Effect of breathing pattern during inhalation challenge on the shape and position of the dose-response curve

To examine the effect of breathing pattern on the dose-response curve, 4 mild asthmatic and 9 normal subjects inhaled increasing concentrations of methacholine (0.03-256 mg/ml) using a quiet tidal breathing pattern or tidal breathing with a forced expiratory phase. The provocative concentration of methacholine causing a 20% decrease in the forced expired volume in 1 s (PC20FEV1) or a 200% increase in pulmonary resistance (PC 200RL) was determined. In addition, the maximal change in FEV1 and RL and the slopes of the dose-response curves were measured. The forced expiratory pattern caused an increase in the central/peripheral deposition ratio of a [99m]technetium-labeled aerosol (n = 3). There were no differences in mean tidal volume, minute ventilation, inspiratory flow rates, or baseline FEV1 or RL between the quiet breathing or forced expiration studies, although mean expiratory flows were increased in the latter (p less than 0.001). PC20FEV1 and PC200 RL decreased (p less than 0.001) but the maximal change in FEV1 and RL was unchanged in the forced expiration studies. Forced expiration during inhalation challenge did not alter the slope of FEV1 or RL dose-response curves. These results suggest that the sensitivity (PC20, PC200) and maximal response of in vivo dose-response curves may be affected independently by factors such as aerosol deposition.     

Analysis of factors associated with bronchial hyperreactivity to methacholine in bronchiectasis

Nonspecific bronchial hyperreactivity (BHR) has been reported to occur in patients with bronchiectasis. To evaluate this further, we studied 77 patients with stable bronchiectasis (noncystic fibrosis) with special reference to the prevalence of BHR to methacholine (MCh), and its relation to lung function, sputum characteristics, concommitant asthma, and atopy. The concentration of MCh required to produce a fall of 20% in forced expiratory volume in 1 s (FEV₁), PC₂₀, was determined by Wright’s nebulization tidal breathing method. BHR defined by a PC₂₀ ≤ 8 mg/ml was found in 21 of 47 (45%) subjects who underwent bronchial challenge. Presence of BHR was positively associated with low baseline spirometric values, diagnosis of asthma, long duration of disease, and elevated total IgE on univariant analysis, and was significantly related to FEV₁/forced vital capacity (FVC) ratio and asthma on multiple regression analysis. Ten of the 21 hyperreactive subjects did not have clinical asthma, whereas all 11 of 22 subjects with clinical asthma who underwent bronchial challenge were hyperreactive. Among those with BHR, there was a positive correlation between PC₂₀ and baseline FEV₁. When patients were further classified into asthmatic and nonasthmatic subjects, a positive correlation between PC₂₀ and FEV₁ was seen only in those without asthma. Frequency of infective episodes and inflammatory score of sputum assessed by average daily volume, purulence, and leukocyte count did not differ significantly in the groups with and without BHR. These results suggest that BHR in patients with bronchiectasis is associated with coexistent asthma and worse spriometric values, and not with the severity of bronchial sepsis. An erratum to this article is available at .     

Airway Responsiveness to Beta‐Adrenergic Agonist (Salbutamol) in Asthma

Despite the controversy of airway responsiveness to β₂‐agonist drugs in asthma, in a previous study we showed increased responsiveness of asthmatic airways to isoprenaline. Therefore, in the present study of airway sensitivity to other β₂‐agonists, salbutamol and its relationship to histamine responsiveness was reexamined. The threshold bronchodilator concentrations of inhaled salbutamol required for a 20% increase in forced expiratory flow in 1 sec (FEV₁), (PC₂₀) was measured in 20 normal and 19 asthmatic adults. Airway responsiveness to histamine, as the concentration that caused a 20% decrease in FEV₁, was also measured in 11 normal and 12 asthmatic subjects; and the correlation between PC₂₀ salbutamol and PC₂₀ histamine was evaluated. Sensitivity to salbutamol was greater in asthmatics (PC₂₀ = 7.24 mg/L) than in non‐asthmatics (PC₂₀ = 124.25 mg/L, p < 0.001). Airway responsiveness to histamine in asthmatics (PC₂₀ = 0.18 g/L) was also significantly greater than in normal subjects (PC₂₀ = 19.46 g/L, p < 0.001). There was a significant correlation between PC₂₀ salbutamol and histamine (Rs = 0.6052, p < 0.005). Maximum response to both salbutamol and histamine and slope of concentration‐response curves of both agents were significantly greater in patients with asthma than in normal subjects (p < 0.001 and p < 0.005 for maximum response and slope, respectively). The increased sensitivity of asthmatics to inhaled salbutamol suggests that they also may be more sensitive to their endogenous adrenaline, which may thus dilate and stabilize their airways.     

