Hypersensitivity to dipyrone in aspirin-exacerbated respiratory disease patients is associated with urticaria.

OBJECTIVE: To phenotype patients with aspirin-exacerbated respiratory disease (AERD) according to the presence of atopy, urticaria and level of peripheral eosinophils. METHODS: This study included adult asthmatic patients with AERD followed up at a tertiary hospital. They were classified according to atopy and/or urticaria, assessing clinical and laboratorial differences among the groups in order to identify possible aggravating factors of the disease. RESULTS: We included 73 patients, 78.1% being female with a mean age of 54.0 years. Severe asthma was observed in 68.5% and respiratory exacerbation with dipyrone in 67.1% of these patients. They had median total serum IgE of 191.6 IU/mL, mean peripheral eosinophils of 718.5 cells/mm3, and 50.7% were atopic. Urticaria was observed in 32.9% of them, and exacerbations were more often triggered by dipyrone (p = .016). Atopic patients were younger than nonatopic patients (p = .023), and had, on average, higher total serum IgE levels (p = .022). We observed a good correlation between asthma severity and peripheral eosinophils count (r2 = 026; p = .021). CONCLUSIONS: In this study, severe asthma was highly prevalent in AERD patients. Likewise, urticaria was quite prevalent and its presence was associated with dipyrone induced hypersensitivity reaction. Atopy was found in half of the patients, with no association with asthma severity. Patients with higher levels of peripheral eosinophils had more severe asthma. Dypirone hypersensitivity may be a marker for concomitant respiratory and cutaneous hypersensitivity reactions.

Immediate reactions to more than 1 NSAID must not be considered cross-hypersensitivity unless tolerance to ASA is verified

Background: Individuals who develop drug hypersensitivity reactions (DHRs) to chemically unrelated nonsteroidal anti-inflammatory drugs (NSAIDs) are considered cross-hypersensitive. The hallmark for this classification is that the patient presents a reaction after intake of or challenge with acetylsalicylic acid (ASA). Whether patients react to 2 or more NSAIDs while tolerating ASA remains to be studied (selective reactions, SRs). Objective: To identify patients with SRs to 2 or more NSAIDs including strong COX-1 inhibitors. Methods: Patients who attended the Allergy Service of Hospital Infanta Leonor, Madrid, Spain with DHRs to NSAIDs between January 2011 and December 2014 were evaluated. Those with 2 or more immediate reactions occurring in less than 1 hour after intake were included. After confirming tolerance to ASA, the selectivity of the response to 2 or more NSAIDs was demonstrated by in vivo and/or in itro testing or by controlled administration. Results: From a total of 203 patients with immediate DHRs to NSAIDs, 16 (7.9%) met the inclusion criteria. The patients presented a total of 68 anaphylactic or cutaneous reactions (mean [SD], 4.2 [2.1]). Most reactions were to ibuprofen and other arylpropionic acid derivatives and to metamizole. Two different NSAIDs were involved in 11 patients and 3 in 5 patients. Conclusions: Patients with NSAID-induced anaphylaxis or urticaria/angioedema should not be considered cross-hypersensitive unless tolerance to ASA is verified (AU)

Introducción: Los individuos que desarrollan reacciones de hipersensibilidad a antiinflamatorios no esteroideos (AINE) no relacionados químicamente se consideran intolerantes cruzados. La característica esencial para ser incluidos en esta categoría es que presenten un resultado positivo tras la administración de AAS. La cuestión de si estos pacientes responden a dos o más AINE y toleran AAS no ha sido estudiada (reacciones selectivas a múltiples AINE, RS). Objetivos: Identificar pacientes con RS a dos o más AINE, incluidos inhibidores potentes de COX-1. Métodos: Se evaluaron los pacientes que acudieron al servicio de alergia del Hospital Infanta Leonor con una historia de hipersensibilidad a AINE desde enero de 2011 a diciembre de 2014. Únicamente se consideraron los casos con dos o más reacciones a AINE diferentes y que se produjeron durante la primera hora tras la ingesta del fármaco (reacciones inmediatas). Tras confirmar la tolerancia a AAS, se evaluó la selectividad de la reacción mediante pruebas in vivo/in vitro o administración controlada del medicamento. Resultados: De un total de 203 pacientes con reacciones inmediatas a AINE 16 (7,9%) se ajustaron a los criterios establecidos. Los pacientes presentaron 68 reacciones anafilácticas o urticaria/angioedema (media de 4,2±2,1). El ibuprofeno y otros derivados arilpropiónicos y el metamizol fueron los fármacos más frecuentemente implicados. En 11 pacientes las reacciones fueron inducidas por dos AINE diferentes, mientras que en otros 5 fueron tres los medicamentos implicados. Conclusiones: Los pacientes con anafilaxia o urticaria/angioedema a diferentes AINE no deben ser incluidos dentro del grupo de intolerancia cruzada hasta verificar su tolerancia a AAS (AU)

