Exhaled nitric oxide can't replace the methacholine challenge in suspected pediatric asthma.

BACKGROUND: In adults, measurement of FENO has been recently suggested as a substitute for the methacholine challenge test (MCT) for diagnosis of asthma. This study aimed to evaluate whether FeNO is a substitute for MCH also in children with suspicious asthma. METHODS: During a single visit steroid naive children (5-17 years) with suspicious asthma underwent skin prick test (SPT), FENO measurement and spirometry prior and during MCT (one concentration procedure). Results of the SPT (atopy/non-atopy) and MCT (asthma/non-asthma) were used for categorization. ROC analysis in atopy non-atopy subgroups yielded sensitivity, specificity, positive and negative predictive value (PPV and NPV) for FENO. RESULTS: The SPT revealed atopy in 134 out of 222 children (age 9.7 ±â€¯3.2 years) investigated and asthma was diagnosed in 114 (77/37 atopy/non-atopy) patients. FENO values in patients with atopic asthma were significantly higher compared to those with either non-atopic asthma or atopia without asthma (18 ppb (5-89) vs 7 ppb (5-36); p < 0.001; 18 ppb (5-89) vs 11 ppb (5-98); p < 0.05). Sensitivity and specificity of FENO for diagnosing atopic asthma (FENO≥15.5 ppb; AUC = 0.635, p < 0.01) were 61.1% and 64.9% and non-atopic asthma (FENO≥ 6.5 ppb; AUC = 0.445, p = 0.382) 54.1% and 39.2%, respectively. The PPV/NPV for FENO were 0.70/0.55 in atopy and 0.39/0.54 in non-atopy patients, respectively. CONCLUSION: In children, FENO is not appropriate to substitute for the MCT. However, in patients with a negative SPT a FENO in the normal range makes the presence of atopic asthma unlikely.

Bronchial Reactivity, Inflammatory and Allergic Parameters, and Vitamin D Levels in Children With Asthma.

BACKGROUND: A low serum vitamin D level may represent a marker of other perplexing factors that may lead to increased asthma prevalence and severity. Our aim was to assess the correlation between vitamin D levels and asthma and allergy markers in a subgroup of children with fewer confounding factors. METHODS: Non-obese children (6-18 y old) with asthma who were not receiving anti-inflammatory treatment were recruited. Subjects underwent spirometry with a methacholine challenge test, and fractional exhaled nitric oxide (FENO), serum vitamin D levels, total immunoglobulin E (IgE) levels, blood eosinophil counts, and high-sensitivity C-reactive protein levels were determined. The primary end point was the correlation between vitamin D level and airway hyper-responsiveness as assessed by a methacholine challenge test. The secondary end point was the correlation between vitamin D level and FENO, systemic inflammatory markers, and allergy. RESULTS: Seventy-one children with asthma (25 females, 35%; 12.5 ± 3.6 y of age) were included. The median vitamin D level was 23 ng/mL (range of 6-48.5, mean of 23.02 ± 7.74), the median IgE level was 305 IU/mL (range of 4.3-4,240), the median provocational concentration of methacholine that produced a 20% decrease in FEV1 was 1.1 mg/mL (range of 0-13.9), and the median FENO was 26.5 ppb (range of 3.6-285). No correlation was found between vitamin D level and response to the methacholine challenge test, FENO, high-sensitivity C-reactive protein levels, IgE levels, eosinophil counts, and frequency of allergic rhinitis or atopic dermatitis. CONCLUSIONS: In our group of children with asthma, no correlation was found between the level of vitamin D and the degree of airway reactivity, airway inflammation, and allergy. The cause-and-effect relationship between vitamin D, asthma, and allergy should be further clarified. (ClinicalTrials.gov registration NCT01287455).

Comparison of the provocative concentration of methacholine causing a 20% fall in FEV1 between the AeroEclipse II breath-actuated nebulizer and the wright nebulizer in adult subjects with asthma.

