Measurements Of Airway Responsiveness Research Articles

Effects of Concentrated Ambient Particles on Airway Responsiveness and Pulmonary Inflammation in Pulmonary Hypertensive Rats

Epidemiological studies have associated particulate air pollution with exacerbation of lung function in human populations. However, the relationship between ambient particles and lung function in animal studies has been inconsistent. In order to investigate the effects of concentrated ambient particles (CAPs) on airway responsiveness, we exposed pulmonary hypertensive rats to CAPs using particle concentrator at an EPA of Taiwan supersite, located at a traffic busy urban area nearing Taipei city. The exposure group (n = 5) was exposed to CAPs for 6 h each day for 3 consecutive days (mean mass concentration = 371.7 μ g/m3), while a control group (n = 6) was exposed to HEPA-filtered air. Whole-body barometric plethysmography was used to measure respiratory frequency, tidal volume, and airway responsiveness before and after exposure. Enhanced pause (Penh) was used as an indicator of airway responsiveness. To improve the accuracy of airway responsiveness measurement, we controlled temperature and humidity. Further, airway responsiveness was determined 5 h after particle exposure to overcome the stress effect in nose-only exposure chambers. After CAPs exposure, we found decreased respiratory frequency and increased tidal volume (p <. 05). Using the methacholine challenge test, a significant difference of Penh measured before and after experiment was observed in the CAPs group (p <. 05), but not in the filtered air group. Further analysis showed that the Penh difference before and after exposure in the CAPs group was significantly greater than that in the filtered air group (p <. 05). We conclude that CAPs could induce airway hyperresponsiveness in pulmonary hypertensive rats.

Rhinovirus-induced interferon-gamma and airway responsiveness in asthma.

The majority of asthma exacerbations are caused by respiratory infections, with rhinovirus (RV) being the most common virus. Recent evidence has suggested that decreased generation of IFN-gamma is associated with more severe colds and delayed elimination of virus. Whether the generation of IFN-gamma also has any relationship to general features of asthma severity has yet to be determined. To evaluate this hypothesis, peripheral blood mononuclear cells from 19 subjects with atopy and asthma were incubated with RV16 for 6 days to determine IFN-gamma and interleukin (IL)-5 production; these responses were then compared with measurements of airflow obstruction and airway responsiveness. RV16-induced IFN-gamma production correlated significantly with the methacholine PD (r = 0.50, p = 0.03), and the ratio of RV16-induced IFN-gamma:IL-5 correlated with % predicted FEV1 (r = 0.53, p = 0.02). In contrast, there were no significant associations between measures of asthma severity and RV-induced IL-5. These findings suggest that a cytokine imbalance with a deficient Th1 response to RV, but not a Th2 response, is associated with measures of asthma severity and support the concept that impaired antiviral responses may be associated with asthma severity.

Correction of bronchial challenge data for age and size may affect the results of genetic association studies in children.

Meaningful studies of asthma genetics require careful definition of airway hyperresponsiveness (AHR). In children, several studies have emphasized the need for correction of bronchial challenge data for baseline parameters, such as age, gender, lung function and atopic status, when undertaking airway responsiveness measurements. However, few studies have suggested how this should be performed in practice. This study describes a method for the correction of dose-response slopes (DRS) and PC20 values for baseline parameters in children, and illustrates the effect of such corrections on the association of AHR with the glutathione S-transferase GSTP1 Ile105Val polymorphism in children. Skin prick and methacholine challenge testing, measurement of total serum IgE concentration and GSTP1 genotyping were performed in 145 unrelated British children aged 7-18 years. Correction of bronchial challenge results, expressed as both DRS and PC20 values, for age, gender, baseline lung function and atopic status was performed using linear regression and discriminant analysis, respectively. Adjusting bronchial challenge results for the age and size of the child altered AHR status, defined as a PC20 methacholine <8 mg/ml, in 37% of children. Correction for baseline parameters also resulted in a significant reduction in mean DRS (original uncorrected DRS 83.6, corrected DRSc 27.4). This had a marked effect on the results of the association study, unmasking a previously unidentified association between the GSTP1 genotype and AHR in children. Age and size adjustment of bronchial challenge data has a significant effect on AHR status and may influence the results of genetic association studies in children.

