Asthma has defied a precise definition acceptable to all, even though clinicians recognize that asthma will present with a constellation of signs and symptoms of intermittent dyspnea, cough, chest tightness, and wheezing. Part of the problem relates to the lack of specificity of these "classic" symptoms of asthma. Despite this variability, the following typical pathophysiologic features both characterize and assist in the diagnostic evaluation of the patient with asthma:
- Reversibility of airflow limitation. This is not always clinically demonstrable, as patients with mild disease often do not have airflow limitation at the time they are tested.
- Variable airflow limitation. As an example, patients with nocturnal asthma may have airflow limitation only after exposure to an asthma trigger or at night.
- Hyperresponsiveness to external triggers. "Twitchy airways" or bronchial hyperresponsiveness (BHR) is defined as an excessive response to an aerosolized provocation that elicits little or no response in a normal person. This feature, at some point in time, appears to distinguish most patients with asthma, and underlies the rationale for bronchoprovocation testing.
Inflammation of the airways is associated with and may underlie airway hyperresponsiveness. Cyclic inflammation may also help explain the observation that both airway hyperresponsiveness and asthmatic symptoms wax and wane over time. As such, it is important to link airway hyperresponsiveness to current symptoms such as wheeze, cough, and nocturnal awakenings, etc.
RATIONALE
Measurement of airway responsiveness by bronchoprovocation testing is potentially useful for several reasons:
- Failure to show airway hyperresponsiveness argues against the diagnosis of asthma.
- At any given point in time, airway hyperresponsiveness may be the sole objective evidence of airway dysfunction.
- Airway hyperresponsiveness is quantitatively associated with the presence and severity of disease.
- The occurrence of airway hyperresponsiveness in an asymptomatic person may help predict the future development of asthma.
- The degree of airway hyperresponsiveness in a symptomatic person can have prognostic and potentially therapeutic implications.
- The periodicity of asthma exists in parallel with changes in the degree of airway hyperresponsiveness.
INDICATIONS
Indications for bronchoprovocation testing include the accurate diagnosis of asthma, assessment of the response to asthma therapy, and, less commonly, identification of triggers for cases involving environmental or occupational asthma.
Diagnosis of asthma — Most practitioners diagnose asthma based upon symptoms or an empiric response to therapy. However, the cost and side effects of asthma treatment frequently warrant objective confirmation of the diagnosis and underscore the importance of appropriate bronchoprovocation testing. Such testing is indicated in several clinical situations, including:
- The patient who has symptoms consistent with asthma but normal pulmonary function test results and no response to a bronchodilator. This situation is commonly encountered in patients with mild or well-managed asthma. Bronchoprovocation testing is the only way to make a positive and objective diagnosis of asthma in this setting.
- Patients who experience atypical symptoms of bronchospasm and therefore present with complaints not usually associated with asthma (eg, insomnia).
- Patients who present with symptoms that could result from asthma, but are ill defined or nonspecific (eg, cough). Asthma is one of the important causes of unexplained chronic cough; however, in the absence of bronchial hyperresponsiveness, a diagnosis other than asthma should be entertained.
Assessment of response to therapy — The only abnormality exhibited by many patients with asthma is airway hyperresponsiveness. As a result, the assessment of changes in airway hyperresponsiveness using bronchoprovocation testing may be preferable to the reliance upon subjective changes in symptoms alone. This is particularly relevant when asthma control requires a complex, costly, and potentially toxic therapeutic regimen.
Identification of specific asthma triggers — Most bronchoprovocation tests use a nonspecific airway irritant to assist in making the diagnosis of asthma. Occasionally, it is necessary to test bronchoreactivity to specific occupational agents, food additives, or environmental antigens. Bronchoprovocation tests with specific occupational agents should only be performed in specialized centers, and may require over 24 hours of monitoring following the challenge procedure to detect and, if necessary, treat a late asthmatic response.
