Aspirin-induced asthma: Hypersensitivity to fenoprofen and ibuprofen in relation to their inhibitory action on prostaglandin generation by different microsomal enzymic preparations

doi:10.1016/0091-6749(76)90102-0

Journal of Allergy and Clinical Immunology

Volume 58, Issue 1, Part 1, July 1976, Pages 10-18

https://doi.org/10.1016/0091-6749(76)90102-0 Get rights and content

Abstract

Eighteen patients with asthma and aspirin hypersensitivity have been challenged with increasing doses of aspirin, fenoprofen, ibuprofen, and dextropropoxyphene. Low doses of the first three drugs induced bronchoconstriction in all the patients as evidenced by fall in peak expiratory flow and appearance of clinical symptoms. There were no reactions to therapeutic doses of dextropropoxyphene. Aspirin, fenoprofen, and ibuprofen, but not dextropropoxyphene, inhibited prostaglandin synthetase activity in three different microsomal preparations, i.e., in bovine seminal vesicles, in rabbit brain and, in rabbit kidney medulla. Expected in vivo antienzymic potency of a drug, calculated from experiments using rabbit brain microsomes, corresponded roughly with its potency to induce bronchoconstriction in the challenge tests. An individual pattern of sensitivity to threshold doses of prostaglandin, synthetase inhibitors was demonstrated for each patient. The results obtained suggest that precipitation of asthmatic attacks by nonsteroidal anti-inflammatory drugs is mediated through inhibition of prostaglandin biosynthesis. The degree of enzymic inhibition, which is sufficient to precipitate bronchoconstriction, is an individual hallmark. Knowing the threshold dose for any of prostaglandin synthetase inhibitors in a patient, one can predict the threshold doses for the rest of aspirin-like drugs in this particular patient.

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Cited by (64)

