Diagnostic Utility of Different Airway Resistance Assessment Techniques in the Methacholine Challenge Test

Diagnostic Utility of Different Airway Resistance Assessment Techniques in the Methacholine Challenge Test

Diagnostic Utility of Different Airway Resistance Assessment Techniques in the Evaluation of Bronchial Hyperreactivity by Methacholine Challenge Testing

The aim of the study is to compare standard spirometric evaluation of methacholine challenge test with plethysmographic, interrupter technique and forced oscillation technique (FOT) evaluation of the airways resistance. The study group will consist of patients referred for methacholine challenge test. All patient will undergo spirometric, plethysmographic, interrupter technique and FOT examinations - before and after inhalation of aerosols. Patients will also undergo the measurement of nitric oxide concentration in exhaled air and laboratory tests, including: blood count, measurement of serum C-reactive protein, sodium, potassium, creatinine, immunoglobulin E and N-Terminal pro-brain natriuretic peptide (NT-proBNP) concentration. The investigators intend to assess, if plethysmographic, and/or interrupter, and/or FOT measurement of bronchial reactivity can replace standard spirometric assessment. Plethysmography, interrupter technique and FOT are much more easier to perform for patients. Furthermore, those two techniques are less dependent on patient's motivation and cooperation ability. Thus, usage of FOT, interrupter technique and/or plethysmography in bronchial hyperreactivity testing could make methacholine challenge test more comfortable and available for more patients. The investigators are also going to analyze the relationship between exhaled nitric oxide and functional indices of bronchial hyperreactivity.

Bronchial hyperreactivity is defined as the increased respiratory tract responsiveness to multiple stimuli, which results in bronchial muscles constriction and bronchial lumen narrowing. Bronchial hyperreactivity is a hallmark of asthma, however it may also be present in other diseases, e.g. chronic obstructive pulmonary disease (COPD). Methacholine challenge test is one of the bronchial reactivity assessment methods. Methacholine acts directly on bronchial smooth muscles receptors and causes bronchoconstriction. Bronchial reactivity is increased in the presence of active inflammation. Methacholine challenge testing is commonly performed in patients with symptoms suggestive of asthma and negative result of spirometry reversibility test. The measurement of methacholine concentration which causes 20% forced expiratory volume at one second (FEV1) decrease in post-inhalation spirometry (PC20) is a standard method of hyperreactivity evaluation. However, above method could be used among patients who are able to perform acceptable spirometry. Furthermore, results of spirometry might be influenced by level of compliance and motivation of patients. Moreover, whereas spirometric methacholine challenge test has high negative predictive values, its positive predictive value is relatively low. Thus, diagnostic utility of other pulmonary function tests should be assessed in methacholine challenge test evaluation. In plethysmography airway resistance is performed during tidal breathing. The increase of specific airway resistance of 200% and the decrease of specific airway conductance of 40% after methacholine inhalation, respectively, are proposed as a cut-off levels for bronchial hyperreactivity diagnosis. In forced oscillation technique (FOT), sinusoidal oscillations are emitted by membrane into airway lumen and airway resistance is calculated on the basis of changes in air flow induced by oscillations. The increase of resistance and decrease of reactance in FOT are typical for bronchoconstriction. Finally, also interrupter technique (IT) allows for airway resistance assessment during tidal breathing. In IT, airway resistance is calculated on the basis of mouth pressure measured directly after airway occlusion and airflow measured directly before occlusion. The aim of the study is to compare standard spirometric evaluation of methacholine challenge test with plethysmographic, interrupter technique and forced oscillation technique (FOT) evaluation of the airways resistance. All patient will undergo: clinical examination measurement of nitric oxide concentration in exhaled air spirometric, plethysmographic, interrupter technique and FOT examinations - before inhalation and after inhalation of aerosols following laboratory tests: blood count, measurement of serum C-reactive protein (CRP), sodium, potassium, creatinine, immunoglobulin E and NT-proBNP concentration Patients will be provided with written and spoken information about study protocol. Written informed consent will be obtained from every patient.

