Salicylate pre-treatment attenuates intensity of bronchial and nasal symptoms precipitated by aspirin in aspirin-intolerant patients

Aspirin (ASA) and other non-steroidal anti-inflammatory drugs, which are cyclooxygenase (COX) inhibitors, precipitate asthmatic attacks in ASA-intolerant patients, while sodium salicylate, hardly active on COX by itself, is well tolerated by these patients. However, salicylate moiety appears to interfere with aspirin inhibitory action on platelets and vascular COX. Such interaction, if present at the level of respiratory tract, may be of interest to pathogenesis of ASA-induced asthma. We performed a double-blind, placebo-controlled, randomized cross-over study on the effect of choline magnesium trisalicylate (CMT, trilisate) pre-treatment on ASA-induced adverse reactions in nine patients. Pulmonary function tests, nasal symptoms score, PNIF and serum salicylate levels were monitored following challenges with threshold doses of ASA. Trilisate administered at a dose of 3000 mg daily for 3 days, offered a moderate protection against ASA-induced symptoms; it diminished the severity and/or delayed the appearance of FEV1 fall. Maximal decreases in FEV1 as well as reaction intensity indexes were significantly lower (P less than 0.02 and P less than 0.002, respectively) after trilisate pre-treatment as compared to placebo. Trilisate also attenuated nasal symptoms in three out of five patients. Although the precise mechanism of the protective action of trilisate is unknown, our data support the possibility of interaction between salicylate and ASA on cyclo-oxygenase locus in the respiratory tract in ASA-intolerant patients.     

Selenium status in relation to reduced glutathione peroxidase activity in aspirin-sensitive asthma

Selenium status and its relationship to lowered platelet glutathione peroxidase activity was investigated in 18 subjects with aspirin (ASA)-induced asthma and in asthmatic and non-asthmatic ASA-tolerant subjects. Mean serum selenium concentration in ASA-tolerant asthmatics (1.25 microns/l; 98.5 micrograms/l) was significantly higher than that in ASA-induced asthma subjects (1.14 microns/l; 89.7 micrograms/l) and than that in healthy controls (1.15 microns/l; 91 micrograms/l). Although there was a correlation between serum selenium concentration and platelet glutathione peroxidase activity, enzyme activity was significantly lower in the ASA-induced asthma group compared to other groups even after correcting for selenium status. These results indicate that lowered platelet glutathione peroxidase activity in ASA-induced asthma is a product of both selenium availability and an unidentified syndrome-specific (possibly genetic) factor.     

Neutrophil chemotactic activity in milk-induced asthma

Four subjects with clinical histories of milk-induced asthma were studied (three allergic to cow's milk; one to soya milk). In each instance, skin prick tests, RAST (IgE and IgG₄), the basophil histamine release, and serum precipitins, using appropriate milk extracts, were negative. After the ingestion of milk all the subjects developed a reproducible and dose-dependent increase in airflow limitation. Three patients (two allergic to cow's milk; one to soya milk) gave a characteristic immediate-type reaction, which was maximal at 30 min after challenge. The fourth individual developed an isolated late-phase response, with maximal airways obstruction 3 hr after ingesting milk. In the three subjects who gave an early reaction, wheezing was accompanied by an elevation in circulating neutrophil chemotactic activity (NCA). This was not observed in the individual with the isolated late reaction. By Sephacryl S-400 gel-filtration chromatography it was shown that NCA of the early reactions eluted with proteins having an estimated molecular weight of 600,000 daltons. The immediate asthmatic response in peak expiratory flow rate and the elevation in NCA were inhibited by the prior oral administration of either disodium cromoglycate (DSCG) or oral beclomethasone dipropionate (BDP). In contrast, DSCG had no effect on airways obstruction in the subject with the isolated late asthmatic response, although inhibition was achieved by BDP.     

