RESUMEN
BACKGROUND: The mechanism of aspirin (acetylsalicylic acid: ASA) hypersensitivity in asthmatic patients is related to arachidonic acid metabolism abnormalities, and specific triggering by ASA of 15-hydroxyeicosatetraenoic acid (15-HETE) generation was observed in leucocytes from aspirin-sensitive (AS) but not from aspirin-tolerant (AT) asthmatics. OBJECTIVE: The aim of this study was to identify the enzymatic pathway involved in ASA-induced 15-HETE generation in AS asthmatics and to assess the regulatory role of prostaglandin EP receptors. METHODS: Peripheral blood leucocytes (PBLs) were isolated from AS (n=18) and AT (n=20) asthmatics and challenged with ASA, with and without pre-incubation with caffeic acid (CA) [15-lipoxygenase (15-LO) inhibitor] or prostaglandin receptor non-specific (misoprostol, sulprostone) and specific EP1-4 receptors agonists. Eicosanoids were measured in supernatants using specific immunoassays. RESULTS: Aspirin triggered 15-HETE generation in PBLs of AS asthmatics (mean increase 292%) but not in AT asthmatics and inhibited prostaglandin(2) (PGE(2)) generation in both groups of patients to the same degree. Leucocytes from AS patients produced less PGE(2), both before and after ASA incubation. Pre-incubation of PBLs with CA decreased basal 15-HETE production in all patients and completely inhibited ASA-induced 15-HETE generation in AS asthmatics. CA did not change basal PGE(2) production but enhanced induced by ASA inhibition of PGE(2). Non-specific agonists of EP receptors (misoprostol and sulprostone) did not affect basal 15-HETE production but inhibited in a dose-dependent manner the ASA-induced increase of 15-HETE generation in AS asthmatics. On the contrary, in AT asthmatics, pre-incubation of PBLs with misoprostol or sulprostone resulted in a significant increase in 15-HETE generation after addition of ASA (200 microm). EP1-3 receptor agonists inhibited (range 72-94%) the ASA-induced 15-HETE production significantly. CONCLUSION: Our study demonstrated that ASA-triggered 15-HETE generation involves the activation of 15-LO and is modulated by prostaglandin EP1-3 receptors. The relevance of these observations to the mechanism of in vivo ASA-induced asthmatic attack remains to be established.
Asunto(s)
Araquidonato 15-Lipooxigenasa/metabolismo , Aspirina/farmacología , Asma/metabolismo , Hipersensibilidad a las Drogas/metabolismo , Ácidos Hidroxieicosatetraenoicos/metabolismo , Receptores de Prostaglandina E/metabolismo , Adolescente , Adulto , Anciano , Aspirina/efectos adversos , Asma/inmunología , Ácidos Cafeicos/farmacología , Dinoprostona/análogos & derivados , Dinoprostona/metabolismo , Dinoprostona/farmacología , Femenino , Humanos , Leucocitos/metabolismo , Inhibidores de la Lipooxigenasa , Masculino , Persona de Mediana Edad , Misoprostol/farmacología , Receptores de Prostaglandina E/agonistasRESUMEN
BACKGROUND: We have previously demonstrated that aspirin triggers specific generation of 15-hydroxyeicosateraenoic acid (15-HETE) from nasal polyp epithelial cells and peripheral blood leukocytes (PBL) from aspirin-sensitive (AS) but not aspirin-tolerant (AT) patients with asthma/rhinosinusitis. The goal of this study was to assess the diagnostic value of ASA-induced 15-HETE generation measurement to identify AS patients. METHODS: PBL were obtained from 43 AS patients with asthma and rhinosinusitis, 35 AT asthmatics and 17 healthy control (HC) subjects. PBL were incubated with 2-200 muM aspirin (ASA) and 15-HETE release was measured in cell supernatants with competitive ELISA. RESULTS: Unstimulated PBL from all three groups of patients generated similar amount of 15-HETE. Incubation with 200 microM ASA resulted in an increase in an 15-HETE generation (mean increase +421%) in AS-asthmatics but small and nonsignificant response in AT-asthmatics or control subjects. Receiver operating curve (ROC) analysis revealed that the sensitivity of the test for confirmation of ASA-sensitivity was 83% and the specificity 82%. Positive predictive value was 0.79 and negative predictive value was 0.86. Naproxen induced a significant increase in 15-HETE only in some AS-asthmatics, but not in AT-asthmatics. CONCLUSION: Our data demonstrate that ASA-induced 15-HETE generation by PBL is a specific and sensitive aspirin-sensitive patients identification test (ASPITest).
