A new tidal breathing measurement device detects bronchial obstruction during methacholine challenge test.

PURPOSE: Bronchial hyperresponsiveness (BHR), a hallmark of bronchial asthma, is typically diagnosed through a methacholine inhalation test followed by spirometry, known as the methacholine challenge test (MCT). While spirometry relies on proper patients' cooperation and precise execution of forced breathing maneuvers, we conducted a comparative analysis with the portable nanomaterial-based sensing device, SenseGuard™, to non-intrusively assess tidal breathing parameters. MATERIALS AND METHODS: In this prospective study, 37 adult participants with suspected asthma underwent sequential spirometry and SenseGuard™ measurements after inhaling increasing methacholine doses. RESULTS: Among the 37 participants, 18 were MCT responders, 17 were non-responders and 2 were excluded due to uninterpretable data. The MCT responders exhibited a significant lung function difference when comparing the change from baseline to maximum response. This was evident through a notable decrease in forced expiratory volume in 1 â€‹s (FEV1) levels in spirometry, as well as in prominent changes in tidal breathing parameters as assessed by SenseGuard™, including the expiratory pause time (Trest) to total breath time (Ttot) ratio, and the expiratory time (Tex) to Ttot ratio. Notably, the ratios Trest/Ttot (∗p â€‹= â€‹0.02), Tex/Ttot (∗p â€‹= â€‹0.002), and inspiratory time (Tin) to Tex (∗p â€‹= â€‹0.04) identified MCT responders distinctly, corresponding to spirometry (∗p â€‹< â€‹0.0001). CONCLUSIONS: This study demonstrates that tidal breathing assessment using SenseGuard™ device reliably detects clinically relevant changes of respiratory parameter during the MCT. It effectively distinguishes between responders and non-responders, with strong agreement to conventional spirometry-measured FEV1. This technology holds promise for monitoring clinical respiratory changes in bronchial asthma patients pending further studies.

Correlation of spirometry and body plethysmography during exercise-induced bronchial obstruction.

BACKGROUND: The exercise challenge is the gold standard for diagnosing exercise-induced bronchoconstriction (EIB). Airway obstructions appear up to 30 min after the challenge, with a maximum decrease in spirometry and a maximum increase in airway resistance. There is evidence that changes in body plethysmography parameters are more sensitive to the exercise challenge and precede those in spirometry. PURPOSE: To compare changes in body plethysmography and spirometry parameters after exercise challenges and to verify the cut-off values of sReff in EIB. PROCEDURES: In 82 subjects with suspected EIB, a total of 473 lung function tests were measured at baseline and at 5, 10, 15, and 30 min after exercise challenges at different stages of bronchial obstruction. FINDINGS: The maximum changes in the body plethysmography parameter sReff significantly preceded the maximum changes in the spirometry parameter FEV1 (sReff: 12.2 min ±8.8, FEV1: 15.2 min ±9.3, p < 0.005). The parameters of sReff and FEV1 had a strong negative correlation (r = -0.63, p < 0.0001) with a nonlinear, polynomial relationship. Furthermore, sReff and Reff had a strong linear correlation (r = 0.86, p < 0.001), and Reff and Rtot had a perfect linear correlation (r = 0.99, p < 0.001). Based on baseline values and on quantile regression, an increase of 0.25 kPa s in sReff was defined as significant. Using this cut-off value, FEV1 and sReff almost equally detected EIB. CONCLUSION: The changes in sReff were more sensitive and better indicated lung impairment than did the changes in FEV1, which underestimated the degree of hyperinflation.

[Environmental exposure chambers (EEC): A novel tool for pathophysiological and pharmaceutical research]. / Les chambres d'exposition environnementale (CEE) : un nouvel outil dans la recherche académique et industrielle.

Airborne allergic diseases (allergic asthma, rhinitis and conjunctivitis) have reached epidemic proportions and are a great burden for both society and individuals. Therefore we need to better understand the physiopathological mechanisms and to increase clinical research in these diseases. However, traditional outpatient studies are difficult and have number of limitations, in particular the variability of allergen exposure. Yet allergen provocation tests, especially bronchial challenges in asthma, are excellent tools to measure the efficiency of anti-allergic therapies. Environmental exposure chambers (EEC) allow the performance of controlled allergen provocation tests on a large scale with remarkable sensitivity, specificity and reproducibility. Moreover, they allow a precise collection of allergic symptoms, making them interesting tools for patho-physiological and clinical studies. During the last thirty years, they have assisted the study of anti-allergic therapies and provided data on their pharmacodynamic characteristics, particularly in allergic rhinitis. However, there are still no EEC tests centered on asthma. The EEC of Strasbourg (ALYATEC®) was developed to fulfill two objectives: to allow standardized allergenic and non-allergenic exposures with better control of the parameters than in other EEC and to offer a place to study asthma and anti-asthmatic therapies safely.

