Prednisone-hydrogen sulfide releasing hybrid shows improved therapeutic profile in asthma.

Introduction: Hydrogen sulfide (H2S) is emerging as an important potential therapeutic option for respiratory inflammatory diseases. In this study, we investigated the effectiveness of a novel corticosteroid derivative, that is chemically linked to an H2S donor, in managing asthma features. Methods: The effects of prednisone (PS), H2S donor (4-hydroxybenzamide; TBZ), and their combination (PS-TBZ) have been evaluated in vitro and in vivo. The in vitro experiments were conducted using lipopolysaccharidestimulated J774 macrophages, while the in vivo experiments utilizing an experimental asthma model. Results: In the in vitro study we found that PS-TBZ exhibited an increased effect compared to the individual parent compounds in modulating the production of inflammatory mediators. TBZ also significantly reduced bronchial contractility and enhanced bronchial relaxation. In the in vivo experiments, where we administered PS, TBZ, or PS-TBZ to ovalbumin-sensitized BALB/c mice, we confirmed that PS-TBZ had a significantly better action in controlling airway hyperreactivity as compared to TBZ or PS alone. Moreover, PS-TBZ was more effective in restoring salbutamol-induced relaxation. The immunohistochemistry analysis demonstrated a significant reduction in the production of α-SMA and procollagen III, indicating the efficacy of PS-TBZ in controlling airway remodeling. Moreover, PS-TBZ also promoted epithelial repair, recovery of the bronchial and parenchyma structure and inhibited mucin production. Discussion: In conclusion, PS-TBZ offers an important opportunity to optimize the beneficial impact of corticosteroids on asthma features.

Reduction of bronchial response to mannitol after partial switch from conventional tobacco to electronic cigarette consumption.

BACKGROUND: Regarding the multiple health effects of e-cigarettes, there are insufficient data on potential effects on bronchial reactivity (BHR). In the present study, we assessed the impact of a switch from conventional to e-cigarettes on BHR under realistic conditions over a period of 3 months. METHODS: Sixty subjects who declared to reduce or stop their tobacco consumption by inhalation of nicotine-containing liquids via e-cigarette, and 20 volunteers participating in a stop-smoking program were included. Data was analysed using parametric and non-parametric statistical procedures. Spirometry, determinations of exhaled carbon monoxide (eCO) and nitric oxide (FeNO), provocation testing with mannitol as an indirect bronchial stimulus, and cotinine measurements were used to investigate BHR and nicotine abstinence. RESULTS: BHR to mannitol significantly decreased in the group using e-cigarettes and nicotine-containing liquids over a period of three months in this real-life setting. Participants reduced their tobacco consumption to about 25% or lower, confirmed by a reduction in eCO. Changes in lung function and FeNO were small and not statistically significant, and changes in the stop-smoking group were similar to those in the e-cigarette group. CONCLUSION: The reduction in BHR that can be expected after a reduction of cigarette consumption was not abolished by the concomitant use of e-cigarettes. Whether the decrease in BHR observed after 3 months is maintained when using e-cigarettes over longer time periods or has an individual prognostic value, must be clarified in long-term studies.

Performance Characteristics of Spirometry With Negative Bronchodilator Response and Methacholine Challenge Testing and Implications for Asthma Diagnosis.

BACKGROUND: In patients with a history suggestive of asthma, diagnosis is usually confirmed by spirometry with bronchodilator response (BDR) or confirmatory methacholine challenge testing (MCT). RESEARCH QUESTION: We examined the proportion of participants with negative BDR testing who had a positive MCT (and its predictors) result and characteristics of MCT, including effects of controller medication tapering and temporal variability (and predictors of MCT result change), and concordance between MCT and pulmonologist asthma diagnosis. STUDY DESIGN AND METHODS: Adults with self-reported physician-diagnosed asthma were recruited by random-digit dialing across Canada. Subjects performed spirometry with BDR testing and returned for MCT if testing was nondiagnostic for asthma. Subjects on controllers underwent medication tapering with serial MCTs over 3 to 6 weeks. Subjects with a negative MCT (the provocative concentration of methacholine that results in a 20% drop in FEV1 [PC20] > 8 mg/mL) off medications were examined by a pulmonologist and had serial MCTs after 6 and 12 months. RESULTS: Of 500 subjects (50.5 ± 16.6 years old, 68.0% female) with a negative BDR test for asthma, 215 (43.0%) had a positive MCT. Subjects with prebronchodilator airflow limitation were more likely to have a positive MCT (OR, 1.90; 95% CI, 1.17-3.04). MCT converted from negative to positive, with medication tapering in 18 of 94 (19.1%) participants, and spontaneously over time in 25 of 165 (15.2%) participants. Of 231 subjects with negative MCT, 28 (12.1%) subsequently received an asthma diagnosis from a pulmonologist. INTERPRETATION: In subjects with a self-reported physician diagnosis of asthma, absence of bronchodilator reversibility had a negative predictive value of only 57% to exclude asthma. A finding of spirometric airflow limitation significantly increased chances of asthma. MCT results varied with medication taper and over time, and pulmonologists were sometimes prepared to give a clinical diagnosis of asthma despite negative MCT. Correspondingly, in patients for whom a high clinical suspicion of asthma exists, repeat testing appears to be warranted.