Group 2 innate lymphoid cells are recruited to the nasal mucosa in patients with aspirin-exacerbated respiratory disease
2017, Journal of Allergy and Clinical Immunology
Citation Excerpt :
Previous work has shown that AERD can be mediated by innate type 2 immunity. First, the potency of the COX-1 inhibition determines the severity of the reaction, which indicates that it is not adaptive recognition of a specific drug structure that activates the immune system.30 Second, 2 danger signals released from epithelial cells, IL-33, an alarmin-like cytokine, and TSLP, an IL-7–like cytokine, have been shown to be upregulated in nasal polyps from patients with AERD and important drivers for COX-1 inhibitor–induced reactions.7,8,31
Aspirin-exacerbated respiratory disease (AERD) is characterized by tissue eosinophilia and mast cell activation, including abundant production of prostaglandin D₂ (PGD₂). Group 2 innate lymphoid cells (ILC2s), which promote tissue eosinophilia and mast cell responses, undergo chemotaxis and cytokine production in response to PGD₂, but it is unknown whether ILC2s are active in patients with AERD.
We sought to determine whether ILC2 numbers change in peripheral blood and the nasal mucosa during COX-1 inhibitor–induced reactions in patients with AERD.
Blood and nasal scrapings were collected at baseline, during reactions, and after completion of ketorolac/aspirin challenge/desensitization in 12 patients with AERD. ILC2s and eosinophils were quantitated by means of flow cytometry. Urine was also collected, and quantification of PGD₂ metabolite and leukotriene E₄ levels was done by using ELISA. Baseline and nonsteroidal anti-inflammatory drug reaction clinical data were correlated with cell changes.
ILC2 numbers significantly increased in nasal mucosal samples and decreased in blood at the time of COX-1 inhibitor reactions in 12 patients with AERD. These changes were not observed in 2 patients without AERD. Furthermore, eosinophil numbers decreased in blood concurrently with significant increases in urinary PGD₂ metabolite and leukotriene E₄ levels. The magnitude of increases in nasal mucosal ILC2 numbers positively correlated with maximum symptom scores during challenges. Furthermore, blood ILC2 numbers during the reaction correlated with time for the reaction to resolve, possibly reflecting reaction severity.
ILC2s are recruited to the nasal mucosa during COX-1 inhibitor–induced reactions in patients with AERD, correlating with enhanced production of prostaglandins and leukotrienes.
A review of ibuprofen and acetaminophen use in febrile children and the occurrence of asthma-related symptoms
2007, Clinical Therapeutics
Background: Although many studies have investigated the safety and tolerability of ibuprofen or acetaminophen (paracetamol) use in children, few have specifically examined the association of ibuprofen or acetaminophen and the occurrence of asthma in pediatric populations.
Objectives: The primary objective of this literature review was to ascertain whether ibuprofen use exacerbates the symptoms of asthma or asthma-related adverse events in febrile children, and how it compares with acetaminophen use. The secondary objective was to develop an algorithm that allows for the consideration of ibuprofen treatment in children by health care professionals.
Methods: Twelve electronic databases (MEDLINE, EMBASE, Cochrane Database, DARE, British Nursing Index, CBIB, Derwent Drug File, International Pharmaceutical Abstracts, Pharm-Line, CINAHL, PASCAL, SCZZ-SciSearch) were searched from their year of inception to June 2007, to identify English-language articles pertaining to ibuprofen or acetaminophen use in the asthmatic pediatric population. The following search terms were used: asthma, child, pediatric, pediatrics, ibuprofen, Nurofen, Brufen, Motrin, Advil, propionic acid, paracetamol, and acetaminophen.
Results: Of 472 articles retrieved, 3 were relevant for the development of the algorithm. Two were subanalyses of a major randomized controlled trial (RCT), the Boston University Fever Study. Therefore, some overlap should be noted. The third article was another RCT. Other studies and review articles identified were used for the discussion. Findings from the literature analysis indicated that the use of ibuprofen in the pediatric population does not exacerbate asthma morbidity. Two of the studies demonstrated that ibuprofen was associated with a lower risk for asthma morbidity in febrile children with or without asthma compared with acetaminophen. In one study, ibuprofen use was associated with a lower relative risk for hospitalization (0.63) and outpatient visits (0.56) for asthma compared with acetaminophen. In the second study, acetaminophen use was associated with the exacerbation of wheezing in febrile children. This observation was corroborated by the findings of other studies that revealed an increased risk for asthma, wheezing, and other atopic outcomes with acetaminophen use.
Conclusions: The evidence reviewed in this article suggests a low risk for asthma-related morbidity associated with ibuprofen use in children and a possible protective and therapeutic effect compared with acetaminophen. The findings also suggest that acetaminophen use in children is associated with an increased risk for wheezing. The pediatric algorithm developed might serve as a guide for health care professionals in assessing suitability for ibuprofen use in children.
Respiratory symptoms in patients with inflammatory bowel disease and the impact of dietary salicylates
2007, Digestive and Liver Disease
Citation Excerpt :
Additionally, therapeutic agents of value in one condition can prove useful in the other (e.g. corticosteroids, cromoglycate) [17]. Many asthmatics are allergic to salicylates, with acute reductions in peak expiratory flow rate (PEFR) and overt bronchoconstriction, usually after exposure to aspirin [18]. Aspirin-induced asthma is increasingly shown to be important in the adult population [19].
Respiratory symptoms are over-represented in inflammatory bowel disease. There are similarities between the epidemiology of inflammatory bowel disease and that of respiratory conditions for which an adverse influence of salicylate has been identified. Natural salicylates exist within our diet.
To determine whether a lower intake of dietary salicylates is associated with less active inflammatory bowel disease and fewer concurrent respiratory symptoms.
Respiratory status, inflammatory bowel disease activity, quality of life, and dietary habits were established in 73 patients with Crohn's disease and 69 with ulcerative colitis, using a self-administered questionnaire and peak expiratory flow rate readings. Harvey–Bradshaw and Simple Birmingham/Royal Free Colitis indices, an internally validated respiratory score, and estimated weekly dietary salicylate intake, were calculated for each patient.