Effects of GABA-B Agonist Baclofen on Bronchial Hyperreactivity to Inhaled Histamine in Subjects with Cervical Spinal Cord Injury

Bronchial provocation studies performed in our research center have consistently demonstrated airway hyperresponsiveness to both inhaled methacholine and histamine in subjects with chronic cervical spinal cord injury (SCI). More recently, we reported that the airways of such subjects maintained on chronic baclofen (γ-aminobutyric acid) therapy were not hyperreactive to inhaled methacholine. In this study we determined whether baclofen also blocks the effects of the bronchoprovocative agent histamine in subjects with cervical SCI. Twenty-four male subjects with cervical SCI participated in this study; 14 were maintained on oral baclofen, and 10 served as age-matched controls. The subjects were challenged with increasing concentrations of aerosolized histamine until either a 20% fall in forced expiratory volume in 1 s (FEV₁) from baseline (defined as PC₂₀) was observed, or a maximum of 25 mg/ml histamine was administered. We found that 11 of the 14 baclofen subjects (78.5%) and 8 of the 10 control subjects (80%) responded (PC₂₀ < 8 mg/ml) to the histamine challenge. Mean PC₂₀ values among responders in the baclofen (PC₂₀= 2.91 ± 2.3) and control (PC₂₀= 2.18 ± 1.9) groups did not differ significantly. Because histamine acts directly on histamine receptors and indirectly on cholinergic pathways, our findings that baclofen blocks bronchoconstriction due to inhaled methacholine, but not that due to histamine, suggests that hyperresponsiveness in subjects with cervical SCI may be secondary to nonspecific airway hyperreactivity. Accepted for publication 21 January 1997     

Effect of Obesity on Asthma Phenotype is Dependent upon Asthma Severity

Background. We recently reported that obese and non-obese patients with asthma have similar airflow limitation and bronchodilator responsiveness, but obese patients have more symptoms overall. There is limited information on the effect of obesity on asthmatics of varying severity measured by objective physiological parameters. Understanding how obesity affects asthmatics of differing severity can provide insights into the pathogenesis of asthma in the obese and a rationale for the therapeutic approach to such patients. Methods. Participants with asthma from two American Lung Association—Asthma Clinical Research Center (ALA-ACRC) studies were grouped by tertiles of airflow obstruction (forced expiratory volume in one second (FEV₁%) predicted, FEV₁/forced vital capacity (FVC)) and methacholine reactivity (PC₂₀FEV₁). Within each tertile, we examined the independent effect of body mass index (BMI), divided into normal weight, overweight, and obese categories, on lung function, airway reactivity, and symptoms. Results. Overall, both FEV₁ and FVC decreased and symptoms worsened with increasing BMI; airway reactivity was unchanged. When stratified by the degree of airflow obstruction, higher BMI was not associated with greater airway reactivity to methacholine. Higher BMI was associated with more asthma symptoms only in the least obstructed FEV₁/FVC tertile. When stratified by degree of airway reactivity, BMI was inversely associated with FVC in all PC₂₀FEV₁ tertiles. BMI was directly associated with asthma symptoms only in those with the least airway reactivity. Conclusions. Obesity does not influence airway reactivity in patients with asthma and it is associated with more symptoms only in those with less severe disease.     