Children with Asthma Have Fixed Airway Obstruction through Childhood Unaffected by Exacerbations.

BACKGROUND: Children with asthma may have a disease course with or without exacerbations, but the relationship between exacerbations and lung function development is poorly understood. OBJECTIVE: To compare lung function trajectories from birth till adolescence in asthmatic children with and without exacerbations. METHODS: Children with asthma from the Copenhagen Prospective Studies on Asthma in Childhood2000 (COPSAC2000) birth cohort had lung function and bronchial reactivity assessed repeatedly from 1 month to 13 years. Exacerbations were diagnosed at the COPSAC clinic defined as symptoms requiring hospitalization, oral or high-dose inhaled corticosteroid treatment. Mixed models were applied to analyze lung function trajectories. RESULTS: Children with asthma with exacerbations (N = 50) had a trajectory of increased, fixed airway obstruction compared with children without exacerbations (N = 47): z-score difference in airway resistance (sRawz) (95% confidence interval [CI]): +0.34 (+0.03; +0.66), P = .03, and maximal mid-expiratory flow (MMEFz): -0.41 (-0.69; -0.13), P = .004, but no differences in forced expiratory volume (FEVz): -0.14 (-0.41; +0.13), P = .29, or bronchial reactivity to methacholine (PDz): +0.08 (-0.26; +0.42), P = .65. This did not change comparing lung function trajectories before and after exacerbations: z-score difference (95% CI) sRawz: -0.04 (-0.35; 0.27), P = .80; MMEFz: 0.01 (-0.02; 0.04), P = .55; FEVz: 0.02 (-0.02; 0.05), P = .42; and PDz: -0.01 (-0.06; 0.05), P = .88. CONCLUSION: Children with asthma with exacerbations compared with children with asthma without exacerbations are characterized by increased airway obstruction since infancy through childhood. The airway obstruction is a fixed trajectory without progression due to exacerbations, suggesting that exacerbations are a consequence rather than a cause of diminished airway caliber in childhood.

Pulmonary function and bronchial reactivity 4 years after the first virus-induced wheezing.

BACKGROUND: Wheezing illnesses among young children are common and are a risk factor for asthma. However, determinants of childhood bronchial reactivity, a key feature of asthma, are largely unknown. The aim of this study was to determine how patient characteristics during the first severe virus-induced wheezing episode are associated with pulmonary function at preschool age. METHODS: Study consisted of 76 children presenting with their first wheezing episode at the ages of 3 to 23 months. At study entry, viral etiology, rhinovirus genome load, atopic and clinical characteristics, and standardized questionnaire were analyzed. At 4-year follow-up visit, impulse oscillometry with exercise challenge was performed. RESULTS: At study entry, the mean age of the children was 12 months (SD 6.0), 57 (75%) were rhinovirus positive, and 22 (30%) were sensitized. At follow-up visit four years later, the mean age of the children was 60 months (SD 7.9) and 37 (49%) were using asthma medication regularly (discontinued before testing in 25 [68%] children). Bronchial reactivity (≥35% change in mean crude values of resistance) after exercise challenge or bronchodilation was present in nine (12%) children. Children with atopic sensitization at the time of the first wheezing episode were more often likely to develop bronchial reactivity (odds ratio 8.8, P = 0.03) than the children without sensitization. No other significant associations were found. CONCLUSIONS: Atopic sensitization at the time of the first severe wheezing episode is an important early risk factor for increased bronchial reactivity at preschool age.

Long-term intense exposure to grass pollen can mask positive effects of allergenic immunotherapy on non-specific bronchial hyperresponsiveness.

