Preschoolers with recurrent wheezing have a high prevalence of sleep disordered breathing.

Objective: Sleep-disordered breathing (SDB) is highly prevalent in school children with poorly-controlled asthma. However, this association has not been assessed in preschoolers with recurrent wheeze, nor in those at risk for asthma. We hypothesized that preschoolers with asthma risk (positive asthma predictive index [API]) have a higher prevalence of SDB and higher inflammatory biomarkers (blood-hsCRP and urinary-LTE4) levels than those with negative API.Method: Children 2 to 5 years of age with recurrent wheezing were classified as positive or negative API. SDB was determined by the pediatric sleep questionnaire (PSQ) and its subscale (PSQSub6). Demographic characteristics, spirometry, blood hsCRP and urinary LTE4 were assessed.Results: We enrolled 101 preschoolers: 70 completed all measurements, 55.4% were males, mean age 4.07 ± 0.87 years, 45% overweight or obese, 70% had positive API, 87.5% had rhinitis. The prevalence of SDB measured by PSQ was 40.8% and by PSQSub6 was 29.6%. However, the proportion of SDB was similar between positive and negative API groups. The hsCRP (mean ± SD) was higher in the positive than in negative API (3.58 ± 0.58 and 1.32 ± 0.36 mg/L, p = 0.69, respectively); moreover, no differences in urinary LTE4 were found between groups. No correlation of PSQ (+) or PSQSub6 (+) with hsCRP and uLTE4 was found. However, preschoolers with positive API had significantly more post-bronchodilator percentage change in FEF25-75 than negative API (24.14 ± 28.1 vs. 4.13 ± 21.8, respectively, p = 0.01).Conclusions: In preschoolers with recurrent wheezing, we should be investigating for the coexistence of SDB, using early screening methods for detecting those conditions.

Urinary leukotriene and Bcl I polymorphism of glucocorticoid receptor gene in preschoolers with recurrent wheezing and high risk of asthma.

BACKGROUND: Urinary leukotriene (LTE4) is an important marker of airway inflammation presence. A relationship between single nucleotide polymorphism in the glucocorticoid receptor (GCR) gene promoter (Bcl I polymorphism), development of asthma and sensitivity to glucocorticoids has been hypothesised. OBJECTIVE: To explore the possible association between the Bcl I polymorphism and baseline levels of urinary LTE4 in preschoolers with recurrent wheezing episodes. We prospectively enrolled and classified 86 preschoolers based on the risk of developing asthma (by the Asthma Predictive Index [API]). METHODS: At admission standardised questionnaires for demographics and respiratory illness characteristics were completed. The Bcl I polymorphism of the GCR was determined by a PCR-RFLP assay from blood samples, and urinary leukotriene was assessed from urine samples by an enzyme immunoassay. RESULTS: We enrolled 86 preschoolers (46 with positive API and 40 with negative API). There were no statistical differences in demographic, respiratory illnesses and wheezing episodes characteristics between both groups. Also, the prevalence of Bcl I polymorphism was similar between positive vs. negative API groups (34.8% vs. 38.9% for homozygote GG, 56.5% vs. 52.8% for heterozygote GC, 8.7% vs. 8.3% for homozygote CC, respectively, p=0.94). However, urinary LTE4 (median [IQR]) was higher in preschoolers with positive than negative API (7.18 [5.57-8.96pg/ml] vs. 6.42 [3.96-8.07pg/ml], p=0.02, respectively). CONCLUSIONS: In our population, wheezing preschoolers with positive API exhibit higher levels of urinary LTE4 than those with negative API; but there were no differences in Bcl I polymorphism of the GCR.

Systemic expression of inflammatory mediators in patients with chronic rhinosinusitis and nasal polyps with and without Aspirin Exacerbated Respiratory Disease.