Formoterol,a new long-acting selectiveβ 2-agonist,decreases airway responsiveness in children with asthma

We compared the protective effect and duration of action of inhaled formoterol with salbutamol and placebo in 16 asthmatic children in a double-blind, cross-over study. All had an FEV₁ ≥ 70% predicted normal and a provocative concentration of methacholine (MCh) required to decrease their FEV₁ by 20% (PC₂₀) ≤ 4 mg/ml. On each study day, FEV₁ was within 10% and PC₂₀ within one doubling-dose of the initial visit. Patients received either placebo, salbutamol 200μg, formoterol 12μg, or formoterol 24μg by metered-dose inhaler. FEV₁ and PC₂₀ were measured repeatedly over 12 h. After salbutamol, peak FEV₁ was 120% of baseline at 30 min and returned to baseline in 3 h. After formoterol (12 or 24μg) peak FEV₁ was 118% at 3 h and remained above baseline for at least 12 h. Protection from MCh by both doses of formoterol was significantly better than by salbutamol. Protection from formoterol 12 and 24μg at 12 h was equivalent to that from salbutamol at 3 h. The PC₂₀ of four children 48 h after formoterol 24μg was more than twice their baseline PC₂₀. Formoterol by inhalation is potent and long-acting and provides significantly better antiasthma protection than salbutamol.     

Are tidal breathing indices useful in infant bronchial challenge tests?

Tidal breathing indices have been used to assess histamine-induced airway obstruction in adults and children. The aim of this study was to see whether they could be used to assess histamine challenge in infants. Tidal flow during quiet breathing was measured using a face mask and pneumotachograph and maximum flow at functional residual capacity (V_maxFRC) was measured from partial forced expirations in 18 sleeping, sedated infants who responded to histamine challenge and in 18 nonresponders. The tidal indices calculated were inspiratory and expiratory time (t₁, and t_e), tidal peak expiratory flow (PEF), mean tidal expiratory flow rate (V_T/t_e) and the expiratory time constant of the respiratory system (t_rs). The time to maximal expiration divided by expiratory time (t_me/t_e) and 2 revised forms of this index (t_me(a)t_e and t_me(b)( t_me(b) /t_e) were also calculated. Recordings of t_me(a) and t_me(b) were taken at 95% of peak tidal expiratory flow, before and after the peak, respectively. In nonresponders, there was an insignificant mean rise in V_maxFRC of 11.8% but no change in any tidal index. In responders, the mean percentage fall in V_maxFRC was 43.3% (range, ?31 to ?81%); t_rs fell from 0.61 s to 0.51 s (P < 0.05) and breathing frequency and mean tidal expiratory flow rate increased from 34.0 to 37.5 min^?1 (P < 0.01) and from 66.6 to 72.6 mL.s^?1 (P < 0.05), respectively, suggesting that infants had adopted a strategy of active expiration in response to bronchial challenge. There was no change either in t_me/t_e, or in the revised indices after challenge., It is therefore concluded that t_me/t_e is an insensitive index of airflow obstruction compared to V_maxFRC and cannot be used to assess the response to bronchial challenge. Changes in other indices were small and related to a presumed pattern of active expiration after challenge. Pediatr Pulmonol. 1994; 17:225–230. © 1994 Wiley-Liss, Inc.     

Effect of interferon-α on pulmonary function and airway responsiveness in patients with chronic hepatitis C

