INTRODUCTION — 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 uncertainty, 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 allergic asthma may have airflow limitation only after exposure to an asthma trigger or patients with nocturnal asthma only at night. (See "Allergen avoidance in the treatment of asthma and allergic rhinitis" and "Nocturnal asthma".)
●Hyperresponsiveness to external triggers. "Twitchy airways" or airway hyperresponsiveness is defined as an excessive response to an aerosolized provocation that elicits little or no response in a normal person.
●Inflammation of the airways is associated with and may underlie airway hyperresponsiveness [1].
Several types of bronchoprovocation testing are available to assess airway responsiveness in specific patient situations, including pharmacologic challenge, exercise challenge, eucapnic voluntary hyperpnea, food additive challenge, and antigen challenge [2].
The appropriate use of bronchoprovocation testing in patients with asthma or suspected of having asthma will be reviewed here. The pathogenesis and diagnosis of asthma and the role of bronchoprovocation testing in the diagnosis of occupational asthma are discussed separately. (See "Pathogenesis of asthma" and "Asthma in adolescents and adults: Evaluation and diagnosis" and "Pulmonary function testing in asthma" and "Occupational asthma: Clinical features, evaluation, and diagnosis".)
ADVICE RELATED TO THE COVID-19 PANDEMIC — Spirometry and other pulmonary function test (PFT) maneuvers can promote coughing and aerosol generation and could lead to spread of coronavirus disease 2019 (COVID-19; due to SARS-CoV-2) by infected patients. It is difficult to screen patients for active SARS-CoV-2 infection, particularly those with underlying respiratory symptoms, and infected but asymptomatic patients can shed the virus. Thus, we agree with expert recommendations that spirometry and other PFTs be limited to patients in whom results are essential to immediate management decisions [3]. Use of nebulizers to administer bronchodilators or methacholine for testing should be avoided. We also avoid other forms of bronchoprovocation testing due to the coughing induced by the testing and the need for multiple spirometric maneuvers.
Measures to prevent spread of COVID-19 should include hand hygiene and personal protective equipment (PPE; gloves, gown, face mask and shield) for staff and anyone else in the testing space (eg, interpreters). N95 masks or powered air purifying respirators (PAPR) are preferred over surgical masks. Patients should be brought to a testing room using an approach that avoids queuing or grouping individuals in a waiting area. Enhanced cleaning of the testing area should be performed between patients.
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 [2,4]
●At any given point in time, airway hyperresponsiveness may be the sole objective evidence of airway dysfunction/asthma [5]
●Airway hyperresponsiveness is quantitatively associated with the presence and severity of disease [6-8]
●Suppression of airway responsiveness is one of the outcomes that can be used to assess new asthma therapies
●The occurrence of airway hyperresponsiveness in an asymptomatic person may help predict the future development of asthma [5]
●The degree of airway hyperresponsiveness in a symptomatic person can have prognostic and potentially therapeutic implications [9,10]
●The periodicity of asthma exists in parallel with changes in the degree of airway hyperresponsiveness
The first four reasons are the ones that are most important clinically; the other reasons are more applicable to research into asthma pathophysiology and the efficacy of asthma medications.
INDICATIONS — Indications for bronchoprovocation testing include the accurate diagnosis of asthma in selected patients, assessment of the response to asthma therapy, and, less commonly, identification of triggers for cases involving environmental or occupational exposures [2,11].
Diagnosis of asthma — The diagnosis of asthma is often strongly suspected based upon the presence and pattern of typical symptoms that respond to specific therapy for asthma. The National Asthma Education and Prevention Program strongly encourages confirmation of the diagnosis with objective testing that shows reversibility of airflow limitation (eg, before and after bronchodilator, in response to ongoing therapy, or bronchoprovocation challenge) [12]. For patients with typical intermittent asthma symptoms and normal baseline spirometry, a clear clinical response to empiric therapy may be adequate diagnostically. However, the cost and side effects of asthma treatment often warrant objective confirmation of the diagnosis with bronchoprovocation testing. Such testing is indicated in several clinical situations where the clinical question is ”does this patient really have asthma?”, 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 [13]. 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, nocturnal awakening).