PRECAUTIONS
Bronchial challenge with either methacholine or histamine is safe and easy to perform. Bronchoprovocation should only be initiated in the absence of signs and symptoms of distressing airflow obstruction. In patients with significant baseline impairment in their FEV1, a bronchodilator reversibility study is usually indicated instead of bronchoprovocation. Cutoff values below which bronchoprovocation testing is not routinely performed vary; guidelines suggest exclusion of patients with an FEV1 <60 percent predicted, or FEV1 < 1.5 liters. American Thoracic Society guidelines regarding patient preparation and contraindications to methacholine challenge are listed in the tables. Personnel performing the test should be able to recognize severe bronchospasm; a rapid acting beta agonist should be immediately available either as a metered dose inhaler or nebulizer treatment. Resuscitation equipment should also be available. The overall safety of bronchoprovocation with methacholine was reported in 88 patients with a baseline FEV1 <60 percent predicted who underwent methacholine challenge testing. In this study, all but 4 of 88 patients returned to >90 percent of their baseline FEV1 following a single inhaled beta-agonist treatment, and the 4 nonresponders improved satisfactorily after a second treatment. No patients in this study experienced any adverse sequelae.
TYPES OF TESTS
Bronchoprovocation testing procedures determine the dose-response characteristics of the airways to a provocative challenge. The principal methods of eliciting hyperresponsiveness involve challenge with a pharmacologic agent, exercise, food, or suspected allergen.
The dose of provocative agent that the patient actually inhales can be difficult to quantify because it is administered as an aerosol. As a result, the dose is reported as the concentration of the agonist (mg/mL) in the nebulizer. In an attempt to standardize the delivered dosage, the agent is inhaled via a standardized aerosol delivery system while the subject performs a specific breathing maneuver. The relative importance of the many factors that influence aerosol delivery is largely unclear. The breathing maneuver typically uses a fixed inhalation scheme, for example, five vital capacity breaths, or two minutes of quiet breathing. The provoking agent (methacholine or histamine) is inhaled in increasing concentrations followed by lung function tests to generate a reproducible dose-response curve.
The five vital capacity breath method is not equivalent to the two minutes of quiet breathing method for patients with mild hyperresponsiveness, probably due to the protective effect of large vital capacity breaths. Therefore, the quiet or tidal volume breathing method yields greater sensitivity.
When performing inhalational challenges, it is crucial that the solutions and nebulizer apparatus are prepared in a standardized fashion.
1) Pharmacologic challenge
Bronchial challenge is most commonly performed with methacholine, a derivative of acetylcholine. Because bronchospasm due to methacholine is of longer duration than that due to acetylcholine, measurement of the response is facilitated by the use of methacholine.
Choice of agents:
- Histamine is also used for bronchial challenge but is much less commonly employed than methacholine, due to its frequent induction of flushing and headaches. Currently, histamine is not commercially available for use in patients. Methacholine and histamine challenge appear to give equivalent results in selected groups of asthmatic subjects, but in theory, they are not equivalent challenges since they stimulate different receptors and histamine is known to activate airway neural reflexes.
- Other compounds that have been used or advocated as pharmacologic agents include:
- bradykinin,
- adenosine monophosphate (AMP),
- hypertonic saline, and
- mannitol.
As an example, one study comparing serial AMP and methacholine challenge testing in 120 asthmatics found that AMP was more closely associated with other markers of airway inflammation, and more sensitive to subtle changes in airway responsiveness. In a separate series of 238 young adults, mannitol inhalation challenge was less sensitive than methacholine for asthma (59 versus 69 percent), but more specific (98 versus 80 percent). Administration of these compounds appears to distinguish patients with asthma from normal subjects; however, clinical experience is more limited than with methacholine or histamine. In addition, normative data on the expected effect of inhaled AMP in normal control subjects is lacking.
2) Methacholine challenge
The American Thoracic Society and the European Respiratory Society have both published guidelines regarding methacholine challenge testing procedures. Depending on the indication for testing, some or all of the patients medications may need to be stopped prior to testing.