INTRODUCTION: There are many potential factors that can modulate bronchial reactivity, including exposure to allergens, viral infections, and medications. The aim of this study was to analyze the effect of grass pollination intensity on the bronchial reactivity in seasonal allergic rhinitis (SAR) patients subjected to subcutaneous allergenic immunotherapy (SCIT). MATERIAL AND METHODS: This study, performed between 2005 and 2008, included 41 patients with confirmed sensitivity to grass pollens and predominating symptoms of SAR, randomly assigned to desensitization by pre-seasonal or maintenance SCIT. Bronchial provocation challenge with histamine was performed before the onset of immunotherapy, and repeated three times after each pollen season covered by this study. Bronchial reactivity was analyzed with regard to grass pollination intensity in 2005-2008 (air concentration of grass pollen grains, seasonal number of days when air concentration of grass pollen reached at least 20 or 50 grains per 1 m(3)). RESULTS: After 3 years of SCIT, a significant decrease in bronchial responsiveness was observed in the analyzed group as confirmed by an increase in PC20 FEV1 histamine values (p = 0.001). An inverse tendency was observed after 2 years of SCIT, however. This second year of SCIT corresponded to the 2007 season, when a significantly higher number of days with at least 50 grains of pollen per 1 m(3) of air was recorded. CONCLUSIONS: FLUCTUATIONS IN POLLINATION INTENSITY OBSERVED DURING CONSECUTIVE YEARS OF IMMUNOTHERAPY CAN INFLUENCE BRONCHIAL REACTIVITY IN PATIENTS SUBJECTED TO SCIT (ISRCTN REGISTER: ISRCTN 86562422).

Airway responsiveness to inhaled aspirin is influenced by airway hyperresponsiveness in asthmatic patients.

BACKGROUND/AIMS: Many patients with aspirin-induced asthma have severe methacholine airway hyperresponsiveness (AHR), suggesting a relationship between aspirin and methacholine in airway response. This study was performed to determine whether methacholine AHR affects the response of asthmatics to inhaled aspirin. METHODS: The clinical records of 207 asthmatic patients who underwent inhalation challenges with both aspirin and methacholine were reviewed retrospectively. An oral aspirin challenge was performed in patients with a negative inhalation response. The bronchial reactivity index (BRindex) was calculated from the percent decrease in lung function divided by the last dose of the stimulus. RESULTS: Forty-one (20.9%) and 14 (7.1%) patients showed a positive response to aspirin following an inhalation and oral challenge, respectively. Only 24.3 and 14.3% of the responders had a history of aspirin intolerance, respectively. The methacholine BRindex was significantly higher in the inhalation responders (1.46 ± 0.02) than in the oral responders (1.36 ± 0.03, p < 0.01) and in non-responders (n = 141, 1.37 ± 0.01, p < 0.001). The aspirin BRindex was significantly correlated with the methacholine BRindex (r = 0.270, p < 0.001). Three of four patients who received the oral challenge, despite a positive inhalation test, showed negative responses to the oral challenge. Two of these patients had severe AHR. CONCLUSIONS: A considerable number of asthmatic patients with no history of aspirin intolerance responded to the inhalation aspirin challenge. The airway response to aspirin was significantly correlated with methacholine-AHR, and a false-positive response to aspirin inhalation test seemed to occur primarily in patients with severe AHR.

Airway Responsiveness to Inhaled Aspirin is Influenced by Airway Hyperresponsiveness in Asthmatic Patients

BACKGROUND/AIMS: Many patients with aspirin-induced asthma have severe methacholine airway hyperresponsiveness (AHR), suggesting a relationship between aspirin and methacholine in airway response. This study was performed to determine whether methacholine AHR affects the response of asthmatics to inhaled aspirin. METHODS: The clinical records of 207 asthmatic patients who underwent inhalation challenges with both aspirin and methacholine were reviewed retrospectively. An oral aspirin challenge was performed in patients with a negative inhalation response. The bronchial reactivity index (BRindex) was calculated from the percent decrease in lung function divided by the last dose of the stimulus. RESULTS: Forty-one (20.9%) and 14 (7.1%) patients showed a positive response to aspirin following an inhalation and oral challenge, respectively. Only 24.3 and 14.3% of the responders had a history of aspirin intolerance, respectively. The methacholine BRindex was significantly higher in the inhalation responders (1.46 +/- 0.02) than in the oral responders (1.36 +/- 0.03, p < 0.01) and in non-responders (n = 141, 1.37 +/- 0.01, p < 0.001). The aspirin BRindex was significantly correlated with the methacholine BRindex (r = 0.270, p < 0.001). Three of four patients who received the oral challenge, despite a positive inhalation test, showed negative responses to the oral challenge. Two of these patients had severe AHR. CONCLUSIONS: A considerable number of asthmatic patients with no history of aspirin intolerance responded to the inhalation aspirin challenge. The airway response to aspirin was significantly correlated with methacholine-AHR, and a false-positive response to aspirin inhalation test seemed to occur primarily in patients with severe AHR.

