Comparison of incremental and bolus dose inhaled allergen challenge in asthmatic patients

BACKGROUND: Attenuation of airway responses to inhaled allergen is increasingly used to evaluate anti-asthma drugs. Many studies use different allergen challenge methods and the presence of the late asthmatic response can be identified by a screening challenge with inhalation of incremental doses of allergen. Once defined, subsequent challenges are often administered as a constant dose based on the dose from the screening challenge. Previously, constant dose challenges have been employed but never validated. OBJECTIVE: A comparative study of two methods of delivering inhaled allergen by evaluating the responses of an incremental dose allergen challenge and the same cumulative dose administered as a bolus over a single inhalation. METHODS: Thirty-five male patients with mild allergic asthma underwent incremental dose challenge followed 3-6 weeks later by a bolus dose challenge. Bronchoconstrictor responses were expressed as the maximum percentage fall in FEV1 from baseline during the early (0-2 h) and late (4-10 h) asthmatic responses and area under the percentage change in FEV1-time curve (AUC). RESULTS: There were no significant differences between the challenges. The mean +/- SEM fall in FEV1 following incremental and bolus dose challenge was 33.1 +/- 1.8% and 29.9 +/- 2.2% during the early response, and 36.9 +/- 2.4% and 34.0 +/- 3.1% during the late response, respectively. The mean +/- SEM AUC following incremental and bolus dose challenge was 35 +/- 3 and 33 +/- 3 Delta%FEV1/h for the AUC0-2 h, 147 +/- 12 and 139 +/- 16 Delta%FEV1/h for the AUC4-10 h, and 204 +/- 14 and 190 +/- 19 Delta%FEV1/h for the AUC0-10 h, respectively. CONCLUSION: Bolus dose allergen challenge is a safe method to administer inhaled allergen in clinical trials with a valid response when compared with incremental dose allergen challenge.     

The effect of an increase in inhaled allergen dose after terfenadine on the occurrence and magnitude of the late asthmatic response

We have attempted to use a potent and selective histamine H1-receptor antagonist terfenadine to allow a larger dose of allergen to be administered to previous single early responders to investigate if an increased dose of allergen could induce a late asthmatic response. Pre-treatment with 180 mg of terfenadine enabled a geometric mean increase in allergen dose of 4.12-fold to be inhaled by eight atopic subjects with mild asthma, who initially were classified as single early responders, with maximal fall in FEV1 3-8 hr after allergen challenge (Lmax) of less than 15% from baseline value. The magnitude of early asthmatic response was similar to that obtained on the control day when allergen challenge was performed in the absence of terfenadine. Two subjects were converted to dual responders with Lmax of 23.1 and 24.3%, which occurred with a 32- and 65-fold increase in allergen dose respectively, and a 6- and 4.9-fold decrease in non-specific airways responsiveness measured as the cumulative provocative concentration of methacholine that caused a 20% fall in FEV1 from baseline. The remaining six subjects failed to achieve an Lmax of greater than 10% even with a 1.29-2.66-fold increase in allergen dose. For the group as a whole an increase in allergen dose was associated with an increase in overall bronchoconstrictor response 3-8 hr after challenge. These results indicate that it is possible to induce a late asthmatic response in a subject who previously demonstrated only an early response by increasing the dose of allergen inhaled.     

Effect of a single dose of the selectin inhibitor TBC1269 on early and late asthmatic responses

BACKGROUND : Selectins participate in the initial phase of leucocyte migration from circulation to inflamed tissues and may play a role in inflammatory cellular influx into airways in asthma. In the sheep asthma model, TBC1269, a pan-selectin antagonist, reduced late allergen response by 74%. OBJECTIVE : To determine whether a single dose of TBC1269 inhibits early (EAR) and late (LAR) asthmatic responses, and whether it inhibits sputum leucocyte influx after inhalation allergen challenge in atopic asthmatic subjects treated with bronchodilators only. METHODS : Twenty-one asthmatic subjects (mean+/-SD, age=32.5+/-6.7 years, 8 males, FEV1 percent predicted=84+/-15%) with known late asthmatic response based on a screening inhalation allergen challenge were randomly assigned to receive intravenous treatment with either placebo (n=11) or TBC1269 (n=10, 30 mg/kg) infused over 15 min immediately prior to a second (post-treatment) allergen challenge at least 4 weeks after the screening challenge. After each challenge, EAR and LAR were monitored for 7 h. In addition, sputum was induced 1 day before and 1 day after each allergen challenge. RESULTS : TBC1269 did not attenuate the EAR compared with placebo (largest fall in FEV1 within 1 h of 34.1+/-13.9% vs. 31.8+/-12.2% for TBC1269 and placebo groups respectively, P=0.61) or the LAR (largest fall in FEV1 between 3 and 7 h of 39.3+/-15.3% vs. 32.6+/-13.8%, P=0.24). TBC1269 had only minor effects on allergen-induced sputum eosinophilia. CONCLUSION : We conclude that TBC1269 administered before allergen challenge as a single intravenous dose does not attenuate early or late asthmatic responses to allergen in asthmatic subjects.     