There was at least one respiratory symptom in 63.4% of patients. The commonest underlying respiratory diagnosis was asthma. Respiratory impairment was similar in ulcerative colitis and Crohn's disease; 56.3% of Crohn's disease patients with an active respiratory diagnosis had other extra-intestinal manifestations. The dietary salicylate intake was independent of respiratory status, but inversely correlated with ulcerative colitis activity (dietary salicylate intake 37.0 mg versus 21.4 mg for low and higher Simple Birmingham/Royal Free Colitis index, respectively; p < 0.02). A similar association was not seen in Crohn's disease.
Respiratory impairment is common in inflammatory bowel disease. Higher intake of dietary salicylates is associated with less active colitis and possibly causally so.
Iatrogenic drug effects in the Respiratory System
2002, Revista Portuguesa de Pneumologia
Entende-se por iatrogenia a doença provocada por actos praticados ou omitidos pelo médico, a vários níveis, destacandose, neste trabalho, o da terapêutica farmacológica. As informações existentes sobre os efeitos adversos dos fármacos ao nível do Aparelho Respiratório são escassas, dispersas e, muitas vezes, antigas, sendo as referências mais recentes sobretudo relacionadas com fármacos de investigação e utilização recente. Os fármacos podem provocar efeitos adversos à vários níveis: no interstício, nos vasos, nas vias aéreas baixas ou altas, no mediastino, na pleura, nos músculos ou nervos que controlam a mecânica ventilatória, etc. Descrevem-se neste trabalho os efeitos adversos de vários fármacos no contexto do Aparelho Respiratório.
REV PORT PNEUMOL 2002; VIII (6): 581-607
Iatrogeny is disease caused by medical action or omission, mainly at the therapeutic level. Recently introduced drugs are commonly investigated extensively as regards adverse effects. Information on this subject is often scarce and disperse when medications in use for a long time are concerned. We review adverse effects of therapeutic agents in the Respiratory System
REV PORT PNEUMOL 2002; VIII (6): 581-607
A clinical study of the impact on consumer health of dyes used in Tunisia
1990, Revue francaise d'allergologie et d'immunologie clinique
Les colorants de synthèse peuvent être à l'origine de manifestations allergiques dont les plus fréquentes sont urticaire et œdème de Quincke mais qui peuvent également se traduire par de l'asthme, des rhinites, de l'eczéma, du prurigo ou du purpura. Les colorants les plus utilisés en Tunisie ont été sélectionnés pour étudier leur incidence dans les manifestations allergiques d'une population tunisienne de la région de Sousse. Ce sont les colorants de synthèse suivants : tartrazine, érythrosine, bleu patenté, jaune de quinoléine, jaune orangé S, jaune orangé GGN et amarante. L'étude a porté sur 83 sujets atteints d'urticaire et/ou d'œdème de Quincke chronique d'étiologie jusqu'alors indéterminée et sur 21 sujets présentant une idiosyncrasie à l'aspirine. L'exploration cutanée a été réalisée à partir de solutions aqueuses de colorants à 1 mg/ml injectées par voie intradermique à la dose de 50 μg par test. Des tests de provocation ont également été réalisés par ingestion de gélules de colorants après un régime d'exclusion de 15 jours. La présence d'un terrain atopique a été observée chez 19 malades sur les 83 sujets urticariens et chez 4 malades sur les 21 sujets intolérants à l'aspirine. 12 sujets ont un test cutané positif sur les 83 sujets urticariens et 2 chez les intolérants à l'aspirine. Les tests de provocation montrent que la tartrazine est le colorant le plus impliqué dans les manifestations allergiques, suivi de l'érythrosine. Ce travail a permis de conclure à une incidence de 19 p. cent des colorants dans les manifestations allergiques étudiées.
Synthetic dyes may cause allergic manifestations, the most of which are urticaria and Quincke's edema, but which may also include asthma, rhinitis, eczema, prurigo or purpura. The dyes most commonly employed in Tunisia were chosen for a study of their involvement in allergic manifestations in a Tunisian population in the region of Sousse. The following synthetic dyes were considered: tartrazine, erythrosin, patent blue, quinoline yelow S, orange yellow GGN amaranthus. The study involved 83 subjects presenting urticaria and/or chronic Quincke's edema of previously undetermined etiology and 21 subjects presenting idiosyncrasy to aspirin. Cutaneous exploration was performed using aqueous 1 mg/ml solutions of dyes injected intradermaly at a dose of 50 μg per test. Challenge tests were also carried out by ingestion of capsules of dyes after a 15-day exclusion diet. The presence of atopy was noted in 19 of 83 subjects with urticaria and in 4 of 21 subjects with idiosyncrasy to aspirin. A positive skin test was noted in 12 of 83 subjects with urticaria and in two of 21 subjects with idiosyncrasy to aspirin. The challenge tests showed that tartrazine was the dye most implicated in allergy, followed by arythrosin. This study demonstrated involvement of dyes in 19% of the cases of allergy examined.
Inhaled lysine-aspirin as a bronchoprovocation procedure in aspirin-sensitive asthma: Its repeatability, absence of a late-phase reaction, and the role of histamine
1989, The Journal of Allergy and Clinical Immunology
Inhalation of an aerosolized solution of lysine-aspirin has previously been described as a safer technique than oral challenge with aspirin for the diagnosis of aspirin-senstive asthma. We describe a modification of this method that involves inhalation of serially doubling incremental concentrations of lysine-aspirin by a standardized technique and allows construction of concentration-response curves. In 11 subjects with asthma, mean (SEM) age 48.2 (2.9) years, the geometric mean (range) provocation concentrations of histamine and lysine-aspirin required to produce a 20% decrease in FEV₁ from baseline were 0.6 (0.04 to 3.2) and 48.3 (15.5 to 219) mg/ml, respectively. No relationship was found between these values. In seven of nine subjects investigated on two consecutive occasions, bronchoconstriction with lysine-aspirin was repeatable to within a single doubling concentration difference. Bronchoconstriction provoked by lysine-aspirin was more rapid than with oral aspirin and was not followed by any late asthmatic reaction or increase in nonspecific airway hyperresponsiveness. In six subjects, premedication with the selective H₁ histamine-receptor antagonist, terfenadine, had no significant effect on bronchconstriction provoked by inhaled lysine-aspirin, indicating little role for release of histamine in the response. We conclude that inhalation of lysine-aspirin may be used as a bronchoprovocation procedure for the diagnosis and investigation of aspirin-sensitive asthma.

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