Exercise-induced asthma and the generation of neutrophil chemotactic activity

Heat-stable neutrophil chemotactic activity (HS NCA) has been demonstrated in serum of subjects with asthma after exercise and after allergen inhalation challenge. Heat-labile neutrophil chemotactic activity (HL NCA) has been investigated only after allergen inhalation challenge. In this study, we have measured HS NCA and HL NCA after exercise of 22 adult patients with asthma, 13 of whom had exercise-induced asthma (EIA). In the 13 patients, the effect of pharmacologic pretreatment on the generation of HS NCA and EIA was evaluated in a double-blind study with inhalation of either disodium cromoglycate, terbutaline, or budesonide 15 minutes before exercise. Additionally, the effect of 4 weeks of treatment with budesonide aerosol was evaluated in an open study. A significant increase (p less than 0.01) in HS NCA was found in the patients with EIA with peak activities 15 minutes after exercise. In patients without EIA, the activity of HS NCA was variable. No HL NCA was detectable after exercise. EIA was inhibited by disodium chromoglycate, terbutaline, and 4 weeks of treatment with budesonide. The generation of HS NCA was more or less inhibited by all three drugs with 4 weeks of treatment with budesonide as the most potent regimen. No late-phase asthmatic reactions to exercise were found. It is concluded that only HS NCA is generated after exercise of subjects with asthma and that this production is controlled by antiasthmatic drugs. However, the generation of HS NCA occurs irrespective of EIA.     

Immunologic release of neutrophil chemotactic activity from human lung tissue

The release of heat-stable neutrophil chemotactic activity (NCA) has been detected after challenge of isolated human lung tissue with anti-IgE. The major NCA released (NCAL) had similar physicochemical properties to the NCA detected in the circulation of asthmatic subjects after bronchial challenge with specific antigen (NCAAG). NCAL and NCAAG (1) had molecular weights of approximately 600,000 daltons as estimated by Sephacryl S-300 gel-filtration chromatography; (2) both eluted from DEAE-Sephacel (pH 7.8) between 0.1 and 0.2 molar NaCl; (3) had isoelectric points of between 6.5 and 6.8 as determined by chromatofocusing on Polybuffer Exchanger 94. In contrast to NCAAG, lung-derived neutrophil chemotactic activity appeared to be more heterogeneous after gel-filtration and anion-exchange chromatography. The release of NCA was complete by 15 min and there was no evidence of further release up to 12 hr. These observations indicate that high-molecular-weight NCA released from human lung tissue has similar properties to NCAAG and would support the view that NCAAG originates from lung tissue after antigen bronchial challenge in asthmatic subjects.     

Neutrophil chemotactic activity in toluene diisocyanate (TDI)-induced asthma

We quantitated serum neutrophil chemotactic activity (NCA), which is associated with mast cell or basophil activation, to determine if mast cell or basophil mediators are released during bronchoprovocation-inhalation challenge with subirritant levels of toluene diisocyanate (TDI). Four subjects with suspected TDI-induced asthma and four mite-sensitive subjects with asthma who served as a comparison group were studied. NCA was measured in a multiwell, microchemotaxis chamber. Blood samples were collected, and FEV1 measurements were performed before challenge and at regular intervals during the subsequent 24 hours. Three of four workers clinically sensitive to TDI reacted to a subirritant TDI exposure. There was no increase in NCA during placebo challenges. NCA increased in the three TDI-sensitive workers during early and late asthmatic reactions in quantities proportional to the FEV1 decline. No increase in NCA was found during TDI exposures in the TDI-negative worker. Gel filtration analysis demonstrated the main NCA fraction eluted with macromolecules of an estimated molecular weight greater than 440,000 daltons. This characteristic is compatible with neutrophil chemotactic factor of basophil or mast cell origin. The kinetics of NCA release were similar in mite- and TDI-induced asthmatic reactions. A high correlation (r = 0.97; p = 0.0006) was obtained between the percent decrease in FEV1 during early asthmatic reactions and percent increase in NCA. These observations support the hypothesis that activation of mast cells or basophils is associated with TDI-induced early and late asthmatic reaction.     

