Allergen-induced increase in airway responsiveness is not inhibited by acute treatment with ketotifen or clemastine.

Allergen-induced increase in airway responsiveness to histamine or methacholine provides a useful model for investigation of prophylactic or "antiinflammatory" asthma treatments. This can be inhibited by corticosteroids or by sodium cromoglycate but not by beta agonists or by theophylline. A single-blind, crossover, random-order trial was conducted to compare ketotifen, clemastine, and placebo in six atopic subjects undergoing allergen inhalation tests. Ketotifen, 2 mg; clemastine, 1 mg; and placebo one tablet were administered twice daily for four days (eight doses) up to and including one hour before allergen inhalation. None of the three produced a significant reduction in the allergen-induced early or late asthmatic responses, or in the allergen-induced fall in methacholine PC20. There was a subtle nonsignificant suggestion of a reduction in the early portion of the early asthmatic response induced by both ketotifen and clemastine. Both ketotifen and clemastine produced a similar 8-fold inhibition of histamine skin test endpoint indicating equal systemic H1 blocking effect at the time of allergen inhalation. Sodium cromoglycate, 10 mg, single dose, by metered dose inhaler ten minutes before allergen challenge, added as an unblinded "positive control", inhibitory effects on the allergen-induced late and presumed inflammatory sequelae. It is possible that longer treatment periods (several weeks or months) might prove effective.

Sensitivity and specificity of histamine PC20 determination in a random selection of young college students.

Histamine provocative concentration causing a 20% drop in FEV1 (PC20) was measured in 500, randomly selected, young (20 to 29 years) university students. Participation was 500/619, or 81%. In this population, by a research assistant-administered questionnaire, we identified 17 subjects with current asthma, 16 with asthma only on allergen exposure, 19 with past (more than 1 year ago) asthma, 158 with rhinitis (77 atopic and 81 nonatopic subjects), and 290 subjects with neither asthma nor rhinitis. Histamine airway hyperresponsiveness (PC20 less than or equal to 8 mg/ml) was observed in 58 subjects and included the 17 subjects with current asthma, 6/16 with asthma only on allergen exposure, 2/19 subjects with previous asthma, 20/158 with rhinitis, and 13/290 subjects with neither asthma nor rhinitis. With "current symptomatic asthma" as the diagnosis and PC20 less than or equal to 8 mg/ml as the positive test, the sensitivity was 100%, the specificity was 93%, and the negative predictive value was 100%; the positive predictive value (for current symptoms of asthma) was only 29%. The strength of this test with a cutoff of 8 mg/ml is the high sensitivity, indicating that a PC20 greater than 8 mg/ml is likely to indicate that current asthma is not present. The weakness is the failure to predict current symptoms of asthma. As the cutoff is lowered, for example, to PC20, 1 mg/ml, the sensitivity falls to less than 50% and the positive predictive value approaches 100%. These data indicate that a PC20 greater than 8 (or 16) mg/ml rules out current asthma in most instances, whereas a PC20 less than 1 mg/ml is almost diagnostic of current asthma. Values between 1 and 8 mg/ml are intermediate in these regards.

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)

Comparative effects of inhaled salbutamol, sodium cromoglycate, and beclomethasone dipropionate on allergen-induced early asthmatic responses, late asthmatic responses, and increased bronchial responsiveness to histamine.

Single-dose salbutamol (200 micrograms), beclomethasone dipropionate (200 micrograms), and sodium cromoglycate (SCG) (10 mg) administered by inhalation 10 minutes before allergen challenge were examined with regard to inhibition of allergen-induced early (EAR) and late (LAR) asthmatic responses and allergen-induced increase in bronchial responsiveness to inhaled histamine. Ten atopic subjects with asthma participated in a blinded, crossover, placebo-controlled trial. The EAR was inhibited by salbutamol and SCG but not by beclomethasone dipropionate or placebo (p less than 0.01). The LAR (p less than 0.01) and the allergen-induced increased bronchial responsiveness to histamine 7 hours (p less than 0.01) and 30 hours (p less than 0.05 and p less than 0.01 for various comparisons) were inhibited by SCG and beclomethasone diproprionate but not by salbutamol or placebo. The allergen-induced LAR and associated increased responsiveness are now believed to be more important clinically than the EAR. The clinical relevance of these results is to stress the importance of the prophylactic nonbronchodilator drugs (SCG and steroids) and the potential inadequacy of bronchodilators used alone in the treatment of both perennial and seasonal allergic asthma.