Early and late phase asthmatic response in lower airways of cat-allergic asthmatic patients--a comparison between experimental and environmental allergen challenge

BACKGROUND: Standardized experimental allergen challenges are usually adopted to investigate the effect of allergen exposure on the lower airways. Environmental (natural) allergen challenges are used less often, mainly because of difficulties in standardizing the method, safety reasons and costs. The aim of this study was to investigate the relationship between an experimental and an environmental bronchial challenge. For this reason a natural challenge model was developed. METHODS: Sixty-two patients with a history of cat allergen-induced symptoms involving the lower airways, positive skin prick test, positive in vitro specific IgE to cat allergen and bronchial hyper-responsiveness were included. All 62 patients underwent an experimental challenge in the laboratory followed by an environmental allergen challenge. RESULTS: All 62 patients developed an early asthmatic response [>or=20% fall in forced expiratory volume in 1 s (FEV1)] in the experimental challenge and 60% (37/62) during the environmental challenge. A late asthmatic response (>or=15% fall in FEV1 within 3-24 h) was seen in 56% (35/62) of the patients after the experimental challenge. Following the environmental challenge 47% (29/62) of the patients developed a late response. Thirty-four per cent (21/62) of the patients developed a late response in both challenge models and 31% (19/62) did not develop a late response in any model. Thus, there was consistency in 65% (40/62) of the patients in both challenge models. CONCLUSION: We found consistency in the pattern of response to inhaled allergen between the two challenge models and we believe that experimental bronchial challenge is likely to reflect the development of relevant inflammation in the lower airways after low-dose allergen exposure in the environment.     

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)     

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)     

Dual asthmatic reactions to inhaled Dermatophagoides pteronyssinus: reproducibility and antagonism by cromolyn sodium

Twenty-four asthmatic patients sensitized to Dermatophagoides pteronyssinus were challenged with a standardized extract of this allergen. All the patients selected on the basis of skin tests and RAST, had an early asthmatic reaction (EAR). Seventeen of them also had a late asthmatic reaction (LAR). Eleven patients were rechallenged in order to study the reproducibility of both EAR and LAR. Six patients were also challenged after cromolyn sodium premedication Results show that (1) reproducibility of both EAR and LAR is satisfactory (coefficient of variation = 14%), (2) patients with reproducible EAR also have reproducible LAR, and (3) a single dose of cromolyn given before challenge can prevent EAR and markedly attenuate LAR.     

Late asthmatic reactions and changes in histamine responsiveness provoked by occupational agents

The temporal and quantitative relationship between increases in airway responsiveness and late asthmatic reactions provoked by inhalation challenge with occupational agents was studied in nine individuals who underwent a total of thirteen active inhalation challenge tests with one of the following agents: toluene diisocyanate (TDI), maleic anhydride (MA), trimellitic anhydride (TMA), carmine, or colophony (pine wood resin). Airway responsiveness to inhaled histamine (histamine PC20) was measured before and at approximately 3 and 24 h after control and active challenge exposure, when, on all but four occasions, FEV1 was within 10% of pre-challenge values. Significant increases (p less than 0.02) in histamine responsiveness were present at 3 h following challenge exposures which subsequently provoked a definite late asthmatic reaction (FEV1 decrease greater than 15% 3-11 h post challenge). These increases in histamine responsiveness were significantly greater than those at 3 h following the challenges which provoked an isolated early (FEV1 decrease less than 6% 3-11 h post-challenge) or equivocal late asthmatic reaction (FEV1 decrease 6-15% 3-11 h post-challenge) (p less than 0.03). Although histamine responsiveness remained high at 24 h after challenges provoking late asthmatic reactions (p less than 0.05), this was less than the increase at 3 h and not significantly different from the PC20 at 24 h after challenges provoking either single early or equivocal late asthmatic reactions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of IVL745, a VLA-4 antagonist, on allergen-induced bronchoconstriction in patients with asthma