●Patients who present with symptoms that could result from asthma, but are ill-defined or nonspecific (eg, cough) [14,15]. 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 considered. (See "Causes and epidemiology of subacute and chronic cough in adults".)
●Patients who are suspected of having occupational asthma, reactive airways dysfunction syndrome, or irritant-induced asthma. (See "Reactive airways dysfunction syndrome and irritant-induced asthma", section on 'Nonspecific bronchoprovocation challenge' and "Occupational asthma: Clinical features, evaluation, and diagnosis", section on 'Advanced testing'.)
●For individuals who require screening test for asthma, such as scuba divers, military personnel, or other individuals in whom bronchospasm would pose an unacceptable hazard.
Assessment of response to therapy — Nonspecific bronchoprovocation challenge is sometimes used in clinical trials as a way to assess the response to a new therapy for asthma [16]. This is particularly useful when evaluating patients with mild asthma not on controller medications whose only physiologic abnormality may be airway hyperresponsiveness and provides an additional and objective endpoint other than symptoms alone. In rare cases, serial bronchoprovocation testing is used to assess the response to avoidance of occupational exposures in occupational asthma, although this is predominantly for research purposes [17].
Identification of specific asthma triggers — Most bronchoprovocation tests use a nonspecific agent (eg, methacholine, mannitol) to assist in making the diagnosis of asthma. On rare occasions, it is necessary to test bronchoreactivity to specific food additives, occupational agents, or environmental antigens. (See "Allergic and asthmatic reactions to food additives", section on 'Asthmatic symptoms' and "Occupational asthma: Clinical features, evaluation, and diagnosis", section on 'Specific inhalation challenge'.)
PRECAUTIONS — Bronchial challenge with nonspecific agents (eg, methacholine, mannitol) is safe and easy to perform, as long as appropriate precautions are taken [2,13,18,19]. Guidelines regarding patient preparation and contraindications to methacholine challenge are listed in the tables (table 1 and table 2 and table 3) [2,4]. Personnel performing the test should be able to recognize severe bronchospasm; a rapid acting beta agonist (eg, albuterol) should be immediately available either as a metered dose inhaler or nebulizer treatment [2,4,20]. Demonstration that the FEV1 has returned to or exceeded baseline should be obtained before the patient leaves the pulmonary function laboratory. Resuscitation equipment should also be available.
Patients with unstable cardiac disease or a myocardial infarction or stroke within the past three months are excluded from bronchoprovocation testing due to the physical exertion of the repeated measurements of spirometry (table 1). However, among adults without cardiac disease, the risk of adverse cardiac effects appears minimal [21].
Bronchoprovocation challenge should only be initiated in the absence of signs or symptoms of significant airflow obstruction. In patients with significant baseline impairment in the forced expiratory volume in one second (FEV1), a bronchodilator reversibility study is usually indicated instead of bronchoprovocation (algorithm 1). Cutoff values below which bronchoprovocation testing is not routinely performed vary; guidelines suggest exclusion of patients with an FEV1 <60 percent predicted (adults or children), or an FEV1 <1.5 liters (adults) [2,4,18]. We typically do not perform a bronchoprovocation challenge in a patient with an FEV1 <70 percent predicted unless a physician is present.
The safety of bronchoprovocation with methacholine for patients with a baseline FEV1 <60 percent predicted was evaluated in 88 patients who underwent methacholine challenge testing [22]. 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 four nonresponders improved satisfactorily after a second treatment. No patients in this study experienced any adverse sequelae. However, bronchoprovocation testing in patients with this degree of baseline airflow obstruction should only be performed with caution.
ENSURING ADEQUATE SPIROMETRY — Reproducible spirometry is key to the performance of bronchoprovocation testing. Nose clips help to prevent leakage through the nasal passages and improve reliability. The testing requires multiple spirometric maneuvers, so it is important to explain to the patient the need for maximal and vigorous efforts and the importance of deep inhalation to full lung capacity for each maneuver. Depending on the protocol used, the exhalation time is six seconds (most common) or two seconds (sometimes called a forced expiratory volume in one second [FEV1] maneuver). The shorter time may be used to decrease the respiratory effort and is often acceptable when vocal cord dysfunction is not a concern. When vocal cord dysfunction is suspected, a full flow volume loop is needed. Usually, two spirometric maneuvers are obtained at baseline and at each time point of the test. Details about proper coaching of patients during testing and assessing the adequacy of the flow-volume or FEV1 tracing are provided separately. (See "Office spirometry", section on 'Coaching the patient' and "Office spirometry", section on 'Adequacy of test'.)