RATIONALE: The American Thoracic Society guidelines for methacholine testing for the diagnosis of asthma recommends the 2-minute tidal breathing protocol with the Wright nebulizer, which produces more aerosol than required, generates a small particle size, and requires cleaning between tests. OBJECTIVES: To evaluate methacholine testing using a disposable, breath-actuated AeroEclipse II, which produces aerosol during inspiration and was developed for single-patient use. METHODS: Forty-six adult subjects with asthma (19 men), aged 27.3 (SD, 9.5) years, with FEV1 98.5 (SD, 18.1) % predicted participated in a randomized, crossover, observational study. Subjects were first screened using the Wright nebulizer, then assigned to 2 minutes of tidal breathing from the Wright or 20 seconds of tidal breathing from the AeroEclipse nebulizer on 2 separate days, in random order. Provocative concentration of methacholine causing a 20% fall in FEV1 (PC20) values were calculated by linear interpolation of log dose-versus-response curves, log-transformed, and compared using paired Student t test and Pearson correlation. MEASUREMENTS AND MAIN RESULTS: The 38 subjects demonstrating reproducible PC20 measurements of within 1.5 doubling concentrations were included in the comparison. The geometric mean methacholine PC20 measured with the AeroEclipse nebulizer was approximately 1 doubling concentration lower than the geometric mean methacholine PC20 of the Wright nebulizer (P < 0.05). The Pearson correlation coefficient between the two nebulizers was 0.86 (P < 0.05). CONCLUSIONS: The PC20 measurements using the two nebulizers were highly correlated; however, the PC20 determined with the AeroEclipse nebulizer was significantly lower than those determined using the Wright nebulizer. Clinical trial registered with www.clinicaltrials.gov (NCT 01919424).

The Effect of Zataria multiflora and its Constituent, Carvacrol, on Tracheal Responsiveness and Lung Pathology in Guinea Pig Model of COPD.

The effects of Zataria multiflora (Z. multiflora) and its constituent, carvacrol, in guinea pigs model of chronic obstructive pulmonary disease (COPD) were examined. Animals were divided into control, COPD, COPD + drinking water containing three concentrations of extract of Z. multiflora (0.4, 0.8 and 1.6 mg/ml), COPD + drinking water containing three concentrations of carvacrol (60, 120 and 240 µg/ml) and COPD + dexamethasone (50 µg/ml). COPD was induced by exposing animals to cigarette smoke for 3 months. Emphysema as a pathological change of the lung and tracheal responsiveness were measured (n = 5 for control and COPD groups and n = 6 for another groups). Tracheal responsiveness (p < 0.05) and emphysema were significantly increased (p < 0.001) in COPD compared to the control group. Tracheal responsiveness in COPD groups treated with two higher concentrations of the Z. multiflora and three concentrations of carvacrol, and emphysema in treated with highest concentration of Z. multiflora and carvacrol were significantly improved compared to COPD group. Studied parameters were also significantly improved in the treated group with dexamethasone compared to COPD animals (p < 0.05 to p < 0.01). The results indicated a preventive effect of Z. multiflora extract and its constituent, carvacrol, on tracheal responsiveness and pathological changes of the lung.

Pituitary Adenylate Cyclase Activating Peptide (1-38) and its analog (Acetyl-[Ala15, Ala20] PACAP 38-polyamide) reverse methacholine airway hyperresponsiveness in rats

The aim of this study was to investigate both functionally and structurally bronchodilator effects of Pituitary adenylate cyclase activating peptide (PACAP38) and acetyl-[Ala15, Ala20] PACAP38-polyamide, a potent PACAP38 analog, in rats challenged by methacholine (MeCh). Male Wistar rats were divided randomly into five groups. Groups 1 and 2 inhaled respectively aerosols of saline or increasing doses of MeCh (0.5, 1, 2.12, 4.25, 8.5, 17, 34 and 68mg/L). The other groups received terbutaline (Terb) (250 µg/rat) (10-6 M), PACAP38 (50 µg/rat) (0.1 mM) or PACAP38 analog (50 µg/rat) associated to MeCh from the dose of 4.25 mg/L. Total lung resistances (RL) were recorded before and 2 min after MeCh administration by pneumomultitest equipment. MeCh administration induced a significant and a dose-dependent increase (p<0.05) of RL compared to control rats. Terb, PACAP38 and PACAP38 analog reversed significantly the MeCh-induced bronchial constriction, smooth muscle (SM) layer thickness and bronchial lumen mucus abundance. PACAP38 analog prevents effectively bronchial smooth muscle layer thickness, mucus hypersecretion and lumen decrease. Therefore, it may constitute a potent therapeutic bronchodilator.