BACKGROUND: Very late antigen (VLA-4) antagonists have been proposed as potential therapies for diseases in which cell recruitment and accumulation are causative. Asthma, which is characterized by airway inflammation involving the accumulation of eosinophils and mononuclear cells, is one such disease. OBJECTIVE: We sought to assess the effect of IVL745, a VLA-4 antagonist, on the early and late asthmatic response (LAR) and on markers of airway inflammation after allergen inhalation. METHODS: The study was of a placebo-controlled, double-blind, randomized, 2-way crossover design. Sixteen subjects with mild-to-moderate asthma controlled with short-acting beta2-agonists only and with a LAR to inhaled allergen participated in the study. At one treatment period they took 20 mg of IVL745 and one treatment period placebo. Both treatments were taken twice daily for 7 days, with a single dose on day 8. Treatments were separated by a washout period of at least 2 weeks. On day 7 of each treatment period, sputum was induced and collected, and exhaled nitric oxide (NO) was measured. On day 8, an inhaled bolus allergen challenge was performed, and blood was taken for pharmacokinetics. On day 9, exhaled NO was measured, and a methacholine challenge was done. On day 10, sputum was induced and collected. Adverse events, peak expiratory flow (PEF), use of short-acting beta2-agonists, and asthma symptoms were recorded daily throughout the study. RESULTS: There was no statistically significant difference between IVL745 and placebo in the effect on the LAR after allergen challenge, as measured by the area under the curve of the percentage change in FEV1 from the prechallenge baseline (mean [SEM], -81.99 [18.80] after IVL745 and -72.58 [21.29] after placebo; 95% CI of difference, -36 to 16.8; P = .46) or by the maximum percentage change from the prechallenge baseline (mean [SEM], -23.44 [4.73] after IVL745 and -21.30 [5.17] after placebo; 95% CI of difference, -11 to 6.29; P = .60). There was a statistically significant decrease in the percentage of eosinophils in sputum on day 7 of treatment with IVL745 (mean [SEM], 7.32 [1.46]) compared with placebo (mean [SEM], 15.00 [1.92]; 95% CI of difference, -13 to -1.2; P = .02). There was no statistically significant difference between IVL745 and placebo with respect to the early asthmatic response, methacholine hyperresponsiveness, exhaled NO, postallergen sputum, symptoms, inhaled beta2-agonist use, or PEF. CONCLUSION: In patients with mild-to-moderate atopic asthma, IVL745 did not affect the early and late response to inhaled allergen or markers of airway inflammation, except for a modest reduction in sputum eosinophils.     

Late bronchial response and increase in methacholine hyperresponsiveness after exercise and distilled water challenge in atopic subjects with asthma with dual asthmatic response to allergen inhalation

We investigated the occurrence of late asthmatic response and increased methacholine responsiveness after exercise and ultrasonically nebulized distilled water (UNDW) inhalation in 12 subjects with asthma with dual asthmatic response and increased responsiveness after allergen challenge. On 3 separate days, allergen, exercise, and UNDW challenges were performed 2 hours after methacholine. FEV1 was measured for 8 hours to detect any delayed change in airway caliber. If there were a further significant reduction in FEV1 after the recovery from the immediate bronchoconstriction, methacholine challenge was performed again when FEV1 had returned to baseline. Reproducibility of any observed late response to exercise and UNDW was also investigated by repeating these challenges on 2 subsequent days. After allergen inhalation only nine subjects had an early asthmatic response, whereas all the tested subjects demonstrated a late reaction and increased methacholine responsiveness. Ten subjects had an immediate response to exercise, and this was followed by a late response in only four patients. Nine subjects demonstrated early response to UNDW inhalation, and five subjects also had a late reaction. These late responses were associated with an increase in methacholine responsiveness in a subset of the tested subjects. Late-phase reactions to exercise and UNDW were not reproducible.     

Influence of a single antigenic challenge on the pattern of airway response to exercise in asthma.