During the testing, the spirometric tracings are observed to make sure that the patient has fully inhaled to total lung capacity (TLC) prior to performing the expiratory maneuver. If the patient does not fully inhale to TLC, a decrease in FEV1 can occur without bronchoconstriction and cause a false positive result [23]. Generally, forced vital capacity (FVC) is not used as an outcome measure for bronchoprovocation. Decreases in FVC usually reflect an inadequate inspiratory effort, incomplete exhalation, or an increase in residual volume (RV) due to airtrapping. Reports show that obesity and asthma cause an increase in the relative fall in FVC [24].
For patients who have difficulty performing spirometry that meets acceptability standards, measures of airway resistance such as the forced oscillation technique or specific airway conductance [sGaw], which require little or less patient effort, can be used as alternative end-points [4,16]. Usually changes in sGaw mirror changes in FEV1, although sGaw changes are more variable. Thus, a larger percent change in sGaw (eg, 45 percent) is required for a positive test. (See "Pulmonary function testing in asthma", section on 'Bronchodilator responses'.)
PHARMACOLOGIC CHALLENGE — Pharmacologic challenge procedures determine the dose-response characteristics of the airways to a provocative challenge [25]. When performing inhalational challenges, it is crucial that the solutions and nebulizer apparatus are prepared in a standardized fashion [2,4].
Depending on the indication for testing, some or all of the patients’ medications may need to be stopped prior to testing (table 2) [2,26]. Generally, inhaled glucocorticoids (ICS) are not stopped as it takes three weeks for the effect to wear off. However, a negative test while the patient is using ICS implies that the patient’s current symptoms are not due to asthma, but does not rule out underlying asthma. To exclude airways hyperresponsiveness, the test would need to be repeated at least three weeks after discontinuation of ICS and when the patient has asthma like symptoms. In addition, a cohort-control study of patients taking controller medication for asthma found that the sensitivity of methacholine challenge is lower in White patients and non-atopic patients, than in African American and atopic patients [27].
Delivery of pharmacologic agents — A number of provocative agents are administered via a nebulizer device (eg, methacholine, histamine, adenosine). The dose of a provocative agent that actually reaches the intrathoracic airways from an aerosol device can be difficult to quantify, but is the basis of the European Respiratory Society Technical Standard for methacholine inhalation challenge [2]. Measurement of nebulizer output (typically by the manufacturer) is used to determine the appropriate dilutions of methacholine for the particular nebulizer. This enables delivery of the desired methacholine dose during the nebulization time. The relative importance of other factors (eg, aerosol particle size, respiratory pattern) that may influence aerosol delivery is less well-characterized [28-31].
In order to improve test standardization, it is advised that the aerosol amount be reported as the dose of the agonist (microg) rather than the concentration (mg/mL). Increasing doses or concentrations of the provoking agent (eg, methacholine, histamine) are followed by spirometry at each step to generate a reproducible dose-response curve. In an attempt to standardize the delivered dosage, the agent is inhaled via a standardized aerosol delivery system (eg, an output of 0.13 mL/min) while the subject performs a specific breathing maneuver [2,28,32].
The preferred breathing maneuver uses a defined period (eg, at least one minute) of quiet (tidal volume) breathing [2,18,33-35]. The method of five vital capacity breaths followed by a breathhold is not equivalent to the quiet breathing method for patients with mild hyperresponsiveness, probably due to the protective and bronchodilator effects of large vital capacity breaths [33]. Therefore, the quiet or tidal volume breathing method yields greater sensitivity. Alternatively, the five inhalations followed by breathhold can be modified to use a submaximal inhalation, approximately 50 or 60 percent below total lung capacity, followed by a breathhold [23,33,36].
