Bronchoprovocation test

Bronchoprovocation test
Presented by:
Ashraf Abbas ELMaraghy,MD.
Lecturer of Chest Diseases,
Ain Shams University.
At the end of this lecture you would be able to:
Define bronchial provocation (bronchoprovocation)
Discuss the indications of bronchoprovocation tests.
List the direct & indirect bronchoprovocation tests.
Describe the contraindications of bronchoprovocation
Categorizate the bronchial responsiveness for
methacholine inhalation challenge.
Bronchial provocation (bronchoprovocation)
tests are performed to assess bronchial
hyperresponsiveness (BHR). They involve the
administration of a stimulus that causes airway
Bronchoprovocation tests are primarily used to
confirm a diagnosis of asthma but are most
clinically useful when the diagnosis is not clear
Asthma is a chronic disorder of the airways
characterized by variable and recurring
symptoms, airflow obstruction, BHR, and
underlying inflammation. The diagnosis of
asthma is most often made with a history of
intermittent respiratory symptoms in
combination with variable airflow obstruction.
While BHR is a key feature of asthma,
bronchoprovocation tests are not often
necessary to establish the diagnosis.
Indications for bronchoprovocation include
1. Establishing a diagnosis of asthma when
atypical features are present: Asthma symptoms
with normal spirometry, a presumptive diagnosis
of asthma that does not improve with asthma
therapy, or nonspecific asthma symptoms such as
persistent cough are common reasons to obtain
2. Evaluating the possibility of occupational
asthma: Bronchoprovocation testing is generally a
sensitive but not specific test for diagnosing
occupational asthma.
3. Excluding a diagnosis of asthma in patients
for whom an erroneous diagnosis has significant
social impact (military recruits, divers, firefighters,
and other high-risk occupations).
4. Monitoring asthma therapy: Symptoms and
lung function may normalize despite ongoing
airway inflammation; BHR correlates well with
airway inflammation, and adjusting therapy based
on BHR may improve outcomes.
5. Identifying specific asthma triggers. It is
rarely necessary to perform specific bronchial
challenge testing with the suspected offending
agent, although it may be performed for research
or legal purposes.
6. Objectively assessing asthma severity.
Severe airflow limitation (FEV1 < 50% 
predicted or <1.0 L)
Acute coronary syndrome or stroke within 3
Severe hypertension (systolic BP >
200 mm Hg or diastolic BP > 100 mm Hg)
Cerebral or aortic aneurysm.
Moderate airflow limitation (FEV1 < 60% predicted
or <1.5 L)
Inability to perform acceptable and repeatable
Nursing mothers*
Current use of cholinesterase inhibitor medication for
myasthenia gravis*
Significant hypoxemia (PaO2 < 60)
Recent upper or lower respiratory tract infection
(within 6 wk)
Failure to withhold medication that may affect test
Vigorous exercise on day of test
Medications affecting the test should be held for an
appropriate period of time determined by the drugs’
duration of effect. Short-acting β-agonists (albuterol)
should be held for 8 hours; medium-acting
bronchodilators (ipratropium) should be held for 24
hours, and long-acting bronchodilators (salmeterol,
formoterol, and tiotropium) should be held for 48
hours. Theophylline preparations should be held for 12
to 48 hours depending on the duration of effect.
Leukotriene modifiers should be held for 24 hours.
Antihistamines have a variable effect of BHR and
should be held for 24 to 72 hours depending on their
duration of effect. Coffee, tea, cola drinks, and
chocolate have small effects on BHR and should be
withheld on the day of the study.
Categories of Bronchoprovocation Tests
There are three broad categories of bronchoprovocation
tests. Bronchial hyperreactivity can be elicited using
specific airway irritants, “direct” stimuli using
nonspecific pharmacologic agents (methacholine and
histamine), and “indirect” stimuli (exercise, eucapnic
voluntary hyperventilation, cold air hyperventilation,
hypertonic saline, mannitol, and adenosine
monophosphate [AMP]). The direct airway challenges
cause airway narrowing via a direct effect on airway
smooth muscle whereas indirect airway challenges cause
airflow obstruction by acting on airway inflammatory
and neuronal cells, which release mediators or cytokines
that provoke bronchoconstriction.
Specific inhalation challenge tests with
substances found in the workplace are
considered the gold standard for confirming or
diagnosing occupational asthma. However, a
negative test may not definitively exclude the
diagnosis of occupational asthma if the wrong
agent or too low a concentration is used.
Moreover, these tests require specialized
equipment and have the potential to trigger
severe life-threatening asthmatic reactions.
They should be performed only at specialized
centers and are not widely available.
Methacholine Inhalation Challenge
Methacholine inhalation challenge testing is
the most widely used method to assess BHR.