BackgroundInterferon (IFN)-α is the only approved treatment for chronic hepatitis C. Interstitial pneumonia and, rarely, exacerbation of bronchial asthma have been reported as adverse pulmonary effects of IFN-α treatment. The purpose of the present study was to clarify whether IFN-α treatment affects pulmonary function and airway responsiveness in patients with chronic hepatitis C.MethodsWe studied 17 patients (nine males and eight females; mean age 46 years; range 30–62 years) with chronic active hepatitis C diagnosed by serum tests and liver biopsy. Pulmonary function tests included vital capacity (VC), forced expiratory volume in 1 s (FEV₁), forced expiratory flow in the middle half of the forced vital capacity (FVC_25–75%), total lung capacity and carbon monoxide diffusing capacity of the lung (D_LCO), which was adjusted for hemoglobin concentration. Airway responsiveness was measured by methacholine inhalation challenge and determination of the provocative concentration of methacholine causing a 20% fall in FEV₁ (PC₂₀). These tests were performed before and 3 months after initiation of IFN-α therapy.ResultsNo patient developed interstitial pneumonia, although there was a tendency for the hemoglobin-adjusted D_LCO to decrease. Other pulmonary function test parameters were not affected. Overall, there was no significant change in PC₂₀ (from 15.0 to 11.4 mg/mL). In three patients whose initial PC₂₀ was within the normal range, airway hyperresponsiveness was induced and one patient developed bronchial asthma after IFN-α therapy.ConclusionsThese findings suggest that IFN-α induces airway hyperresponsiveness to methacholine in a few patients with chronic hepatitis C.     

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 <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 < 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 < 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 < 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 <0.5 mg by Mefar dosimeter.     

Effects of ASM-024, a modulator of acetylcholine receptor function,on airway responsiveness and allergen-induced responses in patients with mild asthma

OBJECTIVES:To evaluate the safety, tolerability and clinical activity of ASM-024, a new cholinergic compound with dual nicotinic and muscarinic activity, in mild allergic asthma.METHODS:The present study involved 24 stable, mild allergic asthmatic subjects. In a cross-over design, ASM-024 (50 mg or 200 mg) or placebo were administered once daily by nebulization over three periods of nine consecutive days separated by a three-week washout. The effect of each treatment on the forced expiratory volume in 1 s (FEV₁), provocative concentration of methacholine causing a 20% decline in FEV₁ (PC₂₀), early and late asthmatic responses, and allergen-induced inflammation were measured.RESULTS:Seventeen subjects completed the study. During treatment with ASM-024 at 50 mg or 200 mg, the PC₂₀ value increased respectively from a mean (± SD) 2.56±3.86 mg/mL to 4.11 mg/mL (P=0.007), and from 3.12±4.37 mg/mL to 5.23 mg/mL (P=0.005) (no change with placebo). On day 7 (day preceding allergen challenge), postdosing FEV₁ increased by 2.0% with 50 mg (P=0.005) and 1.9% with 200 mg (P=0.008) (placebo −1.1%). ASM-24 had no inhibitory effect on early and late asthmatic responses, nor on sputum eosinophil or neutrophil levels. ASM-024 induced no serious adverse events, but caused cough in 22% and 48% of the subjects with 50 mg and 200 mg, respectively, compared with 10% who were on placebo.CONCLUSIONS:ASM-024 did not inhibit allergen-induced asthmatic response and related airway inflammation, but reduced methacholine airway responsiveness and slightly improved lung function. The mechanism by which ASM-024 improves these outcomes requires further study.     

Usefulness of Exhaled Nitric Oxide for Diagnosing Asthma

Rationale. A standard asthma diagnosis is made based on clinical history, reversibility of airway obstruction, and bronchial hyperresponsiveness. Fractional exhaled nitric oxide (FeNO) is a noninvasive airway inflammatory marker that has been suggested as a diagnostic tool for asthma. The aim of this study was to establish a FeNO cut-off value for asthma diagnosis. Methods. One hundred and fourteen consecutive adult patients (mean age 34 ± 13 years) reporting symptoms consistent with asthma, with normal spirometric parameters and a negative bronchodilator test, were included in the study. All underwent a methacholine challenge test following the five-breath dosimeter protocol. FeNO was measured with a portable device (NioxMino, Aerocrine AB, Sweden) just before the methacholine challenge. The sensitivity, specificity, and diagnostic performance of FeNO measurement were calculated. Results. Thirty-five out of the 114 patients (30.7%) were diagnosed with asthma. A positive methacholine challenge was associated with higher FeNO levels and with lower forced expiratory volume in one second (FEV₁) at baseline. No correlation was found between methacholine provocative concentration causing a decrease of 20% in FEV₁ (PC₂₀) and FeNO levels. A receiver-operating characteristic curve was constructed for FeNO levels (area under the curve [AUC]: 0.762; 95% confidence interval [CI]: 0.667-0.857; p < .001). The FeNO cut-off point with maximal specificity and sensitivity for asthma diagnosis was 40 ppb. Conclusions. Patients with confirmed asthma showed higher FeNO levels. A cut-off value of 40 ppb was calculated as the most efficient for asthma diagnosis in our population. The use of FeNO measurement may be a helpful tool to rule out a diagnosis of asthma, especially in patients in whom a methacholine challenge is not feasible or available.     