BACKGROUND: Systemic reactions are related to the pathogenesis of Aspirin Exacerbated Respiratory Disease (AERD). With this work we wanted to study the changes in the systemic levels of inflammatory mediators in both baseline and after oral aspirin challenge in patients with and without AERD. METHODS: Patients with nasal polyposis and asthma with AERD (n=20) and without (n=18) were orally challenged with aspirin in a single-blind placebo controlled study. Serum samples and urine were collected before and 6h after placebo and aspirin oral challenges. Serum levels of inflammatory mediators were assayed by using the Luminex technology and ELISA. The concentrations of 9-alpha, 11-beta prostaglandin F2, and leukotriene E4 (uLTE4) were measured in urine samples by ELISA. The expression of T-cell surface markers was analyzed in peripheral blood mononuclear cells isolated before and after the challenges. RESULTS: AERD patients showed significantly higher baseline levels of s-IL-5R-alpha, uLTE4 and percentage of CD4(+)CD25(+)CD127(pos) and CD4(+)CD45RA(-)CD45RO(+) but decreased levels of TGF-ß1 and number of CD4(+)CD25(+)CD127(neg) cells. Aspirin challenge induced the release of uLTE4, IL-6 and increased the number of CD4(+)CD45RA(-)CD45RO(+) memory T-cells only in AERD patients but failed to reduce the levels of sCD40L as observed in non-AERD subjects. Further, IL-8 and sIL-5R-alpha levels directly correlated with the PD20ASA and the effects of aspirin on IL-6 and number of memory T-cells was more pronounced in subjects showing more strong reaction (bronchial and nasal). CONCLUSIONS: AERD patients have a differential baseline inflammatory pattern that supports the role inflammation as underlying mechanism of the disease. Systemic response to oral aspirin challenge was related to an increase in serum IL-6 and the number of circulating memory T-cells in AERD patients.

Passive smoking induces leukotriene production in children: influence of asthma.

BACKGROUND: Passive smoking is associated with poor asthma control in children, but the mechanism is unknown. Leukotrienes are involved in the asthma pathogenesis and their synthesis is increased in adult subjects who actively smoke. OBJECTIVE: To evaluate whether passive smoking, as assessed by urinary cotinine levels, increases leukotriene production in children with or without asthma. METHODS: This was a prospective, cross-sectional study in which children with stable intermittent asthma (without exacerbation) and healthy control children were studied through spirometry and urinary concentrations of cotinine and leukotriene E(4) (LTE(4)). Both groups were balanced to include children with and without passive smoking. RESULTS: Ninety children (49 with asthma and 41 controls, 54.4% females) aged 9 years (range, 5-13 years) were studied. Urinary LTE(4) concentrations were progressively higher as cotinine levels increased (r(S) = 0.23, p = .03). LTE(4) also correlated with body mass index (BMI) (r(S) = 0.30, p = .004), and multiple regression analysis revealed that BMI was even more influential than cotinine for determining LTE(4) levels. LTE(4) concentrations were unrelated with gender, age, or spirometry. In turn, cotinine inversely correlated with forced expiratory volume in one second (FEV(1)) (r(S) = -0.22, p = .04) and forced vital capacity (FVC) (r(S) = -0.25, p = .02), but when analyzed by groups, these relationships were statistically significant only in children with asthma. CONCLUSIONS: Exposure to environmental tobacco smoke, as assessed by urinary cotinine levels, was associated with an increased urinary concentration of LTE(4), although BMI exerted more influence in determining its concentration. Urinary cotinine was associated with decreased lung function, mainly in children with asthma.

[Airway resistance and urinary LTE4 in children with bronchopulmonary dysplasia. Preliminary report]. / Resistencia de las vías aéreas y LTE4 urinario en niños con displasia broncopulmonar. Informe preliminar.

OBJECTIVE: To assess airway resistance values and urinary leukotriene E4 (LTE4) concentrations before and after salbutamol inhalation in children with bronchopulmonary dysplasia (BPD). MATERIAL AND METHODS: Children with BPD were cross-sectionally studied to measure airway resistance by the interrupter technique (Rint), before and after inhaling 200 ig salbutamol, and to quantify urinary leukotriene E4 (LTE4) by immunoassay. RESULTS: Thirty one children with BPD (15 females) aged between 3 months and 9 years were studied. Our results showed that LTE4 did not correlate with Rint values (r = 0.12, p = 0.52) even after adjusting by gender, atopy history, steroid use, and gastroesophageal reflux. Likewise, LTE4 did not correlate with the degree of the airway response to salbutamol (r = -0.13, p = 0.50). A strong inverse association between age and Rint (r = -0.58, p < 0.001) was observed. CONCLUSION: We concluded that urinary LTE, did not correlate with airway resistance or with the response to a bronchodilator drug in children with BPD, suggesting that leukotrienes are not involved in airway obstruction in this disease.