Testing for Exercise-Induced Bronchoconstriction.

Exercise-induced bronchoconstriction (EIB) is a form of airway hyperresponsiveness that occurs with or without current symptoms of asthma. EIB is an indicator of active and treatable pathophysiology in persons with asthma. The objective documentation of EIB permits the identification of an individual who may be at risk during a recreational sporting activity or when exercising as an occupational duty. EIB can be identified with laboratory exercise testing or surrogate tests for EIB. These include eucapnic voluntary hyperpnea and osmotic stimuli (eg, inhaled mannitol) and offer improved diagnostic sensitivity to identify EIB and improved standardization when compared with laboratory exercise.

Methacholine Challenge: Comparison of Airway Responsiveness Produced by a Vibrating Mesh Nebulizer Versus a Jet Nebulizer.

BACKGROUND: The latest methacholine challenge testing (MCT) guidelines published by the European Respiratory Society recommend the characterization of nebulizers before their use in clinics and research. Such investigations are necessary for accurately determining the provocative dose of methacholine causing a 20% fall in FEV1 (PD20) delivered by a given device. The standard English Wright (Wright) jet nebulizer recommended in the 1999 guidelines by the American Thoracic Society has become difficult to obtain and possesses some characteristics that complicate the calculation of dose delivery from this device (e.g. evaporation). Our objective was to determine if the Aerogen® Solo (Solo) vibrating mesh nebulizer provides similar methacholine challenge test results compared to the currently used Wright jet nebulizer. METHODS: Sixty mild-to-moderate asthmatics were studied across three research sites in a randomized crossover study. Both methacholine challenges were completed at least 24 hours apart within a 2-week period. Testing with the Wright device was performed as per the 2-minute tidal breathing protocol. The Solo study arm followed the same procedure except for a shorter inhalation time of 1 minute. The provocative concentration of methacholine causing a 20% fall in FEV1 (PC20) and the methacholine PD20 were calculated following each methacholine challenge. RESULTS: The geometric mean methacholine PC20 values for the Solo and the Wright differed statistically (0.65 mg/mL vs. 2.58 mg/mL, respectively, p < 0.00001) and clinically. Between-nebulizer geometric mean methacholine PD20 results are comparable by clinical standards [81.7 µg (Solo) vs. 64.7 µg (Wright)], although the slight difference in dose was statistically significant (p = 0.018). CONCLUSIONS: The comparability of PD20 values between the Solo and the Wright validates the importance of reporting airway responsiveness to methacholine in terms of dose and not concentration, as stressed in the latest testing guidelines. This finding along with several benefits associated with the Solo make it a promising nebulizer for performing MCT.

A novel reflex cough testing device.

BACKGROUND: The reflex cough test is useful for detecting silent aspiration, a risk factor for aspiration pneumonia. However, assessing the risk of aspiration pneumonia requires measuring not only the cough reflex but also cough strength. Currently, no reflex cough testing device is available that can directly measure reflex cough strength. We therefore developed a new testing device that can easily and simultaneously measure cough strength and the time until the cough reflex, and verified whether screening with this new instrument is feasible for evaluating the risk of aspiration pneumonia. METHODS: This device consists of a special pipe with a double lumen, a nebulizer, and an electronic spirometer. We used a solution of prescription-grade L-tartaric acid to initiate the cough reflex. The solution was inhaled through a mouthpiece as a microaerosol produced by an ultrasonic nebulizer. The peak cough flow (PCF) of the induced cough was measured with the spirometer. The 70 patients who participated in this study comprised 49 patients without a history of pneumonia (group A), 21 patients with a history of pneumonia (group B), and 10 healthy volunteers (control group). RESULTS: With the novel device, PCF and time until cough reflex could be measured without adverse effects. The PCF values were 118.3 ± 64.0 L/min, 47.7 ± 38.5 L/min, and 254.9 ± 83.8 L/min in group A, group B, and the control group, respectively. The PCF of group B was significantly lower than that of group A and the control group (p < 0.0001), while that of group B was significantly lower than that of the control group (p < 0.0001). The time until the cough reflex was 4.2 ± 5.9 s, 7.0 ± 7.0 s, and 1 s in group A, group B, and the control group, respectively. This duration was significantly longer for groups A and B than for the control group (A: p < 0.001, B: p < 0.001), but there was no significant difference between groups A and B (p = 0.0907). CONCLUSION: Our newly developed device can easily and simultaneously measure the time until the cough reflex and the strength of involuntary coughs for assessment of patients at risk of aspiration pneumonia.

