Changes in sputum cell counts after exposure to occupational agents: what do they mean?

BACKGROUND: Exposure to occupational agents can induce eosinophilic inflammation in subjects with occupational asthma (OA). It might also induce nonspecific changes in airway inflammation in subjects without OA. OBJECTIVES: We sought to investigate the changes in airway inflammation induced by exposure to occupational agents in subjects with and without OA and to determine which changes in sputum eosinophil numbers and bronchial responsiveness to methacholine should be regarded as clinically significant for predicting a 20% fall in FEV(1). METHODS: We performed specific inhalation challenges (SICs) in 3 groups of subjects: subjects reporting a history consistent with OA with a positive SIC response (n = 17); subjects reporting a history consistent with OA with a negative SIC response (n = 14); and asthmatic subjects without any history of OA (n = 10). Induced sputum and methacholine challenges were performed at the end of the control day and again at the end of the last day of exposure; the last day of exposure was always performed in the laboratory. RESULTS: There was an increase in median sputum eosinophil and neutrophil numbers in subjects with positive SIC responses. Cell counts remained unchanged after exposure in asthmatic subjects without OA. A combination of a greater than 0.26 10(6)/mL increase in sputum eosinophil numbers and a decrease in the concentration of methacholine inducing a 20% fall in FEV(1) of at least 1.8-fold compared with baseline values predicted a 20% fall in FEV(1) in 96% (95% CI, 70%-99%) of patients. CONCLUSION: Exposure to occupational agents per se does not induce airway inflammation. Changes in both sputum eosinophil counts and methacholine responsiveness are satisfactory predictors of a significant bronchial responsiveness to occupational agents.     

Comparison of peak expiratory flows and FEV1 in assessing immediate asthmatic reactions due to occupational agents

BACKGROUND: FEV1 is more sensitive than PEF in assessing late asthmatic responses (LAR) after specific inhalation challenges (SIC) with occupational agents. As immediate asthmatic reactions (IAR) mainly involve proximal airways, PEF may, however, be as valid as FEV1. METHODS: Thirty-seven subjects who experienced an immediate fall in FEV1 of > or =20% during SIC with occupational agents and 20 subjects with fall of < or =10% in FEV1 were included. Both FEV1 and PEF were measured in a random order every 10 min for 1 h after exposure. We corrected PEF (PEFc) for inaccuracies of the mini-Wright meters by the Miller equation. RESULTS: Maximum changes in PEFc (30+/-11%) were not significantly different from changes in FEV1 (27+/-5%) (P=0.13). Their timings after exposure were 14+/-11 min and 17+/-17 min, respectively (P=0.4). High sensitivity (92%), specificity (95%), accuracy (93%), and positive predictive value (97%) were found for a 20% fall in PEFc to detect a significant IAR. Results were better and not influenced by meter inaccuracies with a cutoff point of 15% change in noncorrected PEF (PEFnc). An absolute decrease in PEF of 70 l/min gave a good discrimination between reactions with and without an asthmatic response. CONCLUSIONS: PEF is as satisfactory as FEV1 for detecting a significant IAR after exposure to an occupational agent if one considers a cutoff point of 1) 15% fall in PEF 2) 20% fall in PEFc 3) 20% fall and/or 70 l/min decrease in PEFnc.     

Comparison of airway conductance and FEV(1) as measures of airway responsiveness to methacholine. Discrimination of small differences in bronchial responsiveness with Gaw and FEV(1).