Choice of agents — Bronchial challenge tests are often classified as direct or indirect based on postulated mechanisms. Direct stimuli, such as methacholine and histamine, are thought to cause bronchoconstriction via direct stimulation of airway smooth muscle receptors, whereas indirect stimuli (eg, mannitol, adenosine monophosphate, eucapnic hyperventilation) cause bronchoconstriction through one or more intermediate pathways, typically involving release of inflammatory mediators (eg, prostaglandin D2, leukotriene E4) from mast cells [37]. However, direct stimuli such as histamine or methacholine also affect other cells besides smooth muscle, such as nerves and mucous containing cells, so this distinction is somewhat artificial.
Histamine has been used in research studies of bronchial challenge, but is much less commonly employed clinically than methacholine, due to its frequent induction of flushing and headaches [38]. In addition, histamine is not commercially available for this use. 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 [34,39].
Other compounds that have been used or advocated for use in bronchoprovocation challenge include bradykinin, adenosine monophosphate (AMP), hypertonic saline, and mannitol [32,40-53]. 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 [43]. 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 [54].
In general, it appears that methacholine is more sensitive for airway hyperresponsiveness, but less specific than mannitol, and mannitol results are more in agreement with exercise [32,55,56]. The optimal roles of methacholine and mannitol challenge in the assessment of airway hyperresponsiveness for clinical purposes remain unclear. Since the challenge modalities are not equivalent, this supports the notion that airway hyperresponsiveness is the expression of more than one mechanism as seen with animal models.
Methacholine — Methacholine, a derivative of acetylcholine, is the agent most commonly used for bronchoprovocation and is an acceptable form of bronchoprovocation for assessing asthma in Olympic athletes [57]. Bronchoconstriction due to methacholine is of longer duration than that due to acetylcholine, thus facilitating measurement of the response. The American Thoracic Society and the European Respiratory Society have published guidelines regarding methacholine challenge testing procedures (table 1 and table 2 and algorithm 1) [2,4,11,18].
A series of methacholine chloride solutions are prepared, ranging from approximately 0.016 to 0.03 mg/mL (the most dilute) to 16 mg/mL (the most concentrated). As shown in the table, these solutions are usually prepared in two-fold or four-fold dilutions (table 3) [2].
After baseline spirometry that meets criteria noted elsewhere (see "Office spirometry", section on 'Adequacy of test'), usually the diluent is administered by nebulizer during tidal breathing for at least one minute (see 'Delivery of pharmacologic agents' above), although it is also acceptable to start with the most dilute concentration of methacholine. After inhalation of the aerosol, the forced expiratory volume in one second (FEV1) is measured at 30 and 90 seconds with careful coaching of the subject to obtain an acceptable quality FEV1. Each time two maneuvers are performed; if FEV1 is the only outcome being measured, it is acceptable to shorten the expiratory time to about two seconds (from the usual six seconds), unless there is a suspicion of vocal cord dysfunction in which case a full vital capacity maneuver with inspiratory and expiratory phases is performed.
The dose or concentration of methacholine is sequentially increased one step at a time (table 3), until a decrease in FEV1 greater than 20 percent or a 35 to 40 percent decrease in specific airways conductance (SGaw) is observed [2,4,18,29]. Typically, when there is a positive test, the FEV1 decreases more than 20 percent, so the dose of the inhaled agent that would provoke a 20 percent drop in FEV1 is determined by interpolation. This is referred to as the provocative dose or PD20. Generally, a methacholine PD20 of 200 microg or a PC20 of 8 mg/mL (100 microg or 4 mg/mL, for SGaw) or less is considered a positive test [2]. A PD20 greater than 400 microg (PC20 greater than 16 mg/mL) is considered a negative test [2].
Mannitol — Mannitol inhalation is thought to cause bronchoconstriction by increasing the osmolarity of the airway surface, resulting in release of mast cell mediators. The mast cell mediators (eg, prostaglandin D2, leukotriene E4) in turn cause bronchoconstriction. The guidelines published by the American Thoracic Society and the European Respiratory Society for methacholine challenge testing procedures are also appropriate for mannitol bronchoprovocation (table 1 and table 2) [4,18].
