Non specific bronchial reactivity and provocation tests.

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BRONCHIAL
HYPERRESPONSIVENESS
&
BRONCHIAL
PROVOCATION
TESTS - Dr. M.A.WASEEM
PG - Dept. Of Pulmonary Medicine

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Working Definition of Asthma
Asthma is a disorder of the airways with -
• Chronic inflammation
• Variable airflow obstruction
• Hyperresponsiveness to a variety of “triggers”

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“Twitchy” Airways
Bronchial hyper responsiveness is:
• An abnormal increase in airflow limitation following
exposure to a stimulus
•Defined as
“ Dose or concentration - PD20 / PC20 , of inhaled Metha

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NON SPECIFIC BRONCHIAL
HYPER RESPONSIVENESS - NSBH
• Represents a wide biologic spectrum
- determined in part by Heredity
- role of Environmental factors
• NSBH is NOT a Static phenomenon
- Varies considerably following exposure to
infectious agents , env. pollutants & specific
antigens
• NSBH is a result of asthma in addition to being a
risk factor

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PATHOGENESIS

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Inhalation of agonist
pulmonary deposition
ASM Stimulation
ASM Activation
particle size
breathing pattern
airway geometry
epithelial permeability
lymphatic & vascular
removal
inactivation
Agonist - receptor
interaction
calcium influx

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ASM Shortening
External diameter
Airway lumen
RAW - VMax
Proportion of
muscle in
airway
circumference
ASM Activation
Length - tension
load
amount of ASM
Contractility
wall thickness
Secretions
Flow regime

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• NSBH is Sensitive , not Specific of ASTHMA
• also seen in Sarcoidosis , COPD , Extrinsic
Allergic Alveolitis , Cystic fibrosis.
• unrelated to base line FEV1 in asthma ,
significantly related in others

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• Vicious circle of specific & Non specific
responses in asthma
• Allergen exposure —> NSBH —> Response to
• Responsible for most symptoms in asthmatics .
allergen

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• Lack of NSBH does not exclude Asthma
diagnosis
- as in seasonal & occupational asthmatics
• Presence of NSBH alone does not make the
diagnosis , particularly with abnormal baseline
functions
• Serial measurements required in occupational
asthma to see for worsening or improvement of
symptoms with exposure

11. ● BHR can be quantified by BPT
➢WHAT IS BPT ?
● Just opposite of looking for an improvement in lung
function with bronchodilator.
● BPT attempts to provoke airflow obstruction after
inhaling an irritant substance.
BRONCHIAL PROVOCATION TESTS

12. INDICATIONS OF BPT

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1. Establishing a diagnosis of asthma with atypical features :
-Asthma symptoms with normal spirometry
-a presumptive diagnosis of asthma that does not
improve with asthma therapy
-nonspecific asthma symptoms such as persistent
cough
2. Evaluating the possibility of occupational asthma:
- a sensitive but not specific test
3. Excluding diagnosis of asthma in patients for
whom an erroneous diagnosis has significant social impact
(military recruits, divers, firefighters, and other high-risk

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4. Monitoring asthma therapy :
- Symptoms and lung function may normalise
despite ongoing airway inflammation
- BHR correlates well with airway inflammation
- adjusting therapy based on BHR may improve
outcomes.
5. Identifying specific asthma triggers , rarely necessary ,
for research or legal purposes.
6. Objectively assessing asthma severity.

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Contraindications

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ABSOLUTE :
• Severe airflow limitation (FEV1 < 50% predicted
or <1.0 L)
• Acute coronary syndrome or stroke within 3
months
• Severe hypertension (systolic BP > 200 mm
Hg or diastolic BP > 100 mm Hg)
• Cerebral or aortic aneurysm

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RELATIVE :
• Moderate airflow limitation (FEV1 < 60% predicted or
<1.5 L)
• Inability to perform acceptable and repeatable
spirometry
• Pregnancy
• Nursing mothers
• Current use of cholinesterase inhibitor medication for
myasthenia gravis

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• Significant hypoxemia (PaO2 < 60)
• Recent upper or lower respiratory tract infection
(within 6 wk)
• Failure to withhold medication that may affect test
results
• Vigorous exercise on day of test
Modified from Crapo RO, Casaburi R, Coates AL, et al: Guidelines for metha-
choline and exercise challenge testing—1999. This official statement of the American Thoracic Society was adop

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Categories of
Bronchial provocation Tests

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1.Specific airway irritants - Allergen , Aspirin , food
2.“direct” stimuli using nonspecific pharmacologic agents -
Methacholine
Histamine
3.“indirect” stimuli -
exercise,
eucapnic voluntary hyperventilation,
cold air hyperventilation,
hypertonic saline,
mannitol, and
adenosine monophosphate [AMP]

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Types of Stimuli
• Direct Stimulus
Cause airflow limitation by a direct action
on effector cells (e.g., airway smooth muscle cells, mucus producing cells).
➢Acts by binding to agent specific receptors on BSM
➢Highly sensitive but not specific to asthma
➢Used to exclude bronchial asthma
➢Specificity is increased if pre test probability of asthma is
greater

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• Indirect Stimulus
Cause airflow limitation by an action on cells other
than effector cells, which then interact with the
effector cells.
• release endogenous preformed mediators through
neural or humeral pathways, which, in turn, provoke
BSM contraction
➢They reflect ongoing airway inflammation
➢ More specific to identify active asthma.

