Hypersensitivity to intravenous succinate corticosteroids in patients with nonsteroidal anti-inflammatory drug-exacerbated respiratory disease.

Although there are many case reports of asthma exacerbations with intravenous corticosteroids, especially hydrocortisone succinate, in nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (N-ERD), the frequency and mechanism remain unclear. We hypothesized that N-ERD patients are potentially hypersensitive to succinates, especially succinate corticosteroids, based on the results of previous provocation studies and considered specific mechanisms. The objective of this study was to determine the frequency and mechanism of succinate corticosteroids hypersensitivity in patients with N-ERD. Eleven patients with stable, moderate to severe N-ERD were tested with hydrocortisone sodium succinate (HCs), hydrocortisone sodium phosphate (HCp), methylprednisolone sodium succinate (MPSLs), prednisolone sodium succinate (PSLs), and chloramphenicol sodium succinate (CPs, without a steroidal chemical structure) at doses below the normal dose through intravenous administration using a single-blind test. As a comparison, seven patients with aspirin-tolerant asthma (ATA) also underwent an intravenous provocation test of HCs. The positive intravenous provocation test rates of HCs 100-500 mg, HCp 500 mg, MPSLs 80 mg, PSLs 20 mg, and CPs 500 mg in N-ERD patients were 82% (9/11), 9% (1/11), 50% (5/10), 33% (1/3), and 86% (6/7), respectively. Most positive reactions began with a severe cough within 5 min of intravenous injection. The course of these hypersensitivity symptoms differed from those seen with the usual aspirin challenge test. The HCs 100-500 mg intravenous test was negative in all seven patients with ATA. In conclusion, patients with N-ERD have high rates of potential hypersensitivity to the succinate ester structure, which is not linked to the corticosteroid structure, but to the succinate ester structure. We hypothesized that the mechanism of hypersensitivity observed during rapid intravenous administration of succinate corticosteroids is mast cell activation via succinate receptor stimulation, rather than due to the corticosteroid itself.

Aspirin-exacerbated respiratory disease (AERD): Current understanding of AERD.

The characteristics in AERD are severe adult-onset asthma, eosinophilic rhinosinusitis with nasal polyposis, and CysLT overproduction. The cause of AERD have remained unclear, however the decrease in the production of PGE2 caused by the reduction in COX-2 activity is considered to main pathological mechanism of AERD. The mast cell activation and the interaction between platelets and granulocytes are lead to the CysLT overproduction and severe eosinophilic inflammation. The ongoing activation of mast cells is important key pathogenesis in not only stable AERD but exacerbated AERD by aspirin and NSAIDs. In recent years, type 2 inflammation caused by ILC2 activation in patients with AERD have been attracting attention. Omalizumab is effective option for AERD via suppression of mast cell activation and CysLT overproduction. Dupilumab improves sinus symptoms especially in patients with AERD. In near future, anti-platelet drug, CRTH2 antagonist, and anti-TSLP antibody may be useful candidates of therapeutic options in patients with AERD.

Platelet activation markers overexpressed specifically in patients with aspirin-exacerbated respiratory disease.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is characterized by respiratory reactions on ingestion of COX-1 inhibitors and cysteinyl leukotriene overproduction. The hypersensitivity reaction is induced by low doses of aspirin that inhibit COX-1 in platelets. OBJECTIVE: We sought to explore the role of platelets in the pathogenesis of AERD in patients under stable conditions and during an aspirin challenge test. METHODS: Stable patients with AERD (n = 30), aspirin-tolerant asthma (ATA; n = 21), or idiopathic chronic eosinophilic pneumonia (n = 10) were enrolled. Platelet activation was estimated based on expression levels of P-selectin (CD62P), CD63, CD69, and GPIIb/IIIa (PAC-1) in peripheral platelets; percentages of circulating platelet-adherent leukocytes; and plasma levels of soluble P-selectin (sP-selectin) and soluble CD40 ligand (sCD40L). RESULTS: In the stable condition, expression of all surface markers on platelets, the percentage of platelet-adherent eosinophils, and the plasma levels of sP-selectin and sCD40L were significantly higher in patients with AERD compared with those in patients with ATA. P-selectin and CD63 expression on platelets and plasma sP-selectin and sCD40L levels were positively correlated with the percentage of platelet-adherent eosinophils. Among these markers, P-selectin expression and plasma sP-selectin levels positively correlated with urinary concentrations of leukotriene E4. Additionally, plasma sP-selectin and sCD40L levels were negatively correlated with lung function. In contrast, platelet activation markers in patients with AERD did not change during the aspirin challenge test. CONCLUSION: Peripheral platelets were activated more in patients with stable AERD compared with those in patients with stable ATA, patients with idiopathic chronic eosinophilic pneumonia, and control subjects. Platelet activation was involved in cysteinyl leukotriene overproduction and persistent airflow limitations in patients with AERD.

