Chapter 6
Bronchial provocation tests
Bronchial provocation tests assist in identifying airway hyper-responsive ness (AHR—a major feature of asthma) in individuals who have normal spirometry with no bronchodilator (BD) reversibility but have symptoms consistent with asthma.
There are multiple protocols for bronchial provocation tests using multiple stimuli, modes of administration and threshold doses for determining AHR. This chapter reviews the principles of reporting bronchial provocation tests using a number of different methods and stimuli; however, it is necessary to keep in mind that the methods and concentrations/doses of provoking stimuli used in this chapter may not reflect those of your local environment.
Bronchial provocation tests can be divided into two types: direct and indirect challenges.
- Direct challenges
- Act on airway smooth muscle receptors to cause bronchoconstriction (1, 2).
- Inhalation agents include methacholine and histamine.
- Note: AHR associated with direct challenges may also reflect lung injury not associated with asthma.
- Act on airway smooth muscle receptors to cause bronchoconstriction (1, 2).
- Indirect challenges
- Act by causing the release of inflammatory mediators which act on airway smooth muscle receptors to cause bronchoconstriction (1, 3).
- Provide information regarding current airway inflammation.
- Inhalation agents include mannitol, hypertonic saline and adenosine monophosphate.
- Physical challenges include eucapnic voluntary hyperpnea or hyperventilation (EVH), exercise.
- Act by causing the release of inflammatory mediators which act on airway smooth muscle receptors to cause bronchoconstriction (1, 3).
Test procedure:
Inhalation challenges are generally stepped cumulative dose challenges (4, 5) with an upper limit of stimuli delivered. That is, following baseline spirometry, the provoking stimulus is delivered to the airways in steps, with FEV1 measured after each stage. The test is performed within a prescribed time frame to ensure the cumulative effect of the stimulus. A dose–response curve can be constructed by plotting FEV1 against the cumulative dose.
Physical challenges are generally single-dose challenges (5, 6). That is, spirometry (FEV1) is measured before (baseline) and at regular intervals up to 15–30 min after a single provoking stimulus (for example, 6 min of voluntary hyperventilation of a dry gas mixture). A dose–response curve cannot be constructed for single-stimulus dose tests.
Airway responsiveness to the provoking stimulus is described as the stimulus dose or concentration required to provoke a predetermined percentage fall in FEV1. The percentage fall in FEV1 varies dependent on the provoking stimulus (see Table 6.2).
Where a provoking dose (PD) can be calculated (stepped challenge tests), the PD is notated as PDxx, where xx is the per cent fall in FEV1 that identifies a positive challenge (or AHR). For example: for methacholine challenges, the PD is notated as PD20, as a 20% fall in FEV1 is required for the airways to be considered hyper-responsive.
Test quality
Bronchodilators, corticosteroids (inhaled or oral), antihistamines and some foods (e.g. coffee) may affect AHR and these should be avoided prior to bronchial provocation tests (see Table 6.1).
Table 6.1 Medications, foods and other to be avoided prior to challenges.
| Direct challenges: (4) | Time withheld |
| Short-acting inhaled bronchodilators | 8 h |
| Medium-acting bronchodilators | 24 h |
| Long-acting inhaled bronchodilators | 48 h |
| Intermediate-acting theophyllines | 24 h |
| Long-acting theophyllines | 48 h |
| Standard beta-2 agonist tablets | 12 h |
| Cromolyn sodium | 8 h |
| Mast cell stabilizers | 48 h |
| Antihistamines | 3 days |
| Leukotriene antagonists | 24 h |
| Caffeine containing food and drink | Day of test |
| Indirect challenges, as for direct challenges plus: (1, 5) | |
| Leukotriene antagonists | 4 days |
| Vigorous exercise | 4 h, preferably day of test |
| Corticosteroids (when looking for effectiveness of therapy) | Day of test |
| Corticosteroids (when looking for diagnosis) | Up to 6 weeks |
The inability to meet acceptability and repeatability criteria for spirometry will affect test quality and result interpretation (see Chapter 2). An inability to inhale the provoking stimulus (or ventilate sufficiently in the case of physical challenges) also may deliver inconclusive findings.
Interpretation
Steps:
- Check medications, foods and exercise have been withheld/avoided as appropriate. Comment as necessary.
- Check quality of spirometry results. Comment as necessary.
- Assess baseline spirometry (see Chapter 2): baseline airflow obstruction can result in false-positive results with direct challenges and findings must be interpreted cautiously in this situation (4).
- Evaluate challenge results (see Table 6.2).
Determine the likelihood of bronchoconstriction or asthma using sensitivity/specificity data (see Table 6.3).
- Keep in mind that the diagnosis of asthma is usually made by the referring physician in the light of a variety of findings including symptoms, clinical assessment and physiological assessment. A challenge test is only one element in the decision-making strategy.
- There is no ‘gold standard’ against which to measure sensitivity and specificity of different challenges (9). Most often it is measured against a clinical diagnosis of asthma (doctor diagnosed). Differences in methods of administration using the same provoking agent may result in differences in specificity/sensitivity (9).