Airway Hyperresponsiveness

Airway hyperresponsiveness is a characteristic feature of asthma and consists of an increased sensitivity of the airways to an inhaled constrictor agonist, a steeper slope of the dose-response curve, and a greater maximal response to the agonist. Measurements of airway responsiveness are useful in making a diagnosis of asthma, particularly in patients who have symptoms that are consistent with asthma and who have no evidence of airflow obstruction. These tests can be performed quickly, safely, and reproducibly. Certain inhaled stimuli, such as environmental allergens, increase airway inflammation and enhance airway hyperresponsiveness. These changes in airway hyperresponsiveness are of much smaller magnitude than those seen when asthmatic patients with persistent airway hyperresponsiveness are compared to healthy subjects. They are, however, similar to changes occurring in asthmatic patients that are associated with worsening asthma control. The mechanisms of the transient allergen-induced airway hyperresponsiveness are not likely to fully explain the underlying mechanisms of the persistent airway hyperresponsiveness in asthmatic patients.

Bronchial hyperresponsiveness in patients with squamous cell lung cancer.

The aim of this study was to examine the relationship between bronchial hyperresponsiveness, both in vivo and in vitro, and the type of lung cancer (squamous cell or adenocarcinoma). We measured airway responsiveness by methacholine inhalation test in 33 patients with squamous cell lung cancer and 44 patients with lung adenocarcinoma. In addition, airway smooth muscle reactivity to acetylcholine was measured in vitro in specimens from some patients. Seventeen of 33 patients with squamous cell cancer and three of 44 patients with adenocarcinoma showed bronchial hyperresponsiveness (BHR). Multiple regression analysis as used to assess the log of the minimum cumulative dose to decrease respiratory conductance vs six variables: cancer phenotype, FEV1 (% predicted), FEV1/FVC (%), smoking pack years, gender and the location of tumour. The phenotype (squamous cell cancer) was the only factor associated with BHR. However, there was no significant difference in airway smooth muscle reactivity to acetylcholine in vitro in bronchial muscle samples from squamous cell cancer patients (n = 6) and adenocarcinoma patients (n = 6). The present findings suggest that bronchial hyperresponsiveness in patients with squamous cell lung cancer is not determined solely by bronchial smooth muscle hyperreactivity.

Subject discomfort associated with the histamine challenge in a population study

Background: Many review articles report the safety and lack of serious side-effects associated with the histamine challenge. Even though methacholine and hypertonic saline are more commonly used to measure airway responsiveness, histamine challenges are used in many countries around the world. Levels of subjects discomfort after a challenge have not been quantified. This study quantified the incidence, severity and duration of subject discomfort after histamine challenge. Methods: Ninety-nine subjects were recruited in an Australian multi-centre population-based study of the genetic epidemiology of asthma. Subjects completed a histamine challenge with final cumulative dose 3.2μmol. Immediately, and 10min, after challenge subjects rated their discomfort for cough, headache, throat irritation, hoarse voice and flushed. Research personnel also reported their perception of subject discomfort. Results: Subjects and research personnel reported a small degree of subject discomfort for all symptoms immediately after the histamine challenge. Overall, median symptom scores were less than 1.5 out of 10. Discomfort scores improved 10min after challenge and cough, throat irritation and flushed improved significantly. Conclusions: This study confirms the tolerability of the histamine challenge.

Noninvasive measurement of midexpiratory flow indicates bronchoconstriction in allergic rats

This study was designed to evaluate the value and applicability of tidal breathing pattern analysis to assess bronchoconstriction in conscious rats. Using noninvasive, head-out body plethysmography and the decrease in tidal midexpiratory flow (EF(50)), we measured airway responsiveness (AR) to inhaled acetylcholine and allergen in conscious Brown-Norway rats, followed by invasive determination of pulmonary conductance (GL) and EF(50) in anesthetized rats. Dose-response studies to acetylcholine showed that noninvasively recorded EF(50) closely reflected the dose-dependent decreases observed with the invasive monitoring of simultaneously measured GL and EF(50). After sensitization and intratracheal boost to ovalbumin or saline, rats were assessed for early and late AR to aerosolized ovalbumin. Ovalbumin aerosol challenge resulted in early and late AR in allergen-sensitized rats, whereas controls were unresponsive. The allergen-specific AR, as measured noninvasively by EF(50), was similar in degree compared with invasively recorded EF(50) and GL and was associated with enhanced IgE and airway inflammation. We conclude that EF(50) is a noninvasive and physiologically valid index of bronchoconstriction in a rat model of asthma.