O objetivo deste estudo foi investigar funcionalmente e estruturalmente efeito broncodilatador do peptídeo ativador da adenilato ciclase pituitária (PACAP1-38) e da acetil-[Ala15, Ala20]PACAP 38-poliamida, potente análogo do PACAP-38, nos ratos desafiados pelo metacolina (MeCh). Ratos Wistar machos foram aleatoriamente divididos em cinco grupos. Grupos 1 e 2, inalando aerossóis de solução salina ou doses crescentes de MeCh (0,5, 1, 2,12, 4,25, 8,5, 17, 34 e 68 mg/L). Os outros grupos recebendo terbutalina (Terb) (250 µg/rato) (10-6M), PACAP-38 (50 µg/rato) (0.1 mM) ou análogo do PACAP-38 (50 µg/rato) associados a MeCh na dose de 4,25 mg/L. A resistência pulmonar total (RL) foi registrada antes e 2 min após a administração de Mech pelo equipamento pneumomultiteste. A administração MeCh induziu aumento significativo e dose dependente (p<0,05) de RL em comparação com ratos do grupo controle. Terb e PACAP1-38 e análogo do PACAP-38 reverteram, significativamente, a constrição brônquica induzida por Mech, a espessura do músculo liso (SM) e abundância de muco do lume brônquico. O análogo PACAP-38 do mesmo modo que a Terb impediu a responsividade brônquica a MeCh e pode se constituir em um importante regulador no desenvolvimento da doença inflamatório pulmonar. Contudo, o uso do peptídeo nativo para aplicações terapêuticas é limitado por sua baixa estabilidade metabólica. Consequentemente, o análogo metabolicamente estável representa ferramenta promissora no tratamento de doenças pulmonares inflamatórias.

Irritant-induced airway disorders.

Thousands of persons experience accidental high-level irritant exposures each year but most recover and few die. Irritants function differently than allergens because their actions proceed nonspecifically and by nonimmunologic mechanisms. For some individuals, the consequence of a single massive exposure to an irritant, gas, vapor or fume is persistent airway hyperresponsiveness and the clinical picture of asthma, referred to as reactive airways dysfunction syndrome (RADS). Repeated irritant exposures may lead to chronic cough and continual airway hyperresponsiveness. Cases of asthma attributed to repeated irritant-exposures may be the result of genetic and/or host factors.

RUNX transcription factors: association with pediatric asthma and modulated by maternal smoking.

Intrauterine smoke exposure (IUS) is a strong risk factor for development of airways responsiveness and asthma in childhood. Runt-related transcription factors (RUNX1-3) have critical roles in immune system development and function. We hypothesized that genetic variations in RUNX1 would be associated with airway responsiveness in asthmatic children and that this association would be modified by IUS. Family-based association testing analysis in the Childhood Asthma Management Program genome-wide genotype data showed that 17 of 100 RUNX1 single-nucleotide polymorphisms (SNPs) were significantly (P < 0.03-0.04) associated with methacholine responsiveness. The association between methacholine responsiveness and one of the SNPs was significantly modified by a history of IUS exposure. Quantitative PCR analysis of immature human lung tissue with and without IUS suggested that IUS increased RUNX1 expression at the pseudoglandular stage of lung development. We examined these associations by subjecting murine neonatal lung tissue with and without IUS to quantitative PCR (N = 4-14 per group). Our murine model showed that IUS decreased RUNX expression at postnatal days (P)3 and P5 (P < 0.05). We conclude that 1) SNPs in RUNX1 are associated with airway responsiveness in asthmatic children and these associations are modified by IUS exposure, 2) IUS tended to increase the expression of RUNX1 in early human development, and 3) a murine IUS model showed that the effects of developmental cigarette smoke exposure persisted for at least 2 wk after birth. We speculate that IUS exposure-altered expression of RUNX transcription factors increases the risk of asthma in children with IUS exposure.

Endothelin A receptor antagonist modulates lymphocyte and eosinophil infiltration, hyperreactivity and mucus in murine asthma.

Levels of endothelins are particularly high in the lung, and there is evidence that these peptides are involved in asthma. Asthma is a chronic inflammatory disease associated with lymphocyte infiltration. In the present study, we used a murine model of asthma to investigate the role of endothelins in lymphocyte and eosinophil infiltration into the airway hyperreactivity and mucus secretion. Sensitized C57Bl/6 mice were treated with endothelin ETA receptor antagonist (BQ123) or endothelin ETB receptor antagonist (BQ788) 30 min before an antigen aerosol challenge. After 24 h, dose response curves to methacholine were performed in isolated lungs, FACS analysis of lymphocytes and eosinophil counts were performed in bronchoalveolar lavage fluid and mucus index was determined by histopathology. In sensitized and antigen-challenged mice there is a marked increase in the T CD4+, T CD8+, B220+, Tgammadelta+ and NK1.1+ lymphocyte subsets. Treatment with BQ123 further increased these cell populations. The number of eosinophils, airway hyperreactivity and mucus were all reduced by BQ123 treatment. The BQ 788 had no significant effect on the parameters analyzed. Treatment with BQ123 reduced the endothelin concentration in lung homogenates, suggesting that endothelins exert a positive feedback on their synthesis. We show here that in murine asthma the ETA receptor antagonist up-regulates lymphocyte infiltration and reduces eosinophils, hyperreactivity and mucus.