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	Bronchial Provocation (Challenge) Testing

Solution Introduction

The goal of bronchial challenge testing in clinical practice is to detect and quantify airway hypersensitivity. Airway hypersensitivity is a definitive manifestation of bronchospastic airway disease, most notably, bronchial asthma. Bronchospasm is deliberately induced by controlled and measurable exposure to a specific stimulant. Results are most often presented as doseresponse curves that may be used as an index of the patient’s sensitivity to the stimulant in question. Clinical diagnosis is confirmed and in certain cases treatment can be evaluated or followed by repeat testing.

There are two categories of bronchial provocation tests, “direct” and “indirect”. The “direct” category includes the pharmacological agents histamine and methacholine, and were first used more than 50 yrs ago. These agonists cause airway narrowing by acting “directly” on their respective receptors on bronchial smooth muscle to cause contraction. While recognised as sensitive tests for identifying airway hyperresponsiveness to a single “mediator”, it is now appreciated that the airway hyperresponsiveness identified is not specific to the diagnosis of asthma. Healthy, non-asthmatic persons, persons with chronic obstructive lung disease, and smokers can also have airway hyperresponsiveness to these agents. While pharmacological agents are considered sensitive for identifying asthma in patients with clinically recognised asthma referred to a laboratory, they are less sensitive for detecting known asthmatic subjects in field studies. The reason for this may simply relate to only one “mediator” being investigated during a pharmacological challenge, whereas many endogenously-released mediators are involved in the airway narrowing of asthma.

The second category is known as “indirect” challenge tests and include the physical (as in nonchemical) stimuli such as exercise, hyperpnea of dry air, distilled water, hypertonic saline and mannitol, and the pharmacological agent adenosine monophosphate. These stimuli are thought to cause airway narrowing “indirectly” by releasing a wide variety of mediators of bronchoconstriction from inflammatory cells within the airway. These mediators then act on their specific receptors on bronchial smooth muscle to cause contraction, and airway narrowing is a consequence of this. The physical agents are more specific for identifying asthma, though less sensitive for identifying airway hyperresponsiveness in a laboratory population. However, the sensitivity of the “direct” and “indirect” tests to identify airway hyperresponsiveness in the field is very similar. Persons who do not report asthma do not usually respond to “indirect” stimuli. Persons with very mild asthma who are well controlled on inhaled corticosteroids may not respond to “indirect” tests, and the control of exercise-induced asthma by inhaled corticosteroids is a good example of this.

The utility of bronchial provocation tests in assisting a diagnosis of asthma, monitoring asthma therapy, and assessing asthma prevalence in the community has led to a need for standardised tests that are portable, rapid to perform, and inexpensive. There are many different protocols used for administering the many “direct” and “indirect” bronchial provocation tests available, and this has been one of the problems in implementing these tests. A further problem has been the lower specificity of pharmacological tests to identify active asthma. For these reasons Medikro has implemented several ready made bronchial provocation protocols and possibility of creating new to latest Medikro Spirometry Software SENSE version.

Indications for Bronchial Challenge Testing

While bronchial challenge testing has contributed greatly in the research of various airways diseases, the indications for clinical utilization are more limited. The most important clinical indication is for the identification of a typical or occult asthma, which typically presents as an unexplained cough with normal spirometry test results. In this case, the demonstration of airway hypersensitivity establishes the diagnosis of bronchial asthma.
Mannitol challenge is now the accepted method to use for this purpose. It is particularly valuable in evaluating patients who have cough or respiratory distress with noncontributory findings on physical examination as well as a normal or nearly normal spirometry test and who may have failed to benefit from a therapeutic trial with a bronchodilator. A negative result would demonstrate the need for a comprehensive work-up for endobronchial disease, including tumor, chronic bronchitis, bronchiectasis and tuberculosis.

Clinical Indications for Challenge Testing

• History consistent with asthma (or unexplained cough) but normal spirometry
• Confirmation of airway effect of occupational irritant
• Cold air, fog and exercise induced bronchospasm
• Hypersensitivity to atmospheric pollutants and cigarette smoke
• Identification of specific allergens

Bronchial challenge with occupational irritants is also invaluable in the evaluation of occupational asthma. These may include mining operations, manufacturing and other occupations requiring a high degree of exposure to dusty and polluted air, agricultural environments and animal handling. Complaints of cold air, fog and exercise induced bronchoconstriction may be evaluated through challenge testing as well as the suspected effects of atmospheric pollutants including cigarette smoke.

