Classification and practical approach to the diagnosis and management of hypersensitivity to nonsteroidal anti-inflammatory drugs.

Hypersensitivity reactions to aspirin (acetylsalicylic acid) and other nonsteroidal anti-inflammatory drugs (NSAIDs) constitute only a subset of all adverse reactions to these drugs, but due to their severity pose a significant burden to patients and are a challenge to the allergist. In susceptible individuals, NSAIDs induce a wide spectrum of hypersensitivity reactions with various timing, organ manifestations, and severity, involving either immunological (allergic) or nonimmunological mechanisms. Proper classification of reactions based on clinical manifestations and suspected mechanism is a prerequisite for the implementation of rational diagnostic procedures and adequate patient management. This document, prepared by a panel of experts from the European Academy of Allergy and Clinical Immunology Task Force on NSAIDs Hypersensitivity, aims at reviewing the current knowledge in the field and proposes uniform definitions and clinically useful classification of hypersensitivity reactions to NSAIDs. The document proposes also practical algorithms for the diagnosis of specific types of NSAIDs hypersensitivity (which include drug provocations, skin testing and in vitro testing) and provides, when data are available, evidence-based recommendations for the management of hypersensitive patients, including drug avoidance and drug desensitization.

Hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs) - classification, diagnosis and management: review of the EAACI/ENDA(#) and GA2LEN/HANNA*.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are responsible for 21-25% of reported adverse drug events which include immunological and nonimmunological hypersensitivity reactions. This study presents up-to-date information on pathomechanisms, clinical spectrum, diagnostic tools and management of hypersensitivity reactions to NSAIDs. Clinically, NSAID hypersensitivity is particularly manifested by bronchial asthma, rhinosinusitis, anaphylaxis or urticaria and variety of late cutaneous and organ-specific reactions. Diagnosis of hypersensitivity to a NSAID includes understanding of the underlying mechanism and is necessary for prevention and management. A stepwise approach to the diagnosis of hypersensitivity to NSAIDs is proposed, including clinical history, in vitro testing and/or provocation test with a culprit or alternative drug depending on the type of the reaction. The diagnostic process should result in providing the patient with written information both on forbidden and on alternative drugs.

Diagnosis, prevention and treatment of aspirin-induced asthma and rhinitis.

Bronchial asthma is not a homogenous disease. Several variants of asthma can be distinguished. One of them is aspirin-induced asthma. In this distinct clinical syndrome, aspirin and most other nonsteroidal anti-inflammatory drugs that inhibit cyclooxygenase-1 precipitate rhinitis and asthma attacks. This type of asthma affects 5-10% of adult asthmatics, but remains largely underdiagnosed. The natural history of aspirin-induced asthma (AIA) has been described, based on an extensive pan-European survey. Aspirin provocation tests with improved diagnostic accuracy have been developed, although no in-vitro tests has been found to be of diagnostic value. Recent interest in AIA has been stirred by the finding of alterations in arachidonate metabolic pathways, leading to cysteinyl-leukotriene overproduction. LTC4 synthase is overexpressed in bronchi and its mRNA is upregulated in peripheral blood eosinophils. The gene coding for LTC4 synthase exists in two common alleles, one of which appears to be associated with a severe, steroid-dependent type of asthma. New highly specific COX-2 inhibitors appear to be a safe alternative for patients with aspirin-induced asthma.

[Lipoproteins (A) after a history of myocardial infarction, arteriosclerosis obliterans, hypertension and hyperlipidemia]. / Lipoproteina(A) po przebytym zawale serca, w miazdzycy tetnic obwodowych, nadcisnieniu tetniczym i hiperlipidemii.

Serum lipoprotein(a) concentration in men with hypertension, arteriosclerosis obliterans, hypercholesterolemia and after myocardial infarction was measured using Laurell's immunoelectrophoresis. Lp(a) distribution and mean serum concentrations did not differ significantly from the controls, with the exception of a group of premature myocardial infarction (age below 45), in which high values were more frequent.

[A case of tracheal adenoid cystic carcinoma in a young woman]. / Przypadek raka gruczolowato-torbielowatego tchawicy u mlodej chorej.

A case of an adenoid cystic carcinoma of trachea is presented. A 30-year-old non-smoking woman with strong inspiratory dyspnea at rest was admitted to the Dept. of Pulmonary Diseases. At auscultation a respiratory murmur was more silent at right lung and stridor over trachea was heard. CT scan revealed tumor at the bifurcation of the trachea. Bronchoscopy was made and biopsy established the diagnosis: adenoid cystic carcinoma. The tumor was partially removed with rigid bronchoscope and radiotherapy was started. Clinical improvement occurred; in control CT scan tumor vanished. The trachea cancers are rare. Symptoms often mimic asthma or chronic bronchitis. Thus in every patient with chronic cough and dyspnea bronchoscopy should be made. A treatment of choice is primary resection and postoperative radiotherapy.