When defining bronchial responsiveness in healthy, non-asthmatic, subjects exposed in different working situations, it is not clear whether different outcome measures yield similar results. Therefore, the concentration and dose of methacholine that caused a 20% decrease in forced expiratory volume in 1 s (FEV(1)) (PC20(FEV(1)) and PD20(FEV(1))), the corresponding change in Gaw and the relationship between the dose-response slope (DRS) for FEV(1) and Gaw was studied in different working populations and healthy control subjects (n=1038). The two outcome measures were compared in groups of subjects in whom differences in bronchial responsiveness could be anticipated [atopics (n=72) and non-atopics (n= 207) and subjects exposed (n=54) and not exposed (n=32) to saw dust]. A bronchial challenge was also made before and after exposure in a swine confinement building, an exposure known to increase bronchial responsiveness (n=37). PD20(FEV(1)) was 1.7 mg in atopics and 4.9 mg in non-atopics, 7.1 mg in saw dust exposed and >20 mg in non-exposed subjects and 5.3 mg before and 0.79 mg after exposure to organic dust. There was a correlation between DRS(FEV(1)) and DRS(Gaw), r=0.87 (P<0.001). In subjects who were highly sensitive to methacholine a 20% change in FEV(1) corresponded to <40% change in Gaw, while a 20% decrease in FEV1 corresponded to none or a minor decrease in Gaw in subjects with less methacholine-sensitive airways. The ability to detect differences in bronchial responsiveness between groups, or to detect changes in bronchial responsiveness following exposure was approximately the same for FEV(1) and Gaw. The reproducibility was similar for both variables and a second measurement was within one doubling of the methacholine concentration of the first provocation in approximately 95% of all measurements (n=41). In conclusion, with our methacholine provocation method, FEV(1) and Gaw had similar sensitivity in detecting small differences in bronchial responsiveness in healthy subjects.     

Eosinophilic inflammation, remodeling of lower airway, bronchial responsiveness and cough reflex sensitivity in non-asthmatic subjects with nasal allergy

BACKGROUND: It has been reported that nasal allergy influences the lower airway inflammation and functions. We elucidated whether nasal allergy would contribute to lower airway inflammation and functions. METHODS: 266 subjects aged 21-39 years were interviewed with special emphasis on history of asthma and nasal allergies (perennial allergic rhinitis (PAR) and seasonal allergic rhinitis (Japanese cedar pollinosis; PO)). Symptomatic subject was defined when nasal symptoms were present during a 3-week study period. Pulmonary function, provocative concentration of methacholine causing a 20% fall in forced expiratory volume in 1 s (PC20), capsaicin cough threshold defined as capsaicin concentration eliciting 5 or more coughs (C5) and eosinophil percentage in hypertonic saline-induced sputum were measured. RESULTS: Based on the interview, 232 subjects without asthma were divided into symptomatic (n = 25) and asymptomatic (n = 22) PAR, PO on-season (n = 15) and off-season (n = 36), and non-nasal allergy subjects (control) (n = 134). Sputum eosinophils were significantly greater in symptomatic PAR than another four groups (p < 0.01). FEV1/FVC ratio was significantly lower in PAR than control (p < 0.05). Maximum mean expiratory flow was lower in PAR than control (asymptomatic: p < 0.05, symptomatic: p = 0.06). C5 was not different among groups. PAR tended to have a lower PC20 compared to control (symptomatic: p = 0.078; asymptomatic: p = 0.086). CONCLUSIONS: These results suggest that eosinophilic inflammation occurred in symptomatic period of PAR may contribute to development of lower airway remodeling and bronchial hyperresponsiveness. Reversely, PO may not be associated with lower airway eosinophilic inflammation or abnormal bronchial functions. Nasal allergy dose not influence the cough reflex sensitivity.     

The effects of an anti-CD11a mAb,efalizumab, on allergen-induced airway responses and airway inflammation in subjects with atopic asthma