Mannitol for bronchoprovocation is prepared as a dry powder in capsules containing graduated doses that are administered via a dry powder inhaler (Aridol) [51,58]. It is available in a number of countries, including Australia, Canada, Germany, Korea, United Kingdom, and United States. Due to the use of premeasured doses, mannitol inhalation challenge may prove to be more convenient than challenges with methacholine, exercise, or isocapnic hyperventilation.
For the bronchoprovocation procedure, mannitol dry powder is rapidly inhaled in progressively increasing doses (0, 5, 10, 20, 40, 80, 160, 160, 160 mg). The FEV1 is measured at baseline and repeated at one minute after each dose; the highest of two repeatable values is used [33,50]. If the FEV1 decreases by 10 percent after a dose then that dose is repeated. A 15 percent fall in FEV1 at a total cumulative dose of ≤635 mg (known as the provocative dose or PD 15) is considered a positive response, as is a persistent decrease of 10 percent between consecutive doses.
Mannitol challenge appears to be safe; among 592 subjects with and without asthma who underwent mannitol bronchoprovocation, no serious adverse events were noted [49]. However, cough is a common side effect [48,49].
Interpretation — To interpret a bronchoprovocation challenge test, a graph is drawn plotting the fall in the outcome indicator (eg, forced expiratory volume in one second [FEV1]) versus the dose or concentration of the provocative agent (figure 1). The effective dose or concentration that would have resulted in a given change in the outcome indicator is determined by interpolation. This dose of the provocative agent (eg, provocative dose or concentration of methacholine for a 20 percent fall in the FEV1 or provocative dose of mannitol for a 15 percent fall in FEV1) is used to interpret the test.
Through experience with each agent, doses and concentrations in the normal, asthmatic, and indeterminate (for methacholine) ranges have been ascertained.
●As noted above, the PD20-FEV1 for methacholine in patients with asthma is usually 200 microg (PC20 8 mg/mL), or less. A graded system of borderline (100 to 400 microg, 4 to 16 mg/mL), mild (25 to 100 microg, 1 to 4 mg/mL), moderate (6 to 25 microg, 0.25 to 1 mg/mL), and marked (<6 microg, <0.25 mg/mL) airway hyperresponsiveness has been proposed, although the clinical utility has not been fully determined [2]. (See 'Methacholine' above.)
It is difficult to calculate the exact sensitivity of a methacholine challenge for the diagnosis of asthma, as a gold standard for diagnosing asthma does not exist. On the other hand, for a cut-point of 200 to 400 microg (8 to 16 mg/mL) using a non-deep inhalation method, the sensitivity is felt to approach 100 percent [32,59,60]. The positive predictive value is more limited (estimated around 50 percent for a cut-point of 200 microg [8mg/mL]), as false positive results may be seen in patients with allergic rhinitis, cystic fibrosis, heart failure, chronic obstructive pulmonary disease (COPD), and bronchitis [2,4,32]. Thus, the negative predictive value is the most useful aspect of methacholine challenge. (See 'Asymptomatic patient, positive test' below.)
●For incremental mannitol bronchoprovocation testing, the test is negative when the final FEV1 has not decreased by ≥15 percent from baseline or by ≥10 percent from the previous dose [58]. (See 'Mannitol' above.)
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 (up to 26 percent if smokers are included) but are otherwise normal or asymptomatic [61-63]. These individuals may represent the "tail" of a normal bell-shaped population [61], or alternatively they may have asthma but do not perceive any symptoms [4,14]. The latter possibility is supported by the observations that poor perception of airflow limitation occurs in some asthmatics who are at risk for unexpected exacerbations [14], and subjects with "laboratory asthma" may in fact subsequently develop a clinical diagnosis of asthma [5,64].
History suggestive of asthma, negative test — Many studies report that airway hyperresponsiveness, as measured by a methacholine PC20, is consistent and reproducible in asthmatics; however, 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, as seen in certain occupational exposures. After resolution of the late asthmatic response, many patients are hyperresponsive for weeks, but gradually return to normal [1]. On the other hand, some patients show a rapid resolution of hyperresponsiveness. As a result, it is very important to relate the PC20 result to the presence or absence of current respiratory symptoms and exposures. Asthma is, by definition, a variable disease state and likewise hyperresponsiveness can wax and wane and not be reproducible [65,66]. (See "Occupational asthma: Clinical features, evaluation, and diagnosis", section on 'Advanced testing'.)