We studied 14 atopic subjects with mild asthma (six men and eight females) to document whether allergen exposure can change the pattern of response to exercise. Each had an exercise test at 80% of the VO2 max for six minutes before (exercise 1) and 48 hours (exercise 2) after an allergen inhalation test (AIT). FEV1 was measured at regular intervals up to eight hours after each challenge. On the day following AIT, spontaneous changes in FEV1 were measured for eight hours (control day). Airway responsiveness (AR) to histamine was measured at the beginning of the study, then 24 hours after AIT and at the end of the 2nd exercise. Mean early fall in FEV1 after exercise 1, AIT and exercise 2 were, 24.9 +/- 3.2%, 24.5 +/- 2.2%, and 27.6 +/- 3.8%, respectively. Airway responsiveness to histamine was increased at 32 and 56 hours post-AIT with a mean PC20 (SEM) of 0.50 (0.40, 0.62) and 0.93 (0.74, 1.17) mg/mL compared with 1.87 (1.33, 2.61) at baseline (P less than .05). Allergen inhalation test induced an isolated early asthmatic response (EAR) in four subjects, an equivocal response (late fall in FEV1: 5% to 15%) in four and a definite late asthmatic response (LAR) in six. No subject had a LAR before the AIT but two with a LAR after allergen exposure developed a late response to exercise after the AIT. This last was only partly explained by an increased diurnal variation of expiratory flows.(ABSTRACT TRUNCATED AT 250 WORDS)     

Late asthmatic reactions and bronchial variability after challenge with low doses of allergen

Late allergic inflammatory reactions are probably of major importance for the development of asthma. In order to study the occurrence of early and late asthmatic reactions after challenge with different doses of allergen, inhalation provocation tests were performed in 13 patients with mild or moderate symptoms of allergic asthma. The provocation series was started with a low allergen dose (0.1–10 BU), which was then increased in successive ten-fold increments at intervals of 1 week until a pronounced bronchial reaction developed. Three different reaction patterns were observed. Six patients showed an isolated late reaction to relatively low doses of allergen. In four patients an immediate reaction was followed by a late reaction—a so-called dual response, and in three patients only an immediate reaction occurred. In four of the six patients who showed only a late reaction a higher allergen dose was given and this resulted in dual reactions in all four. One patient was challenged with an even higher dose, to which she reacted with an immediate response alone. After a late reaction, bronchial variability with low PEF values was observed over a period of several days. It is thus possible for an isolated late asthmatic reaction to be provoked by a low dose of inhaled allergen. This can be of clinical importance, repeated small doses of allergen may be unnoticed but still give bronchial inflammation and asthmatic symptoms.     

Reproducibility of Standardized Bronchial Allergen Provocation Test

Standardized bronchial allergen provocation was performed twice (with an interval of median 14 days (range 14-44)) in 19 extrinsic, well-defined asthmatic patients to study the reproducibility of the bronchial response. Smoking and medications were strictly withheld prior to the provocation. Ten-fold increasing concentrations of allergen solution 0.9 ml were inhaled by tidal volume breathing for 5 min at 10-min intervals. The actual dose given was expressed by the concentration of the solution used. Forced expiratory volume in the first second (FEV1) was used to determine responses, and the provocation continued until an allergen concentration (allergen PC20) was reached which caused at least 20% decrease of the post-saline FEV1. All provocations were followed by a bronchial reaction within clinically acceptable limits. The reproducibility was high, evaluated by the Spearman rank correlation coefficient Rho = 0.90 (P less than 0.01). It is concluded that bronchial provocation with allergens performed as outlined in this study represents a reproducible test which can be applied in routine allergy diagnostics, and in further investigations concerning specific bronchial reactivity.     

Antiinflammatory-antioxidant treatment with a methane sulfonanilide in allergen-induced asthma.

Two groups of six asthmatic patients with biphasic bronchospastic response to inhaled Dermatophagoides pteronyssinus allergen extract were studied in a double-blind fashion. Early and late asthmatic reactions to allergen inhalation challenge were determined before and at the end of a 2-week treatment period with nimesulide (100 mg bid orally), a sulfonanilide with antioxidant properties, or placebo. Bronchial responsiveness to methacholine was evaluated 24 hours before and after allergen inhalation challenges. The dose of allergen causing EAR (15% decrease in FEV1) and the severity of LAR (maximum FEV1 fall) were similar before and at the end of the treatment period in both groups. In patients treated with nimesulide, bronchial responsiveness to methacholine was significantly increased after allergen inhalation challenge both before and at the end of the treatment period. These results do not support the hypothesis that the production of oxygen-free radicals plays a significant role in the development of bronchial hyperresponsiveness and late phase reaction to allergen in asthma.     