Asunto(s)
Aspirina/efectos adversos , Asma/inmunología , Hipersensibilidad a las Drogas/diagnóstico , Ácidos Hidroxieicosatetraenoicos/biosíntesis , Leucocitos/metabolismo , Adulto , Anciano , Hipersensibilidad a las Drogas/inmunología , Femenino , Humanos , Pruebas Inmunológicas , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Rinitis/inmunología , Sinusitis/inmunologíaRESUMEN
Coronal CT scans have dramatically improved imaging of the nasal cavity and paranasal sinuses. However, quantification of the extent of chronic sinusitis is not possible by simple reviewing of the CT images. The aim of the study was to introduce a CT scoring scale to assess the extend of sinusal pathology. Seventeen patients with clinically recognized aspirin-sensitive rhinosinusitis asthma syndrome (aspirin triad) were studied. The CT scans were reviewed and scored for extent of the disease by two independent radiologists. Repeated readings of the scans showed close correlation between the two assessments. The authors conclude, that CT scoring system for quantitation of the disease extent is reproducible and may be useful in clinical practice.
Asunto(s)
Procesamiento de Imagen Asistido por Computador , Rinitis/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodos , Adulto , Aspirina/uso terapéutico , Enfermedad Crónica , Humanos , Persona de Mediana Edad , Senos Paranasales/diagnóstico por imagen , Rinitis/tratamiento farmacológico , Sinusitis/diagnóstico por imagenRESUMEN
Pyrazolone drug hypersensitivity (PDH) may manifest as angioedema, urticaria, and/or life threatening anaphylactic shock. Although it has been suggested that PDH is an immunologic, probably IgE-mediated reaction, the diagnosis of PDH is still based on clinical history because there is no reliable in vitro diagnostic method currently used in clinical practice. The goal of this study was to evaluate the reliability of various methods to confirm a diagnosis of PDH. Twenty-eight patients with prior history of 71 reactions to pyrazolone drugs were studied. In all patients, pyrazolone drugs induced urticaria and angioedema. In addition, laryngeal edema occurred in 14 patients and anaphylactic shock with loss of consciousness in five patients. Skin prick test and intradermal tests using increasing concentrations of noraminophenazone were performed in 25 patients. Sera of all 28 patients were negative for pyrazolone-specific IgE as determined by an immunoenzymatic method. Peripheral blood mononuclear cells proliferative responses to pyrazolone were studied by a lymphocyte proliferation test with 3H-thymidine incorporation. Incubation of peripheral blood mononuclear cells with increasing concentrations of noraminophenazone did not induce any significant proliferation responses. Our study demonstrated that 1) intradermal skin tests correlate poorly with the clinical history of hypersensitivity reaction; and 2) in vitro tests are not useful in establishing a diagnosis of PDH.
Asunto(s)
Antiinflamatorios no Esteroideos/efectos adversos , Hipersensibilidad a las Drogas/diagnóstico , Pirazoles/efectos adversos , Pirazolonas , Adolescente , Adulto , Hipersensibilidad a las Drogas/patología , Femenino , Humanos , Inmunoglobulina E/sangre , Activación de Linfocitos , Masculino , Persona de Mediana Edad , Pruebas CutáneasRESUMEN
BACKGROUND: In sensitive patients pyrazolone drugs can precipitate adverse reactions ranging from urticaria and angioedema to anaphylactic shock, presumably by immunological, IgE-mediated mechanism. However, up to now no genetic factors influencing the development of allergic reaction have been reported in this type of hypersensitivity. OBJECTIVE: The aim of our study was the investigation whether the susceptibility to development of pyrazolone drugs hypersensitivity (PDH) reactions was associated with HLA class II antigens. METHODS: To test this hypothesis we studied the distribution of HLA-DR and DQ antigens in 26 pyrazolone sensitive patients and control groups including unselected general population and clearly defined atopic and non-atopic groups. RESULTS: Significantly higher frequencies of DQ 7 and DR11 antigens were found in PDH group as compared with control unselected population (RR= 16.48, P < 0.0001; P(cor)< 0.002 and RR = 4.57, P = 0.0002; Pcor = 0.003 for DQ and DR antigen respectively). Similarly, statistically significant increased frequencies of DQ 7 and DR11 in patients with PDH were observed compared with atopic control group (RR= 18.43, P < 0.0001; Pcor <0.002 and RR= 6.33, P= 0.0007; Pcor =0.01, for DQ and DR antigen respectively). However, in comparison to non-atopic control group only the frequency of DQ 7 antigen was significantly increased (RR = 15.42, P = 0.0001; Pcor = 0.0015). DQ 7 antigen was present in 46.1% of PDH patients compared with 4.9%, 4.4% and 5.3% in the general population, atopic and non-atopic groups respectively, suggesting pyrazolone hypersensitivity as a trait positively correlated with this HLA antigen. CONCLUSION: Our data suggest a genetic predisposition to pyrazolone hypersensitivity reactions, linked to HLA-DQ locus.