●Paradoxical vocal cord motion (also known as vocal cord dysfunction) may result in symptoms suggestive of asthma but a negative challenge test result, if the only endpoint is the change in FEV1. This condition is often detected by careful inspection of the inspiratory flow-volume relationship. Patients may have predominantly inspiratory or expiratory vocal cord dysfunction, with corresponding inspiratory or expiratory abnormalities on the flow-volume loop (figure 2). (See 'History suggestive of asthma, atypical spirometry pattern' below and "Inducible laryngeal obstruction (paradoxical vocal fold motion)" and "Flow-volume loops".)
●Central airway obstruction by a tumor, polyp, or foreign body can also mimic asthma symptomatically, but results in a negative methacholine challenge. (See "Airway foreign bodies in adults" and "Clinical presentation, diagnostic evaluation, and management of malignant central airway obstruction in adults", section on 'Diagnostic evaluation and initial management'.)
History suggestive of asthma, atypical spirometry pattern — Upper airway responses to various challenge procedures are common and can lead to confusing results [67]. As an example, patients with vocal cord dysfunction may develop flattening of the inspiratory portion of the flow volume loop in response to pharmacologic bronchoprovocation challenge. Fortunately, this can usually be detected if full inspiratory as well as expiratory flow-volume loops are performed and inspected, although direct laryngoscopy may be required to confirm the diagnosis [4]. (See "Inducible laryngeal obstruction (paradoxical vocal fold motion)" and "Flow-volume loops".)
EXERCISE CHALLENGE — Exercise is thought to be a trigger for bronchoconstriction in virtually all patients with hyperreactive airways and may be the only trigger for a subset of patients with asthma [39]. The identification of exercise-induced bronchoconstriction (EIB) and the documentation of its successful treatment are important and practical considerations for children and active adults [68]. Guidelines from the American Thoracic Society (ATS) state that symptoms alone are inadequate to diagnose EIB, and a challenge test with serial lung function measurements is necessary [69]. Graded exercise in a monitored setting provides an objective test for the evaluation and management of EIB; eucapnic voluntary hyperventilation (EVH) is an alternative. (See "Exercise-induced bronchoconstriction".)
Bronchodilator therapy is withheld prior to testing (table 2), as bronchodilators can block a bronchospastic response to exercise testing, causing a false negative result. After vigorous exercise, some patients have a refractory period during which EIB is suppressed, so vigorous exercise should also be avoided the day of the testing.
The presence of EIB is determined using the following general protocol [4,70]:
●Baseline spirometry values are determined by obtaining two reproducible maneuvers within 3 percent of each other; the best maneuver is used to calculate post exercise falls in FEV1 [70]. If vocal cord dysfunction is suspected, full inspiratory and expiratory maneuvers are performed before and after exercise.
●Monitoring during the test generally includes a continuous electrocardiogram, blood pressure, pulse oximetry, and minute ventilation.
●Airway drying caused by the increased minute ventilation during exercise is thought to be the stimulus for exercise-induced bronchoconstriction, so careful control of the temperature and humidity of the inhaled air are needed to ensure test reliability [69,71,72]. The ATS guidelines suggest having the patient breathe dry air (<10 mg H2O/L air), which can be administered via a gas cylinder with a reservoir bag (Douglas bag apparatus) and a one-way mouth valve [69,70]. Nose clips should be worn during the test to avoid entrainment of ambient air.
●The preferred modes of exercise are either a motor-driven treadmill or the electromagnetically braked cycle ergometer.
●The exercise protocol is selected to allow the patient to achieve 80 to 90 percent of predicted maximum heart rate (estimate at 220 minus age in years) in the first two minutes of exercise and maintain it for the remaining eight minutes of the test. Patients should reach 40 to 60 percent of their predicted maximum voluntary ventilation (MVV). The predicted MVV can be calculated by taking the pretest FEV1 and multiplying by a factor between 35 and 40; for convenience 40 is widely used [73].