Rye flour induces a stronger early bronchial response than wheat flour in occupational asthma

BACKGROUND: Our aims were to compare the doses of wheat and rye flour that induce early bronchial responses in occupationally exposed asthmatic subjects and to assess the effects of the dose of inhaled flour, the duration of exposure and the dose rate. METHODS: Ten patients underwent tests with lactose, wheat flour and rye flour. We compared the decrease in forced expiratory volume in 1 s (FEV(1)) observed during the challenge with flour and with lactose. We also calculated the amount of flour that was instantaneously active. RESULTS: Seven subjects had significantly decreased FEV(1) values following exposure to wheat and rye flour and two subjects only did so for rye flour. The provocative dose (PD, dose required to reduce FEV(1) by 15%) of rye was lower than that of wheat flour (geometric mean; PD(15) rye: 95 microg; wheat: 368 microg). The calculated doses of rye and wheat flour were better correlated with the change in FEV(1) than were the cumulative doses. CONCLUSION: The bronchial response was greater with rye than with wheat flour. The response was related to the dose of allergen inhaled and to the dose rate.     

Early increase in urinary leukotriene E4 (LTE4) is dependent on allergen dose inhaled during bronchial challenge in asthmatic subjects

BACKGROUND: Urinary leukotriene E4 (LTE4) excretion is a good marker of the rate of total body production of sulfidopeptide leukotrienes released during allergen challenge. METHODS: Twenty-three subjects with allergic asthma were challenged with inhaled allergen, and the urinary excretion of LTE4 was determined by immunoenzymatic assay (associated with HPLC separation) at various intervals after challenge. RESULTS: Allergen challenge caused an early airway response (EAR) with a drop in FEV1 of 40.3+/-9.9%. This was associated with an increase in urine LTE4 excretion for 0-3 h after allergen inhalation (296+/-225.25 pg/mg creatinine) in comparison with baseline values obtained during the night before challenge (101.02+/-61.97 pg/mg creatinine). Urinary LTE4 excretion was significantly higher in subjects who inhaled a higher dose of allergen during challenge (LTE4 during EAR: 211+/-192 pg/mg creatinine in subjects with inhaled total dose of allergen <0.1 biologic units; 408+/-223 pg/mg creatinine in subjects with inhaled total dose >0.1 biologic units). All subjects showed a late airway response (LAR) to allergen of different severity, from mild (FEV1 fall: 15-20%) to severe (>30%); no correlation was found between the increase in urine LTE4 excreted during LAR (3-7 h after challenge) and the severity of LAR, but only subjects with severe LAR showed a significant increase in LTE4 during LAR in comparison with baseline value. CONCLUSIONS: A release of sulfidopeptide leukotrienes, as evaluated by urinary LTE4 excretion, can be documented during EAR and LAR to allergen in relation to the dose of inhaled allergen, and it can represent a useful index of the events underlying the airway inflammatory responses during allergen challenge.     

Allergen bronchial challenge tests: variability and reproducibility of the early response

We evaluated allergen bronchial challenge tests (ABCTs) variability and reproducibility during 2-week intervals, respectively, in 28 and 14 Dermatophagoides pteronyssinus-sensitized patients. Increasing doses of Dpt (1.25 to 160 X 10(-3) mg) of lyophilized Dpt extract were administered at 20-minute intervals by doubling the previous dose. Dose-response curves (D-RC) were constructed for each test with the logarithm (base 2) of the allergen dose and the FEV1 in milliliters as ordinate. We analyzed different indices: the allergen doses causing a 15% decrease in FEV1 (PD15) and a 20% decrease in FEV1 (PD20), the slope of the curve beyond PD15, the overall slope, and the area under the parabolic curve. We found considerable intersubject variability in early asthmatic responses to Dpt ABCTs. Bronchoconstriction induced by allergen produced a specific D-RC for each individual. PD20 was significantly correlated with all the indices representing the whole D-RC (i.e., overall slope and area); moreover, PD20 was found on the steepest portion of the curve in 24 of 28 D-RCs. With the methodology used, we obtained a satisfactory reproducibility in a 2-week interval: the linear slope obtained by log base 2 transformation of doses was highly reproducible (p less than 0.001), as was area p under the parabolic curve. PD20 is significantly reproducible in a range of one doubling dose (twofold variation). The reproducibility of ABCTs over a short period permits solid arguments for their use in the evaluation of prophylactic treatment and in clinical research.     