BACKGROUND: Efalizumab is a humanized IgG(1) mAb against the lymphocyte function antigen-1 (LFA-1) alpha chain, CD11a. Blocking of LFA-1/intercellular adhesion molecule interactions could inhibit asthmatic inflammation by blocking adhesion and activation of LFA-1-positive leukocytes. OBJECTIVE: A randomized, double-blinded, placebo-controlled, parallel group, multicenter study investigated the effects of efalizumab on allergen-induced airway responsiveness and airway inflammation. METHODS: Thirty-five nonsmoking subjects with mild allergic asthma were randomized to receive efalizumab (n = 24) or placebo (n = 11) in 8 weekly subcutaneous doses (0.7 mg/kg conditioning dose followed by 7 weekly doses of 2.0 mg/kg). Allergen challenges were performed at screening and after 4 and 8 weeks of treatment. Samples of sputum (n = 18 subjects) and blood (n = 35 subjects) were collected the day before challenges, and sputum was collected again at 7 and 24 hours after each challenge. Nonparametric tests were used to compare allergen-induced differences between efalizumab and placebo groups. RESULTS: Subjects receiving efalizumab developed headache (48%) and flu syndrome (28%) compared to subjects receiving placebo (0%). After 8 weeks of efalizumab, the maximum late percent fall in FEV(1) (late asthmatic response) was inhibited by 50%, but neither the late response nor the late area under the curve was statistically different than placebo (P =.098 and.062, respectively). Efalizumab had no effect on the maximum early percent fall in FEV(1) (early asthmatic response) or early area under the curve compared to placebo (P >.59). Efalizu-mab significantly reduced the postallergen increase in sputum EG2-positive cells and metachromatic cells (P <.05). No other comparisons were statistically different. CONCLUSIONS: Blocking of LFA-1/intercellular adhesion module interactions by efalizumab inhibits the development of allergen-induced cellular inflammatory responses measured in induced sputum and might attenuate the late asthmatic response. Larger studies are needed to confirm this.     

The temporal relationship between increases in airway responsiveness to histamine and late asthmatic responses induced by occupational agents

The temporal relationship between increases in airway responsiveness and the late asthmatic response was assessed in nine patients challenged with occupational agents toluene diisocyanate (one patient), carmine (one patient), maleic anhydride (two patients), colophony (four patients), and trimellitic anhydride (one patient). The provocation concentration of histamine causing a 20% decrease in FEV1 (PC20) was measured before challenge and at approximately 3 hours and 24 hours on control and active-challenge days. Thirteen active challenges provoked eight definite late asthmatic responses (maximum fall in FEV1 greater than 15% at 3 to 11 hours). At 3 hours after the challenges that provoked late responses, there was a significant (p less than 0.02) decrease in PC20 that was more (p less than 0.03) than that observed for the five tests provoking early (late FEV1 fall 0% to 5%) or equivocal late (FEV1 fall 6% to 15%) responses. At 24 hours, PC20 remained decreased (p less than 0.05), although it was less so than at 3 hours (p less than 0.05) and not significantly when compared with challenge tests causing single early or equivocal late responses. The 3-hour decreases in PC20 were identified when FEV1 (five of seven observations) was greater than 90% of prechallenge values. For the nine independent tests, the 3-hour decreases in PC20 correlated (r = 0.72; p less than 0.05) with the magnitude of the late falls in FEV1, whereas this was not observed at 24 hours (r = 0.35; p, not significant).(ABSTRACT TRUNCATED AT 250 WORDS)     

Theophylline does not inhibit allergen-induced increase in airway responsiveness to methacholine

Allergen-induced increase in airway hyperresponsiveness can be used as a model of airway inflammation for assessing antiasthma pharmacologic agents. Steroids and cromolyn, but not beta-agonists, inhibit this increase; theophylline, recently suggested as having anti-inflammatory effects, has not been evaluated in this model. Six atopic subjects with asthma and with late asthmatic responses (N = 5) and postallergen reduction in a provocative concentration of methacholine causing a 20% fall in FEV1 (PC20) (N = 6) were studied. Sustained-release theophylline (Theo-Dur; Astra Pharmaceuticals Canada, Ltd., Mississauga, Canada), 300 mg, and placebo were administered single-blind twice daily for eight doses up to 1 hour before allergen inhalation; cromolyn sodium, 10 mg, was administered in a single dose 10 minutes before allergen inhalation on another day as a "positive control." Mean theophylline levels were in the low therapeutic range, 57 +/- 17 and 58 +/- 13 mumol/L 1 and 8 hours after the last tablet. The FEV1 was 7% and 9% greater after the seventh and eighth doses of theophylline versus placebo (p less than 0.05). Theophylline also produced a significant (p less than 0.05) twofold increase in methacholine PC20. There was a 40% (p = 0.06) reduction in early asthmatic fall in FEV1 and a 25% (not significant) reduction in late FEV1 fall when theophylline was compared to placebo. Theophylline did not influence the geometric mean allergen-induced fall in methacholine PC20 delta log PC20; this was true individually in five of the six subjects. By contrast, cromolyn sodium inhibited all aspects of the allergen response completely.(ABSTRACT TRUNCATED AT 250 WORDS)     

