Eicosanoid mediator profiles in different phenotypes of nonsteroidal anti-inflammatory drug-induced urticaria.

BACKGROUND: The role of arachidonic acid metabolites in NSAID-induced hypersensitivity has been studied in depth for NSAID-exacerbated respiratory disease (NERD) and NSAID-exacerbated cutaneous disease (NECD). However, no information is available for NSAID-induced urticarial/angioedema (NIUA), despite it being the most frequent clinical entity induced by NSAID hypersensitivity. We evaluated changes in leukotriene and prostaglandin metabolites for NIUA patients, using patients with NECD and single-NSAID-induced urticaria/angioedema or anaphylaxis (SNIUAA) for comparison. METHODS: Urine samples were taken from patients with confirmed NSAID-induced urticaria and healthy controls, at baseline and at various time intervals after ASA administration. Eicosanoid measurement was performed using high-performance liquid chromatography-tandem mass spectrometry and gas chromatography-mass spectrometry. RESULTS: No differences were found between groups at baseline. Following ASA administration, LTE4 and 9α,11ß-PGF2 levels were increased in both NIUA and NECD patients compared to baseline, rising initially, before decreasing toward initial levels. In addition, the levels of these metabolites were higher in NIUA and NECD when compared with the SNIUAA and control groups after ASA administration. No changes were found with respect to baseline values for SNIUAA and control groups. CONCLUSIONS: We present for the first time data regarding the role of COX-1 inhibition in NIUA. Patients with this entity show a similar pattern eicosanoid levels following ASA challenge to those with NECD. Further studies will help ascertain the cell populations involved and the underlying molecular mechanisms.

Metabonomics delineates allergic reactions induced by Shuang-huang-lian injection in rats using ultra performance liquid chromatography-mass spectrometry.

Shuang-huang-lian Injection (SHLI) is the first successfully developed drug from traditional Chinese medicine (TCM) powder for injection, since its use for the treatment of acute respiratory tract infection, pneumonia, influenza, etc. At the same time, its allergic reactions have also emerged, which limits clinical applications. However, few scholars pay attention to the mechanism of allergic reactions. In this present study, metabonomics technology was used to explore the changes in endogenous metabolites in urine of the rat model of SHLI induced allergic reaction; we and analyzed the metabolites, metabolic pathway, and the mechanism which were closely related to the allergic reactions. The levels of serum histamine and tryptase were examined and changes in histomorphology were also observed. Based on the UPLC-Q-TOF/MS metabonomics, we carried out the pattern recognition analysis, selected potential biomarkers associated with allergic reactions, and explored the pathological mechanism for SHLI induced allergic reaction, which laid the foundation for the safety research of SHLI. Our results showed that SHLI increased the levels of serum histamine and tryptase in rats with allergic reaction; we determined 15 biomarkers in rat allergic reaction model induced by SHLI and found multiple metabolic pathways involved, such as metabolism of linolenic acid, phenylalanine, amino acid, 2-oxo acid, and purine and other metabolic pathways.

Urinary Leukotriene E4 to Determine Aspirin Intolerance in Asthma: A Systematic Review and Meta-Analysis.

BACKGROUND: Urinary leukotriene E4 (ULTE4) may be a biomarker that distinguishes aspirin-intolerant asthma from other asthma subtypes. OBJECTIVE: To estimate the diagnostic testing accuracy of ULTE4 as a marker of aspirin intolerance in patients with asthma using previously published studies. METHODS: We identified relevant clinical studies from a systematic review of English and non-English articles using MEDLINE, EMBASE, and CENTRAL (inception to February 10, 2015). Articles were screened at the abstract and full-text level by 2 independent reviewers. We included previously published studies that analyzed ULTE4 in human subjects with asthma characterized as having or not having aspirin intolerance on the basis of a specified definition: convincing history of aspirin intolerance, positive aspirin challenge, or both as the criterion standard. Individual-level data points from all included studies were obtained and analyzed. RESULTS: The search strategy identified 867 potential articles, of which 86 were reviewed at the full-text level and 10 met criteria for inclusion. The sensitivity, specificity, positive predictive value, and negative predictive values of ULTE4 to determine aspirin intolerance in subjects with asthma were 0.55, 0.82, 0.75, and 0.66 (Amersham-enzyme immunoassay); 0.76, 0.77, 0.70, and 0.78 (Cayman-enzyme immunoassay); 0.70, 0.81, 0.86, and 0.79 (mass spectrometry); and 0.81,0.79, 0.65, and 0.88 (radioimmunoassay) at optimal thresholds of 192, 510, 167 to 173, and 66 to 69 pg/mg Cr, respectively. The diagnostic odds ratio for each methodology was 6.0, 11.9, 10.5, and 19.1, respectively. CONCLUSIONS: ULTE4 is a marker for aspirin-intolerant asthma and could potentially be used as a clinical test to identify the risk of aspirin intolerance in subjects with asthma.