- Individuals may be positive to one type of challenge but not another (10).
- Keep in mind that the diagnosis of asthma is usually made by the referring physician in the light of a variety of findings including symptoms, clinical assessment and physiological assessment. A challenge test is only one element in the decision-making strategy.
- Add clinical context, if possible, taking into consideration medication use.
- Table 6.4 describes the clinical context for mannitol and hypertonic saline results with use of inhaled corticosteroids (ICSs).
- ICSs may reduce AHR or in some cases eliminate AHR in response to methacholine challenge, but results are inconsistent (4). Direct challenges are not considered to be useful for assessing response to ICS therapy (9).
- Table 6.4 describes the clinical context for mannitol and hypertonic saline results with use of inhaled corticosteroids (ICSs).
Table 6.2 Factors for determining if a bronchial provocation test result is positive, negative or inconclusive.
| Provoking stimulus (provoking dose/ concentration) | Response | Requirement |
| Methacholine (4) (PD20 or PC20) | Positive | ≥20% drop from baseline FEV1 after inhalation of diluent or ≥20% drop in FEV1a and PD20 < 2 mgb or PC20 < 16 mg/mLb |
| Negative | <20% drop in FEV1a and PD20 > 2 mgb or PC20 > 16 mg/mLb | |
| Hypertonic saline (5) (PD15) | Positive | ≥15% drop from baseline FEV1 and PD15 < 23.5 mL |
| Negative | <15% drop from baseline FEV1 and PD15 > 23.5 mL or ≥15% drop from baseline FEV1 and PD15 > 23.5 mL | |
| Inconclusive | <15% drop from baseline FEV1 and <23.5 mL saline delivered | |
| Mannitol (5, 11) (PD15) | Positive | ≥15% drop from baseline FEV1 and PD15 < 635 mg or ≥10% drop in FEV1 between consecutive doses |
| Negative | <15% drop from baseline FEV1 and PD15 ≥ 635 mg | |
| Inconclusive | <15% drop from baseline FEV1 and <635 mg mannitol inhaled | |
| EVH (5) (no provoking dose for EVH) | Positive | ≥10% drop from baseline FEV1 |
| Negative | <10% drop from baseline FEV1 and target ventilation was maintained (>85% MVV) | |
| Inconclusive | <10% drop from baseline FEV1 and target ventilation not maintained (<85% MVV) | |
| Exercise (5) (no provoking dose for exercise) | Positive | Paediatrics > 13% fall from baseline FEV1 Adults > 10% fall from baseline FEV1 Elite athletes > 7% fall from baseline FEV1 |
| Negative or inconclusive | A challenge that is not positive may be inconclusive rather than negative due to difficulties in ensuring that subjects exercise at sufficient intensity to achieve and sustain adequate ventilation to provoke exercise-induced bronchoconstriction |
PD, provoking dose; MVV, maximum voluntary ventilation.
a Using post-diluent FEV1 as reference point.
b Maximum dose/concentration delivered varies according to method used. Check what your local laboratory uses as the maximal dose/concentration.
Table 6.3 Sensitivity/specificity of challenge tests for a diagnosis of asthma.
| Provoking agent | Sensitivity/specificity (compared to a clinical diagnosis of asthma) | Comments |
| Direct challenges | ||
| Methacholine (4, 10) | High sensitivity | A negative challenge excludes AHR, but not exercise-induced bronchoconstriction |
| Low specificity | A positive challenge indicates AHR, but is not specific for asthma | |
| Indirect challenges | ||
| Mannitol and Hypertonic saline (10, 11) | Low sensitivity | Unable to rule out asthma with a negative challenge |
| High specificity | Positive result is highly specific for asthma | |
| Physical challenges | ||
| EVH, Exercise (10, 12, 13) | Low sensitivity | Unable to rule out asthma with a negative challenge |
| High specificity | Positive result is highly specific for exercise-induced asthma |
Table 6.4 Clinical context for indirect challenges.
| For mannitol and hypertonic saline bronchial provocation tests (3, 11): | ||
| Result | Using ICS? | Clinical context |
| Positive | No | Consistent with asthma with active airway inflammation |
| Positive | Yes | Consistent with asthma with suboptimal control of airway inflammation |
| Negative | No | Asthma cannot be excluded. Consider further investigation if clinically indicated or an alternate diagnosis |
| Negative | Yes | Consistent with asthma with controlled airway inflammation or consider an alternate diagnosis |
ICS, inhaled corticosteroid.
Severity scales
Severity scales for methacholine, hypertonic saline, mannitol and eucapnic voluntary hyperventilation challenges are available (4, 5), though are not used in this book.
Comparisons to previous results
There is little in the literature regarding the value of interchallenge variation over time as part of the interpretation strategy.
The repeatability of the majority of stepped dose bronchial provocation tests is within one to two doubling doses (1, 14), suggesting that changes of more than two doubling doses may be clinically important. Similarly, a repeated challenge that moves from positive to negative (or vice versa) is probably a clinically important change.
Examples of interpretation of bronchial provocation challenges
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