Predictors of loss of asthma control induced by corticosteroid withdrawal

BACKGROUND

Asthma guidelines recommend reducing the dose of inhaled corticosteroids after establishing control.

OBJECTIVE

To identify predictors of loss of control and the kinetics of symptoms, and inflammatory and physiological measurements when inhaled corticosteroids are reduced in patients with stable asthma.

PATIENTS AND METHODS

In a single-blind study, the daily dose of inhaled corticosteroid was reduced by one-half at intervals of 20±2 days in 17 adults with controlled asthma until loss of asthma control occurred or until the corticosteroid was replaced with placebo for 20 days. The patients recorded symptoms and peak expiratory flow each day, and forced expiratory volume in 1 s (FEV₁), the provocative concentration of methacholine causing a 20% fall in FEV₁ (PC₂₀), exhaled nitric oxide, and eosinophils in sputum and blood were measured every 10 days. A loss of asthma control was defined as a worsening of the symptoms score of at least 20%, and either a decrease in FEV₁ of at least 15% or a decrease in PC₂₀ of at least fourfold.

RESULTS

Two patients had a respiratory infection and were withdrawn from the study. In eight patients, asthma became uncontrolled after a mean of 33 days (range 13 to 48 days). This was accurately reflected by a worsening of all parameters. The first parameter to change was the sputum eosinophil percentage (20 days before the loss of asthma control). Significant changes in exhaled nitric oxide, FEV₁ and methacholine PC₂₀ were observed only when the symptoms became uncontrolled. A high blood eosinophil count at baseline (risk ratio of 2.5, 95% CI 1.0 to 6.5) and an increase in sputum eosinophil count after the reduction of corticosteroids were predictors of loss of asthma control.

CONCLUSION

In patients whose asthma is controlled on inhaled corticosteroid, it is prudent not to reduce the dose further if the blood eosinophils are increased or if the sputum eosinophils increase by as little as 1% after the reduction of corticosteroids.     

The Response to Bronchodilators in Adults is not Predictive of Bronchial-hyperreactivity

Background. In some subjects with suspected asthma who have normal spirometry, administration of bronchodilators (BD) improves expiratory flow rates. The predictive value of this phenomenon in adults is not known. Objectives. To evaluate the predictive value of the response to BD for bronchial hyper-responsiveness (BHR) using the metacholine challenge test (MCT). Patients and methods. The study population included 62 non-smoking adult patients (41.9% women) 29.5 ± 15.5 years of age (range 18–64 years) with suspected asthma with normal spirometry that underwent MCT within 1 week. The response to BD (200 μ g inhaled salbutamol) was compared between subjects with positive and negative MCT using cutoff levels of provocative concentrations of metacholine causing a 20% decrease in forced expiratory volume in 1 second (FEV₁) (PC₂₀) of 4 and 8 mg/mL. Results. Mean (± SD) baseline FEV₁ was 87.8 ± 12% of predicted. After BD administration the mean FEV₁ increased by 4.3 ± 3.9%. The prevalence of BHR was 17.7% and 25.8% for PC₂₀ for PC₂₀ of 4 mg/mL and 8 mg/mL, respectively. The post-BD FEV₁ increment for subjects with positive and negative MCT tests was 3.9% ± 3.3% versus 4.4% ± 4.1%, respectively; p = 0.89, using cutoff of 4 mg/mL. The corresponding figures for cutoff of 8 mg/ml were 4.3% ± 3.1% vs. 4.3% ± 4.2%, respectively; p = 0.8465. There was no correlation between post-BD FEV₁ increment and PC₂₀ values in patients with positive MCT test for the above-mentioned cutoff levels (correlation coefficient r = 0.1645, p = 0.6289; and r = 0.2417, p = 0.4051, respectively). Conclusions. In adults with suspected asthma who have normal spirometry, the response to BD cannot be used to predict BHR.     