Diagnostic Utility of Urinary LTE4 in Asthma, Allergic Rhinitis, Chronic Rhinosinusitis, Nasal Polyps, and Aspirin Sensitivity.

BACKGROUND: Urinary leukotriene E4 (LTE4) is a well-validated marker of the cysteinyl leukotriene pathway, and LTE4 elevation has been described in conditions such as asthma, aspirin sensitivity, and chronic rhinosinusitis (CRS). There have been a number of reports investigating the role of spot urine LTE4 to predict aspirin sensitivity; however, variability in urinary LTE4 may affect the accuracy of this approach. OBJECTIVE: Here, we explored the utility of 24-hour urinary LTE4 in 5 clinical diagnoses of allergic rhinitis, asthma, chronic rhinosinusitis with nasal polyps (CRSwNP), CRS without nasal polyps, and aspirin sensitivity. METHODS: This was a retrospective review of patients who had 24-hour quantification of urinary LTE4 by a clinically validated liquid chromatography tandem mass spectrometry method and their assigned diagnoses after assessment and clinical care. RESULTS: Twenty-four-hour urinary LTE4 elevations were seen in those with asthma and those with CRSwNP but influenced by underlying aspirin sensitivity. Elevation in LTE4 was significant in those with CRSwNP after adjusting for aspirin sensitivity. Allergic rhinitis was not associated with elevated LTE4 excretion. Receiver operator characteristic analysis of 24-hour urinary LTE4 showed that a cutoff value of 166 pg/mg Cr suggested the presence of history of aspirin sensitivity with 89% specificity, whereas a cutoff value of 241 pg/mg Cr discriminated "challenge-confirmed" aspirin-sensitive subjects with 92% specificity. CONCLUSIONS: Elevated 24-hour excretion of urinary LTE4 is a reliable and simple test to identify aspirin sensitivity in patients with respiratory diagnoses.

Incidence of aspirin hypersensitivity in patients with chronic rhinosinusitis and diagnostic value of urinary leukotriene E4.

INTRODUCTION: Chronic rhinosinusitis (CRS) with nasal polyposis (NP) may be associated with hypersensitivity to nonsteroidal anti-inflammatory drugs, representing a syndrome of aspirin-exacerbated respiratory disease (AERD). OBJECTIVES: The aim of the study was to validate a simple measurement of urinary leukotriene E4 (uLTE4) excretion for the diagnosis of AERD in patients with CRS and indication for surgery. PATIENTS AND METHODS: Subjects requiring functional endoscopic sinus surgery (FESS) were recruited from the Department of Otolaryngology (n = 24). Before surgery, a standard oral placebo-controlled aspirin challenge was performed to diagnose aspirin hypersensitivity. Urine samples were collected on the placebo day and both before and within 2 to 4 hours after aspirin challenge for uLTE4 measurement. RESULTS: All patients with CRS had sinusitis confirmed by computed tomography. Previous ear, nose, and throat surgery was performed in 70% of the patients, NP was present in 86%, and asthma was diagnosed in 62.5%. AERD was diagnosed in 8 subjects (7 women and 1 man). Five of those patients had bronchoconstriction. At baseline, median uLTE4 was 7.5-times higher in AERD subjects than in the remaining patients. It increased almost 6-fold following the challenge, while remained unchanged in patients without aspirin hypersensitivity. Pretest uLTE4 had a sensitivity of 87.5% and specificity of 93.75% to diagnose aspirin hypersensitivity in patients with CRS. After the challenge, the values improved to 100% sensitivity and 93% specificity. CONCLUSIONS: Among CRS subjects requiring FESS, as many as 33.3% may have AERD and respond to a small provocative dose of aspirin with bronchoconstriction and/or mucosal and skin edema. A simple and inexpensive measurement of uLTE4 can help diagnose AERD in patients with CRS with sensitivity of 87.5%, but its specificity is limited and depends on the arbitrary threshold of uLTE4.

Allergic to all medicines and red coloured urine.