Accelerated-type reactions to high parenteral doses of metamizole in patients who tolerated therapeutic doses of oral metamizole and other NSAIDs

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IgE-mediated metamizol allergy and the usefulness of the cellular allergen stimulation test.

Metamizol is a pyrazolone-derivative nonsteroidal anti-inflammatory drug that is commonly associated with hypersensitivity reactions. Some of these reactions are IgE-mediated and potentially severe, which limits the diagnosis based on oral drug challenge. We describe 6 selective metamizol hypersensitivity cases, regarding clinical evaluation and diagnosis management, with focus on the usefulness of skin tests and the cellular allergen stimulation test (CAST). All patients were female, aged 27 to 50 years old. All had immediate reactions after metamizol administration: 3 had anaphylaxis and 3 had urticaria and angioedema. Skin prick tests with metamizol were positive in 2 patients. Intradermal tests were positive in the remaining, all with 1/100 dilution, and elicited systemic reactions in 2 of them. CAST to metamizol was negative in all cases. The patients tolerated other nonsteroidal anti-inflammatory drugs. Skin tests proved to be a good diagnostic method to identify IgE-mediated metamizol allergy, although skin tests elicited systemic symptoms in some cases. Despite this being a small sample, our results showed a very low sensitivity for CAST which differs from data previously reported in the literature.

Immunoglobulin E-mediated immediate allergic reactions to dipyrone: value of basophil activation test in the identification of patients.

BACKGROUND: Pyrazolones are a major cause of immediate IgE-mediated reactions to drugs in many countries. OBJECTIVE: The aim of the study was to evaluate a group of patients with this type of reaction by basophil activation test (BAT), focusing on the influence on positivity of the time between the reaction and this study. METHODS: The study included 51 patients with selective immediate allergic reactions to pyrazolones and 56 controls. Patients were defined by skin testing or a drug provocation test and BATs with pyrazolones were carried out in all cases. Patients who were BAT positive were followed-up for 30 months to establish the rate of decline in positive tests. RESULTS: BAT was positive in 28 (54.9%) cases. BAT sensitivity was higher in those who were skin-test positive (85.7%) compared with those who were skin-test negative (33.3%). The time between the initial reaction and this study was significantly shorter in those who were skin-test positive (P=0.005) and those who were BAT positive (P=0.017). Follow-up of the BAT-positive patients showed a decrease over time, with 60% of these patients becoming negative after 6 months. CONCLUSIONS: BAT is a useful complement to skin testing for the evaluation of immediate allergic reactions to pyrazolones. Although not optimal, BAT sensitivity was also positive in patients with a negative skin test and it is a reasonable alternative in patients with severe reactions who may develop symptoms after skin testing. The time of performance of the test is critical to obtain a positive response.

Usefulness of intradermal test and patch test in the diagnosis of nonimmediate reactions to metamizol.