Urinary leukotrienes in patients with nasal polyposis.

OBJECTIVES: To compare urinary leukotriene E4 (ULT) level in patients with nasal polyposis (NP) with and without aspirin intolerance and allergic rhinitis (AR), and correlate it with disease severity. STUDY DESIGN AND SETTING: Prospective study from November 2005 to November 2006. Patients with NP (n = 30) and AR (n = 35) were included. The concentration of ULT was measured in both groups. Oral provocation test with aspirin was performed to patients with NP. ULT level between both groups was compared and correlated with NP disease severity. RESULTS: ULT concentration was elevated on NP and AR. The patients with NP and aspirin intolerance (n = 4) presented higher levels of ULT compared to aspirin-tolerant patients. Leukotriene concentration was not correlated with NP severity. CONCLUSIONS: Patients with NP and aspirin intolerance have increased ULT excretion; thus their measurement can be used as an indicator of arachidonic acid metabolism alteration.

Airway eicosanoids in acute severe respiratory syncytial virus bronchiolitis.

We prospectively studied the levels of eicosanoids in intubated patients with severe bronchiolitis and compared them to electively intubated non-infected infants. LeukotrieneE(4) (LTE(4)), leukotrieneB(4) (LTB(4)), and prostaglandinE(2) (PGE(2)) levels were significantly increased (P <.01) from endotracheal (ET) aspirates of infants with bronchiolitis compared with controls, as were urinary LTE(4) levels (P <.001). We conclude that eicosanoids are increased in the tracheal aspirates and urine of children with bronchiolitis.

[Aspirin induced asthma, urinary leukotriene E4 and zafirlukast]. / Asma inducida por aspirina, leucotrieno E4 en orina y zafirlukast.

OBJECTIVE: To evaluate the efficiency of zafirlukast in patients with aspirin-induced-asthma trough a measurement of VEF1, during the treatment and the symptoms daily reported. To evaluate the safety of treatment through a record of adversed events and laboratory and cabinet monitoring, to know the effect of zafirlukast on urine LTE4 level. MATERIAL AND METHODS: It was an open, controlled, prospective, longitudinal, observational study. Twenty patients with aspirin-induced asthma were included and 10 extrinsic asthma patients as a group control. On the aspirin-induced asthma, age range was between 28-82 years old patients with an average of 55. 17 female and three male and group control with demographic similar features. All patients were included in a 30 days wash period avoiding anti-inflammatory medication like steroids, cromons, etc., on the initial phase treatment. A determination of blood cell count, transaminases, bilirubins, immunoglobulins, GAME, electrocardiogram, thorax study and LTE4 urine analysis was carried out. Twice a day 20 mg. zafirlukast dosis was administered to both groups, VO, during eight weeks. A symptoms report diary was given to each of the patients. A weekly and beginning sphirometric was carried out along the study to determine VEF1. Same laboratory and cabinet variables were determined on the final checking. RESULTS: 17 patients from the study group were analyzed and 10 from control group, an improvement of 12% average was reported on final VEF1, in comparison to the basal for both groups (p < .001) having this relation with the clinic improvement in the diary symptoms report. LTE4 urine levels diminished in similar form on both groups. This reduction was important (p < .001). Just three limited slight cephalalgia cases were reported (7.9%). CONCLUSION: Asthmatic patients belonging to extrinsic or aspirin-induced asthma groups irrespectively showed an improvement from zafirlukast treatment on spirometric and clinic levels. No serious disadvantage was found associated to zafirlukast and side effects were slight after two months. In LTE4 level drop was found in urine, in possible relation with zafirlukast, interruption on the pulmonary chronic inflammatory process.