Aerosol Use in the Pulmonary Function Lab.

Aerosolized medications are frequently used in the pulmonary function laboratory. The 2 most common implementations are bronchodilators and bronchial challenge agents. Bronchodilator administration is not well standardized, largely because of the various methods of delivery available for clinical practice. Metered-dose inhalers used with spacer devices are the most common route for bronchodilator administration, but many laboratories use small-volume nebulizers. Interpretation of pre- and post-bronchodilator studies is confounded by the definitions of airway obstruction and bronchodilator responsiveness. Protocols for administering bronchial challenge aerosols (methacholine, mannitol, hypertonic saline) are well defined but are susceptible to some of the same problems that limit comparison of bronchodilator techniques. Bronchial challenges with inhaled aerosols are influenced not only by the delivery device but by the patient's breathing pattern, particularly in protocols that include deep inspiratory efforts.

In vivo diagnosis of allergic diseases--allergen provocation tests.

The allergen challenge test has been the mainstay of diagnosis of allergic diseases for a long time since it offers a direct proof of the clinical relevance of a particular allergen for the allergic disease symptoms and severity. Standardisation and availability for daily practice (including safety issues) are still to be refined but most of the challenge tests have safely crossed the border from research tools to diagnostic tests available for daily practice for a well trained clinical staff.

Adenosine dry powder inhalation for bronchial challenge testing, part 1: inhaler and formulation development and in vitro performance testing.

Dry powder administration of adenosine by use of an effective inhaler may be an interesting alternative to nebulisation of adenosine 5'-monophosphate in bronchial challenge testing, because of a shorter administration time and more consistent delivered fine particle dose over the entire dose range. In this study, we tested various powder formulations and classifier based dispersion principles and investigated the in vitro performance of the most promising formulation/classifier combination in a new test inhaler system. Spray-dried formulations of either pure adenosine (100%) or adenosine and lactose as diluent (1% and 10% adenosine) were prepared to cover the entire expected dose range for adenosine (0.01-20mg). All three powders, in all 12 suggested doses, dispersed well with the newly developed test inhaler with a multiple air jet classifier disperser, into aerosols with an average volume median diameter of 3.1µm (3.0-3.3µm). For eleven out of 12 dose steps, the fine particle fractions<5µm as percent of the loaded dose varied within the range of 67-80% (mean: 74%). The new test concept allows for more consistent aerosol delivery over the entire dose range with narrower size distributions than nebulisation and thus may improve adenosine administration in bronchial challenge testing.

Impulse oscillometry for leukotriene D4 inhalation challenge in asthma.

BACKGROUND: The value of impulse oscillometry (IOS) for bronchial provocation testing is poorly defined. We investigated the positive threshold derived from the parameters and diagnostic power of IOS for asthma with the leukotriene D(4) bronchial provocation test. METHODS: We enrolled 62 subjects with asthma and 21 healthy subjects. IOS was employed to perform the leukotriene D(4) bronchial provocation test, followed by spirometry. The positive threshold was determined based on the cutoff point in the receiver operating characteristic curve, from which the parameters with the highest diagnostic power were obtained. RESULTS: Airway impedance at 5 Hz (Z(5)), resistance at 5 Hz (R(5)), and resonance frequency had the highest diagnostic power (areas under curve 0.82, 0.82, and 0.81, respectively), with increases of 57%, 43%, and 63%, corresponding to a 20% decrease in FEV(1), respectively. IOS indices yielded assay sensitivity and specificity similar to that of spirometry. The positive threshold for IOS, defined as either a 57% increase in Z(5) or a 63% increase in resonance frequency in the bronchial provocation test, yielded an assay accuracy of 0.6 in subjects with asthma. CONCLUSIONS: IOS during the leukotriene D(4) bronchial provocation test has a diagnostic power similar to that of spirometry. Either a 57% increase in Z(5) or a 63% increase in resonance frequency may be regarded as a surrogate of FEV(1) decrease to determine airway hyper-responsiveness in asthma.

Bronchial allergen challenge using the Medicaid dosimeter.