Immunologic studies in allergen-induced late-phase asthmatic reactions

We have measured plasma histamine, serum neutrophil chemotactic activity (NCA) and complement (C3 and C4) over a 24-hour period in patients experiencing either early- and late-phase (dual) or single early asthmatic reactions to inhaled allergens. There was a significant biphasic elevation in plasma histamine, which paralleled the fall in forced expiratory volume in 1 sec in 10 patients with dual responses, whereas in seven subjects with single early reactions, only a single early increase in histamine concentrations was observed. In general, in the individual subjects, the changes in plasma histamine paralleled both the elevations in serum NCA and the decreases in forced expiratory volume in 1 sec. By gel filtration on Sephacryl S-400, anion exchange chromatography on DEAE Sephacel, and chromatofocusing with Polybuffer Exchanger 94, the major NCA of both the early and the late reactions was associated with proteins having an estimated molecular size of 600,000 daltons, an elution from DEAE Sephacel at 0.15M to 0.30M of NaCl (pH 8.1), and a pI of approximately 6.5. There were no appreciable changes in serum C3 and C4 up to 24 hr after challenge in subjects with late-hase responses. The patterns of asthmatic response were not related to either the total or allergen-specific serum IgE or IgG₄ concentrations. These results support the view that mediators of hypersensitivity participate in late-phase as well as early asthmatic reactions.     

Effect of sodium cromoglycate on asthmatic reactions to environmental temperature changes

Immediate asthmatic reactions, with falls in FEV₁ of 16–42.5% were elicited by exposure in a cold room at 3°C in five out of eight subjects with histories of asthma provoked by falls in environmental temperature. In four of the subjects pretreatment by inhalation of sodium cromoglycate gave complete inhibition of the asthmatic reaction in two, partial inhibition in one and had no effect in one case.     

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 disodium cromoglycate on asthmatic reactions to alcoholic beverages

Eleven asthmatic patients with a history of asthma with or without rhinitis following the ingestion of alcoholic drinks were challenged by oral ingestion of the suspected drink, and some with equivalent amounts of ethyl alcohol. Asthma was provoked in six cases, four having falls in the FEV₁ of more than 15%. Three of the latter studied in detail gave immediate asthmatic reactions to the alcoholic beverage, but not to the ethyl alcohol tested by oral ingestion, and in one case by administration through a naso-gastric tube. Pre-treatment by inhalation of disodium cromoglycate inhibited the asthmatic reactions to the alcoholic beverages.     

Heat-labile neutrophil chemotactic activity in subjects with asthma after allergen inhalation: relation to the late asthmatic reaction and effects of asthma medication

Neutrophil chemotactic activity (NCA) in serum is raised in subjects with asthma after inhalation of an allergen. Two kinds of NCA have been demonstrated, heat-stable and heat-labile. In addition, inhibitory activity is generated after inhalation challenge. In the present study we have investigated the relationship of heat-labile NCA to the development of the late asthmatic reaction (LAR) in 13 subjects with asthma after allergen challenge and the effects of asthma medication on the formation of this activity. Heat-labile NCA peaked 120 to 240 minutes after challenge and demonstrated at this time significant (p less than 0.001) quantitative relationships to the ensuing LAR. The inhalant corticosteroid, budesonide, significantly inhibited (p less than 0.001) the generation of heat-labile NCA and the development of LAR both after a single dose and after 4 weeks of pretreatment. Single-dose disodium cromoglycate pretreatment, initially, slightly enhanced (p less than 0.05) heat-labile NCA but, after 120 minutes, slightly inhibited (p less than 0.05) the activity. Disodium cromoglycate also slightly abrogated the development of LAR. Single-dose pretreatment with the beta 2-agonist, terbutaline, inhibited generation of heat-labile NCA (p less than 0.001) but was without effect on LAR. It is concluded that the generation of heat-labile NCA is related to the development of the LAR and may be of importance for the attraction of inflammatory cells to the lung in the development of the inflammatory reaction probably responsible for LAR. However, the pharmacologic control of heat-labile NCA indicates that the process is multifactorial and not solely dependent on the generation of NCAs detected in serum.     