Controvérsias na associação entre diabetes mellitus tipo 1 e asma / Controversies in the association between type 1 diabetes and asthma

OBJETIVO: Revisão crítica da literatura sobre a associação entre asma e diabetes mellitus tipo 1 (DM1). FONTE DOS DADOS: Pesquisa bibliográfica na base de dados MEDLINE e LILACS nos últimos vinte anos. SíNTESE DOS DADOS: Muitos estudos mostram associação inversa entre asma, atopia e o risco de desenvolver DM1. De acordo com a "Hipótese da Higiene", o risco de doenças alérgicas diminui com infecções precoces na infância no sentido de afastar-se do perfil Th2, predominante ao nascimento, em direção ao fenótipo Th1. No entanto, outros trabalhos demonstram associação positiva ou ausência de associação entre DM1 e alergias. Existe a possibilidade de fatores ambientais contribuírem para ocorrência de doenças mediadas por células Th1 e Th2 no mesmo indivíduo, por provável deficiência de mecanismos imunomodulatórios mediados pela interleucina-10 e células regulatórias. CONCLUSÃO: As informações sobre a associação inversa entre doenças mediadas por resposta Th1 (por exemplo, DM1), e aquelas mediadas por resposta Th2 (por exemplo, alergias) são conflitantes, requerendo mais estudos para esclarecer esta questão.

OBJECTIVE: Critical review of the literature to investigate the relationship between asthma and type 1 diabetes mellitus (DM1). SOURCE OF DATA: Bibliography search in MEDLINE and LILACS databases in the last twenty years. SUMMARY OF DATA: Several studies demonstrate an inverse relationship between asthma, atopic diseases and the risk to develop DM1. According to the "Hygiene Hypothesis", the risk of allergic diseases decreases with infections early in childhood, towards distance of Th2 profile, common at birth, to the Th1 phenotype. Other articles described lack of association or positive association between DM1 and allergies. There is a possibility of environmental factors interfering in the development of disorders mediated by Th1 and Th2 cells, in the same individual, due to the absence of immunomodulatory mechanisms mediated by interleukin-10 and regulatory cells. CONCLUSION: The existing information about the inverse association between Th1-mediated diseases (e.g., DM1), and those that are Th2-mediated (e.g., allergies) are conflicting requiring more investigation to explain this question.

Clinical Impact of Bronchial Reactivity and Its Relationship with Changes of Pulmonary Function After Asthmatic Attack Induced by Methacholine / 결핵

BACKGROUND: Bronchial reactivity is known to be a component of airway hyperresponsiveness, a cardinal feature of asthma, with bronchial sensitivity, and is increments in response to induced doses of bronchoconstric tors as manifested by the steepest slope of the dose-response curve. However, there is some controversy regarding methods of measuring bronchial reactivity and clinical impact of such measurements. The purpose of this study was to evaluate the clinical significance and assess the clinical use by analyzing the relationship of the bronchial sensitivity, the clinical severity and the changes in pulmonary function with bronchial reactivity. METHOD: A total of 116 subjects underwent a methacholine bronchial provocation test. They were divided into 3 groups : mild intermittent, mild persistent, moderate and cough asthma. Severe patients were excluded. Methacholine PC20 was determined from the log dose-response curve and PC40 was determined by one more dose inhalation after PC20. The steepest slope of log dose-response curve, connecting PC20 with PC40, was used to calculate the bronchial reactivity. Body plethysmography and a single breath for the DLCO were done in 43 subjects before and after methacholine test. RESULTS: The average bronchial reactivity was 38.0 in the mild intermittent group, 49.8 in the mild persistent group, 61.0 in the moderate group, and 41.1 in the cough asthma group. There was a weak negative correlation between PC20 and bronchial reactivity. A heightened bronchial reactivity tends to produce an increased clinical severity in patients with a similar bronchial sensitivity and basal spirometric pulmonary function. There were significant correlations between the bronchial reactivity and the initial pulmonary function before the methacholine test in the order of sGaw, Raw, FEV1/FVC, MMFR. There were no correlations between the bronchial sensitivity and the % change in the pulmonary function parameters after the methacholine test. However, there were significant correlations between the bronchial reactivity and the PEF, FEV1, DLCO. CONCLUSION: There was weak significant negative correlation between the bronchial reactivity and the bronchial sensitivity, and the bronchial reactivity closely reflected the severity of the asthma. Accordingly, measuring both the bronchial sensitivity and the bronchial reactivity can be of assistance in assessing of the ongoing disease severity and in monitoring the effect of therapy.