Aspirin-intolerant asthma (AIA) assessment using the urinary biomarkers, leukotriene E4 (LTE4) and prostaglandin D2 (PGD2) metabolites.

The clinical syndrome of aspirin-intolerant asthma (AIA) is characterized by aspirin/nonsteroidal anti-inflammatory drug intolerance, bronchial asthma, and chronic rhinosinusitis with nasal polyposis. AIA reactions are evidently triggered by pharmacological effect of cyclooxygenase-1 inhibitors. Urine sampling is a non-invasive research tool for time-course measurements in clinical investigations. The urinary stable metabolite concentration of arachidonic acid products provides a time-integrated estimate of the production of the parent compounds in vivo. AIA patients exhibits significantly higher urinary concentrations of leukotriene E(4) (LTE(4)) and 1,15-dioxo-9α-hydroxy-2,3,4,5-tetranorprostan-1,20-dioic acid (tetranor-PGDM), a newly identified metabolite of PGD(2), at baseline. This finding suggests the possibility that increased mast cell activation is involved in the pathophysiology of AIA even in a clinically stable condition. In addition, lower urinary concentrations of primary prostaglandin E(2) and 15-epimer of lipoxin A(4) at baseline in the AIA patients suggest that the impaired anti-inflammatory elements may also contribute to the severe clinical outcome of AIA. During the AIA reaction, the urinary concentrations of LTE(4) and PGD(2) metabolites, including tetranor-PGDM significantly and correlatively increase. It is considered that mast cell activation probably is a pathophysiologic hallmark of AIA. However, despite the fact that cyclooxygenease-1 is the dominant in vivo PGD(2) biosynthetic pathway, the precise mechanism underlying the PGD(2) overproduction resulting from the pharmacological effect of cyclooxygenease-1 inhibitors in AIA remains unknown. A comprehensive analysis of the urinary concentration of inflammatory mediators may afford a new research target in elucidating the pathophysiology of AIA.

Immunoglobulin E oligomers identified in blood components activate mast cells: relevance to anaphylactic transfusion reaction.

BACKGROUND: In most cases of anaphylactic transfusion reaction, the mechanisms underlying its development are unclear. We found a donor whose transfused blood components were implicated in two cases of anaphylactic transfusion reaction, and we found that the donor plasma showed mast cell degranulation activity. STUDY DESIGN AND METHODS: The donor plasma was examined to identify the mast cell-activating factors in it. Cultured mast cells prepared from cord blood were used for in vitro degranulation assay. Serum prepared from the donor plasma was fractionated by three-step chromatography using mast cell degranulation activity as a marker. The fractions selected from the third step of chromatography were analyzed by mass spectrometry after separation by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The characteristics of the identified proteins and other plasma samples that had been donated by the donor over several years were examined. RESULTS: Two plasma proteins of high molecular weight were detected in the anion-exchange fractions and identified as human immunoglobulin (Ig)Es of 500 kDa and higher. The mast cell degranulation activity of the IgEs decreased in the presence of monomeric human IgE as well as an anti-human IgE antibody. Mast cell degranulation activity was detected in the donor plasma since January 4, 2002, when the first case was reported. CONCLUSION: We identified high-molecular-weight IgEs as the mast cell-activating factors in the donor plasma. Results of analysis suggest that these IgEs were dimeric and trimeric and that they directly activated the transfusion recipient's mast cells by triggering the crosslinking of Fcε receptor I, thereby inducing an anaphylactic transfusion reaction.

Increase in salivary cysteinyl-leukotriene concentration in patients with aspirin-intolerant asthma.