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Specific inhalation challenge tests :
• gold standard for diagnosing occupational asthma.
• a negative test may not definitively exclude the
diagnosis (wrong agent or too low a concentration)
• require specialised equipment
• potential to trigger severe life-threatening asthmatic
reactions.
• performed only at specialised centres

27. Methacholine Inhalation Challenge
METHACHOLINE:
• Synthetic cholinergic agent
• most frequently used , most safe .
• directly stimulates specific receptors on bronchial smooth
muscle
• sensitivity 85%-90% - for diagnosing asthma, including
occupational asthma, cough variant asthma, and EIB

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• specificity is relatively poor
• false-positive tests :
Allergic rhinitis, COPD, patients who smoke,
cystic fibrosis, bronchiectasis, bronchiolitis,
and recent respiratory tract infections

29. STANDARDIZATION OF TEST
-Delivery of a 0.6.s pulse of airflow at 20 lb into a
nebuliser, which in turn discharges particles of 0.3-4 uM
in diameter in to airways.
● The two methods most commonly used are:
1. Two minute tidal breathing method (more sensitive)
2. Five breath dosimeter method

30. DOING PROTOCOLS
• Methacholine aerosol prepared by using bicarbonate
buffered isotonic saline as a diluent in concentration
ranging from 0.1 to 25 mg /ml
● The cumulative dose delivered is expressed in
inhalation units
● One IU =inhalation of a solution containing
1mg of methacholine per ml

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33. PROCEDURE
➢Counsel regarding symptoms
➢The pt is then asked to wear a nose clip and breathe
normally through the mouthpiece of a De vilbiss 646
nebulizer
➢Measure the baseline FEV1

34. Continue…..
➢ Give inhalation of methacholine for 2minutes at
interval of 5 min beginning with 0.03 mg/ml and
increased up to 16mg/ml.
➢ Measure the FEV1 at 30 and 90 seconds after the
nebulisation is completed until the FEV1 falls >20
%

35. Continue…..
• The test is stopped when
-Fall of FEV1 >20% at any dose
-highest concentration is reached
(16mg) at any FEV1
WHAT IS PC 20 ?
Provocation Concentration producing 20% fall in
FEV1
• The PC20 is universally lower than 8mg in
asthmatics.

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Provocative Concentration (PC)
• The exact concentration that causes a specific fall in
a PFT parameter:
• PC20
FEV1
Concentration that causes a 20% fall in FEV1
• PC40SCaw
Concentration that causes a 40% fall in
specific conductance ( in plethysmography)

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39. PRE CHALLENGE
● Just before BPT Pts should be screened for factors
that may result in false-positive or negative
responses.
● FALSE-POSITIVE
● FACTORS THAT INCREASE BHR
➢Recent viral infections -eg.- RSV
-CMV
-parainfluenzae

40. Continue…..
➢ Exposure to environmental antigens
➢ Occupational sensitisers
➢ Irritants (smoke)
➢ Pollutants
➢ Chemicals

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Factors that increase Bronchial
Hyper responsiveness

42. INTERPRETATION OF TEST RESULTS
• PC 20.Mg/ml DEGREE OF BHR
1. >16mg Normal
2. 4-16mg borderline
3. 1-4mg Mild BHR (+)
4. <1mg Moderate to severe BHR
Modified from Crapo RO, Casaburi R, Coates AL, et al: Guidelines for metha- choline and exercise challenge testing—1999. This official statement of the American Thoracic Society was
adopted by the ATS Board of Directors, July 1999. Am J Respir Crit Care Med 161:309–329, 2000.

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Indirect Bronchoprovocation Tests
• less sensitive than direct challenges for diagnosis of
asthma but are more specific.
• better tests for assessing airway inflammation and
determining response to an inhaled corticosteroid than
methacholine testing.
• useful for titrating the dose of inhaled corticosteroid

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Exercise testing
• commonly performed in the evaluation of exercise-
induced bronchospasm.
• is less sensitive - due to the inability to achieve
adequate exercise levels due to reconditioning,
musculoskeletal limitations, or sub maximal effort.
• is highly specific in differentiating asthma from
normal.
• performed in laboratory, on treadmill or bicycle
ergometer.