Factors influencing the occurrence of late bronchial reactions after allergen challenge

Forty-seven patients with allergic bronchial asthma were challenged with the relevant allergen. Forty-eight per cent of the provocations resulted in a positive immediate reaction followed by a late bronchial response. Late bronchial obstruction was more common among patients with a high than with a low RAST score. Ten patients were challenged with different allergens on two different occasions, but the same type of bronchial response was observed in only six of them. Nine patients with an isolated immediate response were rechallenged with higher allergen doses, the early bronchial response being partially counteracted by terbutaline inhalations in clinically appropriate doses before and during the inhalation of allergen. The treatment alleviated the early reaction in six of the patients. A late reaction occurred in all patients with an immediate response. The non-specific bronchial reactivity to methacholine was assessed in 24 patients before allergen challenge. No relation was found between this reactivity and the observed patterns of reactions to allergen. It was concluded that the occurrence of a late bronchial response probably depends on the dose of allergen administered but is independent of the degree of unspecific bronchial responsiveness to methacholine prior to the challenge.     

Validated safety predictions of airway responses to house dust mite in asthma

BACKGROUND: House dust mite (HDM) is the most common aeroallergen causing sensitization in many Western countries and is often used in allergen inhalation challenges. The concentration of inhaled allergen causing an early asthmatic reaction [provocative concentration of inhaled allergen causing a 20% fall of forced expiratory volume in 1 s (FEV(1))(PC(20) allergen)] needs to be predicted for safety reasons to estimate accurately the severity of allergen-induced airway responsiveness. This can be accomplished by using the degree of non-specific airway responsiveness and skin sensitivity to allergen. OBJECTIVE: We derived prediction equations for HDM challenges using PC(20) histamine or PC(20) methacholine and skin sensitivity data obtained from patients with mild to moderate persistent asthma and validated these equations in an independent asthma population. METHODS: PC(20) histamine or PC(20) methacholine, skin sensitivity, and PC(20) allergen were collected retrospectively from 159 asthmatic patients participating in allergen challenge trials. Both the histamine and methacholine groups (n=75 and n=84, respectively), were divided randomly into a reference group to derive new equations to predict PC(20) allergen, and a validation group to test the new equations. RESULTS: Multiple linear regression analysis revealed that PC(20) allergen could be predicted either from PC(20) methacholine only ((10)log PC(20) allergen=-0.902+0.741.(10)log PC(20) methacholine) or from PC(20) histamine and skin sensitivity (SS) ((10)log PC(20) allergen=-0.494+0.231.(10)log SS+0.546.(10)log PC(20) histamine). In the validation study, these new equations accurately predicted PC(20) allergen following inhalation of HDM allergen allowing a safe starting concentration of allergen of three doubling concentrations below predicted PC(20) allergen in all cases. CONCLUSION: The early asthmatic response to inhaled HDM extract is predominantly determined by non-specific airway responsiveness to methacholine or histamine, whereas the influence of the cutaneous sensitivity to HDM appears to be rather limited. Our new equations accurately predict PC(20) allergen and hence are suitable for implementation in HDM inhalation studies.     

Venous blood platelets decrease during allergen-induced asthmatic reactions

To determine whether circulating platelets alter during asthmatic reactions induced by allergens, we studied nine subjects previously shown to develop an early or dual asthmatic reaction after inhalation challenge with extracts of house dust mite or grass pollen. In each subject, FEV1, circulating platelets and leucocytes were measured before, 15, 30 and 60 min, and 2, 4, 6 and 8 hr after inhalation of allergen and diluent control administered in a single-blind, randomized fashion. The same procedure was repeated in six of the nine subjects after bronchoconstriction induced by methacholine. Each subject developed an early asthmatic reaction after allergen inhalation challenge, which was followed by a late asthmatic reaction in six subjects and by an equivocal late asthmatic reaction in two of them (fall in FEV1 of 15 and 17% respectively). Compared with the control day, circulating platelets significantly decreased during the allergen-induced early asthmatic reaction (P less than 0.025, at 30 min). Platelet counts returned to baseline values within 4 hr and remained steady thereafter both in subjects who did and did not develop a late asthmatic reaction. No changes in platelet counts occurred after bronchoconstriction induced by methacholine. Diurnal increase of leucocyte numbers occurred after challenge with both allergen and diluent control. These results suggest that platelets may be involved in the pathogenesis of allergen-induced asthmatic reactions.