Changes in bronchial responsiveness to histamine at intervals after allergen challenge.

Bronchial responsiveness to inhaled histamine was measured two, seven, and 30 hours after allergen inhalation challenge in 19 atopic subjects. The provocative histamine concentrations causing a 20% fall in FEV1 (PC20) at these three times were compared with the baseline value, with values obtained two and seven hours after diluent inhalation, and with those obtained five to seven days after allergen challenge in the 12 late responders. Seven subjects had allergen induced isolated early asthmatic responses (delta FEV1 22.6% (SD 6.6%)) with less than a 5% late fall in FEV1. There was no change in the six histamine PC20 values measured in these seven subjects; the geometric mean PC20 was 1.0-1.3 mg/ml on all six occasions. Twelve subjects had an allergen induced early asthmatic response (delta FEV1 26.3% (9.8%)) followed by a definite (greater than 15% delta FEV1, n = 7) or equivocal (5-15% delta FEV1, n = 5) late asthmatic response. The geometric mean histamine PC20 was not significantly different two hours after allergen inhalation either from baseline (0.67 v 0.78 mg/ml) or from that seen two hours after diluent (0.67 v 0.95). It was significantly reduced at seven (0.24 mg/ml) and at 30 hours (0.44 mg/ml) but had returned to baseline when repeated five to seven days later (0.74 mg/ml). In 10 subjects with a dual response who had a repeat antigen challenge the mean early and late response and delta PC20 at seven and 30 hours were similar. These data show that bronchial responsiveness to a non-allergic stimulus has not increased two hours after allergen inhalation following spontaneous recovery of the early asthmatic response but before the start of the late asthmatic response.

Prediction of airway responsiveness to allergen from skin sensitivity to allergen and airway responsiveness to histamine.

Previous data have indicated that airway responsiveness to allergen, expressed as the provocation concentration causing a 20% FEV1 fall (PC20), was dependent on nonallergic airway responsiveness (histamine PC20) and sensitivity to allergen (skin sensitivity or end-point titration). From retrospective data in 24 subjects, we developed a formula to predict allergen PC20 and examined its accuracy prospectively in 26 new subjects undergoing allergen inhalation test with doubling allergen concentrations. Allergen PC20 (APC20) was predicted from histamine PC20 (HPC20) and skin sensitivity (SS) by the formula: Log10 (APC20) = 0.69 Log10 (HPC20 X SS) + 0.11 (r = 0.85). Allergen PC20 was accurately predicted in 6, and overestimated or underestimated by 1 doubling concentration in 11, by 2 concentrations in 6, by 3 concentrations in 3, and by greater than 3 concentrations in none. From the total of 50 subjects, a new relationship was developed: Log10 (APC10) = 0.68 log10 (HPC20 X SS) (r = 0.82) from which 46 of 50 (92%) of allergen PC20 values fall within 2 doubling concentrations of the regression line (and all within 3). Early airway responsiveness to a given allergen can be predicted within a +/- 8-fold range, which is better than some investigator's test reproducibility of +/- 1 log (10-fold). Allergen inhalation tests to determine early asthmatic responsiveness to different IgE-mediated allergens can probably be replaced by the simpler and safer determinations of allergen sensitivity (SS, RAST) and histamine or methacholine airway responsiveness.

Relationship between atopy and bronchial responsiveness to histamine in a random population.

Although there are theoretical reasons to suggest that atopy might predispose to non-allergic bronchial hyperresponsiveness, previous studies have yielded conflicting results. We assessed this by determining the atopic status and bronchial responsiveness to inhaled histamine in 400 randomly selected college students. An atopy score was determined as the number of "+"s from a standard battery of seven allergy prick skin tests each graded from + to +, and the atopic status was graded as non-atopic (no +'s) mildly atopic (1 to 4 +'s), moderately atopic (5 to 8 +'s), or markedly atopic (greater than 8 +'s). Non-allergic bronchial responsiveness to inhaled histamine was measured with a standardized histamine inhalation test from which the histamine provocation concentration producing a 20% FEV1 fall (PC20) was calculated. The prevalence of bronchial hyperresponsiveness to histamine (PC20 less than or equal to 8 mg/ml) was 10.3% in the entire population. There was a progressive increase from 6.1% in the non-atopic group to 33% in the markedly atopic group (p less than 0.001). In 43 subjects with both measurable atopy score (greater than or equal to 1) and PC20 (less than or equal to 16 mg/ml), a regression of atopy score vs. log PC20 produced a small (r = -0.36) but significant (p less than 0.02) correlation. These data indicate a significant relationship exists between atopic status and increased non-allergic bronchial responsiveness to histamine. Although cause and effect cannot be inferred from this study, it is hypothesized that atopy is one factor, among others, which predisposes to non-allergic bronchial hyperresponsiveness.