A series of methacholine chloride solutions are prepared, ranging from approximately 0.03 mg/mL (the most dilute) to 25 mg/mL (the most concentrated). These solutions are usually prepared in two-fold dilutions.
After baseline spirometry (that meets criteria noted above), either diluent (most common) or the most dilute concentration of methacholine is administered by nebulizer, using either a tidal breathing or dosimeter method. Both of these methods are acceptable under ATS guidelines; however, the tidal breathing method appears to result in lower PC20 values (more sensitive) than the dosimeter method, possibly due to a bronchodilator effect resulting from the deep inhalation and breathhold of the dosimeter method. Based on this observation, adjusting the dosimeter method to use inhalations that are half of inspiratory capacity, rather than total lung capacity, may improve the sensitivity of this method.
After inhalation of the aerosol by one of these methods, the FEV1 is measured at 30 to 90 seconds with careful coaching of the subject to obtain an acceptable quality FEV1. The concentration is increased one step sequentially, following this procedure, until a decrease in FEV1 greater than 20 percent or a 35 or 40 percent decrease in specific airways conductance (SGaw) is observed. As determined by interpolation, the dose of the inhaled antagonist that provokes a 20 percent drop in FEV1 is referred to as the PC20. Generally, a methacholine PC20 of 8 mg/ml (< 4 mg/mL, for SGaw) or less is considered a positive test.
More complete details on the methodological procedures used can be found by consulting American Thoracic Society (ATS) or European Respiratory Society (ERS) guidelines.
3) Exercise challenge
Graded exercise in a monitored setting provides a useful challenge employed in the evaluation of exercise-induced bronchospasm (EIB). Although patients with EIB may represent a subset of all patients with hyperreactive airways, there may be some in whom exercise is the only trigger of asthma. The determination of the presence of EIB and the documentation of its successful treatment are important and practical considerations for children and active adults.
The presence of EIB is determined using the following general protocol:
- Baseline spirometry values and any other endpoints are determined. An electrocardiogram should be obtained during the exercise.
- The preferred modes of exercise are either a motor-driven treadmill or the electromagnetically braked cycle ergometer.
- The patient is exercised on a treadmill or cycle ergometer to 80 to 90 percent of predicted maximum heart rate for six to eight minutes. Patients should reach 40 to 60 percent of their predicted maximum voluntary ventilation.
- Spirometry is performed prior to exercise, and at 5, 10, 15, 20, and 30 minutes thereafter. It is important to assess lung function serially after exercise, as bronchoconstriction usually occurs 10 to 15 minutes after the end of exercise.
- A test is generally considered positive if the FEV1 falls by 10 percent, although a fall of 15 percent is more diagnostic.
An inadequate exercise stimulus is the most common problem with this test, and may result in a false negative result. If this occurs, other provocative maneuvers that may elicit bronchospasm include free running, the addition of cold air, or Isocapnic hyperventilation. Cold air challenge is a useful adjunct to exercise testing when the patient relates that cold air is the only factor that induces EIB.
A false negative result with exercise testing may also occur if testing of the patient occurred soon after the last bronchodilator treatment, thereby blocking any bronchospastic response, or if the patient has recently undertaken exercise and is still in the refractory period.
4) Food additive challenge
Another form of bronchoprovocation testing involves challenge with food additives, which can be useful in patients who describe food intolerances. Sulfites (found in food preservatives as an antioxidant) and tartrazine (found in orange food color) are the food additives most commonly studied. Oral ingestion of sulfites may result in bronchoconstriction due to the inhalation of sulfur dioxide (SO2), which is produced by the acidification of metabisulfite in the stomach.
The interpretation of the results of food additive challenge may be difficult because one can only estimate the amount of dietary exposure from these preservatives. Nevertheless, since the response to these agents can be quite severe, a negative test result can be clinically important, because it will free patients from concern about the ingestion of these compounds.
