (22—age)
Positive: ≥ 10% drop of FEV1

Eucapnic voluntary hyperpnea
• Inhale dry air with 5% CO2 for 6 minutes, targeting a minute ventilation of 30 x FEV1,
equivalent to 85% of the calculated maximum voluntary ventilation (MVV)
• Measure FEV1 before and after EVH for up to 10-15 mins
• Mechanism of bronchoconstriction: osmotic challenge from excessive drying of airway
mucosa same to Exercise-induced bronchoconstriction
Positive: ≥ 10% drop of FEV1

Hypertonic saline
• Mechanism of bronchoconstriction is osmotic effect
• Serve a dual purpose (evaluate AHR and sputum induction-cellular analysis)
• Inhaling 4.5% saline form high 0utput ultrasonic nebulizer (1.2 mL/min) for doubling
amounts of time ranging from 0.5-8 minutes
• Measure FEV1 at time points similar to those of the histamine and methacholine
challenges

Adenosine challenge
• Adenosine/adenosine monophosphate à non-osmotic release of mast cell mediators
• Method identical to that for histamine and methacholine except for concentrations
used (doubling concentrations up to 400 mg/mL)

• Direct challenges with no deep inhalation
- Positive: support a diagnosis of asthma
- Negative: rule out clinically current asthma with reasonable certainty but should be followed by more
specific test in possible EIB case
• Indirect challenges
- Assess asthma control from other airway disease (COPD)
- Inferring exposure to sanitizer in evaluation of occupational asthma
• Positive indirect challenge and methacholine PC 20 <1 mg/mL (normal spirometry) probably high
specificity and PPV for asthma

Fractional exhaled NO (FENO)
Khatri SB, et al. Am J Respir Crit Care Med. 2021 Nov 15;204(10):e97-e109.
• Nitric oxide: gas can measure in exhaled breath
• Fractional exhaled NO (FENO): measuring the fraction of this gas during a steady-
state exhalation
• Airway epithelium inflammation à inducible NOS2 (iNOS2) enzyme increase in asthma
• Function attributed to NO
• Vasodilator
• Bronchodilator
• Neurotransmitter
• Mediator of inflammation
• Bactericidal and cytotoxic effected (in host defense)

• FeNO correlated with sputum airway eosinophilic inflammation: non invasive way to
access T2 airway inflammation
• FeNO levels correlated with elevated total IgE or SPT in atopic asthma
• Although FENO levels do not correlate well with the degree of baseline airflow
obstruction, they tend to correlate well with the severity and features of “indirect” or
“endogenous” AHR, such as exercise-induced bronchoconstriction

• Elevated FENO level is not entirely specific to asthma and levels can be elevated in
people with atopy who do not have other features of asthma
• Recent studies have further delineated the relationship between eosinophilic
inflammation and FENO by suggesting that T2-targeted biological therapy that blocks
IL- 13/IL-4 leads to a reduction in FENO levels and that therapies targeting
eosinophils with anti– IL-5–directed therapies may also lead to a reduction in FENO
levels

Factors Influencing FENO Measurement
• FENO values can be affected by
several factors
• A wide variety of other extrinsic and
intrinsic factors, including cigarette
smoking, dietary nitrate
consumption, and sinonasal disease
Rupani H, et al. Chest. 2022 Apr;161(4):906-917.

The Role of FENO in Asthma Management

The Role of FENO in Asthma Management
• Guide ICS Therapy
• Assess Treatment Adherence
• Management of patients with severe asthma who are receiving
biologic agents

Using FENO to Guide ICS Therapy
• FENO have a role in predicting response to corticosteroid therapy in both ICS-
naïve patients and in those receiving established ICS therapy
• Measurement of FENO may facilitate safe step-down of ICS therapy in patients
with well-controlled asthma
• In patients already receiving established ICS therapy, an elevated FENO does not
seem to be a reliable predictor of benefit from increasing ICS dose, but a low
FENO has significant negative predictive value in assessing the usefulness of a
step-up in corticosteroid therapy

Using FENO to Assess Treatment Adherence
• The relative ease of measuring FENO, along with its responsiveness to ICS,
• The use of FENO suppression testing (FST) as a marker of ICS adherence has
led to its use as an adherence assessment tool in patients with difficult asthma
• Home FST, in which the patient is given an FENO monitoring device to use at
home, has been shown to be feasible and can identify patients successfully for
whom good ICS adherence will lead to significant

Using FENO in the Management of Patients With
Severe Asthma Who Are Receiving Biologic Agents
• Prospective Observational Study to Evaluate Predictors of Clinical Effectiveness in
Response to Omalizumab (PROSPERO) study showed no clinically meaningful
difference in outcomes after 12 months of omalizumab therapy between patients
with an FENO of > or < 25 ppb at baseline
• Real-world effectiveness study, baseline FENO levels were not predictive of
treatment response to either mepolizumab or benralizumab, with similar reductions in
exacerbation rate and oral corticosteroid exposure and improvements in ACQ scores
and lung function

• FENO can be used to support the diagnosis of asthma, as a predictor of response to
ICS therapy, to monitor adherence, to predict future risk of exacerbations, and to
facilitate choice of biologic therapies
• Its measurement is subject to a wide variety of confounding factors, and it has an
imperfect relationship with direct measures of airway inflammation
• In diagnosing asthma, FENO should be interpreted in the broader clinical context,
rather than viewed as a stand-alone diagnostic tool

Pulmonary function test, bronchial challenge test, and FeNO.pdf

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Pulmonary function test, bronchial challenge test, and FeNO.pdf