Seasonal variation of airway function in allergic rhinitis

We set out to examine seasonal variation in airway bronchoconstriction in patients with seasonal allergic rhinitis. Airway conductance and response to methacholine challenge were measured during pollen season, as well as in winter when pollen exposure was not present. Airway conductance and spirometry were performed on 17 subjects during allergy season and in winter. In eight of these subjects the measurements were repeated in the successive allergy season. Methacholine bronchoprovocation was performed on 17 of the subjects in winter and in eight subjects in allergy season. We found airway constriction in both allergy seasons as evidenced by specific airway conductance (SGaw) of 0.188 +/- 0.06 and 0.203 +/- 0.03. In contrast, SGaw during winter was 0.27 +/- 0.11. When winter and summer seasons were compared, both summer SGaw values were significantly lower than winter SGaw, p less than 0.01 and p less than 0.05, respectively. Mean airway sensitivity to methacholine during allergy season was 16.1 breath units and not different than out of season 11.7 breath units; p = NS. The reactivity to methacholine (slope of the dose-response curve) and spirometry (FVC, FEV1, FEV1/FVC) in and out of allergy season were likewise not different. The data indicate that patients with allergic rhinitis have unique physiologic behavior separating them from patients with asthma or normal subjects. They develop seasonal bronchoconstriction unassociated with clinical bronchospasm, but this seasonal bronchoconstriction does not potentiate their sensitivity to methacholine. However, they have increased airway sensitivity to methacholine, and this feature distinguishes them from normal subjects.     

The relationship between airway hyper‐responsiveness, markers of inflammation and lung function depends on the duration of the asthmatic disease

BACKGROUND: The combination of airway hyper-responsiveness, eosinophilic airway inflammation, and lung function impairment is considered as a hallmark of bronchial asthma. Since airway function might change with time in chronic asthma, the association between parameters which are characteristic of asthma could be different in subjects with different durations of the disease. OBJECTIVE: We assessed whether in patients with asthma the relationship between airway hyperresponsiveness, non-invasive markers of airway inflammation, and baseline lung function depended on the duration of the disease. METHODS: Sixty-six non-smoking patients with mild to moderate allergic asthma without corticosteroids were assigned to two groups, according to a duration of the disease (time interval since doctor's diagnosis) of either < or = 16 years (median 8 years; mean FEV1, 92.6% pred.; n = 34) or > 16 year (median 25 years; mean FEV1, 87.9% pred.; n = 32). RESULTS: Groups did not differ statistically in PC20FEV1 of methacholine, sputum composition, levels of exhaled nitric oxide (NO), lung function parameters, or history of treatment. There were significant correlations between PC20FEV1, eosinophils and NO in patients with a duration of the disease < or = 16 year, but no relation to lung function. In contrast, patients with a duration > 16 year showed a correlation between PC20FEV1 of methacholine and lung function but not eosinophils or NO. In both groups, eosinophils and NO were associated with each other. These results were corroborated by the statistical procedure of factor analysis that revealed 'inflammation' and 'lung function' as major entities and found 'responsiveness' to be associated with only one of them in each group. CONCLUSION: Our data demonstrate that with a shorter duration of the asthmatic disease airway hyper-responsiveness is associated with airway inflammation, whereas with a longer duration it is associated with impaired lung function, suggesting that in chronic asthma ongoing alterations become the primary determinant of functional characteristics.     