A bronchospastic response to a food additive is a relatively uncommon problem in asthma, since less than 5 percent of the asthmatic population is thought to be sensitive to these compounds. Testing, which should be done in specialized laboratories, involves blinded challenge with the food in question and serial monitoring of lung function.
5) Antigen challenge
The accurate identification of a specific inhaled allergen by antigenic challenge permits the patient to consciously avoid the offending agent and thereby prevent bronchospasm. In turn, a negative test may allow exposure of the patient to the previously suspected allergen.
Allergen inhalation challenge is a specialized procedure and should not be undertaken by individuals unfamiliar with the technique. Some patients may have a severe response requiring hospitalization. In certain cases, however, challenge with a specific antigen is indicated. As an example, it is common to perform an antigen challenge with cat or dog antigens. In this setting, a patient's attachment for the family pet can be so strong that it is only in the presence of clear proof (as provided by the antigen challenge) that a patient will be persuaded to part with the pet.
INTERPRETATION
To interpret a bronchoprovocation challenge test, a graph is drawn plotting the fall in the outcome indicator (eg, FEV1 or SGaw) versus the concentration of provocational agent. The effective concentration that would have resulted in a given change in the outcome indicator is determined by interpolation. This dose of provocative agent, eg, provocative concentration for a 20 percent fall in the FEV1 (PC20-FEV1), is used to interpret the test.
Through experience with each agent, concentrations in the normal, asthmatic, and indeterminate range have been ascertained. As noted above, the PC20-FEV1 for methacholine in patients with asthma is usually 8 mg/mL or less.
Although most practitioners only measure the FEV1, reliance upon this measurement alone can lead to both false negative and false positive results. As examples:
One study reported that the sensitivity of a methacholine challenge determined by FEV1 alone was only 60 percent, but increased to 97 percent after changes in FVC, SGaw, and thoracic gas volume (TGV) were added to the analysis. This result is in keeping with the known axial heterogeneity of the response of airways of different caliber to bronchoactive agents.If one does not fully inhale to TLC, a fall in FEV1 can occur and cause a false positive result.
Upper airway responses to various challenge procedures are common and can also lead to confusing results. Fortunately, this can usually be detected if one is careful to inspect all the data, including the original spirometric tracings and to perform full inspiratory as well as expiratory flow-volume loops.
Generally, the sensitivity of a positive methacholine challenge test for the diagnosis of asthma is 85 percent. The positive predictive value is more limited, as false positive results may be seen in patients with allergic rhinitis, cystic fibrosis, heart failure, COPD, and bronchitis.
Difficult interpretations — The results of bronchoprovocation testing can be difficult to interpret when a patient with a positive test has no symptoms of asthma, or when a patient with a negative result has symptoms suggestive of asthma.
Asymptomatic patient, positive test — Epidemiologic studies indicate that approximately 1 to 7 percent of the population have reactive airways but are otherwise normal. These individuals may represent the "tail" of a normal bell-shaped population, or alternatively they may have asthma but do not perceive any symptoms. The latter possibility is supported by the observations that poor perception of airflow limitation occurs in some asthmatics at risk for unexpected exacerbations, and subjects with "laboratory asthma" may in fact subsequently develop a clinical diagnosis of asthma.
History suggestive of asthma, negative test — Although many studies report that airway hyperresponsiveness, as measured by PC20, is consistent and reproducible in asthmatics, these studies largely evaluated patients with stable asthma. The following clinical settings are examples of situations in which a patient may report a convincing history of asthma but have a negative challenge.
The inhalation of an antigen with a subsequent late asthmatic response. After resolution of the late asthmatic response, many patients are hyperresponsive for weeks, but gradually return to normal. On the other hand, some patients show a rapid resolution of hyperresponsiveness. As a result, it is very important to relate the PC20 to the presence or absence of current respiratory symptoms.Vocal cord dysfunction may result in symptoms suggestive of asthma but a negative challenge test result. This condition is often detected by careful inspection of the inspiratory flow-volume relationship, although direct laryngoscopy may be required to make the diagnosis.
References: UTD