Aspirin and tartrazine oral challenge: Incidence of adverse response in chronic childhood asthma

Reports of adverse response to acetylsalicylic acid (ASA) and tartrazine in asthma disagree widely on the incidence of these phenomena. The present study seeks to define these incidences for asthmatic children in a statistically acceptable, standardized, and simple fashion. Fifty-four chronic asthmatic children 10 to 17 yr of age underwent blinded oral provocation challenge with ASA, tartrazine, and placebo on separate days. The pulmonary function results were expressed in percent predicted units and the absolute change from the subject's baseline to ASA and tartrazine were compared to the normal variation encountered to placebo challenge. Five children developed sustained decreases of one-second forced expiratory volume (L) (FEV₁) or forced expiratory flow rate at 25% to 75% of effort (L/sec) (FEF_0.25–0.75) exceeding 2 SD of the group mean response to placebo following oral ASA; none did following tartrazine. Two additional patients included in this population sample were considered to have adverse pulmonary response (APR) by history and were consequently not challenged. There were no clinical or laboratory findings associated with APR to ASA. Adverse response to ASA is sufficiently common among our population of children with chronic asthma to warrant ASA avoidance, unless ASA therapy is needed for another condition, such as rheumatoid arthritis, in which case careful provocation testing should be considered.     

Oral and Inhaled Sodium Cromoglycate in Challenge Test with Food Allergens or Acetylsalicylic Acid

The prophylactic effect of oral and inhaled sodium cromoglycate (SCG) in challenge tests of patients with IgE-mediated food allergy or sensitivity towards acetylsalicylic acid (ASA) was investigated. In food allergic patients SCG administered orally protected against an asthmatic reaction whereas inhaled SCG was without effect. In ASA sensitivity neither oral nor inhaled SCG protected the patients against bronchospasms. SCG seems to act on mucosal surfaces and may inhibit uptake of macromolecular antigens but not affect the absorption of ASA.     

Effects of nedocromil sodium on bronchospasm and HS-NCA release induced by allergen inhalation in asthmatic patients

The aim of this study was to assess the ability of nedocromil sodium (NS) to prevent the immediate asthmatic reaction and the increase in the scrum level of heal stable neutrophil chemotactie activity (HS-NCA) induced by antigen inhalation. In a double-blind, cross-over study. 13 atopic subjects affected with seasonal asthma underwent a bronchial provocation lest with a preselected dose of grass pollen allergen (enough to cause a decrease of ≥ 20% in FEV₁:FEV₁ PD20) after pre-treatment with 4 mg NS or placebo. Serum samples were withdrawn from 11 subjects for HS-NCA determination. After NS administration the decrease in FEV₁ was significantly less than after placebo administration at all lime points after challenge (2 min P= 0.0004; 7 min, P= 0.0005; 17 min P= 0.0002 and 27 min P= 0.0005). The percentage increase in HS-NCA was significantly higher after placebo than after NS inhalation, both 10 (P= 0.0048) and 2d (P= 0.0068) min after challenge. Our study confirms previous investigations, showing that NS inhibits the immediate asthmatic response to allergen inhalation in atopic, asthmatic subjects and moreover it shows that this drug prevents in vivo the increase of the serum HS-NCA. This last finding has not been previously reported.     

A comparison of the protective effect of fenoterol and Sch 1000 on allergen-induced asthma.