Outpatient monitoring of asthma.

Monitoring asthma outcomes is an essential step to the successful implementation of national asthma guidelines. Symptoms, airflow obstruction and exacerbations can be monitored by patients with asthma and by physicians. Patients who practise self-monitoring in conjunction with use of a written action plan and regular medical review have significantly fewer hospitalizations, emergency room visits and lost time from work. Additional monitoring tools are under evaluation, and these include measures of airway responsiveness, airway inflammation, and Internet-based monitoring systems.

European Community Respiratory Health Survey calibration project of dosimeter driving pressures.

Two potential sources of systematic variation in output from Mefar dosimeters, the system used in the European Community Respiratory Health Survey (ECRHS) study have been evaluated: individual nebulizer characteristics and dosimeter driving pressure. Output variation from 366 new nebulizers produced in two batches for the second ECRHS were evaluated, using a solute tracer method, at a fixed driving pressure. The relationship between dosimeter driving pressure was then characterized and between-centre variation in dosimeter driving pressure was evaluated in an Internet-based survey. A systematic difference between nebulizers manufactured in the two batches was identified. Batch one had a mean+/-SD output of 7.0+/-0.8 mg x s(-1) and batch two, 6.3+/-0.7 mg x s(-1) (p<0.005). There was a wide range of driving pressures generated by Mefar dosimeters as set, ranging between 70-245 kPa, with most outside the quoted manufacturer's specification of 180+/-5%. Nebulizer output was confirmed as linearly related to dosimeter driving pressure (coefficient of determination (R2)=0.99, output=0.0377 x driving pressure-0.4151). The range in driving pressures observed was estimated as consistent with a variation of about one doubling in the provocative dose causing a 20% fall in forced expiratory volume in one second. Systematic variation has been identified that constitutes potentially significant confounders for between-centre comparisons of airway responsiveness in the European Community Respiratory Health Survey, with the dosimeter driving pressure representing the most serious issue. This work confirms the need for appropriate quality control of both nebulizer output and dosimeter driving pressure, in laboratories undertaking field measurements of airway responsiveness. In particular, appropriate data on driving pressures need to be collected and factored into between-centre comparisons. Comprehensive collection of such data to optimize quality control is practicable and has been instigated by the organizing committee for the European Community Respiratory Health Survey II.

Airway responsiveness and peak flow variability in the diagnosis of asthma for epidemiological studies.

Airway responsiveness and variability in peak expiratory flow (PEF) are widely used as objective diagnostic measures of asthma, but it is not clear how these variables should be calculated or adjusted to obtain the highest diagnostic validity for physician-diagnosed asthma in the community. Data from a community-based sample of 1,513 adults has been used. Airway responsiveness to methacholine and 7-day PEF data were obtained in 1991, asthma and respiratory symptoms were diagnosed by questionnaires in 1991 and 1999. Airway responsiveness was expressed as the provocative dose causing a 20% fall in forced expiratory volume in one second (PD20), two-point and least-squares regression slopes. PEF variability was expressed as daily amplitude, weekly standard deviation and mean of the two lowest readings. Continuous measures were adjusted for measures of baseline airway calibre by linear regression. Measures of airway responsiveness had greater sensitivity for specificity for self-reported diagnosed asthma than expressions of PEF variability, before and after adjustment for airway calibre. Diagnostic validity was substantially better in adults aged <50 yrs; PD20 provided the best sensitivity for specificity (61% for 95% at 8.3 micromol). In those aged > or =50 yrs, no measure was closely related to diagnosed asthma. In younger age groups, provocative dose causing a 20% fall in forced expiratory volume in one second provides a valuable objective measure of asthma for epidemiological studies, but is unable to distinguish between asthma and chronic obstructive pulmonary disease in older people.

Asthma outcome measures

Asthma outcome measures

Measurements of resistance by the interrupter technique and of transcutaneous partial pressure of oxygen in young children during methacholine challenge.