●Spirometry is performed prior to exercise, and at 5, 10, 15, 20, and 30 minutes thereafter [4]. 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 considered positive if the forced expiratory volume in one second (FEV1) decreases by 10 percent, although a fall of 15 percent is more diagnostic.
●A high prevalence of positive tests is observed in elite athletes [74], and the prevalence in recreationally active subjects approaches 13 percent [75].
●Asthma symptoms and bronchoconstriction provoked by the testing are treated with inhalation of a short-acting beta agonist (eg, albuterol). (See 'Precautions' above.)
An inadequate exercise stimulus that fails to raise the minute ventilation sufficiently 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 eucapnic voluntary hyperpnea [71,76,77].
For patients with a positive exercise challenge test, the efficacy of preventative medications (eg, short-acting beta agonist, antileukotriene agent) can be assessed by repeating the test on medication, although this is not necessary in most patients [69].
EUCAPNIC VOLUNTARY HYPERPNEA — Eucapnic voluntary hyperpnea (EVH, also known as isocapnic voluntary hyperventilation) is another type of challenge for assessing airway hyperresponsiveness. It is thought that dry air hyperventilation causes drying and hyperosmolarity of the airway surface (similar to the effect of exercise), resulting in release of inflammatory mediators from inflammatory cells such as mast cells (similar to mannitol inhalation) [70]. EVH is one of the recommended challenge tests for identifying exercise-induced bronchoconstriction (EIB) in Olympic athletes [57,78,79]; EIB is the leading medical problem in elite athletes [74]. (See "Exercise-induced bronchoconstriction".)
For the procedure, baseline spirometry is performed twice to obtain two values for forced expiratory volume in one second (FEV1) that are reproducible; the best value for FEV1 is used to calculate the post challenge changes. The patient wears nose clips and orally inhales a mixture of dry hypercapnic air (4.5 to 5 percent CO2, 21 percent O2, balanced N2). The hypercapnic air ensures that the subject remains eucapnic during the test, as hypocapnia can cause bronchoconstriction. It is not necessary to chill the inspired air as it is believed that the water content and not the air temperature is the essential feature that leads to bronchoconstriction in patients with airway hyperresponsiveness [70,80].
The patient is instructed to breathe the dry hypercapnic air for six minutes at a minute ventilation of 30 times the baseline FEV1 [69,79,81]. For subjects who are unable to achieve this target, the minimum ventilation for a valid test for untrained subjects is 21 times the FEV1 [69,82]. After the completion of the challenge, two reproducible postexercise spirometry maneuvers are performed at each time point of 5, 10, and 15 minutes. A test is generally considered positive if the FEV1 decreases by 10 percent or more [57,79].
ANTIGEN CHALLENGE — The accurate identification of a specific inhaled allergen by antigenic challenge is largely a research tool for investigation of mechanisms of asthma, the efficacy of new therapeutic agents, and suspected occupational allergens [4,83]. 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.
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 [84]. (See "Occupational asthma: Clinical features, evaluation, and diagnosis", section on 'Specific inhalation challenge'.)
ASPIRIN CHALLENGE — Aspirin-exacerbated respiratory disease (AERD) is characterized by asthma, chronic rhinosinusitis with nasal polyposis, and reactions to ingestion of aspirin or other cyclo-oxygenase-1 inhibiting nonsteroidal anti-inflammatory drugs (NSAIDs). The reactions to aspirin and NSAIDs typically begin 30 minutes after ingestion and involve marked nasal congestion and bronchospasm. Oral aspirin challenge is performed in patients with suspected AERD who have a medical indication for aspirin or NSAID therapy at a time when their asthma is under good control.
The technique for aspirin challenge requires safeguards such as premedication with a leukotriene modifying agent (eg, montelukast), ensuring that the patient’s asthma is well-controlled at the time of challenge, performing the challenge in a medically-monitored setting, and obtaining intravenous access prior to the challenge. A detailed description of the challenge procedure is provided separately. (See "Diagnostic challenge and desensitization protocols for NSAID reactions".)
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 [85-89]. 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 [88].
The interpretation of the results of food additive challenge is 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 [90]. Testing, which should be done in specialized laboratories, involves blinded challenge with the agent in question and serial monitoring of lung function.
