Urinary leukotriene E4 levels during early and late asthmatic responses

The sulphidopeptide leukotrienes C4 and D4 (LTC4, LTD4) are potent bronchoconstrictor mediators, released from human lung fragments after challenge with specific allergens in vitro. The purpose of this study was to measure urinary LTE4 (metabolite of LTC4 and LTD4) in subjects undergoing inhalation challenges with allergens or occupational sensitizing agents in the laboratory. Eighteen subjects with previously documented isolated early asthmatic responses (EARs), isolated late asthmatic responses (LARs), or dual (both early and late) asthmatic responses were studied. Urinary LTE4 levels increased in subjects who developed either isolated EARs (mean fall in FEV1, 27.98%) or early responses preceding LARs (mean fall in FEV1, 15.01%). The baseline levels of LTE4 were 150.26 (SEM, 49.5) pg/mg of creatinine in the isolated responders and 66.60 (SEM, 13.5) pg/mg of creatinine in the dual responders. These levels increased to 1816 (SEM, 606.1) pg/mg of creatinine (p = 0.041) and 174.80 (SEM, 40.1) pg/mg of creatinine (p = 0.025), respectively, after the EAR. The degree of maximal bronchoconstriction during the EAR correlated with the levels of LTE4 (r = 0.68; p = 0.001). No significant increase in urinary LTE4 levels occurred during the LAR. These results suggest that the LTE4 precursors, LTC4 and LTD4, are important bronchoconstrictor mediators causing EARs after allergen inhalation.     

Pituitary and adrenal functions during late asthmatic responses

The purpose of the present study was to examine the role of low cortisol levels which were observed during late asthmatic responses (LAR). Selective functions of the adrenals and pituitary glands were studied in three groups of asthmatics who showed LAR, immediate asthmatic responses (IAR), and DAR (dual asthmatic responses). Serial plasma ACTH levels in each group showed no apparent abnormalities when compared with diurnal levels. The cortisol response to ACTH changed within the normal range in all three groups with minor differences. We suggest that low cortisol levels that appear during LAR are not principally due to any dysfunction in the pituitary adrenal system.     

Factors predisposing to exercise-induced late asthmatic responses

Seventeen children developed reproducible early and late asthmatic responses (dual reactions) after cycle ergometer exercise. There was a significant correlation between the magnitude of their early and late reactions, emphasizing the direct relationship of these events. No significant differences were observed in the clinical severity of asthma, diurnal variations in FEV1, and extent of the early reaction after exercise between children with dual responses and 19 children with single reactions. These findings suggest that the occurrence of late reactions after exercise is not determined by differences in severity of disease or baseline airway reactivity in the asthmatic subjects. This view is supported by the finding that there was no significant difference in the dose of acetylcholine necessary to elicit a 20% decrease in FEV1 between eight children with dual response and seven children with single early response after exercise. The rate of spontaneous recovery from early reactions was slower in children with dual responses, suggesting that this variable may predict development of late-phase reactions in exercise-induced asthma.     

Prevalence and characteristics of late asthmatic responses to exercise

The prevalence and characteristics of late asthmatic responses to exercise were studied in an adult asthmatic population. Twenty-four subjects (eight male and 16 female), aged 17 to 39 years (mean, 23.7 years), performed a 6-minute exercise on a bicycle ergometer at 75% of their maximum oxygen intake. FEV1 was measured at regular time intervals up to 8 hours after exercise. Seven subjects demonstrated a late asthmatic reaction defined as a fall in FEV1 greater than 10% between 2 to 8 hours. Bronchial reactivity to histamine was unchanged 24 hours after the exercise, compared to baseline. On a control day, a fall in FEV1 similar to the one observed after exercise was induced by methacholine inhalation. Measurements of FEV1 were done at the same time intervals as on exercise day. Neutrophil chemotactic activity was measured in the serum of 15 subjects, on exercise day for early responders, and on the 3 test days for subjects with a dual response. There was no difference between subjects with an isolated early or late response for age, sex, or atopic status. Baseline expiratory flows and nonspecific bronchial reactivity to histamine were similar in both groups. These results demonstrate the occurrence of a late asthmatic response in 30.4% of the population studied. There was no significant change of nonspecific bronchial responsiveness after the late asthmatic response to exercise. No significant increase in neutrophil chemotactic activity could be observed.     