BACKGROUND: Metamizole is a pyrazolone derivative, and its most common reactions are IgE-mediated reaction and idiosyncratic reactions. Non-immediate reactions are poorly described and there are very few reports on non-immediate reactions to pyrazolones. MATERIALS AND METHODS: We evaluated 12 patients (nine men) who consulted for a non-immediate reaction after metamizol administration. We performed cutaneous tests (skin prick tests and immediate and delayed intradermal tests) and epicutaneous tests, and, if necessary, an oral challenge test. RESULTS: All skin prick and intradermal tests, if necessary, were negative in immediate reading. Delayed intradermal tests were positive in six of 10 patients (60%) and epicutaneous tests were positive in four of 11 patients (36%). Three cases (25%), were diagnosed by a positive oral challenge test. DISCUSSION: Delayed-reading intradermal tests and patch tests are useful tools in the diagnosis of nonimmediate reactions to pyrazolones and should be considered the first step when evaluating these type of reactions. Intradermal test appears to be more sensitive than patch test. The positivity of skin tests suggests an immunological reaction, probably mediated by T lymphocytes, but further studies are required.

Drug-induced anaphylaxis : case/non-case study based on an italian pharmacovigilance database.

OBJECTIVE: To identify the number of cases of anaphylaxis reported in association with different classes of drugs and compare it with other reports contained in the same database. METHODS: The data were obtained from a database containing all of the spontaneous reports of adverse drug reactions (ADRs) coming from the Italian regions of Emilia Romagna, Lombardy and the Veneto, which are the main contributors to the Italian spontaneous surveillance system. The ADRs reported between January 1990 and December 2003 with a causality assessment of certainly, probably or possibly drug related (according to the WHO criteria) were analysed using a case/non-case design. The cases were defined as the reactions already coded by the WHO preferred terms of 'anaphylactic shock' or 'anaphylactoid reaction' (this last term also included anaphylactic reaction) and those with a time of event onset that suggested an allergic reaction and involved at least two of the skin, respiratory, gastrointestinal, CNS or cardiovascular systems; the non-cases were all of the other ADR reports. The frequency of the association between anaphylaxis and the suspected drug in comparison with the frequency of anaphylaxis associated to all of the other drugs was calculated using the ADR reporting odds ratio (ROR) as a measure of disproportionality. RESULTS: Our database contained 744 cases (including 307 cases of anaphylactic shock with 10 deaths) and 27 512 non-cases. The percentage of anaphylaxis cases reported in inpatients was higher than that among outpatients (59.1% vs 40.9%). This distribution is significantly different from that of the other ADR reports that mainly refer to outpatients. After intravenous drug administrations, anaphylactic shock cases were more frequent than anaphylactoid reactions or other ADRs, but more than one-third of these reactions were caused by an oral drug. Blood substitutes and radiology contrast agents had the highest RORs. Among the systemic antibacterial agents, anaphylaxis was disproportionally reported more often for penicillins, quinolones, cephalosporins and glycopeptides, but diclofenac was the only NSAID with a significant ROR. As a category, vaccines had a significantly lower ROR, thus indicating that anaphylaxis is reported proportionally less than other ADRs. CONCLUSIONS: Anaphylaxis is a severe ADR that may also occur with commonly used drugs. It represents 2.7% of all of the ADRs reported in an Italian spontaneous reporting database.

The flow-cytometric determination of basophil activation induced by aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) is useful for in vitro diagnosis of the NSAID hypersensitivity syndrome.

BACKGROUND: Hypersensitivity reactions to non-steroidal anti-inflammatory drugs (NSAIDs), manifested by cutaneous symptoms and/or airway manifestations represent 20-25% of all hypersensitivity reactions to drugs. Today, it is still claimed that no in vitro diagnostic tests exist for that condition and that the only way to confirm the diagnosis is a provocation challenge. OBJECTIVE: The objective of this study was to assess whether NSAIDs may provoke blood basophil activation in vitro in such patients, as detected by a flowcytometric technique. METHODS: Sixty NSAID hypersensitive patients (38 with cutaneous, 20 with airway and two with cutaneous and airway symptoms) and 30 control patients (15 asthmatics) were selected. Their hypersensitivity was confirmed by documented history indicating at least two clinical episodes to two or more different NSAIDs or by positive oral provocation challenge. Isolated buffy coat leukocytes were stimulated in vitro with aspirin, paracetamol, metamizol, diclofenac, and naproxen. The percentage of activated basophils was evaluated by an anti-CD63. RESULTS: Aspirin showed a sensitivity of 43.3%, a specificity of 100%, a positive predictive value of 100% and a negative predictive value of 99.4%. For the other NSAIDs, the sensitivity and specificity values were: for paracetamol 11.7% and 100%, for metamizol 15% and 100%, for diclofenac 43.3% and 93.3% and for naproxen 54.8% and 74.1%. When considering the first four NSAIDs, the global sensitivity raised to 63.3% and specificity to 93.3%. If the number of tests is to be limited for practical reasons, the combination of acetylsalicylic acid and diclofenac at two concentrations yields a sensitivity of 58.3% and a specificity of 93.3%. CONCLUSIONS: Flowcytometric determinations of basophil activation following stimulation with NSAIDs show a high sensitivity (60-70%) with specificity above 90%. So this test may help avoiding some cumbersome and dangerous provocation challenges.