Exposure to a sensitizing occupational agent can cause a long-lasting increase in bronchial responsiveness to histamine in the absence of significant changes in airway caliber

A 58-year-old subject with a history of occupational asthma to red-cedar sawdust underwent specific inhalation challenges with this product. Significant increases in airway responsiveness to histamine (tenfold fall in PC20 FEV1) were documented 7 hours after exposure for 5 minutes to red cedar while baseline spirometry remained unchanged. A dual asthmatic reaction was induced during the following days by exposing the subject to red-cedar sawdust for 30 minutes and plicatic acid for 7 minutes. After recovery of PC20, the subject was reexposed to plicatic acid for 15 and 30 seconds on 2 consecutive days. No significant changes in FEV1, forced vital capacity, and residual volume were demonstrated in the following 8 hours, although minimal changes in forced expiratory flow rate between 25% and 75% of FVC were observed. PC20 dropped significantly and required 2 weeks to recover. This example illustrates that bronchial hyperresponsiveness to histamine can precede the changes in airway caliber after an antigen challenge. It also demonstrates that such changes can persist for up to 2 weeks after the challenge, even when no significant changes in FEV1 are induced.     

The effects of inhaled leukotriene E4 on the airway responsiveness to histamine in subjects with asthma and normal subjects

Eight subjects with asthma inhaled on separate occasions leukotriene E4 (LTE4) (6.1 nmol, geometric mean), methacholine, and diluent, which produced an average 41.0%, 37.0%, and 3.3% decrease in specific airway conductance (SGaw), respectively. When the SGaw had recovered to baseline levels at 60 minutes after challenge, the provocative dose of inhaled histamine that produced a 35% decrease in SGaw (PD35) was determined. The histamine PD35 observed after inhalation of LTE4 was 0.46 mumol, and this was significantly less than the histamine PD35 observed after inhalation of methacholine (0.88 mumol; p less than 10(-4) and diluent (0.97 mumol; p less than 10(-5). Histamine responsiveness was also enhanced by a fiftyfold lower dose of LTE4 (p = 0.005), and the enhancement was less than that elicited by the higher dose of LTE4 in the same individuals (p = 0.02). The changes in histamine PD35 during a 1-week period after LTE4 and methacholine challenges were compared in four subjects with asthma. There was a time-dependent enhancement in histamine responsiveness that reached a maximal of 3.5-fold at 7 hours after LTE4. The enhancement had disappeared by 1 week. Similar changes were not observed after methacholine challenge, which elicited the same degree of bronchoconstriction as LTE4. Inhalation of LTE4 in five normal subjects that produced a mean 37.6% decrease in SGaw did not change histamine responsiveness for up to 7 hours. These findings suggest that LTE4 may play a role in the perpetuation of nonspecific airway hyperresponsiveness in bronchial asthma.     

Airway responses to antigen challenge in allergic rhinitis and allergic asthma

The density dependence of the maximum expiratory flow-volume curve, functional residual capacity (FRC), and specific airway conductance (SGaw) were determined before and during bronchial provocation with ragweed extract in 27 subjects with ragweed hypersensitivity and a history of either bronchial asthma (16 subjects) or allergic rhinitis (11 subjects). Mean baseline SGaw was significantly lower while mean volume of isoflow (Visov) and FrC were significantly higher in subjects with bronchial asthma. During antigen challenge, 10 of 16 subjects with bronchial asthma (63%) and five of 11 subjects with allergic rhinitis (45%) showed a greater than 35% decrease in SGaw ("reactors"): mean relative decreases in SGaw from baseline were 46% and 53%, respectively. The remaining subjects showed a less than 35% decrease in SGaw ("nonreactors") with mean relative decreases of 9% (allergic asthma) and 6% (allergic rhinitis). Mean Visov increased in all subjects with bronchial asthma and in eight of 11 subjects with allergic rhinitis. A significant increase in FRC (6%) was seen only in the "reactors" with bronchial asthma. Following antigen challenge, the beta adrenergic agonist, isoetharine, increased SGaw and decreased Visov. We conclude that in asymptomatic subjects with ragweed hypersensitivity, (1) central and peripheral airway function is more abnormal in subjects with bronchial asthma than in subjects with allergic rhinitis, (2) subjects of both groups show quantitatively and qualitatively comparable airway responses during antigen challenge with a decrease in SGaw or an increase in Visov, possibly representing increase in central and/or peripheral airflow resistance, respectively, (3) Visov may be a more sensitive indicator of airway response to antigen challenge than SGaw, and (4) the bronchodilator effects of a beta adrenergic agonist on antigen-induced bronchospasm are similar in both groups.     