The protective effects of inhaled Sch1000 (80 μg), inhaled fenoterol (800 μg), and placebo on the early asthmatic response induced by inhaled allergen were compared in 10 subjects in a single-blind investigation. Allergen inhalation produced early asthmatic responses in all 10 subjects, with a mean 1-sec forced expiratory volume (FEV₁) fall of 31.1% (range, 23% to 40%). The similarity of the responses to allergen inhalation following no pretreatment and following placebo showed that the allergen-induced response was highly reproducible, with coefficients of variation for the maximum percentage FEV₁ fall of ± 7.2%. Sch1000 produced a slight nonsignificant reduction in the magnitude of the early asthmatic response of 20.7% ± 39.7% (p > 0.10) for the maximum FEV₁ fall. Fenoterol, however, produced a highly significant reduction in the magnitude of the early of 76.4% ± 23.5% (p < 0.001) for the maximum FEV₁ fall, which was significantly greater than that produced by Sch1000 (p < 0.001). These results show that β-adrenergic agonists, such as fenoterol, are more effective than cholinergic antagonists, such as Sch1000, in preventing the early asthmatic response induced by inhaled allergen. Reflex parasympathetic bronchoconstriction is involved to a variable and minor extent in the production of allergen-induced early asthmatic responses.     

Generation and partial characterization of eosinophil chemotactic activity and neutrophil chemotactic activity during early and late-phase asthmatic response

Asthma has been recognized to consist of hyperresponsive airways and cellular inflammation. Allergen bronchoprovocation (BPC) may define the early (EAR) and late-phase asthmatic response (LAR). The LAR has now been associated with increased nonspecific airway hyperresponsiveness and cellular inflammation consisting of neutrophils and eosinophils. We used BPC to demonstrate EAR and LAR in 12 subjects with seasonal allergic asthma. One normal subject and one subject with asthma who had been treated with allergy immunotherapy were challenged but did not respond. Plasma was sampled at frequent intervals during these aeroallergen challenges and assayed for eosinophil chemotactic activity (ECA) and neutrophil chemotactic activity (NCA). Of the 12 subjects with asthma who were challenged, nine had dual responses (both EAR and LAR), and three subjects demonstrated only an LAR. Those subjects who had dual airway responses had biphasic rises in both ECA (early = 267 +/- 28%; late = 286 +/- 28%) and NCA (early = 279 +/- 24%; late = 215 +/- 15%) in their plasma, whereas those subjects who demonstrated only an LAR had only a late rise in ECA (218 +/- 61%) and NCA (188 +/- 31%). The two individuals who did not respond to aeroallergen challenge demonstrated no change in their plasma chemotactic activity toward either eosinophils or neutrophils. Those individuals with the most severe LAR (greater than or equal to 1,000 mm2) had combined ECA plus NCA peak values of greater than 500%.(ABSTRACT TRUNCATED AT 250 WORDS)     

Oral aspirin challenges in asthmatic patients: a study of plasma histamine

Under carefully controlled conditions, seven aspirin-intolerant asthmatic patients were challenged with oral aspirin and experienced respiratory tract reactions with a decline in forced expiratory volume in 1 sec (FEV₁), ranging from 26 to 64%. Venous blood samples, which were collected during the challenges, showed a rise in plasma histamine in all seven patients. The increase in plasma histamine occurred at the onset of their respiratory reactions and those patients with the most severe asthmatic responses were found to have the highest and most prolonged levels of plasma histamine. The same aspirin-intolerant asthmatic patients were able to ingest Maalox® or sodium salicylate without untoward effects, decline in FEV₁ values or changes in plasma histamine levels. Ten non-asthmatic individuals and eight out of ten asthmatic control patients were able to ingest aspirin without any reactions or changes in their plasma histamine levels. However, two asthmatic control individuals, with severe asthma requiring treatment with moderate dosages of corticosteroids, were found to have elevated pre-challenge plasma histamine levels which increased during their ASA challenges despite the absence of respiratory reactions or changes in FEV₁ values. It is possible that these two individuals were unsuspected aspirin-intolerant asthmatics. These studies demonstrate that asthmatic reactions to acetylsalicylates are associated with release of histamine into plasma in the subgroup of asthmatic patients with the aspirin-intolerance syndrome. Such a finding suggests that histamine may be one of the mediators of bronchospasm in aspirin-induced asthma.     