Early and late onset asthmatic responses following lysine-aspirin inhalation in aspirin-sensitive asthmatic patients

Inhalation of aerosolized lysine-aspirin (L-ASA) has been described as an alternative diagnostic method in aspirin-sensitive asthma. To further understand the pathogenetic mechanism of aspirin-sensitive asthma, we performed L-ASA (Inyesprin®) bronchoprovocation test (BPT) in 51 asthmatic patients (45 non-atopic and six atopic asthma). Twenty-six patients showed significant bronchoconstriction after the inhalation of L-ASA. Bronchoprovocation test produced immediate asthmatic responses in 13 cases as well as dual asthmatic responses in four cases, whose late onset asthmatic response was noted at 4–7 h after L-ASA inhalation. We conclude that L-ASA bronchoprovo-cation might be a useful method for the diagnosis and investigation of aspirin-sensitive asthma. However, L-ASA inhalation can also induce late onset asthmatic responses.     

Prediction of late asthmatic responses to inhaled allergen

Relationships between cutaneous and bronchial responses to allergen were examined in nineteen atopic asthmatics. Allergen inhalation tests elicited an isolated early asthmatic response (EAR) in ten subjects and a dual asthmatic response (DAR) in nine subjects. Ragweed IgE RAST, performed with the sera of those patients tested with ragweed antigen, yielded higher values in all but one patient who experienced DAR than any of the patients with EAR. In one patient with annual symptoms in the ragweed season, positive skin tests with ragweed antigen and DAR to inhaled ragweed extracts, the IgE RAST was entirely negative and the serum IgE concentration was low. Dilutions of the allergen used in each individual for inhalation were also used in skin-prick tests. Early cutaneous allergic response (ECAR) mean wheal diameters were obtained at 10 min and late cutaneous allergic response (LCAR) mean diameters at 6-8 hr. Early asthmatic response (EAR) subjects differed modestly from DAR subjects in the relationships between ECAR and LCAR; in the EAR group, a significantly larger wheal diameter (P < 0.01) was required before an LCAR ensued, however there was some overlap. Once LCAR developed, there was no difference between EAR and DAR groups in the magnitude of the LCAR. There was a trend (not significant) towards a requirement for a higher antigen concentration in the EAR group to elicit an LCAR. In conclusion, correlates of an isolated EAR from inhaled antigen include: (i) a low positive IgE RAST result with the antigen, (ii) ECAR 6 mm or greater with the antigen which does not proceed to a LCAR, and (iii) a high concentration of antigen is needed in skin tests to elicit an LCAR. Correlates of a DAR include:(i) a high IgE RAST result with the antigen, (ii) an ECAR wheal diameter less than 5 mm with the antigen proceeds to a LCAR, and (iii) a low antigen concentration in skin tests elicits an LCAR. The observed correspondence between the tendency to late skin and late airway responses is evidence of a common immunologic basis.     

Theophylline inhibits early and late asthmatic reactions induced by allergens in asthmatic subjects

To determine whether oral slow-release theophylline inhibits asthmatic reactions and the associated increase of airway responsiveness to methacholine induced by allergens, we examined six asthmatic subjects who developed a dual asthmatic reactions after allergen bronchoprovocation with Dermatophagoides pteronyssinus or with grass pollen. We gave oral slow-release theophylline and placebo to each subject for seven days in two series of experiments in a double-blind, randomized, crossover study. The individual daily dose of theophylline (4.7 to 16.6 mg/kg/day, divided into two doses) was calculated for each subject by measuring individual theophylline clearance and optimal daily dosage. During treatment with placebo, the subjects developed dual asthmatic reactions, ie, FEV1 decreased from 4.1 +/- 0.17 L before bronchoprovocation to 3.2 +/- 0.14 L at 15 minutes and to 3.2 +/- 0.19 L at seven hours after allergen bronchoprovocation. By contrast, during active treatment FEV1 decreased from 4.2 +/- 0.28 L to 3.9 +/- 0.26 L at 15 minutes, and to 3.8 +/- 0.13 L at seven hours (both cases, P less than .03 compared with placebo). Mean serum theophylline concentration was 13.2 +/- 0.6 mg/L. Although 1 week's treatment with slow-release theophylline did not modify significantly either prechallenge airway responsiveness to methacholine or its increase after allergen inhalation challenge, in five out of six subjects theophylline significantly inhibited the increase of airway responsiveness to methacholine induced by allergens compared to placebo and control day (P less than .05). These results suggest that slow-release theophylline may inhibit allergen-induced asthmatic reactions and the associated increase of airway responsiveness, suggesting some antiinflammatory effects for this drug.     