Use of CD63 expression as a marker of in vitro basophil activation and leukotriene determination in metamizol allergic patients.

BACKGROUND: We assessed the reliability of basophil activation test (FAST) and sulphidoleukotriene production (CAST) in the in vitro diagnosis of allergy to metamizol, evaluating its sensitivity and specificity. METHODS: Twenty-six patients allergic to metamizol and 30 control individuals were studied. Skin tests with metamizol, FAST, and CAST were performed. RESULTS: FAST sensitivity was 42.3% and specificity 100%. The PPV of FAST is 100% and the NPV 99.4%. The likelihood ratio for a positive value cannot be calculated because the specificity is 100% and the likelihood ratio for a negative value is 0.58. CAST sensitivity was 52%, and specificity 90%. The PPV of the test is 5% and the NPV 99.5%. The likelihood ratio for a positive result was 5.2 and that for a negative result 0.53. FAST detects a larger number of cases when patients are studied within the first 6 months after the clinical reaction (chi = 4.2, P = 0.04) than later. Together with skin tests, FAST allowed detection of 69.2% patients allergic to metamizol, the same as CAST 76%. The joint use of the three techniques allowed identification of 76.9% of cases. CONCLUSIONS: FAST and CAST are useful for the diagnosis of allergy to pyrazolones. Its usefulness clearly increases when recent reactions are studied.

Efficacy of leukotriene receptor antagonist in bronchial hyperresponsiveness and hypersensitivity to analgesic in aspirin-intolerant asthma.

BACKGROUND: Albeit its exact pathogenesis is still ambiguous; aspirin-intolerant asthma is one of several types of asthma for which antileukotriene therapy is useful, because it is widely accepted that bronchial over-production of leukotrienes may be involved in its pathogenesis. Pranlukast (8-[p-(4-phenylbutyloxy) benzol] amino-2-(tetrazol-5-yl)-4-oxo-4H-1-benzopyran hemihydrate), a selective cysteinyl leukotriene receptor antagonist, is now widely used in the treatment of asthma. OBJECTIVE: This study was designed to investigate the protective effect of pranlukast on airway sensitivity to sulpyrine provocation testing, bronchial responsiveness to methacholine provocation testing, and to investigate whether this protective activity is associated with a reduction in aspirin-induced excretion of urinary LTE4 (uLTE4), a marker of the cysteinyl leukotriene (LT) overproduction that participates in the pathogenesis of aspirin-induced asthma. METHODS: We assessed the effects of pretreatment with pranlukast on bronchoconstriction precipitated by inhalation of methacholine and sulpyrine in 16 adult patients with mild or moderate aspirin-intolerant asthma; those who were in stable clinical condition and were hypersensitive to sulpyrine provocation testing were allocated to this study. A double-blind, randomized, crossover design was used. uLTE4 was measured using combined reverse-phase high-performance liquid chromatography (rp-HPLC)/enzyme immunoassay. RESULTS: Pranlukast protected against analgesic-induced bronchoconstriction through mechanisms that were not related to the bronchodilator property, but were related to the improvement both of bronchial hyperresponsiveness and hypersensitivity to analgesic (P < 0.005 and P < 0.0001). Pranlukast showed little effect on excretion of uLTE4. CONCLUSION: These results support the hypothesis that cysteinyl leukotriene is one of the most important components in the pathogenesis of aspirin-intolerant asthma. Pranlukast improves not only hypersensitivity to analgesic, but also bronchial hyperresponsiveness in aspirin-intolerant asthma. It is also possible that pranlukast has another anti-asthmatic effect besides that of a leukotriene receptor antagonist.