Conditions Which Affect Test Results

There are a number of factors which may affect the results of a bronchial challenge test and should be taken into account at the time of testing. Of greatest impact is the medication currently being used by the patient. Most bronchodilators and possibly antihistamines may inhibit challenges. Acute viral infections, influenza can increase responsiveness, as do ambient pollutants such as nitrous oxide and sulfur dioxide.

Procedural variability can greatly affect the results. As with any pulmonary function test, patient effort throughout the procedure must be at an optimum. Submaximal effort at any point during the procedure will render the results uninterpretable.

Consistent, measurable administration of the stimulant is essential. Great variability can occur in aerosol generators and administration of the challenge agent. These include the nebulizer design which influences aerosol particle size, consistent output and site of deposition in the airways. Patient variables include interval of aerosol delivery, initial lung volume, inspiratory flowrate, residence time, airway caliber and epithelial permeability. Many of these variables are adequately controlled by use of the nebulization dosimeter or other delivery devices and methods.

Patients with a well-established diagnosis of asthma and those with abnormal spirometry should not undergo challenge testing for diagnostic purposes.

Procedure

We limit our following procedure description to the widely accepted mannitol challenge. This procedure is encouraged for broad utilization in clinical practice due to its safety, ease and repeatability of performance.

Mannitol is a naturally occurring sugar alcohol which is a stable compound with few side-effects and is commonly used as a pharmaceutical excipient and food additive.

Mannitol dry powder for inhalation is prepared by spray drying mannitol to produce fine particles of respirable size which are then encapsulated and delivered via a dry powder inhaler.

Inhalation of mannitol is deposited on the airway surface which causes an increase in osmolarity of the airway surface liquid. Water then moves out of the epithelial cells in an attempt to restore balance, causing the epithelial cells to shrink. As the cells attempt to regain their volume, intracellular calcium rises, which is thought to trigger the release of inflammatory mediators such as histamines, prostaglandins and leukotrienes. In sensitive individuals the release of these mediators causes the bronchial smooth muscle to contract and the airways to narrow. This is measured by a fall in FEV1 (Forced Expiratory Volume in one second).

The test is a cumulative dose challenge that is performed by asking the patient to inhale increasing doses consisting of 0 (empty capsule acting as a placebo), 5, 10, 20, 40, 80, 160, 160 and 160 mg of mannitol. The doses of 80 mg and 160 mg are administered in multiple doses of 40 mg capsules, and the total number of capsules containing mannitol required for the challenge test is eighteen. After inhalation of each capsule patients are instructed to perform a 5-second breath hold, then 60 sec after the complete dose is given at least two repeatable FEV1 manoeuvres are performed and the highest FEV1 is recorded. The FEV1 value measured after the 0 mg capsule is taken as the prechallenge FEV1 and is used to calculate the percentage decrease in FEV1 in response to the mannitol challenge. If the patient has a greater than 10% fall in FEV1 in response to a single dose, the same dose is repeated. The challenge is completed when a 15% fall in FEV1 is documented or a cumulative dose of 635 mg has been administered. Most patients recover spontaneously after the challenge test, however those with a positive challenge or who experience aggravation of asthma should receive a standard dose of a bronchodilator, to expedite recovery. Those with a negative challenge may also receive a standard dose of a bronchodilator to expedite recovery. Following administration of a bronchodilator, FEV1 usually returns to baseline within 10-20 minutes. Patients should be monitored until their FEV1 has returned to within 5% of baseline levels.

Presentation of Data

The FEV1 value from the best spirogram at each dose level is plotted and a dose-response curve constructed. In the case of a positive test (15% fall in FEV1 of prechallenge) this curve provides the determination of PD15 FEV1 which is the dose of mannitol necessary for a 15 percent drop in the FEV1.
The provocative dose, i.e., the PD15 FEV1 value, is a measure of the sensitivity of the airways to the inhaled stimulant. The term reactivity, on the other hand, reflects the slope of the dose-response curve.

Conclusion

Airways hypersensitivity may occur as the only evidence of pulmonary dysfunction. Because of its strong association with the presence and degree of disease, the ability to measure and quantitate airway sensitivity is important. The demonstration of hypersensitivity in the asymptomatic patient has potential predictive value, while in the symptomatic patient it has prognostic and therapeutic value. Factors which may affect variability, validity and difficulty with interpretation include patient preparation, medication regimen, preparation and storage of challenge agent, patient effort, aerosol delivery methods and a history of recent viral infection.
Challenge testing is a valuable diagnostic tool that should be encouraged for much broader utilization by the practicing clinician.

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21 Apr 2009 11:09 AM

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