BACKGROUND: Cysteinyl-leukotrienes (CysLTs; LTC4, LTD4, and LTE4) play a considerable role in the pathophysiology of aspirin-intolerant asthma (AIA). Saliva has recently been validated as novel, simple, and noninvasive method for investigating inflammation in patients with asthma. The aim of this study is to clarify the molecular species of CysLT in saliva and to evaluate the CysLT and LTB4 concentrations in saliva in AIA patients. We also examined how the CysLT concentration in saliva reflects that of their corresponding urinary metabolite. METHODS: We preformed an analytical cross-sectional study. CysLT and LTB4 concentrations in saliva were quantified by enzyme immunoassay (EIA) following purification by high-performance liquid chromatography (HPLC). RESULTS: 1. When analyzed by EIA in combination with HPLC, saliva was found to consist of LTC4, LTD4 and LTE4 in similar amounts. 2. In saliva analysis among the three groups (AIA patients, aspirin-tolerant asthma [ATA] patients, and healthy subjects), both the concentrations of CysLTs and LTB4 were significantly higher in AIA patients than in ATA patients and healthy subjects. 3. We found significant correlations between CysLT concentration and LTB4 concentration in saliva in each group. 4. No significant correlation was found between the concentration of LTE4 in urine and that of CysLTs in saliva. CONCLUSIONS: In this study, we found higher concentrations of CysLTs and LTB4 in saliva from AIA patients than in saliva from ATA patients, suggesting that the quantification of CysLT and LTB4 concentrations in saliva may be another diagnostic strategy for AIA.

Profile of eicosanoid generation in aspirin-intolerant asthma and anaphylaxis assessed by new biomarkers.

BACKGROUND: It has recently demonstrated that a free radical-mediated pathway generates prostaglandins (PGs) and the corresponding prostaglandin enantiomers (ent-PGs). Aspirin-intolerant asthma and anaphylaxis accompany PGD(2) overproduction, possibly associated with mast cell activation via the COX pathway. However, free radical-mediated PG generation in the pathophysiology of these diseases, which can be demonstrated by measuring urinary ent-PGF(2)alpha, has not been reported. OBJECTIVES: To evaluate the characteristic profile of eicosanoid generation via the COX and/or free radical-mediated pathway underlying aspirin-intolerant asthma and anaphylaxis. METHODS: A comparative group analysis consisted of asthma (n = 17) and anaphylaxis (n = 8, none with aspirin-induced anaphylaxis) cases. Urinary eicosanoid concentrations were quantified as follows: 2,3-dinor-9alpha,11beta-PGF(2) by gas chromatography-mass spectrometry; leukotriene E(4), 9alpha,11beta-PGF(2), and PGs by enzyme immunoassay. RESULTS: 2,3-Dinor-9alpha,11beta-PGF(2) is a more predominant PGD(2) metabolite in urine than 9alpha,11beta-PGF(2). At baseline, the aspirin-intolerant asthma group (n = 10) had significantly higher leukotriene E(4) and lower PGE(2) concentrations in urine than the aspirin-tolerant asthma group. During the reaction, the urinary concentrations of leukotriene E(4) and PGD(2) metabolites correlatively increased, but with markedly different patterns of the mediator release, in the aspirin-intolerant asthma group and the anaphylaxis group, respectively. The urinary PGD(2) metabolites and primary PGs were significantly decreased in the aspirin-tolerant asthma group. Urinary ent-PGF(2)alpha concentrations were significantly increased in the anaphylaxis group but not the aspirin-intolerant asthma group. CONCLUSIONS: When assessed by urinary 2,3-dinor-9alpha,11beta-PGF(2), PGD(2) overproduction during aspirin-intolerant bronchoconstriction was clearly identified, regardless of COX inhibition. It is evident that free radical-mediated PG generation is involved in the pathophysiology of anaphylaxis.

CD203c expression on human basophils is associated with asthma exacerbation.

BACKGROUND: CD203c is a basophil cell surface marker used to diagnose and monitor various allergic diseases, but its relationship to asthma is not clear. OBJECTIVE: We determined whether CD203c expression levels are associated with stable and exacerbated asthma. METHODS: We used flow cytometry to compare spontaneous expression levels of surface markers on basophils from patients with stable or exacerbated asthma and from healthy subjects. Longitudinal changes in these expression levels were measured after basophil stimulation by IgE-dependent or IgE-independent mechanisms and compared with patients' asthma status. RESULTS: Spontaneous expression levels of CD203c were significantly higher on basophils from patients with asthma exacerbation than patients with stable asthma or healthy subjects. In contrast, no differences in spontaneous expression levels of CD63 or CD69 were observed among the 3 groups. Anti-IgE-induced expression of CD203c significantly increased in basophils during asthma exacerbation (P = .005). Low concentrations of Dermatophagoides pteronyssinus or IL-3 induced higher expression levels of CD203c during asthma exacerbation than during clinical improvement; induction of CD203c expression by these antigens therefore correlates with asthma control. In the patients with clinical improvement, there was a correlation between spontaneous CD203c expression levels and the percent predicted values of FEV(1) (r = -0.761; P = .022). CONCLUSION: Asthma exacerbation was accompanied by increased expression of CD203c on basophils that decreased significantly during remission. Basophil expression levels of CD203c might therefore be used to monitor asthma in patients.