Asma por ejercicio: utilidad de marcadores en orina / Exercise induced asthma: utility of urinaria markers

Antecedentes: los metabolitos estables de la Prostaglandina D2 (PGD2) mastocitaria 9 O11ß Prostaglandina F2 (9 O11ßPGF2) y de los cis-leucotrienos (LTE4) medidos en orina reflejan la producción de estos mediadores. Objetivos: determinar el rol de los leucotrienos y de la Prostaglandina D2 a través de la relación existente entre la provocación del asma por ejercicio (AIE) y los niveles urinarios de Laucotrieno E4 (LTE4) y 9 O11ßPGF2. Materiales y métodos: fueron estudiados 24 niños con asma (6-14 años) y 9 niños sanos como control. En todos los asmáticos y en 5 controles se evaluó la presencia de AIE mediante prueba de carrera libre durante 7 min, alcanzando el 80 por ciento de frecuencia cardíaca máxima para la edad. Se realizaron espirometrías basales y post prueba (secuenciales) y se colectó orina inmediatamente antes y 45 minutos despues de la prueba. LTE4 y 9 O11ßPGF2 fue evaluada por enzimainmunoensayos específicos. Resultados: Los 5 controles normales no presentaron asma por ejercicio, de los 24 pacientes asmáticos 12 no presentaron AIE y en 12 la prueba fue posititva (VEF1s cae > 15 por ciento). Las medias de los valores basales y post ejercicio de LTE4 y 9 O11ßPGF2 en pg/mg creatinina se tabulan a continuación: Asma por ejercicio: 9 O11ßPGF2: Basal: 3,39; Post: 7,95; p=0,001; LTE4: Basal: 4,00; Post: 9,39; p=0,002. Asma sin ejercicio: 9 O11ßPGF2: Basal: 3,98; Post: 6,28; p=0,02; LTE4: Basal: 5,91; Post: 7,04; p=0,242. Los niveles de 9 O11ßPGF2 y LTE4 de los controles normales no variaron significativamente post ejercicio. Conclusión: en los pacientes con asma por ejercicio se verifica activación mastocitaria con liberación de PGD2 que se demuestra como aumento de 9 O11ßPGF2 urinaria, y de los leucotrienos aumento del LTE4. El aumento de LTE4 es específico para asma por ejercicio en tanto que la 9 O11ßPGF2 aumenta en ambos grupos (AU)

Asma por ejercicio: utilidad de marcadores en orina / Exercise induced asthma: utility of urinaria markers

Antecedentes: los metabolitos estables de la Prostaglandina D2 (PGD2) mastocitaria 9 Ó11ß Prostaglandina F2 (9 Ó11ßPGF2) y de los cis-leucotrienos (LTE4) medidos en orina reflejan la producción de estos mediadores. Objetivos: determinar el rol de los leucotrienos y de la Prostaglandina D2 a través de la relación existente entre la provocación del asma por ejercicio (AIE) y los niveles urinarios de Laucotrieno E4 (LTE4) y 9 Ó11ßPGF2. Materiales y métodos: fueron estudiados 24 niños con asma (6-14 años) y 9 niños sanos como control. En todos los asmáticos y en 5 controles se evaluó la presencia de AIE mediante prueba de carrera libre durante 7 min, alcanzando el 80 por ciento de frecuencia cardíaca máxima para la edad. Se realizaron espirometrías basales y post prueba (secuenciales) y se colectó orina inmediatamente antes y 45 minutos despues de la prueba. LTE4 y 9 Ó11ßPGF2 fue evaluada por enzimainmunoensayos específicos. Resultados: Los 5 controles normales no presentaron asma por ejercicio, de los 24 pacientes asmáticos 12 no presentaron AIE y en 12 la prueba fue posititva (VEF1s cae > 15 por ciento). Las medias de los valores basales y post ejercicio de LTE4 y 9 Ó11ßPGF2 en pg/mg creatinina se tabulan a continuación: Asma por ejercicio: 9 Ó11ßPGF2: Basal: 3,39; Post: 7,95; p=0,001; LTE4: Basal: 4,00; Post: 9,39; p=0,002. Asma sin ejercicio: 9 Ó11ßPGF2: Basal: 3,98; Post: 6,28; p=0,02; LTE4: Basal: 5,91; Post: 7,04; p=0,242. Los niveles de 9 Ó11ßPGF2 y LTE4 de los controles normales no variaron significativamente post ejercicio. Conclusión: en los pacientes con asma por ejercicio se verifica activación mastocitaria con liberación de PGD2 que se demuestra como aumento de 9 Ó11ßPGF2 urinaria, y de los leucotrienos aumento del LTE4. El aumento de LTE4 es específico para asma por ejercicio en tanto que la 9 Ó11ßPGF2 aumenta en ambos grupos