Enhanced serum neutrophil chemotactic activity was noted in both early and late asthmatic responses during lysine-aspirin bronchoprovocation test in ASA-sensitive asthmatic patients

To investigate the pathogenic mechanism of late asthmatic response in comparison to early asthmatic response, changes of serum neutrophil chemotactic activity (NCA) using the Boyden chamber method and histamine level using the automated fluorometric analyzer were observed in 13 aspirin (ASA)-sensitive asthma subjects (group I: 7 early responders and group II: 6 dual responders) during lysine aspirin bronchoprovocation test (L-ASA BPT). Sera were collected before, and 30 min and 240 min after L-ASA BPT. Serum NCA increased significantly after 30 min (p=0.02) and decreased significantly at 240 min (p=0.02) in group I, while serum NCA of group II increased significantly at 30 min (p=0.04), tending to increase further up to 240 min with no statistical significance. NCA at 240 min in group II subjects was significantly higher than baseline NCA (p=0.02). The serum NCAs collected before and 240 min were significantly higher in group II than in group I (p<0.05, respectively). There were no significant changes in serum histamine levels during L-ASA BPT in both groups. NCA derived from mast cell may contribute to the development of early asthmatic response induced by L-ASA inhalation. There may be a possible involvement of NCA derived from mononuclear cells during late asthmatic response.     

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.     

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.     

Blood markers of early and late airway responses to allergen in asthmatic subjects. Relationship with functional findings

We evaluated the relationship between blood markers of mast-cell (plasma histamine and serum level of heat-stable neutrophil chemotactic activity [NCA]) and eosinophil (serum eosinophil cationic protein [ECP]) activation during early airway response (EAR) and late airway response (LAR) to allergen inhalation in 24 asthmatic subjects. After EAR, 14 subjects showed significant LAR (FEV₁ fall: 25%), while 10 subjects showed equivocal LAR (FEV₁ fall: 15–20%). A significant increase from baseline value was observed in plasma histamine and in serum NCA during both EAR and LAR, while serum ECP significantly increased only during LAR. The sensitivity of different markers to detect significant FEV₁ fall during EAR and LAR was low, except for NCA. Changes in blood mediators were similar in both groups with significant and equivocal LAR. There was a significant relationship between the increase in NCA during EAR and the severity of LAR. Stepwise regression between changes in different blood markers showed a significant relationship between histamine increase during EAR and ECP increase during LAR. Thus, serum NCA is a more sensitive marker of EAR and LAR than plasma histamine and serum ECP, and its increase during EAR seems predictive of the severity of the subsequent LAR.     

Der p 1 and Der p 2 induce less severe late asthmatic responses than native Dermatophagoides pteronyssinus extract after a similar early asthmatic response