Methacholine acts by directly stimulating
specific receptors on bronchial smooth muscle,
causing bronchoconstriction and airway
narrowing. Methacholine inhalation challenge
is a sensitive test (sensitivity 85%-90%) for
diagnosing asthma, including occupational
asthma, cough variant asthma, and exerciseinduced bronchoconstriction.
The specificity of methacholine testing is relatively
poor, especially in general population studies. Allergic
rhinitis, COPD, patients who smoke, cystic fibrosis,
bronchiectasis, bronchiolitis, and recent respiratory
tract infections can all result in false-positive tests. The
test consists of performing spirometry at baseline and
then after each dose of nebulized methacholine. An
initial methacholine concentration of 0.031 mg/mL or
0.0625 mg/mL is used and subsequent doses are
increased by two- to fourfold until the FEV1 falls by
20% from the baseline value or a concentration of
16 mg/mL is reached. If the FEV1 falls by 20% from
the baseline value, bronchodilator (albuterol 2 puffs)
should be administered and the FEV1 repeated in 10
The provocative concentration that results in a
20% reduction in FEV1 (PC20) is determined by
interpolation. The results are most accurately
interpreted if clinical information is available.
When the pretest probability of asthma is
between 30% and 70%, a PC20 less than
1.0 mg/dL strongly suggests asthma. Conversely,
a PC20 greater than 16 mg/dL suggests the
patient does not have asthma and alternative
diagnoses need to be considered. Results in the
borderline area (between 4.0 and 16 mg/mL)
require clinical information for meaningful
Categorization of Bronchial Responsiveness
for Methacholine Inhalation Challenge
 PC20 (mg/mL) Interpretation
 >16
Normal BHR
 4.0–16
Borderline BHR
 1.0–4.0
Mild BHR (positive test)
 <1.0
Moderate to severe BHR
Indirect Bronchoprovocation Tests
Indirect challenges may be less sensitive than
direct challenges for the diagnosis of asthma
but are more specific. Some asthmatics,
especially those with mild BHR, respond to
challenges. Indirect challenges are better tests
for assessing airway inflammation and
determining response to an inhaled
corticosteroid than methacholine testing.
Of the indirect methods, standard exercise
tests are less useful for diagnosing asthma.
Exercise testing is most commonly performed
in the evaluation of exercise-induced
bronchospasm. In this setting, it is less
sensitive than other indirect challenge tests and
direct challenge tests. The lack of sensitivity is
likely due to the inability of some patients to
achieve adequate exercise levels due to
deconditioning, musculoskeletal limitations, or
submaximal effort. Exercise testing is highly
specific in differentiating asthma from normal.
If exercise is chosen as the provoking agent,
testing can be performed in the laboratory, using
a treadmill or bicycle ergometer, or performing
specific exercise tests in the field. Whichever
method is used, the patient should 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. Sensitivity improves if dry
air, rather than ambient air, is inhaled. FEV1 is
the primary outcome variable and it should be
obtained 5, 10, 15, 20, and 30 minutes
postexercise. A reduction in FEV1 of 10%
compared with baseline is considered a positive
Hypertonic saline and mannitol are indirect challenge tests
that 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 that has recently been FDA approved for
bronchoprovocation testing. Spirometry is performed
serially after inhalation of these agents at 0, 5, 10, and 20
minutes, and a 10% reduction in FEV1 compared with
baseline is considered a positive study. Mannitol may be
more sensitive than the other indirect challenges for
detecting mild BHR. Inhalation of hypertonic saline or
mannitol is a sensitive stimuli for provoking exerciseinduced bronchospasm. Mannitol is a more clinically useful
test than is histamine for determining improvement with
inhaled corticosteroids.
AMP is a purine nucleotide that acts as an
indirect bronchoprovocation agent. Airway
response to adenosine appears to be a sensitive
marker of mast cell priming; atopic asthmatics are
more responsive to AMP than to methacholine.
There are limited data comparing AMP with
other indirect agents and with methacholine.
However, AMP appears to be more specific than
methacholine for distinguishing pediatric asthma
from other obstructive diseases such as
bronchiectasis and bronchiolitis obliterans. It may
also be useful in separating nonsmoking adults
with COPD from those with asthma.
Methacholine is often positive in both groups
whereas AMP is more often positive only in the
patients with asthma.
is administered with a nebulizer
using either the five-breath dosimeter or
2-minute tidal breathing technique.
Similar to methacholine challenge testing
described previously, the concentration of
inhaled AMP is gradually increased, with
measurement of FEV1 after each dose. A
20% reduction in FEV1 is considered a
positive test. AMP is not FDA approved
for bronchoprovocation.

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