Abnormal platelet hydrogen peroxide metabolism in aspirin hypersensitivity

The generation and degradation of hydrogen peroxide (H2O2) by platelets was investigated in aspirin hypersensitive and tolerant allergic subjects, and compared to that in general medical patients and healthy controls. H2O2 generation following triggering with anti-IgE, specific allergen, and with aspirin (ASA) and indomethacin was examined using a chemiluminescence assay. Platelet levels of the main intracellular enzyme responsible for H2O2 metabolism--glutathione peroxidase--were measured by a quantitative functional assay. H2O2 secretion could be triggered by anti-IgE in platelets from 15/29 ASA-tolerant atopics, and by relevant allergen in platelets passively sensitized with allergen-specific IgE. A similar response was observed following triggering with ASA, and with indomethacin, in platelets from 8/25 ASA-sensitive subjects. Mean platelet glutathione peroxidase activity was significantly lower in subjects with ASA-induced asthma, but not in subjects with non-asthmatic reactions to ASA, compared to all other groups. Within the ASA-sensitive group there was no correlation between low peroxidase activity and ASA-triggered chemiluminescence. Our findings emphasize the heterogeneity of ASA-intolerance syndromes and point to abnormal oxygen/peroxide metabolism as a common pathway underlying ASA-induced asthma.     

Allergen-induced increase in non-allergic bronchial reactivity

Non-allergic bronchial hyper-reactivity is a feature of most patients with asthma. We have measured non-allergic bronchial reactivity to inhaled histamine and methacholine in thirteen asthmatic subjects before and after allergen inhalation in the laboratory. The allergen inhalation produced mild early asthmatic responses (19–40% FEV₁ fall) in all thirteen, additional definite late asthmatic responses (17–29% FEV₁ fall) in four, and equivocal late asthmatic responses (5–11% FEV₁ fall) in five. Following allergen inhalation, non-allergic bronchial reactivity increased in seven for up to 7 days. The seven included all four with definite late asthmatic responses and three of the five with equivocal late asthmatic responses. We conclude that allergens make asthma worse, partly through non-allergic mechanisms, and that avoidance of allergens is important in reducing non-allergic bronchial hyper-reactivity.     

Effect of Sch1000 in allergen-induced asthma

Carefully controlled allergen inhalation tests were carried out in twelve subjects to provoke early asthmatic responses with a mean maximum FEV₁ fall of 30·7 ± 5·2% (mean ± s.d.). Four subjects had additional late asthmatic responses with a maximum mean FEV₁ fall of 21·0 ± 5·9%. The tests were repeated at intervals of 7 days in an identical way, following inhalation of Sch1000 (80 μg) and placebo, each given 45 min before the onset of the early asthmatic response. This dose of Sch1000 produced a marked and uniform inhibition of methacholine-induced bronchoconstriction in the same subjects. The allergen-induced responses were reproducible in eleven out of the twelve subjects; the coefficient of variation for the decrease in FEV₁ in the early responses being ±7% and in the late response ±43%. Sch1000 produced a slight and variable inhibition of early asthmatic responses (P<0·02) and no inhibition of late asthmatic responses. We examined the relationship between the degree of inhibition of the early asthmatic response by Sch1000 and: (a) the degree of inhibition produced by Sch1000 on histamine- and methacholine-induced bronchoconstriction; (b) the level of non-specific bronchial reactivity measured by inhaled histamine and methacholine; and (c) the degree of bronchodilatation produced by Sch1000. No relationship was found.