BACKGROUND: Bronchial allergen provocations are well established in asthma research. We evaluated the reproducibility of single-concentration, single-step allergen challenges in volunteers with grass pollen allergy. METHODS: Forty-seven subjects underwent bronchial challenges using the aerosol provocation system nebulizer (Medicaid Sidestream) with incremental doses of grass pollen to define the individual allergen dose that causes a 20% drop in FEV(1) (PD(20)FEV(1)). In 39 subjects this procedure was followed by single-step challenges. Early and late asthmatic responses were monitored, and increases in exhaled nitric oxide were measured before and 24 h after single-step challenges. RESULTS: After the first single-step challenge, the maximum drop in FEV(1) was 21.3% ± 8.0. A comparison of the drop in FEV(1) to the initial incremental challenge (29.7% ± 7.5) revealed an intraclass correlation of -0.30 (p < 0.05). In the second single-step challenge, the mean drop in FEV(1) was 20.9% ± 7.2. Compared with the first single-step challenge, the intraclass correlation was 0.37 (p < 0.05) and the 95% limits of agreement according to Bland and Altman were -17.5 to 18.1%. The increases in exhaled nitric oxide revealed substantial agreement in repeated single-step challenges (26.8 ppb ± 27.8 and 21.8 ppb ± 21.9, ICC 0.62, p < 0.001). CONCLUSIONS: The use of aerosol provocation system to calculate the PD(20)FEV(1) allergen is a timesaving procedure and is less prone to errors because only one dilution of the allergen is used. The repeatability in well-defined subjects is excellent to study the mechanisms of allergen-induced airway inflammation and the development of new treatments for allergic diseases.

New methodology for specific inhalation challenges with occupational agents.

BACKGROUND: Inhalation challenges are used for diagnosing occupational asthma (OA). The initial methodology consisted of a "realistic" exposure without monitoring nor controlling exposure. Our aim was to design an equipment, called the GenaSIC, that allows the generation of various agents regardless of the formulation and to assess the feasibility of its use in patients investigated for OA. RESULTS: GenaSIC can generate lactose, flour, malt, isocyanates, formaldehyde and N-butyl acetate with precise and fairly stable concentrations. Using N-butyl-acetate as a control agent and real time measurement, we show that normal breathing has a negligible effect on the concentration. We exposed forty-four different subjects to a control agent and/or to a suspected occupational agent. Nineteen of the subjects were only exposed to N-butyl acetate as a control agent without experiencing any significant irritant effect (no significant changes in spirometry thereafter). Eight subjects who were exposed to both N-butyl acetate and formaldehyde did not show significant reactions. Seven subjects were exposed to dry particles (flour in six instances, malt in the other) and five showed immediate asthmatic reactions which changes in FEV1 from 20% to a maximum of 28%. Finally, ten subjects were exposed to isocyanates, four of whom showed a positive reaction, including one subject with immediate maximum changes in FEV1 of 22%. CONCLUSION: GenaSIC offers the possibility of reliable and safe exposures to dry particles, formaldehyde and isocyanates in the investigation of OA.

Assessing the effectiveness of intubation as a challenge model in contagious bovine pleuropneumonia vaccine experiments.

A study was carried out to assess the effectiveness of a bronchoscope in administering a pathogenic field strain of Mycoplasma mycoides subsp. mycoides (MmmSC) in cattle challenge experiments. Out of 16 animals inoculated using the bronchoscope, 10 (62.2%) showed clinical disease as evidenced by fever and 15 (93.8%) displayed typical lesions of CBPP from which MmmSC was isolated. Serum samples collected weekly were tested by Complement Fixation Test (CFT) and competitive enzyme-linked immunosorbent assay (c-ELISA). Antibodies to MmmSC were detected in 10 out of the 16 animals by the CFT and 11 out of the 16 animals by c-ELISA. The onset of clinical disease was as early as 2 days post-inoculation, and most of the animals developed clinical disease 2 to 3 weeks post-infection. These results clearly demonstrate that nasotracheal inoculation of pathogenic strain of MmmSC with the aid of a bronchoscope can lead to early onset of clinical disease; similar to previous studies but with higher numbers of animals showing clinical disease. This is in contrast with previous studies where early clinical disease was observed in as little as 15% of inoculated animals. This nasotracheal inoculation method using a bronchoscope can, therefore, be adopted for use in experimental challenge infections of cattle. This method is found to be a better replacement to the contact transmission method whose drawback includes extra cost of donor animals and unpredictable rate and timing of transmission from intubated to challenge animals.

Interrupter technique and pressure oscillation analysis during bronchoconstriction in children.