Bronchial Hyperreactivity, Bronchial Provocation Tests, Methacholine Chloride, Respiratory Function Tests, Spirometry, Airway Resistance, Plethysmography

Patients will undergo Methacholine Challenge Test assessed by forced oscillation technique (FOT), plethysmography, interrupter technique and spirometry.

Forced oscillation technique test, plethysmography, interrupter technique test and spirometry will be performed in a row before any intervention and after inhalation of aerosols - normal saline, followed by increasing concentrations of methacholine: 0.03 mg/ml; 0.06 mg/ml; 0.125 mg/ml; 0.25 mg/ml, 0.5 mg/ml, 1 mg/ml, 2 mg/ml, 4 mg/ml, 8 mg/ml, 16 mg/ml. In case of FEV1 decrease of ≥ 20% of the initial value methacholine challenge test will be ceased and patient will be administered 200 µg of salbutamol in inhalation. Then, pulmonary function tests will be performed after 15 minutes.

In case of FEV1 decrease of > 20% from baseline PC (20) will be calculated by logarithmic interpolation.

Change in FOT resistance and reactance from post-diluent baseline after inhalating consecutive methacholine aerosols

Airway resistance and reactance will be measured by FOT after inhalating methacholine aerosols until FEV(1) fall of >20% from baseline

Change in plethysmographic airway resistance from post-diluent baseline after inhalating consecutive methacholine aerosols

Airway resistance will be measured by plethysmography after inhalating methacholine aerosols until FEV(1) fall of >20% from baseline

Change in interrupter airway resistance from post-diluent baseline after inhalating consecutive methacholine aerosols

Airway resistance will be measured by interrupter technique after inhalating methacholine aerosols until FEV(1) fall of >20% from baseline

FEV (1) will be measured by spirometry after inhalating methacholine aerosols until FEV(1) fall of >20% from baseline

Patients will receive visual analogue scale form assessing difficulty level and problems related to performing each test

after methacholine challenge test (up to 2 hours two hours from the start of the methacholine challenge test)

Patients will receive visual analogue scale form assessing difficulty level and problems related to performing each test

after methacholine challenge test (up to 2 hours two hours from the start of the methacholine challenge test)

Patients will receive visual analogue scale form assessing difficulty level and problems related to performing each test

after methacholine challenge test (up to 2 hours two hours from the start of the methacholine challenge test)

Patients will receive visual analogue scale form assessing difficulty level and problems related to performing each test

after methacholine challenge test (up to 2 hours two hours from the start of the methacholine challenge test)

Nitric oxide concentration in exhaled air will be measured once, immediately before performing methacholine challenge test

Participanst will undergo measurement of nitric oxide concentration in exhaled air immediately before bronchial challenge test, total time of measurement: approximately 10 minutes

Following laboratory tests will be performed: blood count, measurement of serum C-reactive protein, sodium, potassium, creatinine, immunoglobulin E and NT-proBNP concentration

Patients will undergo laboratory tests once before perfoming methacholine challenge test; maximum period between the methacholine challenge test and performing laboratory tests: one month

Inclusion Criteria: presence of asthma symptoms without confirmation of diagnosis by standard methods dyspnea and/or cough of unknown etiology Exclusion Criteria: FEV1 <1.2 L or <60% of predicted value acute heart failure myocardial infarction in last 3 months transient ischaemic attack or stroke in last 3 months aneurysms methacholine allergy pregnant and lactating women administration of β2-mimetic, anticholinergic agent or theophylline before methacholine challenge test in 6, 8 and 24 hours, respectively respiratory tract infection in last 6 weeks patient inability to cooperate

Urbankowski T, Przybylowski T. Methacholine Challenge Testing: Comparison of FEV1 and Airway Resistance Parameters. Respir Care. 2021 Mar;66(3):449-459. doi: 10.4187/respcare.08331. Epub 2020 Nov 17.