Measurement of bronchial airway responsiveness requires noninvasive techniques in young children. The study was designed to examine the changes in resistance as measured using the interrupter technique (Rint) at the dose of methacholine (M) that induced a fall in transcutaneous partial pressure in O2 (P(tc)O2) > or = 20% (PD(20)P(tc)O2) in young children. Rint was calculated using the linear back-extrapolation method (Rint(L)) and the end-interrupter method (Rint(EI)). Twenty-two children (mean age, 5.2 +/- 1.1 years; range, 3.4 - 7.1 years) with nonspecific respiratory symptoms (mainly chronic cough, n = 17) were tested. P(tc)O2, Rint(L), and Rint(EI) were measured before the test, after saline challenge (baseline (B)), after each dose of M delivered by a dosimeter, and after bronchodilator (BD) inhalation. P(tc)O2 decreased significantly during M challenge, from 85 +/- 6 mmHg (B) to 62 +/- 9 mmHg (P < 0.05), and increased after BD inhalation, to 82 +/- 8 mmHg. Rint(L) and Rint(EI) increased significantly during M challenge, from 0.94 +/- 0.2 KPa/L/s and 1.11 +/- 0.19 KPa/L/s (B) to 1.27 +/- 0.35 KPa/L/s and 1.47 +/- 0.37 KPa/L/s, respectively (P < 0.05), and decreased after BD inhalation to 0.80 +/- 0.17 KPa/L/s and 0.95 +/- 0.18 KPa/L/s, respectively. Nineteen of 22 children reached the PD(20)P(tc)O2 at a dose of M ranging from 50-400 microg. At the PD(20)P(tc)O2, significant changes in Rint(L) and Rint(EI) (sensitivity index (SI) > or = 2) were found in 79% and 63% of children, respectively. We conclude that: 1) M challenge using P(tc)O2 is safe in young children; and 2) our findings are not in favor of the use of Rint as the only indicator of bronchial reaction in young children during M challenge.

Tidal midexpiratory flow as a measure of airway hyperresponsiveness in allergic mice.

A method for the noninvasive measurement of airway responsiveness was validated in allergic BALB/c mice. With head-out body plethysmography and the decrease in tidal midexpiratory flow (EF(50)) as an indicator of airway obstruction, responses to inhaled methacholine (MCh) and the allergen ovalbumin were measured in conscious mice. Allergen-sensitized and -challenged mice developed airway hyperresponsiveness as measured by EF(50) to aerosolized MCh compared with that in control animals. This response was associated with increased allergen-specific IgE and IgG1 production, increased levels of interleukin-4 and interleukin-5 in bronchoalveolar lavage fluid and eosinophilic lung inflammation. Ovalbumin aerosol challenge elicited no acute bronchoconstriction but resulted in a significant decline in EF(50) baseline values 24 h after challenge in allergic mice. The decline in EF(50) to MCh challenge correlated closely with simultaneous decreases in pulmonary conductance and dynamic compliance. The decrease in EF(50) was partly inhibited by pretreatment with the inhaled beta(2)-agonist salbutamol. We conclude that measurement of EF(50) to inhaled bronchoconstrictors by head-out body plethysmography is a valid measure of airway hyperresponsiveness in mice.

Increased airway responsiveness and decreased alveolar attachment points following in utero smoke exposure in the guinea pig.

Maternal smoking during pregnancy has been shown to result in abnormalities in lung function in newborn infants, including reduced expiratory flow and increased airway responsiveness to inhaled agonists. The mechanisms by which this occurs remain unclear. Using a guinea pig model of in utero smoke exposure, we measured airway responsiveness and lung morphology in a group of neonatal guinea pigs 21 d after delivery. Pregnant guinea pigs were exposed to cigarette smoke from Day 28 to term (Day 68 of gestation). After delivery newborn animals did not receive any smoke exposure. Airway wall thickness, smooth muscle area, and the number of points where the alveoli attached to the airway adventitia were measured. Airway responsiveness was increased (p < 0.05) and the mean distance between alveolar attachment points was increased (mean 0.052 +/- SE 0.001 mm versus 0.046 +/- 0.001, p = 0.001) in animals exposed to cigarette smoke in utero compared with nonexposed animals. Although not statistically significant, both the inner and outer airway wall and the smooth muscle area were greater in exposed animals compared with nonexposed animals. The increased mean distance between alveolar attachments in the smoke-exposed group was the result of a reduction in the number of attachments and an increase in the outer airway wall perimeter. These findings suggest that the increased airway responsiveness observed in postnatal animals, subsequent to in utero cigarette smoke exposure, may be the result of decreased alveolar attachment points to the airways and changes in airway dimensions.