Allergen sensitization and bronchial hyper-responsiveness to adenosine monophosphate in asthmatic patients

BACKGROUND: Indirect bronchoprovocation using adenosine monophosphate (AMP) is related to atopic phenotype expression. OBJECTIVE: To evaluate the putative relationship between skin prick allergen sensitization and bronchial hyper-responsiveness to AMP in a retrospective cross-sectional database analysis. METHODS: We retrospectively evaluated two groups of non-smoking asthmatics (forced expiratory volume in 1 s (FEV)1>/=60% predicted) who were reactive (responders) or unreactive (controls) to inhaled AMP. The main outcome measure was the difference in sensitization to individual allergens and the total atopic load according to the presence or absence of bronchial hyper-responsiveness. RESULTS: We initially identified 180 (44%) non-smoking asthmatics with PC20/=1600 mg/mL. For those who had a skin prick test, the responders (n=151) and controls (n=151) were found to be matched for age, sex, inhaled corticosteroid dose and number of patients using inhaled corticosteroids. There were significant differences in the number of responders vs. controls in terms of sensitization to house dust mite (77% vs. 62%, P=0.004), aspergillus (19% vs. 9%, P=0.014), cat (61% vs. 48%, P=0.028), total atopic load (493 vs. 380 positive tests, P<0.001) and forced mid-expiratory flow (60% vs. 68% predicted, P<0.001). CONCLUSION: Sensitization to common aeroallergens increased the likelihood of bronchial inflammation as reflected by bronchial hyper-responsiveness to inhaled AMP, independently of both FEV1 or inhaled corticosteroid use. This in turn suggests an association between allergen exposure and AMP responsiveness in asthmatics. Further prospective long-term evaluation is indicated to assess whether allergen avoidance strategies can modify the airway response.     

Repeatability of allergen-induced airway inflammation.

BACKGROUND: Allergen inhalation challenge is a useful clinical model to investigate the effects of asthma therapies on allergen-induced airway responses; however, the repeatability of allergen-induced airway inflammation is not known. OBJECTIVE: The purpose of this study was to investigate the repeatability of allergen-induced increases in sputum eosinophils. This information will allow the prediction of the number of subjects required in studies evaluating asthma therapies. METHODS: Seventeen subjects completed 2 allergen challenges using the same dose of allergen, at least 3 weeks apart. Allergen-induced airway responses were measured for 7 hours after challenge. Differential cell counts from induced sputum were determined the day before and 7 and 24 hours after challenge; methacholine PC20 was measured the day before and 24 hours after challenge. RESULTS: The intraclass correlation coefficient for maximum percent late fall in FEV1 was 0.32 and for the area of the late response was 0.61. The sample size predicted to be necessary to observe 50% attenuation of the maximum percent late fall in FEV1 and the late area under the curve with a power of 0.95 was 9 subjects. The intraclass correlation coefficient for percent of allergen-induced sputum eosinophils was 0.60 at 7 hours and 0.53 at 24 hours after challenge. With a randomized cross-over study design, the sample size predicted to be necessary to observe 50% attenuation of allergen-induced percent of eosinophils with a power of 0.95 was 5 subjects. CONCLUSION: Allergen inhalation challenge with measurements of sputum eosinophils is a noninvasive and reliable method for evaluating the anti-inflammatory effects of asthma therapies.     