Combination of MS protein identification and bioassay of chromatographic fractions to identify biologically active substances from complex protein sources.

Purification of biologically active proteins from complex biological sources is a difficult task, usually requiring large amounts of sample and many separation steps. We found an active substance in a serum response element-dependent luciferase reporter gene bioassay in interstitial cystitis urine that we attempted to purify with column chromatography and the bioassay. With anion-exchange Mono Q and C4 reversed-phase columns, apparently sharp active peaks were obtained. However, more than 20 kinds of proteins were identified from the active fractions with MS, indicating that the purification was not complete. As further purification was difficult, we chose a candidate molecule by means of studying the correlation between MS protein identification scores and bioassay responses of chromatographic fractions near the active peaks. As a result, epidermal growth factor (EGF) was nominated as a candidate molecule among the identified proteins because the elution profile of EGF was consistent with that of the bioassay, and the correlation coefficient of EGF between MS protein identification scores and bioassay responses was the highest among all the identified proteins. With recombinant EGF and anti-EGF and anti-EGF receptor antibodies, EGF was confirmed to be the desired substance in interstitial cystitis urine. This approach required only 20 ml of urine sample and two column chromatographic steps. The combination of MS protein identification and bioassay of chromatographic fractions may be useful for identifying biologically active substances from complex protein sources.

Hyperleukotrieneuria in patients with allergic and inflammatory disease.

Cysteinyl leukotrienes (CysLTs: leukotrienes C(4), D(4), and E(4)) have long been implicated in the pathogenesis of asthma and several allergic diseases. LTE(4) has been identified as a major metabolite of LTC(4), and urinary LTE(4) (U-LTE(4)) is considered as the most reliable analytic parameter for monitoring the endogenous synthesis of CysLTs. From recent studies on the U-LTE(4) associated with adult stable asthma we identified four factors for hyperleukotrieneuria, namely, aspirin intolerance, eosinophilic nasal polyposis (ENP), vasculitis, and severe asthma. In ENP, there is prominent infiltration of eosinophils in the sinus and polyp tissues, which is linked to adult asthma and aspirin sensitivity, and ENP is the most important factor for the overproduction of CysLTs in asthmatics. We also demonstrated that anaphylaxis and eosinophilic pneumonia (EP) are associated with a marked increase in the U-LTE(4) concentration. Under these disease conditions, U-LTE(4) may be one of the candidate biomarkers. Moreover, the changes in U-LTE(4) concentrations may provide valuable information concerning therapeutic targets.

Increased concentration of neutrophil elastase in urine from patients with interstitial cystitis.

OBJECTIVE: To identify proteins associated with interstitial cystitis (IC), protein profiles were analyzed using a proteomics-based approach. The study tested whether neutrophil elastase in urine correlates with the symptomatic condition of IC. MATERIAL AND METHODS: Proteins in urine from IC patients and healthy subjects were analyzed through a comparative proteomics approach using two-dimensional difference in-gel electrophoresis and nano-liquid chromatography-tandem mass spectrometry. Neutrophil elastase activity was measured by the digestion of peptide substrate. RESULTS: The urinary neutrophil elastase concentration was significantly higher in IC patients with pain than in healthy subjects. It was significantly increased in patients with small bladder capacity (median 6.31 ng/ml in IC with a bladder capacity < 200 ml vs 1.15 ng/ml in IC with a bladder capacity > or = 200 ml and 0.18 ng/ml in healthy bladders, p < 0.01). The concentration of neutrophil elastase did not correlate with the neutrophil count in the urine of IC patients. CONCLUSION: The concentration of neutrophil elastase increased in the urine of the IC patient subset with bladder pain and small bladder capacity.