Monitoring the patient with asthma: An evidence-based approach

The monitoring of symptoms, airflow obstruction, and exacerbations is essential to asthma management. Patients who practice self-monitoring in conjunction with use of a written action plan and regular medical review have significantly fewer hospitalizations, emergency department visits, and lost time from work. Either symptom monitoring or peak expiratory flow monitoring is satisfactory, provided the results are interpreted with reference to the patient’s own baseline asthma status. Regular monitoring by physicians also improves health outcomes for patients, provided the physician is systematic and monitors control, medications, and skills at regular intervals. Additional monitoring tools are under evaluation, and these include measures of airway responsiveness, airway inflammation, and Internet-based monitoring systems. Administrators need to monitor the quality and cost of care, as well as compliance with national management guidelines. Assessment of the hospitalization rate and regular audit may achieve these aims in the hospital setting. The best way to assess and monitor asthma in primary care remains an unresolved yet crucial issue because primary care physicians manage the vast burden of illness caused by asthma. Monitoring asthma outcomes is an essential step toward the successful implementation of national guidelines for the management of asthma. (J Allergy Clin Immunol 2000;106:17-26.)

HRCT imaging of airway responsiveness: effects of anesthetics.

The noninvasive imaging method, high resolution computed tomography (HRCT), has been developed in animal models and applied to humans with obstructive lung disease for assessing regional and individual airway responsiveness. The ability to directly view airway responses during provocations such as tracheal intubation in an asthmatic could greatly enhance our understanding and treatment of airway hyperresponsiveness. HRCT uses increased kilovoltage peak (kVp) and milliamperage (mAs) settings, thin slices, high spacial frequency reconstruction algorithms, and small fields of view to resolve structures as small as 200 microm. Therefore, airways as small as 1-2 mm in diameter can be viewed and measured. HRCT is a more sensitive technique for resolving airway caliber changes than clinical or research methods of pulmonary function tests. HRCT allows direct in vivo measurement of airway responsiveness to pharmacological and physiological stress that induces bronchoconstriction or bronchodilation. Using HRCT, we are able to measure airway dilation at baseline airway tone with inhalation anesthetics, differentiate the bronchodilating properties of inhalational agents in airways with tone, assess bronchodilating agents commonly used as premedications prior to anesthesia, and measure airway heterogeneity at baseline tone and their response to a variety of stimuli. This ability of HRCT to measure airway caliber and response heterogeneity in vivo noninvasively will dramatically improve our understanding of pulmonary physiology in general and the effects of anesthetics on the airways specifically.

Comparison of two standardized methods of methacholine inhalation challenge in young adults

In the European Community Respiratory Health Study (ECRHS), airway responsiveness to methacholine was determined using the Mefar dosimeter protocol. Elsewhere, the 2-min tidal breathing method has become the preferred standardized method. The relationship between measurements of responsiveness by these two methods is not well established. This study measured airway responsiveness to methacholine by dosimeter and tidal breathing methods in 47 healthy asthmatic subjects aged 20-44 yrs. Tests were performed within 1 week and in random order. Baseline forced expiratory volume in one second (FEV1) varied by &lt;10% between tests in 42/47 subjects. There was a close association between responsiveness determined by the two methods. A provocative concentration of methacholine causing a 20% fall in FEV1 (PC20) value of &lt; or =8.0 mg x mL(-1) (tidal method) used to categorize airway hyperresponsiveness agreed most closely with a provocative dose of methacholine causing a 20% fall in FEV1 (PD20) value of &lt; or =0.5 mg (dosimeter method) (kappa statistic 0.78). Each doubling or halving of PC20 to define a level of hyperresponsiveness agreed closely with a doubling or halving of PD20. Assessment of airway responsiveness as provocative dose of methacholine causing a 20% fall in forced expiratory volume in one second by the Mefar dosimeter protocol gave a close and predictable relationship with provocative concentration of methacholine causing a 20% fall in expiratory volume in one second assessed using the tidal breathing method. Airway hyperresponsiveness as determined by the accepted criterion of provocative concentration of methacholine causing a 20% fall in expiratory volume in one second &lt; or =8 mg x mL(-1) was best correlated with provocative dose of methacholine causing a 20% fall in forced expiratory volume in one second &lt;0.5 mg by Mefar dosimeter.