Dermatitis artefacta is a disorder in which the skin is the target of self-inflicted injury. We report a case of dermatitis artefacta, in which the patient developed skin lesions, after taking each and every medication. Additionally he also had red coloured urine after taking certain group of medications, which, on further investigations, was found to be associated with glucose 6-phosphate dehydrogenase (G6PD) deficiency. This case illustrates the presence of factitious dermatitis and physical co-morbidity simultaneously, which was missed before psychiatric referral. Every symptom in a patient with a factitious disorder should not be labelled as feigned without a proper workup.

[Urinary leukotriene E4 concentration in patients with bronchial asthma and intolerance of non-steroids anti-inflammatory drugs before and after oral aspirin challenge]. / Stezenie leukotrienów E4 w moczu chorych na astme oskrzelowa z nietolerancja NLPZ w wywiadzie przed doustna prowokacja aspiryna i po prowokacji.

BACKGROUND: Leukotrienes (LTC4, LTD4, LTE4) belong to eicosanoids and they play important role in allergic inflammation. Leukotrienes are 5-lipooxygenaze products of arachinoid acid. It is known that concentration of LTE4 increases in patients with bronchial asthma, after some allergy provocation and in patients with bronchial asthma and intolerance of on steroids anti-inflammatory drugs. The aim of the study was estimated the urinary concentration of LTE4 in patients with bronchial asthma and intolerance of no steroids anti-inflammatory drugs. MATERIAL AND METHODS: The study group consisted of 21 patients with asthma and intolerance of non steroids antiinflammatory drugs (F 19, M 2) in age from 21 to 72 years old (mean = 49 +/- 14), with middle time of asthma duration mean = 13.4 +/- 12.9 years In study group 11 person had positive skin test, 7 nasal polyps, and 8 person positive family history of bronchial asthma. After oral provocation aspirin challenge in 5 subjects' aspirin induced asthma was confirmed, 3 persons were not qualified to test. Urinary concentration of LTE4 before and 24 h after aspirin provocation was analyzed in all the patients. Leukotriene were detected by enzymatic Leukotriene E4, EIA Kit, Cayman Chemical test. RESULTS: In group of patients with aspirin asthma basic concentration of LTE4 was 416.6 +/- 374.4 pg/mL, and after provocation 496.6 +/- 485.3 pg/mL, in the group without sensitivity to aspirin appropriate 262.9 +/- 404.0 vs 261.2 +/- 259.66 pg/mL, and in the group disqualified to test 181.6 +/- 55.75 pg/mL. CONCLUSION: 1 Patients with aspirin asthma have higher concentration of LTE4. 2. Excretion of LTE4 in patients with aspirin induced asthma raised after oral aspirin provocation and higher level was detected is til 24 hours after challenge. 3. This results confirmed the role of cysteinic leukotrienes in pathogenesis of aspirin induced asthma.

Urinary metabolites of histamine and leukotrienes before and after placebo-controlled challenge with ASA and food additives in chronic urticaria patients.

BACKGROUND: The recovery of mediator metabolites from urine has the potential to provide a rapid, safe, and easily available index of release of mediators. We aimed to determine urinary metabolites of both histamine and leukotrienes (LTs) in patients affected by chronic urticaria (CU). METHODS: Twenty patients with CU were studied. They were selected on the basis of double-blind placebo-controlled challenge (DBPC) with acetyl salicylic acid (ASA) and food additives. Ten patients (group B) were negative to both challenges. Ten patients (group C) presented urticaria and/or the appearance of angioedema during or 24 h after challenge, with reactions to ASA (five patients) or food additives (five patients). We recruited 15 healthy volunteers as controls (group A). During a second challenge, groups B and C were challenged double-blind with a single dose of ASA, or a specific food additive, or placebo. The healthy group was challenged only with a placebo (talc capsule). Patients in groups B and C were challenged twice: with placebo (as groups B1 and C1) and with ASA (groups B2 and C2) or food additives (C2). Four samples of urine were collected; one during the night before the specific or sham challenge (baseline), and three at 2, 6 and 24 h after the challenge. Urinary methylhistamine (N-MH) and LTE4 were analyzed and normalized for urinary creatinine. RESULTS: For urinary N-MH at baseline, there was a significant difference only between group A and groups B1, B2, C1 and C2 (A vs. B1, P < 0.0001; A vs. B2, P < 0.0001; A vs. C1, P < 0.0001; A vs. C2, P < 0.0001). We detected a significant variation in urinary methylhistamine excretion only in group C2 after 2 h, 6 h and 24 h (P < 0.0001). However, no variations were observed in N-MH excretion rate in the other groups (A, B1, C1) after challenge with placebo, and in B2 after challenge with ASA 20 mg. For urinary LTE4 at baseline no differences were found between the mean values for the different groups. After specific challenge, only C2 patients showed significantly increased excretion rates of urinary LTE4 compared with the other groups challenged with placebo (A, B1, C1), or ASA (B2) (P < 0.0001). No significant correlation was seen between urinary LTE4 and methylhistamine excretion rate in any patients. CONCLUSION: Our results show that urinary excretion of N-MH and LTE4 is different for CU patients without ASA or food hypersensitivity, compared to those with CU with ASA or food additive hypersensitivity after specific challenge.