Increase in inflammatory mediator concentrations in exhaled breath condensate after allergen inhalation.

BACKGROUND: Although a number of studies have been carried out to examine the baseline concentrations of inflammatory mediators in asthmatic patients, the clinical utility of exhaled breath condensate (EBC) in allergen-induced bronchoconstriction has not yet been clarified. OBJECTIVE: We examined whether the release of inflammatory mediators can be detected in EBC after allergen-induced bronchoconstriction in asthmatic patients. METHODS: We quantified mast cell-associated mediators in EBC and their corresponding urinary metabolites before and after allergen inhalation. RESULTS: Early asthmatic responses (EARs) caused significant increases in the concentrations of cysteinyl leukotrienes (CysLTs; median, 10.4 vs 99.0 pg/mL; P < .0001) and prostaglandin D(2) (PGD(2); median, 2.26 vs 8.72 pg/mL; P = .0077), but not that of histamine, from baseline concentrations. Significant increases in the concentrations of urinary leukotriene E(4) and 9alpha, 11beta-prostaglandin F(2) were detected in patients with EARs. However, the percentage increases in the concentrations of CysLTs and PGD(2) in EBC did not correlate with those of their corresponding urinary metabolites. The increases in concentrations of CysLTs and PGD(2) in EBC in patients with EARs correlated with each other and correlated with the extent of decrease in FEV(1). An insignificant difference in tyrosine concentration before and after the inhalation test demonstrated that errors caused by dilution of inflammatory mediators are negligibly small in EBC collected over a short period. CONCLUSION: In patients with allergen-induced EARs, pulmonary generation of mast cell-associated mediators can be evaluated by quantifying CysLTs and PGD(2) in EBC, suggesting that the quantification of EBC mediators might be useful in monitoring acute asthmatic airway inflammation.

[Relationship between cysteinyl leukotriene in exhaled breath condensate and the severity of asthma in adult asthmatics in Japan].

BACKGROUND: The measurement of several mediators in exhaled breath condensate (EBC) can be useful as the biomarker for asthma. But there are a few reports about EBC of asthmatics in Japan. AIM: We examined the safety of the collection of EBC and the utility of cysteinyl leukotriene (cysLTs) in EBC as the biomarker of asthma. METHODS: Fifty-three asthmatics and eleven subjects without asthma were recruited. After the measuring of exhaled nitric oxide (eNO) and spirometory, EBC were collected. The levels of cysLTs in EBC were measurement by ELISA within 2 months. RESULTS: The collection of EBC did not induce any other symptoms in all subjects. In 48 subjects, the collection significantly increased their FEV1 and MMF level (DeltaFEV1: 2.27+/-0.77%, DeltaMMF 14.6+/-3.92% (mean+/-SEM). The level of cysLTs in EBC on asthmatics treated with high-dose ICS was significantly high compared with control group (p=0.0034), steroid-naïve asthmatics or asthmatics treated with low-dose ICS (steroid naive vs. high dose ICS, p=0.041, low dose ICS vs. high dose ICS, p=0.021). The relationship between cysLTs in EBC and the levels of LTE4 in urine was significantly correlated (n=34, r=0.32, p=0.0435). The relationship between cysLTs in EBC and the levels of eNO was significantly correlated only in steroid-naïve asthmatics (r=-0.57, p=0.0369). There was no relationship between cysLTs in EBC and FEV1, or log PC20Ach. CONCLUSION: The collection of EBC was perfectly non-invasive. The level of cysLTs can be useful as a biomarker of asthma.

Increased number of apoptotic endothelial cells in bladder of interstitial cystitis patients.

In this study, we aimed to investigate possible abnormality of bladder endothelial cells in interstitial cystitis patients by detecting morphological changes such as apoptosis in bladder endothelial cells. A bladder biopsy specimen was collected from interstitial cystitis patients immediately after hydrodistension therapy. The patients were classified into two groups on the basis of their predominant symptom, one group of patients with bladder pain and another group of patients with urinary urgency. Dissociated cells from the biopsy specimen were analyzed by flow cytometry after staining with Annexin V and an anti-CD105 antibody. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) and electron microscopy were performed to confirm morphologic changes indicative of apoptosis. The percentage of Annexin V binding, an early apoptosis marker, was significantly higher in bladder endothelial cells from interstitial cystitis patients with pain [median 24.7% (range 15.1-77.2), n = 20, P < 0.01) than that from interstitial cystitis patients with urinary urgency [9.3% (range 0.7-19.11) n = 17) or control patients [1.5% (range 0.8-9.1), n = 7]. TUNEL staining showed apoptotic cells in microvascular endothelial cells but not in the endothelial cells of a venule. By electron microscopy, endothelial cells showed morphological changes indicative of apoptosis such as nuclear fragmentation. Our results indicate that increased apoptosis of bladder microvascular endothelial cells may play an important role in the pathogenesis of interstitial cystitis accompanied by bladder pain.