Factors associated with severity of occupational asthma with a latency period at diagnosis

BACKGROUND: Severity of occupational asthma at diagnosis is an important prognostic factor. The aim of this study was to determine which factors affect the severity of occupational asthma with a latency period at diagnosis. METHODS: The study population consisted of 229 consecutive subjects with occupational asthma with a latency period recruited by four occupational health departments and divided into two groups according to the severity of the disease at diagnosis. The moderate-severe (FEV(1) <70% predicted, or PD(20) methacholine /=70% predicted and PD(20) methacholine >300 microg, n = 128) groups were compared in terms of clinical and demographic parameters. Multivariate analysis using logistic regressions was performed to examine factors associated with asthma severity. RESULTS: Duration of symptoms before diagnosis was significantly longer in the moderate-severe group (mean +/- SD: 6.3 +/- 6.8 years vs 3.4 +/- 4.4 years, P < 0.001). Sex ratio, age, atopy, smoking habits, duration of exposure before symptoms, and molecular weight of the causal agent were not significantly different between the two groups. On multivariate analysis, only duration of symptoms before diagnosis was associated with asthma severity (aOR = 1.12, 95% CI 1.05-1.18, P < 0.001). CONCLUSIONS: Severity of occupational asthma with a latency period at diagnosis was associated with duration of symptoms before diagnosis, but not with the type of causal agent. This finding emphasizes the need for early diagnosis and avoidance of exposure.     

Monitoring of peak expiratory flow rates in subjects with mild airway hyperexcitability

Twenty-seven subjects with mild symptoms of bronchial hyperexcitability (cough, dyspnea, wheezing) and low to moderate degree of airway response to histamine monitored their peak expiratory flow rates (PEFR) for a mean +/- SD of 14.4 +/- 4.0 days. This assessment was performed without the use of any medication in 15 subjects, and before and after inhalation of salbutamol in 12 others. 100% and 52% of individuals, respectively, showed baseline FEV1 and maximum mid-expiratory flow rates greater than 80% of predicted. The improvement in FEV1 after salbutamol was less than 20% in every subject and from 10 to 20% in 15%. The mean daily percentage changes in PEFR were greater than the ones observed in normal individuals in only 21% and 50% of the subjects on no medication and on salbutamol, respectively. Diurnal changes in PEFR were significantly negatively correlated with the response to histamine (r = -0.51; p less than 0.01) and baseline FEV1 (r = -0.49; p less than 0.02). We conclude that there are minor fluctuations of PEFR in subjects with mild symptoms and low degree of airway excitability.     

Passive cigarette smoke-challenge studies: increase in bronchial hyperreactivity.

Degree and duration of bronchial hyperreactivity (BHR) after environmental tobacco smoke (ETS) inhalation was assessed in 31 smoke-sensitive subjects with asthma who exhibited lower airway symptoms on ETS exposure (group I) and 39 smoke-sensitive subjects without asthma who manifested only upper airway symptoms on cigarette-smoke exposure (group II). Subjects were challenged with ETS for 4 hours in a static-test chamber. The atmosphere was continuously monitored for airborne particulate levels (800 cpm), total suspended particulates (1266 +/- 283 micrograms/m3), and airborne nicotine levels (226 +/- 49 micrograms/m2). Methacholine challenges were performed before and serially after cigarette-smoke exposure, and the provocative dose causing a 20% fall in FEV1 was determined. Five of the 31 smoke-sensitive subjects with asthma and none of the smoke-sensitive subjects without asthma reacted to cigarette-smoke challenge (greater than or equal to 20% fall from baseline FEV1). Thirty-two percent (10/31) of the subjects with asthma demonstrated increased BHR at 6 hours, 29% (9/31) at 24 hours, and 13% (4/31) up to day 14 after ETS challenge. Of the subjects without asthma, 18% (7/39) demonstrated increased BHR at 6 hours, 10% (4/39) at 24 hours, and 8% (3/39) at 3 weeks. These studies demonstrated an increase in BHR after cigarette-smoke challenge in a number of study subjects (although they were clinically asymptomatic) and suggest that prolonged subclinical airway inflammation can occur in the absence of demonstrable change in airway caliber on exposure to ETS.     