Cambios metabólicos del ácido araquidónico en la desensibilización a la aspirina / Aspirin, metabolic change in arachidonic acid in the desensitization

La sensibilización de la aspirina se presenta en acerca del 10 por ciento de todos los pacientes asmáticos. En esta clase de asmáticos la congestión nasal y el broncoespasmo ocurren entre los 30 a 180 minutos después de la ingestión de la aspirina. Luego de la reacción respiratoria a la aspirina todos los pacientes pueden ser desensibilizados a la misma mediante la introducción repetida de pequeñas a grandes cantidades de aspirina hasta que los sujetos asmáticos pueden ingerir 650 mg del fármaco sin ningún efecto adverso. Los mecanismos de la sensibilidad a la aspirina no están totalmente esclarecidos, y las razones por las cuales la desensibilización en los pacientes asmáticos sensibles a la aspirina (ASA) ocurre de manera universal se desconocen. En este estudio, pacientes ASA y testigos asmáticos no ASA se expusieron a dosis provocadoras de aspirina. Se colectaron muestras de orina antes, durante el broncoespasmo inducido, y después de la ingestión de 650 mg de aspirina, cuando los efectos adversos habían desaparecido (fenómeno de desensibilización). Se dertminaron los niveles de los productos tipo y cicloxigenados en las muestras de orina. En este trabajo se analizan los resultados y se expone una explicación del probable mecanismo de la desensibilización

[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.

Enhanced urinary excretion of leukotriene E4 in patients with mevalonate kinase deficiency.

In patients with mevalonate kinase deficiency, urinary excretion of the leukotriene LTE4 was found to be elevated. A positive linear relationship between increased urinary excretion of mevalonate and LTE4 (n = 5) suggests that increased cysteinyl leukotriene synthesis is involved in the pathomechanisms of this disease.

ICI 198615 is an antagonist of leukotriene C4, leukotriene D4 and leukotriene E4 vasopressor responses in the conscious rat.

The purpose of these studies was to evaluate the effects of the peptidoleukotriene (LT) receptor antagonist, ICI 198615, on the vasopressor responses produced by LTC4, LTD4 and LTE4. Conscious, normotensive rats were prepared with arterial and venous catheters for measurement of changes in arterial blood pressure and administration of drugs, respectively. Complete dose-response curves were first generated to LTC4, LTD4 and LTE4: those agents produced dose-dependent increases in arterial blood pressure, with ED20 values (i.e. dose to increase blood pressure 20 mm Hg) of 1.7 +/- 0.2, 2.1 +/- 0.2 and 19.8 +/- 3.7 nmol/kg i.v., respectively. ICI 198615 (intravenous bolus followed by a continuous infusion) produced dose-dependent, parallel shifts to the right in the LTC4 dose-response curve. At doses of 0.2 mg/kg + 1 mg/kg/h, 1 mg/kg + 3 mg/kg/h or 2 mg/kg + 10 mg/kg/h, ICI 198615 produced dose ratios of 4.5, 17.1 and 50.0, respectively. Against LTD4 responses, ICI 198615 at a dose of 0.1 mg/kg + 0.3 mg/kg/h produced a dose ratio of 3.4, whereas at doses of 0.2 mg/kg + 1 mg/kg/h, 1 mg/kg + 3 mg/kg/h or 2 mg/kg + 10 mg/kg/h ICI 198615 produced dose ratios of 16.3, 24.9 and 16.2, respectively. The difference in the dose ratios between these three groups was not statistically significant (p greater than 0.05). However, a dose of 10 mg/kg + 30 mg/kg/h produced a dose ratio of greater than 100. Against LTE4 responses, ICI 198615 at doses of 0.2 mg/kg + 1 mg/kg/h or 1 mg/kg + 3 mg/kg/h produced dose ratios of 4.1 and 11.3, respectively. The similarity in the LTD4 dose ratios despite a 3- or 10-fold increase in the dose of ICI 198615 suggests the existence of high- and low-affinity LTD4 receptor sites, whereas the responses to LTC4 and LTE4 appeared to be mediated via a single receptor population. These results indicate that ICI 198615 is a potent and competitive antagonist of LTC4, LTD4 and LTE4 vascular responses in the rat.