Treatment for Churg-Strauss syndrome: induction of remission and efficacy of intravenous immunoglobulin therapy.

Churg-Strauss syndrome (CSS) is characterized by the presence of asthma, eosinophilia, and small-vessel vasculitis with granuloma. It is a distinct entity, as determined from all classifications of systemic vasculitis. The poor prognostic factors in CSS are renal insufficiency, cardiomyopathy, severe gastrointestinal (GI) tract, and central nervous systems (CNS) involvement. The initial management of CSS should include a high dose of a corticosteroid: prednisone at 1 mg/kg/day or its equivalent for methylprednisolone with tapering over 6 months. In patients with severe or rapidly progressing CSS, the administration of methylprednisolone pulse at 1 g/body/day for 3 days is recommended. When corticosteroid therapy does not induce remission, or when patients have poor prognostic factors, immunosuppressive cytotoxic therapy is indicated. However, some patients with severe CSS often show resistance to conventional treatment. We think that IVIG therapy is a hopeful candidate for second-line treatment for CSS patients, particularly in the case of neuropathy and/or cardiomyopathy, which are resistant to conventional therapy. However, there is not much evidence supporting the effectiveness of IVIG in CSS, and the mechanisms underlying the action of IVIG remain unclear. Now we are performing clinical trials of IVIG therapy for CSS patients who are resistant to conventional treatment, through a nationwide double-blinded placebo-controlled study in Japan.

Quantification of leukotriene B4 glucuronide in human urine.

We have developed a method for measuring leukotriene B4 glucuronide, a marker of systemic leukotriene B4 biosynthesis, in human urine. This method involves the separation of two positional isomers of leukotriene B4 glucuronide by high-performance liquid chromatography, followed by hydrolysis with beta-glucuronidase and then leukotriene B4 quantification by enzyme immunoassay after purification by high-performance liquid chromatography. One of two positional isomers of leukotriene B4 glucuronide was predominantly present in urine. The concentration of the isomer increased in urine from aspirin-intolerant asthma patients after aspirin challenge. Urinary leukotriene E4 and leukotriene B4 glucuronide concentrations in 13 normal healthy adults were 94.6 pg/mg-creatinine (median) and 22.3 pg/mg-creatinine, respectively. Urinary LTE4 concentration increased during the first 3h after allergen inhalation in atopic patients. However, allergen-induced bronchoconstriction was not associated with an increased concentration of LTB4 glucuronide in urine. The method enabled us to precisely determine urinary leukotriene B4 glucuronide concentration.

[Clinical aspects of patients with MCS - from the standpoint of allergy].

BACKGROUND: "Sick House Syndrome" is thought to be an illness caused by indoor environments such as allergens, bacteria and chemical compounds. But it is not yet an established clinical entity. "Sick House Syndrome" overlaps in part with Multiple Chemical Sensitivity (MCS) whose symptoms are induced by very small amount of volatile chemical compounds. METHODS: We selected possible cases of MCS from patients who visited our specially built facility for"Sick House Syndrome" by tentative criteria as follow: (1)histories of chemical compounds exposure, (2)multi-organ symptoms, (3)exclusion of other disease(s) which may be responsible for symptoms, (4)chronic symptoms. Clinical aspects of the possible cases were examined. RESULTS: Fifty out of about 130 patients were the possible cases of MCS, 38 females and 12 males, aged 15 to 71 years old. Forty two out of 50 patients (84%) had a history and/or a complication of allergic diseases. This rate is much higher than the rate of prevalence of allergic diseases in Japanese population. Allergic rhinitis was the most popular allergic disease in the possible cases. Total IgE values were relatively low, 32 patients (64%) showed the IgE value below 200 IU/ml. No patients showed anti-formaldehyde IgE antibody. Decreased reactivity and decreased sensitivity of histamine release from peripheral blood were observed after challenge tests with chemical compounds. CONCLUSION: Allergic reactions can not be the causative mechanism(s) of the MCS, which is induced by multiple and different chemical compounds. Our results, however, suggest that patients having allergic diseases may be easily suffered from MCS or MCS may strengthen symptoms of allergic diseases.