Comparison of airway reactivity induced by cold air and methacholine challenges in asthmatic children

Bronchial responsiveness to isocapnic hyperventilation with cold air (CAH) and to inhaled methacholine (MCH) was compared in 17 children with bronchial asthma. The response to cold air was expressed as the percent drop in FEV₁ from baseline at 4 min. after the challenge (Δ% FEV₁ CAH), and the response to methacholine as the provocative concentration required to reduce the FEV₁ by 20% from baseline (PC₂₀MCH). Both tests were sensitive (94%) for detecting airway hyperreactivity. There was no statistically significant relationship between A% FEV, CAH and the log PC₂₀MCH (r = 0.39; P = 0.12). In clinical practice, methacholine test is easier to perform, but in the research field cold air challenge may be preferable because it avoids potential drug effects. © 1995 Wiley-Liss, Inc.     

Validation of the clinical utility of sGaw as a response variable in methacholine challenge testing

Background and Objective

Airway hyperresponsiveness (AHR) is commonly assessed by a methacholine challenge test (MCT), during which a provocative concentration causing a 20% reduction in forced expiratory volume in 1 second (FEV₁) (PC₂₀) < 8 mg/ml is considered a positive response. However, a fall in specific airway conductance (sGaw) may also have clinical significance. The purpose of this study was to assess whether AHR determined by a provocative concentration causing a 40% reduction in sGaw (PC₄₀) < 8 mg/ml corresponds to a clinical diagnosis of asthma.

Methods

We analysed the changes in spirometry, lung volumes and sGaw during MCT in 211 randomly selected patients being evaluated for AHR to support a clinical diagnosis of asthma.

Results

The mean (SD) age of the group was 53 (15) years, with 141 women (67%). Overall lung function was normal, with FEV₁ = 92 (15) % predicted, total lung capacity = 97 (13) % predicted and sGaw = 0.19 (0.15–0.23) L/s/cm H₂O/L, (median, 25–75 IQR). There were many more patients who responded by PC₄₀ only (n = 120) than who responded by PC₂₀ (n = 52). There was no significant difference in asthma diagnosis between the PC₂₀ (98%) and PC₄₀ (93%) groups, and we estimate 34% of patients with a diagnosis of asthma would have been classified as having no AHR if only the FEV₁ criterion was used.

Conclusion

Changes in sGaw during MCT indicate clinically significant AHR in support of a clinical diagnosis of asthma among patients being evaluated for asthma.     