EAACI/GA2LEN guideline: aspirin provocation tests for diagnosis of aspirin hypersensitivity.

Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most common causes of adverse drug reactions. Majority of them are of the hypersensitivity type. The two frequent clinical presentations of aspirin hypersensitivity are: aspirin-induced bronchial asthma/rhinosinusitis (AIA/R) and aspirin-induced urticaria/angioedema (AIU). The decisive diagnosis is based on provocation tests with aspirin, as the in vitro test does not hold diagnostic value as yet. Detailed protocols of oral, bronchial and nasal aspirin provocation tests are presented. Indications, contraindications for the tests, the rules of drug withdrawal and equipment are reviewed. Patient supervision and interpretations of the tests are proposed.

The atopy trait in hypersensitivity to nonsteroidal anti-inflammatory drugs.

The prevalence of atopy was evaluated in two groups of subjects with hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAID): 1) 78 patients with aspirin-induced asthma (AIA) confirmed by oral or bronchial provocation challenges 2) 42 subjects with hypersensitivity to pyrazolone drugs (case history and positive skin tests to noramidopyrine/aminophenazone) who tolerated aspirin well. Fifty sex- and age-matched persons from an unselected general population, with no hypersensitivity to NSAID, formed the control group. Atopy was estimated from the results of the following clinical and biologic parameters: 1) personal and family history of atopic diseases 2) skin prick tests with 16 aeroallergens 3) serum levels of specific IgE to five aeroallergens 4) total serum IgE level. Different definitions of atopy were used, consisting of constellations of two or three of the above-mentioned features. The results of the study revealed that the prevalence of atopy varied according to the criteria used for its definition. Irrespective of the definition used, a similar distribution of atopy was observed in both groups of patients with hypersensitivity to NSAID. Atopy was more frequent in either group of patients with intolerance of NSAID than in the control group. Thus, atopy is related to adverse drug reactions to NSAID.

Exhaled eicosanoids following oral aspirin challenge in asthmatic patients.

BACKGROUND: Biochemical analysis of expiratory breath condensate is an emerging non-invasive technique for assessment of airway inflammation. OBJECTIVE: We wondered whether application of expiratory breath condensate could facilitate diagnosis of aspirin-intolerant asthma and reproduce eicosanoids mediators' abnormalities described in this disease. METHODS: We measured prostaglandins (PGs) E(2), F(2 alpha), 9 alpha 11 beta F(2) and iso-F(2) by gas-chromatography/mass-spectrometry and cysteinyl leukotrienes (cys-LTs) by radioimmunoassay in breath condensates of asthmatic patients undergoing oral aspirin challenge. Fourteen patients with aspirin-induced asthma and 20 aspirin-tolerating asthmatics, most of them on chronic inhaled corticotherapy, were studied and compared with 10 healthy subjects. Additionally, plasma 9 alpha 11 beta PGF(2), the metabolite of PGD(2) and urinary leukotriene (LT) E(4) were measured before and following the challenge. RESULTS: At baseline, PG did not differ between the groups, except for lower 9 alpha 11 beta PGF(2) in aspirin-intolerant asthma. Their concentrations were not changed by the challenge. Breath condensate cys-LTs were similar in the groups studied at base, and after aspirin challenge increased only in aspirin-intolerant patients. Elevated baseline urinary LTE(4) and its further increase following aspirin challenge was highly diagnostic for aspirin-intolerant asthma. The discriminatory value of cys-LTs increase in breath condensates was lower (72.8%) than either basal (99%) or post-challenge increase (94%) of urinary LTE(4). CONCLUSIONS: In asthmatic patients on chronic corticotherapy measurement of urinary LTE(4) excretion rather than cys-LTs in breath condensate is of greater value for diagnosis of aspirin hypersensitivity.

Plasma 9alpha,11beta-PGF2, a PGD2 metabolite, as a sensitive marker of mast cell activation by allergen in bronchial asthma.