The lung parenchymal strip as a model of peripheral airway responsiveness

Twenty-four patients scheduled for surgery for carcinoma of the lung were challenged with inhaled methacholine. A greater than 20% fall in the forced expiratory volume in 1 s (FEV1) was recorded in nine of these patients. The PD20 (dose of methacholine producing a 20% fall in FEV1) values ranged from 0.6 to 5.6 mumol methacholine. Following surgery, lung tissue was prepared as lung parenchymal strips for in vitro studies. There was no correlation between in vivo airway responsiveness to methacholine (PD20) and in vitro sensitivity as measured by the EC50 (the concentration of agonist producing half the maximal tension [Tmax]) for carbachol (r = -0.17; n = 16) or histamine (r = 0.23; n = 24). The variation in in vivo and in vitro responsiveness was not due to the presence of inflammatory cells in the peripheral lung tissue. Of the 38 lung parenchymal strips studied with histamine, 17 demonstrated a variable relaxation response at low concentrations followed by contraction at higher concentrations. The presence or absence of this relaxation response could not be explained in terms of variable proportions of airway or vascular smooth muscle.     

Comparison of the intensity and duration of effects of inhaled bitolterol and albuterol on airway caliber and airway responsiveness to histamine

Inhaled beta-agonists can produce bronchodilatation and reduce airway hyperreactivity in patients with asthma. Using these two measures, we compared inhaled bitolterol (three puffs, 1110 micrograms), albuterol (two puffs, 180 micrograms), and placebo administered by metered-dose inhaler in a blinded, crossover study of 40 subjects with chronic asthma. On each study day, subjects underwent histamine challenges at 1 1/2 hours before, and 1/2, 2, 4, 6, and 8 hours after inhaling one of the three test-drug treatments. Both drugs produced significant bronchodilatation at 30 minutes through 4 hours and significant effects on airway reactivity at 30 minutes through 2 hours (p less than 0.05). Bitolterol also produced small but significant bronchodilator effects at 6 hours and effects on airway reactivity at 4 hours (p less than 0.05). Effects of bitolterol on airway reactivity diminished significantly more slowly than effects of albuterol in subjects with baseline provocative concentration causing a 20% fall in FEV1 greater than or equal to 1.0 mg/ml of histamine (half-life of biologic effect 1.37 versus 0.92 hours; p less than 0.05) but not in subjects with baseline provocative concentration causing a 20% fall in FEV1 less than or equal to 1.0 mg/ml (half-life of biologic effect of 1.01 versus 1.00 hours; p greater than 0.05).     

Sputum eosinophilia: an early marker of bronchial response to occupational agents

Background: False‐negative responses to specific inhalation challenge (SIC) with occupational agents may occur. We explored whether assessing changes in sputum cell counts would help improve the identification of bronchial reactivity to occupational agents during SICs. Methods: The predictive value of the changes in sputum cell counts after a negative FEV₁ response to a first challenge exposure to an occupational agent was determined using the changes in airway calibre observed during repeated challenges as the ‘gold standard’. The study included 68 subjects investigated for work‐related asthma in a tertiary centre. After a control day, the subjects were challenged with the suspected occupational agent(s) for up to 2 h. All subjects who did not show an asthmatic reaction were re‐challenged on the following day. Additional challenges were proposed to those who demonstrated a ≥ 2% increase in sputum eosinophils or an increase in nonspecific bronchial hyperresponsiveness to histamine after the second challenge day. Results: Six of the 35 subjects without changes in FEV₁ on the first challenge developed an asthmatic reaction on subsequent challenges. ROC analysis revealed that a >3% increase in sputum eosinophils at the end of the first challenge day was the most accurate parameter for predicting the development of an asthmatic response on subsequent challenges with a sensitivity of 67% and a specificity of 97%. Conclusions: An increase in sputum eosinophils is an early marker of specific bronchial reactivity to occupational agents, which may help to identify subjects who will develop an asthmatic reaction only after repeated exposure.