45. MECH. OF BRONCHO CONSTRICTION :
1.Mucosal drying and increased osmolarity –
Stimulating mast cell degranulation .
2.Rapid airway rewarming after exercise causing –
Vascular congestion
-Increased permeability and edema ,
leading to obstruction
• Symptoms peak 8-15 min post exercise and resolve
spontaneously in about 60 min

46. INDICATIONS
1. In making a diagnosis of EIB –in asthmatics with
history of SOB during or after exercise.
2. To evaluate the ability of performing life saving
works (military, police) in persons with a history
suggestive of asthma.
3. To determine the effectiveness and optimal dosing
of medications prescribed to prevent asthma.

47. PROCEDURE
• exercise for a total duration of 6 to 8 minutes with 4
to 6 minutes of exercise at near-maximum levels
• The minute ventilation should achieve 50% to 60% of
MVV and the heart rate should reach 90% of
predicted maximum
• FEV1 is the primary outcome variable and it should
be obtained 5, 10, 15, 20, and 30 minutes
postexercise.

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• A reduction in FEV1 of 10% compared with baseline is
considered a positive test.
• Exercise test should be stopped when
-Patient is distressed
-Breathing is laboured
-Ventilation is reduced
-SaO2 falling during exercise.

49. • In children an exercise challenge is better than
methacholine at distinguishing asthma from chronic
airway disorders
eg.-Cystic fibrosis
-Bronchiectasis
-Bronchiolitis obliterans
-Pulm.ciliary dyskinesia.

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Eucapnic Voluntary Hyperventilation
[ EVH ]
• most sensitive test for diagnosing EIB.
• patient breathes deep and fast a gas mixture of 5%
CO2 and balance room air for 6 to 8 minutes.
• A target minute ventilation is set at 30 × FEV1.
• Spirometry at 5, 10, and 20 minutes.
• A positive test is defined as a 10% reduction in FEV1.

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Hypertonic saline and mannitol :
• cause an increase in airway osmolarity, resulting in
mediator release and bronchoconstriction.
• Hypertonic saline challenge tests involve the
nebulization of 4.5% saline.
• Mannitol capsules are inhaled using a dry powder
inhaler.
• Spirometry is performed at 0, 5, 10, and 20 minutes,
• 10% reduction in FEV1 compared with baseline is
considered a positive study.

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• Osmotic stimuli helpful for monitoring asthma
• Bronchial challenge with hypertonic saline can be
combined with an induction of sputum to assess
airway inflammation

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AMP
• Airway response to adenosine is a sensitive marker of mast
cell priming
• atopic asthmatics are more responsive to AMP than to
methacholine.
• more specific in distinguishing pediatric asthma from other
obstructive diseases such as bronchiectasis and
bronchiolitis obliterans.

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• separates non-smoking adults with COPD from those with as
• administered similar to methacholine
• A 20% reduction in FEV1 is considered a positive test.

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➢AMP response in children is a more sensitive predictor of
effect of anti- inflammatory therapy
➢PC20 to AMP better reflects airway inflammation than
methacholine
➢inverse correlation between sputum eosinophilia and PC20
to AMP and PC20 to methacholine , is stronger with AMP
➢Corticosteroid treatment is associated with greater
improvement in PC20 to AMP
All the above suggest that AMP is a better indicator of
airway inflammation

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Precautions for Patient Safety
• Trained staff close enough to respond quickly to an emergency
• Medications to treat bronchospasm must be present in testing area

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Precautions for Technician Safety
• Try to minimise technician exposure
• Testing room should have adequate ventilation (> 2 AC/hr)
• Use of exhalation filters.
• Those with asthma are at increased risk and should take extra precautions to
minimise their exposure

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REACTIVE AIRWAYS DYSFUNCTION SYNDROME
[ RADS ]
• Acute exposure to certain Gases / vapours
• producing severe bronchial / bronchiolar injury —> hyper
responsiveness & narrowing
• most cases develop in Work place
• Pathology :
- sloughing of epithelium ,
- replacement by a fibrinohemorrhagic exudate

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• Differs with Occupational Asthma :
- Minimal or absent Latency ( < 24 hrs )
- Greater Fixed airflow obstruction ( submucosal fibrous tiss
- No BM or Smooth muscle changes as in asthma

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Agents causing RADS :
Isocyanates - Plumbers
Ethylene oxide
Diethylaminoethanol
Metal Fumes - Welding
Pesticides - farmers
Chlorine - household cleaning products,
paper mills ,
swimming pool workers
Sulfur dioxide
NH3, H2S - Oil industry
Bromine , - Disinfectant in hot tub
hydrobromic acid

61. THANK YOU