Measurement of responsiveness to inhaled histamine using FEV1: comparison of PC20 and threshold.

Two methods of interpreting histamine inhalation dose-response curves were compared in 27 normal and 41 asthmatic subjects. The histamine provocation concentration producing a 20% fall (PC20) in forced expiratory volume in one second (FEV1) was calculated on the basis of the lowest FEV1 after inhalation of saline and the lowest value after inhalation of histamine. The histamine threshold was determined as the first histamine concentration causing the FEV1 to fall more than 2 SD below the mean of five pre-histamine (three pre-saline, two post-saline) FEV1 determinations. The PC20 was on average one doubling concentration larger than the threshold. The PC20 provided better discrimination between asthmatic and normal subjects than did the histamine threshold and was significantly more reproducible. These findings suggest that the histamine threshold may prove useful for studies on populations, particularly those with a low degree of responsiveness to histamine, because of the possibility of measuring a response at a lower histamine concentration. On the other hand, the PC20 is preferable for clinical use in individuals because of its better discriminating power and better reproducibility.

Unimodal distribution of bronchial responsiveness to inhaled histamine in a random human population.

The population distribution of bronchial responsiveness to inhaled histamine was examined in 300 randomly selected caucasian college students (aged 20 to 29 years). Bronchial responsiveness was measured as the histamine threshold, defined as the concentration producing an FEV1 fall greater than 2 SD below the mean of five prehistamine FEV1 measurements. The cumulative prevalence of asthma was 9.3 percent, including 2.7 percent with current asthma, 3.3 percent with asthma following allergen exposure only, and 3.3 percent with remote asthma. Allergic rhinitis was present in 10.7 percent; nonallergic rhinitis in 16.3 percent; 63.7 percent had neither asthma nor rhinitis. Histamine threshold ranged from unmeasurable (greater than 8 mg/ml) in 36 percent to 0.125 mg/ml in 0.3 percent. The distribution of histamine threshold values in the responsive range was unimodal, the asthmatic subjects representing a subgroup within the hyperresponsive distribution tail rather than a separate distribution peak. Examination of the FEV1 response to 8 mg/ml showed a range between 2.8 SD increase and 100 SD reduction; the population distribution of this variable was unimodal and log normal. We concluded that there is a continuous unimodal log normal distribution of bronchial responsiveness to inhaled histamine in a random human population. Rather than representing a separate (bimodal) peak or a sharp cutoff (of a unimodal tail), the asthmatic subjects show substantial overlap with the remainder of the population.

Bronchial response to inhaled histamine in asymptomatic young smokers.

Non-specific bronchial response to inhaled histamine was measured in 21 young (21.2 +/- 1.9 years) asymptomatic smokers (2.9 +/- 2.1 pack years) and in 21 age, sex, and height matched asymptomatic controls. Following a 2 min inhalation of histamine 8 mg/ml, the smokers showed smaller reduction in FEV1 (3.4 +/- 3.3% vs 7.0 +/- 6.2%, p less than 0.05) and in MMF (7.6 +/- 15.6% vs 21.1 +/- 17.3%, p less than 0.02) than did the non-smokers. The threshold concentration of histamine was defined as that concentration where FEV1 consistently was greater than 2 SD below the mean of that obtained from 5 to 7 prehistamine spirograms. A histamine threshold between 2 and 8 mg/ml was detectable in seven smokers, and a threshold between 1 and 8 mg/ml was seen in 14 non-smokers. Histamine threshold was not measurable (i.e. greater than 8 mg/ml) in 14 smokers and seven non-smokers (p less than 0.05). Thus, these young asymptomatic smokers of brief duration failed to show increased response to histamine; in fact, they appeared to respond less to histamine than did matched controls. This may be the result of selection (who chooses to smoke) or alternatively it may be due to an acquired loss of sensitivity (development of tolerance) to inhaled irritants.