Association of urinary leukotriene E4 excretion during aspirin challenges with severity of respiratory responses.

BACKGROUND: Asthmatics with aspirin- (ASA) sensitive respiratory disease (ASRD) have a spectrum of respiratory reactions during oral ASA challenge that vary in severity and are temporally associated with leukotriene (LT) formation. OBJECTIVE: This study investigates the relationship of the severity of ASA-induced respiratory reactions to urinary LTE(4) excretion. METHODS: Asthmatics with suspected ASRD underwent oral ASA challenges. Urinary LTE(4) levels were measured at baseline, during the reaction, and after acute ASA desensitization. RESULTS: Asthmatics who had respiratory reactions during oral ASA challenges were divided into 3 groups: asthmatics with naso-ocular reactions and <15% decline from baseline FEV(1) values (group 1), asthmatics with a decline in FEV(1) of 20% to 30% (group 2), and asthmatics with a decline in FEV(1) of >30% (group 3). There were no significant differences in age, baseline FEV(1) values, use of inhaled corticosteroids, daily prednisone doses, prednisone bursts, duration of reactions, or average provoking doses of ASA among the groups. At baseline group 3 asthmatics had significantly higher urinary LTE(4) levels than those in groups 1 or 2. At the time of respiratory reaction to ASA, the urinary LTE(4) levels rose significantly in all groups but were significantly greater among group 3 asthmatics compared with those in groups 1 and 2. CONCLUSION: The severity of the respiratory reactions during oral ASA challenges was associated with the degree of elevation of baseline LTE(4) synthesis. Our results suggest that asthmatics with ASRD have a spectrum of respiratory tract reactions in which leukotrienes play a distinguishing role.

[Importance of the urinary leukotriene E4 level. Preliminary study]. / Intérêt du dosage des leucotriènes E4 (LTE4) dans les urines Etude préliminaire.

Post-anesthesia anaphylactic reactions or those seen during drug provocation tests with a systemic clinical reaction may be confirmed by the sequential release into blood of plasma histamine, tryptase and leukotriene C4 and into urine of urinary methylhistamine and leukotriene E4.

[Metabolic changes in arachidonic acid during aspirin desensitization]. / Cambios metabólicos del ácido araquidónico en la desensibilización a la aspirina.

Aspirin sensitivity occurs in 10% of all asthmatics patients. In this subset of asthmatics, nasal congestion and bronchospasm occurs between 30-180 minutes after ingestion of aspirin. Following a respiratory reaction to aspirin, all patients can be desensitized to aspirin by repetitively introducing small and then larger doses of aspirin until the asthmatic subject can ingest 650 mg of aspirin without adverse effect. The mechanism of aspirin sensitivity are incompletely understood. And the reasons why ASA desensitization occurs universally are unknown. In this study, known ASA sensitive and control insensitive asthmatics were challenged with ASA. Urine was collected before, during induced bronchospasm, and after ingestion of 650 mg of ASA when the adverse effect (ie., acute desensitization) had subsided. Excretion levels of cyclo-oxygenase and lipoxygenase products in the urine were determined.

Determination of inflammatory markers in allergic reactions to drugs.

Serum tryptase (Tryp) and eosinophil cationic protein (ECP) and urine N-methylhistamine (N-MH) were quantitated in a group of 13 subjects who had experienced immediate allergic reactions to different drugs. Results indicated that both Tryp and N-MH were involved and the levels were related to the severity of the reaction. Results of serum ECP levels failed to provide relevant information concerning the participation of eosinophils in immediate reactions to drugs.

The effect of aspirin desensitization on urinary leukotriene E4 concentrations in aspirin-sensitive asthma.