Agranulocytosis associated with "Mexican aspirin" (dipyrone): evidence for an autoimmune mechanism affecting multipotential hematopoietic progenitors.

A case of acute, transient agranulocytosis and thrombocytopenia associated with ingestion of dipyrone is reported. This once widely used analgesic, which is now banned in the United States, was obtained by the patient as "aspirin" while traveling in Mexico. Studies of the effects of this patient's serum on purified CD34+ marrow cells, which were highly enriched for hematopoietic progenitors, showed not only a drug-dependent suppression of the in vitro growth of myeloid progenitors, as has been reported previously, but also a drug-dependent suppression of primitive multipotential progenitors (CFU-Mix) and erythroid progenitors (BFU-E). These findings indicate that autoimmune, antibody-hapten interactions which have been reported to occur in dipyrone- and aminopyrine-induced agranulocytosis are not restricted to the neutrophil lineage.

Immune-mediated agranulocytosis related to drugs and their metabolites: mode of sensitization and heterogeneity of antibodies.

Two major unresolved problems in drug-related immune agranulocytosis are understanding the mechanism by which sensitization takes place in vivo, and verification of the diagnosis. Using a sensitive, competitive enzyme-linked immunoassay (ELISA) we were able to characterize the causative antibodies in 13 patients with drug-related agranulocytosis [metamizole (n = 5), penicillin (n = 5), dimethylaminophenazone (n = 1), propyphenazone (n = 1) and diclofenac (n = 1)]. Irrespective of the causative drug, the majority of patients appear to have developed autoantibodies (aab) in addition to drug-dependent antibodies (ddab) of the IgG and/or IgM classes. In all cases related to metamizole, and in the single case related to diclofenac, the ddab appeared to recognize only metabolites of the drug since they were reactive in the presence of ex vivo antigens (urine from individuals receiving therapeutic levels of the drugs), but not the native drugs. Only a few ddab were reactive with granulocytes pretreated with the drug (cell-drug complexes); the majority of ddab could not be detected unless the drug or ex vivo antigen was added to the incubation mixture as well as the solution used for subsequent washes. Our results indicate that drugs and/or their metabolites interact with target cells and thereby directly function as immunogenic haptens, even when the drugs do not bind tightly to the cells.

Lymphocyte transformation test in drug-induced toxic epidermal necrolysis.

Lymphocyte transformation tests (LTT) to drugs remain widely used in drug reactions, despite controversies about their real usefulness. We tested the lymphocytes of 12 patients recovering from a drug-induced Toxic epidermal necrolysis (TEN). There was no difference between the amounts of thymidine incorporated when patients' lymphocytes were cultivated with culprit or innocent drugs. In both situations the lymphocytes from patients reacted like the lymphocytes from controls cultivated with the same panel of drugs. These negative results do not exclude that a hypersensitivity reaction may play a role in the physiopathology of TEN. Anyhow, they clearly indicate that testing lymphocyte transformation to drugs has no practical value in the diagnosis of TEN.

Further production and characterization of antibodies reactive with pyrazolone derivatives.

A sensitive radioimmunoassay for pyrazolone derivatives has been developed. Anti-antipyrine antisera were produced in rabbits by repeated immunization with 4-succinamidoantipyrine coupled to bovine serum albumin. Less than 1 ng of antipyrine could be detected by this procedure. Various substituents on the carbon-4 position of the pyrazolone ring decreased the affinity for the antibody. The concentrations in ng of various pyrazolone derivatives required to inhibit [3H]antipyrine binding by 50% were: antipyrine, 6.8; aminopropylon, 8.5; sulpyrine, 35.5; isopropylantipyrine, 1320; and aminopyrine, 2820. The antibody showed no cross-reactivity with any other antipyretics such as pyrazolidine or aniline derivatives. The determination of antipyrine and sulpyrine concentrations in rat serum after i.p administration was also carried out.