BACKGROUND: Prostaglandin D(2) (PGD(2)) is a major cyclooxygenase product generated by activated mast cells during an allergic response. Assessment of PGD(2) and its metabolites in patients with asthma has mostly been performed in urine, bronchoalveolar lavage fluid and induced sputum, whereas human plasma determinations have been performed only sporadically. METHODS: In 32 patients with allergic asthma and 50 healthy non-allergic controls, baseline plasma and urinary levels of 9alpha,11beta-PGF(2), a primary PGD(2) metabolite, were assessed by gas chromatography/mass spectrometry. Serum tryptase levels were measured by fluoroenzyme immunoassay and urinary leukotriene E(4) (LTE(4)) by ELISA. In a subgroup of 10 asthmatics (randomly selected from the 32 study patients) in whom bronchial allergen challenges with specific allergens (Dermatophagoides pteronyssinus, n = 4, mixed grass pollens, n = 6) were carried out, measurements were taken both before and after provocation. RESULTS: At baseline no significant differences between mean plasma and urinary levels of the PGD(2) metabolite and serum tryptase levels were found in asthmatics or controls. Asthmatic patients had significantly higher urinary LTE(4) levels. Allergen challenge resulted in a significant early increase in the mean plasma 9alpha,11beta-PGF(2) level and only a borderline but significant increase in the urinary 9alpha,11beta-PGF(2) level within 2 hours after provocation. The challenge did not produce statistically significant changes in serum tryptase levels. Urinary LTE(4) levels remained significantly increased 4 hours after provocation. CONCLUSIONS: PGD(2) is actively involved in the early asthmatic response to allergens. Measurement of 9alpha,11beta-PGF(2) release into plasma rather than urine following allergen challenge is a sensitive marker of enhanced PGD(2) synthesis, most probably due to mast cell activation.

Safety of a specific COX-2 inhibitor in aspirin-induced asthma.

In a subset of patients with asthma, aspirin and several other non-steroidal anti-inflammatory drugs (NSAID) that inhibit simultaneously cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) precipitate dangerous asthmatic attacks. We tested the hypothesis that in patients with aspirin-induced asthma the attacks are triggered by inhibition of COX-1 and not COX-2. In twelve asthmatic patients (seven men, five women, average age 39 years) oral aspirin challenge precipitated symptoms of bronchial obstruction with fall in FEV1 > 20%, and a rise in urinary leukotriene E4 (LTE4) excretion; also in five patients the stable metabolite of PGD2, 9alpha11betaPGF2, increased in urine. The patients then entered a double-blind, placebo-controlled, cross-over study in which they received either placebo or rofecoxib in increasing doses 1.5-25.0 mg for 5 consecutive days, separated by a 1-week wash-out period. No patient on rofecoxib developed dyspnoea or fall in FEV1 > 20%; mean urinary LTE4 and 9alpha11betaPGF2 urinary levels, measured on each study day for 6 h post-dosing, remained unchanged. Two patients on placebo experienced moderate dyspnoea without alterations in urinary metabolites excretion. At least 2 weeks after completion of the study, all patients received on an open basis 25 mg rofecoxib without any adverse effects. NSAID that inhibit COX-1, but not COX-2, trigger asthmatic attacks in patients with asthma and aspirin intolerance. Rofecoxib can be administered to patients with aspirin-induced asthma.

Prevalence of asthma with aspirin hypersensitivity in the adult population of Poland.

BACKGROUND: Acetylsalicylic acid (ASA) and other nonsteroid anti-inflammatory drugs (NSAIDs) are reported to account for 21-25% of all adverse drug reactions. Some asthmatics may react to ASA and other NSAIDs with acute bronchoconstriction, profuse rhinorrhea and skin flushing. This is a distinct clinical syndrome called aspirin-induced asthma (AIA). The prevalence of AIA among asthmatic patients in Poland has not been previously assessed. METHODS: A questionnaire survey of 12,970 adults of both sexes, randomly selected from the population of Poland. RESULTS: The prevalence of AIA in the general population of Poland was estimated as 0.6%. Thirty patients (4.3%; 95% CI: 2.8-5.8) of 703 asthmatics (5.4% of general population) reported symptoms attesting to hypersensitivity to aspirin. In 27% of them the reactions were precipitated by aspirin, whereas in the remaining subjects by other NSAIDs. CONCLUSIONS: The prevalence of AIA in Poland is 4.3%, being somewhat lower than in Finland and Australia, where it was recently reported to account for 8.8 and 10.9% of the adult asthmatics, respectively. These figures indicate that aspirin hypersensitivity might be a significant community problem.

Treatment of steroid-dependent bronchial asthma with cyclosporin.