Urinary eicosanoid and tyrosine derivative concentrations in patients with vasculitides.

BACKGROUND: Vasculitides are classified on the basis of the type of cell involved, namely, eosinophilic vasculitides such as Churg-Strauss syndrome (CSS) and noneosinophilic vasculitides. However, knowledge on inflammatory mediators and oxidative tissue damage associated with vasculitides is insufficient. OBJECTIVE: We measured the urinary concentrations of inflammatory mediators and tyrosine derivatives to assess biomarkers associated with the pathophysiology of vasculitides. METHODS: Urine was collected from 9 patients with CSS during acute exacerbation and during clinical remission, 24 patients with rheumatoid arthritis in stable condition, and 8 patients with vasculitis diseases (VDs) during acute exacerbation. Leukotriene E 4 (LTE 4 ), 9alpha,11beta prostaglandin F 2 , and eosinophil-derived neurotoxin (EDN) concentrations were determined by enzyme immunoassay. 3-Bromotyrosine (BrY) and 3-chlorotyrosine (ClY) concentrations were determined by gas chromatography-mass spectrometry. RESULTS: The urinary LTE 4 , EDN, BrY, and ClY concentrations were significantly higher in the patients with CSS during acute exacerbation than in healthy control subjects and, except for urinary ClY concentration, significantly decreased during clinical remission. The urinary EDN and BrY concentrations were significantly higher in patients with CSS during acute exacerbation than in patients with VD during acute exacerbation. Only urinary LTE 4 concentration was significantly different between the patients with rheumatoid arthritis in stable condition and the patients with VD during acute exacerbation. CONCLUSION: Oxidative tissue damage caused by eosinophil peroxidase is a pathophysiological characteristic of eosinophil-associated diseases such as CSS. Urinary LTE 4 concentration may reflect a pathophysiological event involved in eosinophilic and noneosinophilic vasculitides. Cysteinyl-leukotriene pathways are potential therapeutic targets for small-vessel vasculitides.

Clinical features of asthmatic patients with increased urinary leukotriene E4 excretion (hyperleukotrienuria): Involvement of chronic hyperplastic rhinosinusitis with nasal polyposis.

BACKGROUND: The urinary leukotriene E4 (U-LTE4) concentration is significantly increased in patients with aspirin-intolerant asthma (AIA). However, the relationship between the clinicopathogenetic factors of asthma and the U-LTE4 concentration remains undetermined. OBJECTIVE: We sought to examine the clinical features of asthmatic patients with increased excretion levels of U-LTE4 (hyperleukotrienuria). METHODS: We measured the U-LTE4 concentrations in 137 asthmatic patients (including 64 patients with AIA) who were in clinically stable condition. A U-LTE4 concentration of 150 pg/mg creatinine or greater (mean U-LTE4 + 3 SDs of normal healthy control subjects) was indicative of hyperleukotrienuria. RESULTS: The basal concentration of U-LTE4 was significantly higher in the patients with AIA than in those with aspirin-tolerant asthma (ATA; median, 227.2 vs 90.3 pg/mg creatinine; P <.01). Compared with normal leukotrienuria in the patients with AIA, hyperleukotrienuria in the patients with AIA was associated with older age and decrease in pulmonary function. On the other hand, compared with normal leukotrienuria in the patients with ATA, hyperleukotrienuria in the patients with ATA was associated with severe asthma and chronic hyperplastic rhinosinusitis with nasal polyposis (CHRS/NP), which are well-known symptoms of the aspirin triad, as well as hypereosinophilia and anosmia. The patients with ATA with CHRS/NP excreted U-LTE4 at significantly high concentrations. There were significant decreases in the U-LTE4 concentrations before and after the sinus surgery in both the AIA and ATA groups (P <.05). CONCLUSION: Cysteinyl leukotrienes are not strictly associated with aspirin intolerance itself but rather with clinical features, such as CHRS/NP, that are similar to those seen in AIA. CHRS/NP might be involved in cysteinyl leukotriene overproduction in asthmatic patients.