Heightened cough response to bronchoconstriction in cough variant asthma

Background and objective: The pathophysiology of cough variant asthma (CVA) is poorly understood. We compared bronchoconstriction‐triggered cough between CVA patients and normal control (NC) subjects. Methods: There were two protocols in the study. We measured bronchial responsiveness to methacholine (MCh) and counted the number of coughs in nine CVA patients and seven NC subjects (Study A). Using partial and full flow–volume curves, expiratory flow of the partial flow–volume curve at 40% above residual volume level (PEF40) and FEV₁ were used to measure bronchoconstriction. Mild bronchoconstriction was defined as a 35% fall in PEF40 (PC₃₅‐PEF40), and more severe bronchoconstriction as a 20% fall in FEV₁ (PC₂₀‐FEV₁). In study B, the same measurements were obtained in six CVA patients before and after therapy. Results: In study A, more coughs were provoked at PC₃₅‐PEF40 in CVA patients (median, 60 coughs/32 min post challenge; range, 12–135) than in NC subjects (median, 0/32 min; range, 0–13; P < 0.05). At PC₂₀‐FEV₁, more coughs were provoked in CVA patients (median, 60/32 min; range, 12–150) than in NC subjects (median, 20/32 min; range, 0–54; P < 0.05). In study B, the six CVA patients who underwent re‐examination after treatment had less coughs at PC₃₅‐PEF40 (median, 3/32 min; range, 0–14) and PC₂₀‐FEV1 (median, 13/32 min; range, 3–26) after therapy than before therapy (median, 54/32 min; range, 33–125 and 52/32 min, 45–96, respectively; P < 0.05). Conclusions: We identified heightened cough response to bronchoconstriction as a feature of CVA.     

Airway Hyperresponsiveness: A Comparative Study of Methacholine and Exercise Challenges in Seasonal Allergic Rhinitis with or without Asthma

Background. Asymptomatic airway hyperreactivity in allergic rhinitis is a risk factor for later development of asthma. Although non-specific bronchial hyperresponsiveness (BHR) has been measured by several stimuli, the most appropriate measurement technique still remains unclear. Objective. To investigate whether an exercise challenge can be used to predict BHR in seasonal allergic rhinitis patients with or without asthma and to compare this bronchial reactivity with a methacholine challenge technique. Methods. Forty-six consecutive patients with seasonal allergic rhinitis only (n = 31) and with both seasonal allergic rhinitis and asthma (n = 15) were included in the study during the pollination period. Subjects underwent first methacholine (mch) and then exercise challenge testing (ECT). There was a 1-week interval between the tests. ECT was performed on a bicycle ergometer. Positive result was defined as a 15% decrease in forced expiratory volume in 1 second (FEV₁) post-exercise. A patient's bronchial reactivity to methacholine was considered as hyperresponsive if PC₂₀ was less than 8 mg/mL. Results. Mch PC₂₀ values were significantly lower in patients with both rhinitis and asthma (p < 0.062). Among the 46 patients, mch PC₂₀ values were significantly different between patients who had positive and negative exercise challenge tests (p = 0.007). All patients with rhinitis alone had a negative ECT and 10 had a positive mch challenge. Change in FEV₁ values after ECT was significantly higher in patients with both rhinitis and asthma compared to those with rhinitis alone (p = 0.009). There was a significant relation between positivity of mch and exercise challenges (p = 0.025). ECT positivity was found to be a significant confounding factor in the diagnosis of asthma (p = 0.001). Specificity and sensitivity values were 100% and 24% for ECT and 68% and 100% for mch, respectively. Conclusion. Exercise challenge presents poor diagnostic value for detecting bronchial responsiveness in individuals with allergic rhinitis alone during the pollen season.     

Disparity Between Proximal and Distal Airway Reactivity During Methacholine Challenge

There is an increasing awareness of the role of distal airways in the pathophysiology of obstructive lung diseases including asthma and chronic obstructive pulmonary disease. We hypothesize that during induced bronchoconstriction: 1) disparity between distal and proximal airway reactivity may occur; and 2) changes in distal airway function may explain symptom onset in subjects with minimal FEV₁ change. 185 subjects underwent methacholine challenge testing (MCT). In addition to spirometry, oscillometry was performed at baseline and after maximum dose of methacholine; 33/185 also underwent oscillometry after each dose. Oscillometric parameters included resistance at 5 and 20 Hz (R_5, R₂₀) and heterogeneity of distal airway mechanics assessed by frequency dependence of resistance 5–20 Hz (R_5–20) and reactance area (AX). R₅ varied widely during MCT (range -0.8 – 11.3 cmH₂O/L/s) and correlated poorly with change in FEV₁ (r = 0.17). Changes in R₅ reflected changes in both R₂₀ and R_5–20 (r = 0.59, p<0.05; r = 0.87, p<0.0001). However, R₂₀ increased only 0.3 cmH₂O/L/s, while R_5–20 increased 0.7 cmH₂O/L/s for every 1cmH₂O/L/s change in R_5, indicating predominant effect of distal airway mechanics. 9/33 subjects developed symptoms despite minimal FEV₁ change (<5%), while R₅ increased 42% due to increased distal airway heterogeneity. These data indicate disparate behavior of proximal airway resistance (FEV₁ and R₂₀) and distal airway heterogeneity (R_5–20 and AX). Distal airway reactivity may be associated with methacholine-induced symptoms despite absence of change in FEV₁. This study highlights the importance of disparity between proximal and distal airway behavior, which has implications in understanding pathophysiology of obstructive pulmonary diseases and their response to treatment.     