Background The models for exposure to house dust in research and clinical practice are selected with respect to their role in IgE‐mediated immediate hypersensitivity. The use of isolated major allergens instead of complex allergen extracts is becoming increasingly popular as it offers some important advantages for quantitative measures in diagnosis and research. Objective To compare house dust mite extract and isolated mite major allergens with respect to their ability to induce early and late asthmatic responses and bronchial hyperreactivity. Methods Bronchial responses to house dust mite (HDM, Dermatophagoides pteronyssinus) extract and isolated major allergens from HDM (Der p 1 and Der p 2) were compared in a double‐blind, randomized, cross‐over study in 20 patients with mild to moderate asthma who were allergic to HDM. Allergen was titrated to a standardized early asthmatic response. Bronchial hyper‐responsiveness to histamine (PC₂₀histamine) was determined before and after allergen inhalation to assess allergen‐induced bronchial hyper‐responsiveness and IL‐5 was measured in serum. In addition, the allergens were applied in intracutaneous skin tests and activation of basophil leucocytes and proliferation of peripheral blood mononuclear cells was tested in vitro. Results After a similar early asthmatic response (mean Δforced expiratory volume in 1 s (FEV₁)_,max?29.4 (SD 7.2) vs. ?33.1 (8.6) %; mean difference 3.6 (95% CI ?0.9 to 8.2) %), the late asthmatic response (mean ΔFEV_1,max?45.9 (21.9) vs. ?32.7 (22.3) %; mean difference 13.2 (3.8–22.3) %), the degree of allergen‐induced bronchial hyper‐responsiveness (mean ΔPC₂₀histamine, 1.8 (1.0) vs. 1.2 (0.9) doubling dose; mean difference 0.6 (0.2–1.1) doubling dose) and serum IL‐5 at 6 h were found to be significantly higher after bronchial challenge with HDM extract than after challenge with an isolated HDM major allergen. Likewise, there was an increased late skin reaction with HDM compared with isolated major allergen after a similar early skin reaction. Conclusion Constituents of HDM extract, other than Der p 1 or Der p 2, with no significant influence on the IgE‐mediated early asthmatic response contribute significantly to the allergen‐induced late asthmatic response and bronchial hyper‐reactivity.     

Protective effect of inhaled furosemide on allergen-induced early and late asthmatic reactions

The movement of ions and water across the membranes of bronchial cells is part of the control of the bronchial obstructive response to physical stimuli. In a double-blind, randomized, crossover study, we compared the effect of an aerosol of the loop diuretic furosemide with that of a placebo on the early (within 60 minutes) and late (4 to 12 hours) asthmatic responses to a specific inhaled allergen. We studied 11 subjects with mild allergic asthma, who had both early and late asthmatic responses to a specific inhaled allergen in a preliminary challenge. After placebo administration, the maximal changes (mean +/- SE) from base line in the forced expiratory volume in one second (FEV1) and specific airway resistance were, respectively, a decrease of 35 +/- 4 percent and an increase of 288 +/- 56 percent between 0 and 60 minutes after inhalation of the allergen (early response) and a decrease of 35 +/- 5 percent and an increase of 301 +/- 40 percent between 4 and 12 hours (late response). After furosemide administration (4 ml; 10 mg per milliliter), the early response to inhaled allergen was markedly attenuated in all the subjects, and the late response in all but one. The maximal changes in the FEV1 and specific airway resistance were, respectively, a decrease of 11 +/- 2 percent and an increase of 61 +/- 2 percent between 0 and 60 minutes and a decrease of 20 +/- 4 percent and an increase of 178 +/- 25 percent between 4 and 12 hours (P less than 0.05 for all comparisons). No significant differences were seen in the bronchoconstrictor response to inhaled methacholine after furosemide or placebo administration. We conclude that a furosemide-sensitive mechanism in the airways is involved in the pathogenesis of the reactions of patients with allergic asthma. Whether inhaled furosemide might be useful in the treatment of allergic asthma is uncertain and will require further study.     

The late asthmatic response

Since LARs are associated with increases in airways reactivity, their significance may go well beyond the increase in symptoms due just to the allergen exposure. This is especially true since the increase in non-specific airways reactivity can last for weeks after a single exposure to allergen. Every effort should be made to search for possible allergic triggers in patients suspected to have LARs. Careful attention to historical information and skin test reactivity are critical in this evaluation. In situations where this approach is not revealing and where serious concerns remain about potential environmental triggers, a bronchial challenge to the suspected antigen can be considered. Since the nonspecific airways reactivity in patients with LAR may possibly be due to inflammation in the airways, the potential risk of transient induction of airways inflammation must be carefully weighed against the value of information that can be obtained from this procedure. Bronchial challenge should be performed only in an inpatient setting by experienced personnel under the supervision of a physician. A full explanation of the potential risks and benefits of this type of evaluation must be given to the patient and family. Treatment is primarily directed at allergen avoidance with use of a prophylactic drug, such as cromolyn sodium, when allergen avoidance is not possible.