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) tests. Discuss the indications of bronchoprovocation tests. List the direct & indirect bronchoprovocation tests. Describe the contraindications of bronchoprovocation tests. Categorizate the bronchial responsiveness for methacholine inhalation challenge.

Introduction: Bronchial provocation (bronchoprovocation) tests are performed to assess bronchial hyperresponsiveness (BHR). They involve the administration of a stimulus that causes airway narrowing in susceptible patients. Bronchoprovocation tests are primarily used to confirm a diagnosis of asthma but are most clinically useful when the diagnosis is not clear cut.

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: 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 the test. 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.

Contraindications: ABSOLUTE Severe airflow limitation (FEV mm Hg or diastolic BP > 100 mm Hg) Cerebral or aortic aneurysm.

RELATIVE Moderate airflow limitation (FEV 1 < 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* Significant hypoxemia (Pa O 2 < 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*

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 exercise- induced 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 mg/mL or mg/mL is used and subsequent doses are increased by two- to fourfold until the FEV 1 falls by 20% from the baseline value or a concentration of 16 mg/mL is reached. If the FEV 1 falls by 20% from the baseline value, bronchodilator (albuterol 2 puffs) should be administered and the FEV 1 repeated in 10 minutes.

The provocative concentration that results in a 20% reduction in FEV 1 (PC 20 ) 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 PC 20 less than 1.0 mg/dL strongly suggests asthma. Conversely, a PC 20 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 interpretation.

Categorization of Bronchial Responsiveness for Methacholine Inhalation Challenge PC 20 (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 direct challenges but not indirect 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. FEV 1 is the primary outcome variable and it should be obtained 5, 10, 15, 20, and 30 minutes postexercise. A reduction in FEV 1 of 10% compared with baseline is considered a positive test.

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 FEV 1 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 exercise- induced 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.

AMP 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 FEV 1 after each dose. A 20% reduction in FEV 1 is considered a positive test. AMP is not FDA approved for bronchoprovocation.

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