Oral food challenges for the diagnosis of food allergy are discussed separately. (See "Oral food challenges for diagnosis and management of food allergies", section on 'Performance of an OFC'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Exercise-induced bronchoconstriction" and "Society guideline links: Pulmonary function testing".)
SUMMARY AND RECOMMENDATIONS
●Several types of bronchoprovocation testing are available to assess airway responsiveness in specific patient situations, including pharmacologic challenge, exercise challenge, eucapnic voluntary hyperpnea, food additive challenge, and antigen challenge. (See 'Rationale' above.)
●Nonspecific bronchoprovocation testing (eg, methacholine, mannitol, exercise) is indicated when the diagnosis of asthma is in question (eg, symptoms are atypical, baseline spirometry is normal), when a patient is suspected of having occupational asthma, reactive airways dysfunction syndrome (RADS), or irritant-induced asthma, and when a screening test for asthma is required for scuba divers, military personnel, or other individuals in whom bronchospasm would pose an unacceptable hazard. (See 'Indications' above.)
●The contraindications to bronchoprovocation challenge and a list of medications that need to be discontinued prior to testing are listed in the tables (table 1 and table 2). (See 'Pharmacologic challenge' above.)
●Methacholine inhalation challenge is the most common type of pharmacologic challenge. Patients breathe progressively stronger doses of methacholine according to a protocol (algorithm 1). The dose of methacholine that provokes a 20 percent drop in forced expiratory volume in one second (FEV1) is referred to as the PD20. Generally, a PD20 of 200 to 400 microg (PC20 8 mg/mL) methacholine or less is considered a positive test. (See 'Pharmacologic challenge' above.)
●Mannitol inhalation challenge is mediated by release of bronchoconstrictive mediators. The contraindications and a list of medications that need to be discontinued are the same as for methacholine (table 1 and table 2). Mannitol challenge is performed by oral inhalation of a dry powder at progressively increasing doses. A 15 percent fall in FEV1 at a total cumulative dose of ≤635 mg (known as the provocative dose or PD15) is considered a positive response. (See 'Mannitol' above and 'Interpretation' above.)
●Exercise testing and eucapnic voluntary hyperpnea (EVH) are forms of bronchoprovocation used for patients with symptoms suggestive of asthma during exercise, but with normal spirometry at rest. A small portion of patients with exercise-induced bronchoconstriction have negative tests to pharmacologic bronchoprovocation tests, so exercise testing and EVH are needed for diagnostic purposes and sometimes to assess the response to therapy. (See 'Exercise challenge' above.)
●For formal exercise challenge tests, the patient is exercised on a treadmill or cycle ergometer to 80 to 90 percent of predicted maximum heart rate (220 minus age in years) 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. A test is generally considered positive if the FEV1 decreases by 10 percent, although a fall of 15 percent is more diagnostic. (See 'Exercise challenge' above and "Exercise-induced bronchoconstriction".)
●For eucapnic voluntary hyperpnea testing, the patient breathes dry hypercapnic air for six minutes at a minute ventilation of 30 times the FEV1. Spirometry is performed prior to the test, and at 5, 10, and 15 minutes after completion. A test is generally considered positive if the FEV1 decreases by 10 percent or more. (See 'Eucapnic voluntary hyperpnea' above.)
●Inhalation of nebulized allergens (eg, dust mite, animal danders, occupational agents) carries greater risk and is reserved for research purposes, occupational asthma, and rare clinical situations. (See 'Antigen challenge' above and "Occupational asthma: Clinical features, evaluation, and diagnosis", section on 'Specific inhalation challenge'.)
●The indications, contraindications, and technique of oral aspirin challenge in patients suspected of having aspirin-exacerbated respiratory disease are discussed separately. (See "Diagnostic challenge and desensitization protocols for NSAID reactions".)
●Rarely, oral challenges with food additives (eg, sodium metabisulfite) are performed in specialized laboratories for the evaluation of suspected intolerance. Oral ingestion of sulfites is thought to result in bronchoconstriction due to the inhalation of sulfur dioxide (SO2), which is produced by the acidification of metabisulfite in the stomach. (See 'Food additive challenge' above and "Allergic and asthmatic reactions to food additives", section on 'Asthmatic symptoms'.)