New Considerations About Measuring Airway Hyperresponsiveness

Measuring airway responsiveness to inhaled bronchoconstrictor stimuli, such as methacholine or histamine, has become an important tool in the diagnosis of asthma. This is measured by patients inhaling increasing closes or concentrations of the bronchoconstrictor stimulus until a given level of bronchoconstriction is achieved. Inhaled allergens initiate processes that increase airway inflammation and enhance airway hyperresponsiveness in asthmatic subjects. Studies using inhaled allergen challenges have provided insight into how changes in airway hyperresponsiveness are regulated by induced inflammatory processes. These changes in airway hyperresponsiveness (1-2 doubling doses) have been shown to be of much smaller magnitude than those demonstrated when asthmatics with stable airway hyperresponsiveness are compared to normals (4-8 doubling doses). These allergen-induced changes would be of little relevance in subjects with normal airway responsiveness, because they would not increase the degree of airway responsiveness into the asthmatic range. They are, however, important in asthmatics who already have airway hyperrespon-siveness because they are similar to changes associated with worsening asthma control. It is likely that the mechanisms responsible for the changes in airway hyperresponsiveness following experimental allergen exposure are similar to those producing transient worsening of control in asthmatics. Nevertheless, it is unlikely that the mechanisms of the transient allergen-induced airway hyperresponsiveness will explain the underlying mechanisms of the persistent airway hyperresponsiveness in asthmatic patients when compared with normal individuals.

Use of peak flow variability and methacholine responsiveness in predicting changes from pre-test diagnosis of asthma

Asthma is usually diagnosed clinically. This study investigated how methacholine challenge and peak expiratory flow monitoring influenced change from a pretest clinical diagnosis. Records of 132 patients referred with respiratory symptoms, who subsequently had reliable measurements of both airway responsiveness (provocative concentration of methacholine causing a 20% fall in forced expiratory volume in one second (FEV1 (PC20)) and peak expiratory flow variability (PEFV) were reviewed. Initial and final diagnoses for each patient were classified as: a) definite asthma; b) possible asthma; and c) definitely not asthma. The predictive value of PEFV and PC20 regarding overall change from pre- to post-test diagnosis, change from initial diagnosis of possible or definitely not asthma, and change from initial diagnosis of definite asthma, were tested by multiple logistic regression analysis. Odds ratios for PC20 were expressed per doubling dose, and for PEFV per 5% variability. Clinical diagnosis of definite asthma and definitely not asthma were confirmed in 70% and 79% respectively. PC20, but not PEFV, predicted an overall change between pre- and post-test diagnosis. Both PC20 and PEFV independently predicted change to definite asthma. PEFV and interaction between PC20 and PEFV predicted a change in those whose initial diagnosis was definite asthma. Although both measurements showed a significant correlation, there was poor agreement between positive tests. Both peak expiratory flow variability and provocative dose of methacholine causing a 20% fall in forced expiratory volume in one second influence diagnostic decision-making in patients with a high pre-test probability of asthma.

Lack of a late asthmatic response after hypertonic saline challenge in children.

Hypertonic saline challenge has become a standardized method for measuring airway responsiveness. However, there is still uncertainty about the occurrence of a late asthmatic response. Therefore, the present study was designed to assess a possible late asthmatic response after hypertonic saline challenge in children. Twenty-one children with mild to moderate bronchial hyperresponsiveness were studied. On days 1 and 2, forced expiratory volume in one second (FEV1) was measured hourly from 10:00 h to 22:00 h to assess diurnal variation of lung function. On the third study day, a hypertonic saline challenge was performed and FEV1 was measured as on control days. The possibility of a late asthmatic response was tested by comparing FEV1 levels up to 12 h after the challenge on the intervention day to FEV1 levels on control days. In no subjects were the FEV1 values following the challenge found to be considerably below the individual mean of the control days. Furthermore, a nonparametric approach was applied for each child and the population looked into as a whole. Again, no late asthmatic response was detectable. The results of this study suggest that in children with mild to moderate bronchial hyperresponsiveness a late asthmatic response does not occur 4-12 h after a 4.5% saline challenge.