The use of interrupter resistance (R(int)) is a feasible method of measuring bronchodilator responsiveness and bronchial hyperresponsiveness in preschool children. It has been suggested that analysis of recorded oscillations of the mouth pressure may provide additional indices of changes in airway mechanics. The aim of our study was to determine whether amplitude or damping properties of oscillations were more sensitive than R(int) in describing changes during bronchoconstriction. Data from 44 children (24 boys) who completed tripling dose methacholine (Mch) challenge were analysed. The median (range) age of children was 4.9 (3.1-6.1 years). In addition to baseline and maximal R(int) after Mch [mean (SD) were 0.92 (0.19) and 1.44 (0.35) kPa l(-1) s, respectively], obtained from a commercial device we analysed the following parameters: difference between the first maximum and minimum (A(MxMn)), maximum instantaneous amplitude (A(inst)), amplitudes of fitted mathematical model and the dominant frequency, sum of frequency component amplitudes, two damping factors and frequency. All amplitude parameters changed significantly after Mch. For comparison of the decrease in amplitudes and increase in R(int) we additionally used reciprocals of amplitudes. Using the sensitivity index (SI) i.e. the change after intervention divided by the baseline SD, 1/A(inst) and 1/A(MxMn) were the most sensitive indices to describe the change (with median SI of 6.29 and 6.28, respectively). R(int) had a median SI of 5.13. Frequency and damping factors were less sensitive, with median SI values <1. These findings suggest that oscillation amplitude analysis implemented in the software of commercial devices could have further applications in assessing respiratory mechanics.

Capsaicin provocation using two different inhalation devices.

BACKGROUND: Sensory hyperreactivity (SHR) has been suggested as one explanation for chemically induced airway symptoms; it can be diagnosed with a capsaicin inhalation test. Previous capsaicin inhalation studies of SHR have used a Pari Boy device. This model of inhalator device has become outdated, hence it is necessary to abandon it in favour of a new device. The aim of this study was to transfer the capsaicin inhalation test using the Pari Boy device to a corresponding model using the Maxin MA3 device. METHODS: Twenty-one patients with SHR and 44 healthy controls visited the clinic twice and underwent a randomised protocol. The participants were provoked with saline and capsaicin using one of two devices, Pari Boy and Maxin MA3. Eight patients also underwent two additional capsaicin provocations with Maxin MA3. A new series of capsaicin concentrations was chosen for Maxin MA3. The results from each device were analysed, the agreement between the two devices and the repeatability of the Maxin MA3 were evaluated. RESULTS: Among all participants, the mean number of coughs with the Pari Boy was 5.5 (95% CI: 2.7; 8.2) after inhalation of 0.4 micromol/L capsaicin and 20.0 (95% CI: 14.1; 25.9) after 2.0 micromol/L. With the Maxin MA3, the mean number of coughs was 3.6 (95% CI: 1.3; 4.0) after 0.06 micromol/L capsaicin, and 17.8 (95% CI: 12.0; 23.6) after 0.3 micromol/L. The Maxin MA3 showed good repeatability and the agreement between the devices with the capsaicin concentrations chosen for each device was considered to be good.

Methacholine dry powder inhaler as a new tool for bronchial challenge test.

BACKGROUND: The methacholine (MCH) challenge test is performed to detect bronchial hyperresponsiveness in subjects suffering from asthma. It is conducted by inhaling spasmogen substances at increasing doses and measuring FEV1-PD20 variation following the bronchoconstriction evoked. AIM: This paper describes a new method for MCH challenge test using pre-metered respirable powders of MCH at different doses for facilitating test execution. The availability of a series of pre-metered doses gives higher control over aerosolized dose and fine particle fraction (respirable dose), improving the accuracy and repeatability of the test. Dosimetric tests with MCH solution and pre-dosed powder challenge tests were clinically compared. METHODS AND MATERIALS: The inhalation powders were prepared by spray drying of solutions of methacholine, mannitol and hydroxypropylmethylcellulose in which different concentrations of MCH were included. The methacholine powders prepared were carefully characterized in terms of aerodynamic properties. RESULTS: Inhalation powders containing methacholine from 12.5 to 200 microg per metered dose, having a fine particle fraction between 40 and 60%, were prepared using mannitol and cellulose polymer. Eighteen subjects (12 hyperresponsive and six normal) were subjected to both the MCH solution and powder tests in random sequence. No significant differences in FEV1 and PD20 values were found between the challenge tests performed with liquid and powder formulations of methacholine. CONCLUSIONS: Powders of MCH having high respirability of the delivered doses can be prepared by spray drying. They allow for the performance of a challenge test using a dry powder inhaler. The powder dose series can be an alternative to the current dosimetric test with MCH solutions.