The treatment of chronic severe asthma is unsatisfactory for many patients. The aim of the study was to determine the effects of treatment of steroid-dependent asthma with cyclosporin. We performed a double-blind, placebo-controlled, randomized, parallel group trial on the effect of cyclosporin on pulmonary function, asthma severity and tapering of prednisone in 34 steroid-dependent asthmatics (mean oral prednisone dose: 16 mg.day-1). The study consisted of: 1) baseline period (12 weeks); 2) experimental period divided into two parts: Part I (12 weeks) cyclosporin or placebo treatment; Part II (22 weeks) cyclosporin or placebo treatment and oral prednisone reduction; and 3) follow-up observation (8 weeks). Asthma symptoms score, pulmonary function tests (daily peak expiratory flow (PEF) and bi-weekly forced vital capacity (FVC), forced expiratory volume in one second (FEV1) and maximal mid-expiratory flow (MEF50), biochemical profile and blood cyclosporin levels were monitored throughout the study. Following cyclosporin administration, a slight beneficial effect on some subjective parameters of asthma severity was observed. At the same time, no beneficial effect on pulmonary function was noted. The time trends analysis of mean daily prednisone doses between the treatment groups revealed a statistically significant difference indicating that, during prednisone reduction, cyclosporin seemed to be slightly more efficient than placebo in reducing the requirement for systemic corticosteroid, even though the steroid reduction was accompanied by slight impairment of some pulmonary function. However, there was no significant difference in the final dose reduction between the treatment groups. These data and the known toxicity of the drug suggest a limited place for cyclosporin treatment in steroid-dependent bronchial asthma.

Aspirin-induced asthma and HLA-DRB1 and HLA-DPB1 genotypes.

BACKGROUND: Aspirin-induced asthma (AIA) affects one in 10 individuals with adult-onset asthma. It is not known if aspirin sensitivity is due to immune mechanisms or to interference with biochemical pathways. OBJECTIVE: The study aimed to test for possible involvement of the genes of the Major Histocompatibility Complex (MHC) in AIA. METHODS: HLA-DPB1 and HLA-DRB1 genotyping was carried out by DNA methods in 59 patients with positive challenge tests for AIA and in 48 normal and 57 asthmatic controls. RESULTS: The DPB1*0301 frequency was increased in AIA patients when compared with normal controls (19.5% vs 5.2%, Odds Ratio = 4.4, 95% Confidence Interval (CI) 1.6-12.1, P = 0.002), and compared with asthmatic controls (4.4%, OR = 5.3, 95% CI = 1.9-14.4, P = 0.0001). The frequency of DPB1*0401 in AIA subjects was decreased when compared with normal controls (28.8% vs 49.0%, OR = 0.42, 95% CI = 0.24-0.74, P = 0.003) and asthmatic controls (45.6%, OR = 0.48, 95% CI = 0.28-0.83, P = 0.008). The results remained significant when corrected for multiple comparisons. There were no significant HLA-DRB1 associations with AIA. CONCLUSION: The presence of an HLA association suggests that immune recognition of an unknown antigen may be part of the aetiology of AIA.

Benefits from adding the 5-lipoxygenase inhibitor zileuton to conventional therapy in aspirin-intolerant asthmatics.

From bronchoprovocation studies and investigations of the acute effects of drugs that inhibit leukotrienes (LT), the hypothesis has emerged that leukotrienes are important mediators of airway obstruction and other symptoms in aspirin-intolerant asthma (AIA). However, it has yet not been shown if subjects with AIA respond favorably to clinical treatment with leukotriene inhibitors. Therefore, in a double-blind placebo-controlled crossover study, we examined the effects of 6 wk of treatment with the leukotriene-pathway inhibitor zileuton (600 mg, four times daily) in 40 patients with well-characterized AIA. The treatment was added to existing therapy, which included medium to high doses of inhaled (average daily dose 1,030 microg of beclomethasone or budesonide) or oral glucocorticosteroids (4 to 25 mg/d) for all but one of the patients. On top of this treated baseline, there were no significant effects of adding placebo, indicating that their asthma was kept relatively stable. However, there was an acute and chronic improvement in pulmonary function after treatment with zileuton, expressed both as increased FEV1 from baseline compared with placebo, and higher morning and evening peak expiratory flow rate (PEFR) values on zileuton treatment compared with placebo. The improvements occurred despite lower use of rescue bronchodilator with zileuton. Zileuton also diminished nasal dysfunction, which is one of the cardinal signs of AIA. There was a remarkable return of smell, less rhinorrhea, and a trend for less stuffiness and higher nasal inspiratory flow during treatment with zileuton. Zileuton caused a small but distinct reduction of bronchial hyperresponsiveness to histamine and inhibited aspirin-induced bronchoconstriction. Zileuton inhibited urinary excretion of LTE4 but did not change airway reactivity to inhaled LTD4, supporting that zileuton specifically inhibited leukotriene biosynthesis. The findings indicate that leukotrienes are important mediators of persistent airway obstruction and chronic nasal dysfunction in AIA. The study also suggests that addition of a leukotriene pathway inhibitor such as zileuton may bring about greater control of asthma than what is achieved by treatment with medium to high doses of glucocorticosteroids alone.