Low Attenuation Area Is Associated with Airflow Limitation and Airway Hyperresponsiveness

Background. Asthma is a chronic inflammatory disorder of the airways characterized by airflow limitation and airway hyperresponsiveness. Lung density indices on quantitative computed tomography (QCT) are assumed to reflect the degree of air trapping originated from airflow limitation in airway diseases. Purpose. The present study investigated the availability of lung density indices on QCT in clinical evaluation of asthma. Methods. Eleven asthmatic patients and 48 healthy control subjects were prospectively evaluated by QCT, pulmonary function testing, and a methacholine challenge test. High-resolution computed tomography scans were performed at full-inspiratory and full-expiratory phases, and percentage of lung field occupied by low attenuation area (LAA%) and mean lung density (MLD) at both inspiratory and expiratory phases were measured. Results. MLD values at inspiratory phase were significantly increased in asthmatic patients compared with those in healthy control subjects. Inspiratory LAA% values were significantly decreased in asthmatics compared with the values in control subjects. On expiratory scans, MLD values of asthmatics were significantly lower than the values of control subjects. Expiratory LAA% values of asthmatics were significantly higher than the values of control subjects. The LAA% in the expiratory phase showed significant negative correlation with forced expiratory volume in 1 second (FEV₁), FEV₁/forced vital capacity, and the provocative dose of methacholine causing a 20% decrease in FEV₁ in asthmatic patients. Conclusion. These results suggest that lung density indices on QCT may be useful for clinical evaluation of asthmatic patients and increased LAA% in the expiratory phase is associated with airflow limitation and airway hyperresponsiveness in asthma.     

Shape of forced expiratory flow-volume curves in infants

An inflatable cuff was used to generate partial forced expiratory flow-volume (FEFV) curves in 36 infants with and without obstructive airway disease. Curves were recorded in each infant over a range of compression pressures as high as and exceeding the pressure required for the maximal partial FEFV curve. The maximal curves were quantitated and compared with passive compliance and conductance of the respiratory system and absolute lung volume measured by whole-body plethysmography. In some infants, the transmission of pressure between cuff and pleural space was determined. Partial FEFV curve shapes generated with a standardized compression pressure calculated from the transmission of pressure data to give an increase in pleural pressure at FRC of 10 cm H2O were compared between infants. For these standardized compressions, infants with convex curves tended to have better respiratory function than did those with concave curves. The combination of a concave curve and flow limitation during tidal expiration was associated with the worst function. Two parameters, the ratio of forced maximal expiratory flow (measured from the maximal partial FEFV curve) to tidal expiratory flow (measured from the expiratory flow-volume curve of tidal breathing) at midtidal volume (Vm1d(forced/tidal] and the minimal compression pressure required to generate maximal expiratory flow at FRC (Pmin), satisfactorily quantified respiratory function without the need for size correction with absolute lung volume. In addition, Vm1d(forced/tidal) provides an index of expiratory flow reserve. We conclude that useful information can be provided from the shape of a partial FEFV curve in an infant, provided that curves are generated by a standardized compression pressure.(ABSTRACT TRUNCATED AT 250 WORDS)