Patients with aspirin sensitive asthma (ASA) can be desensitized to aspirin but the mechanisms by which this happens are unknown. To test the hypothesis that there may be a reduction in aspirin-induced leukotriene release following aspirin desensitization, we studied nine patients with ASA, 37 +/- 2.3 yr of age (mean +/- SEM) with a baseline FEV1 of 94 +/- 3.5%. Urinary leukotriene E4 (LTE4) and FEV1 were measured before and after ingestion of a threshold dose of aspirin leading to a 15% decrease in FEV1, and then at intervals following desensitization, when a maintenance dose of 600 mg aspirin was ingested. Prior to desensitization, the maximum decrease in FEV1 following ingestion of a threshold dose of aspirin was 15.3 +/- 3.9%, and urinary LTE4 rose from a baseline value of 235 +/- 79.4 pg/mg creatinine to 1,714 +/- 783 pg/mg creatinine at 3 h. Immediately after acute desensitization, which was performed over several days, 600 mg aspirin provoked a maximum decrease in FEV1 of only 3.3 +/- 2.4%, and urinary LTE4 increased from a baseline of 645 +/- 223 pg/mg creatinine to 1,256 +/- 456 pg/mg creatinine. Following ingestion of 600 mg aspirin for 9 +/- 3.2 mo (n = 5; chronic desensitization), urinary LTE4 rose from a basal level of 432 +/- 127 pg/mg creatinine to 749 +/- 257 pg/mg creatinine at 3 h after 600 mg aspirin, and this was accompanied by a maximum decrease in FEV1 of 7.4 +/- 4.5%. Although there was significantly less aspirin-induced LTE4 excretion after acute desensitization, substantial amounts of LTE4 were still produced without any significant change in lung function.(ABSTRACT TRUNCATED AT 250 WORDS)

[Practical aspects of leukotriene E4 determination in urine]. / Aspects pratiques du dosage du leucotriène E4 dans les urines.

Leukotrienes constitute a class of potent biological mediators of inflammation and anaphylaxis. However, their routine assay in various biological fluids is restricted by the complexity of the methodology. Previously this could only be performed by research laboratories with high pressure liquid chromatography and radioimmunological capabilities. The recent availability of kits for immunoenzymatic assay of leukotrienes offers a new tool for clinical laboratories provided the limitations of the method are understood. We suggest a simplified methodology for direct urinary LTE4 detection and outline a number of areas of concern encountered with this method.

Increased urinary excretion of angiotensin during anaphylactoid reactions.

Immunoreactive angiotensin I (ANG I) and angiotensin II (ANG II) were measured in human urine, after purification on octadecasilyl-silica cartridges. The total daily excretion of ANG I and II in healthy volunteers was 292.2 +/- 62.5 and 12.2 +/- 2.5 pmol/24 h (mean +/- SEM; n = 14). No differences in the concentrations of ANG I or II were detected between females and males. Although lower levels of ANG I and II were found during the nighttime, no clear-cut circadian rhythm in the excretion of the peptides was found. ANG II was not degraded in acidified urine which shows the effective inhibition of ANG-II-degrading enzymes. Oral provocation tests (OPT) in patients with a history of anaphylactoid reactions (AR) to drugs, foods and food additives were associated with elevated ANG I and II concentrations when symptoms of anaphylaxis occurred. The excretion of ANG I increased by a factor of 7.8 +/- 2.4 and the excretion of ANG II by a factor of 6.1 +/- 1.6 (mean +/- SEM; n = 15). In patients with negative OPT and no clinical symptoms of anaphylaxis, the levels of ANG I and II remained unchanged (n = 26). It is concluded that angiotensin peptides play a role during the events of AR. The peptides may be considered as counteracting factors which stabilize cardiovascular functions.

[Fundamental studies on the measurement of urinary leukotriene E4].

We undertook fundamental studies on the measurement of urinary leukotriene E4, a stable end-product of peptidoleukotrienes, and obtained the following results. 1) After addition of 3H-LTE4 to 2 ml of urine, LTE4 was extracted with a commercial C18 mini-column, and purified by high performance liquid chromatography and then LTE4 in the elute was measured with an enzyme immunoassay kit. 2) As total recovery of LTE4 was 35.3 +/- 0.9% (n = 76), the amount of LTE4 was calculated after correction of the recovery with 3H-LTE4. 3) Before extraction of LTE4 by C18 column, the column was washed by ethyl acetate to remove interfering substances. This procedure greatly facilitated the following high performance liquid chromatographic analysis. 4) The basal levels of urinary LTE4 of seven aspirin-sensitive asthmatics were elevated as compared with five asthmatics without aspirin sensitivity (358.9 +/- 114.0 versus 77.9 +/- 47.3 pg/mg.cr; p < 0.05). 5) In two asthmatic patients, improvement of their symptoms was accompanied with decrease in the LTE4 level in urine. This method enabled us to measure LTE4 concentrations in a small volume of urine (2 ml), and would be useful for evaluating the pathogenesis of bronchial asthma.