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Biomedical subjects

P M O'Byrne

Publications and source records attributed to P M O'Byrne.

At least 19 recordsLinked to original sources
PubMed2006

Effects of inhaled ciclesonide on circulating T-helper type 1/T-helper type 2 cells in atopic asthmatics after allergen challenge.

BACKGROUND: The predominance of T-helper type 2 (Th2) lymphocytes is thought to underlie the pathogenesis of asthma. Allergen inhalation challenge in atopic asthmatic subjects is associated with decreased interferon-gamma (IFN-gamma) positive CD4+ and CD8+ lymphocytes in peripheral blood and induced sputum. OBJECTIVE: This study examined the effects of an inhaled corticosteroid on these previously described allergen-induced changes in circulating Th1 and Th2 lymphocytes. METHODS: Subjects were randomized to 7 days of placebo, 40 or 80 micro g ciclesonide in a crossover study. Airway responses and peripheral blood were measured before and after treatment, and 24 h after allergen challenge. RESULTS: Ciclesonide 40 and 80 micro g significantly attenuated the late response and sputum eosinophils at 8 h post-allergen (P<0.05). Circulating IFN-gamma positive CD4+ lymphocytes decreased after allergen challenge with placebo (P<0.05), and this was inhibited by 40 micro g ciclesonide treatment (P<0.05). There was no effect of allergen inhalation or ciclesonide on IL-4-positive CD4+ lymphocytes or IFN-gamma and IL-4-positive CD8(high) lymphocytes. The allergen-induced change of IFN-gamma/IL-4 ratio on CD4+ cells correlated with the allergen-induced change of peripheral blood eosinophils. CONCLUSIONS: The results of this study suggest that attenuation of allergen-induced airway responses by ciclesonide may be mediated through regulation of IFN-gamma-positive CD4+ cells.

Administration, Inhalation↗
PubMed2006

Effects of intranasal fluticasone and salmeterol on allergen-induced nasal responses.

BACKGROUND: Combination of inhaled steroid and long-acting beta-agonists has synergistic effects in asthma. OBJECTIVE: To investigate whether nasal corticosteroid and long-acting beta-agonists have synergistic effects on allergen-induced nasal responses. METHODS: The effects of intranasal treatment with fluticasone p-MDI (50 microg bid), salmeterol p-MDI (25 microg bid), their combination, and placebo, on nasal symptoms, eosinophil differential cell count and albumin in nasal lavage fluid (measures of inflammation and leakage respectively) and nasal electrical potential difference (measure of epithelial integrity) were studied in 11 atopic subjects with rhinitis, in a randomized, partially-blinded, 4-period, cross-over study. The measurements were made at baseline, at the end of 1 week of treatment, and immediately after a nasal allergen provocation. RESULTS: Allergen-induced sneeze, postnasal drip and nasal obstruction were significantly reduced by fluticasone, but not by salmeterol. Eosinophil count in postallergen nasal lavage fluid was significantly less after fluticasone (median 1.9%, IQR 4.6) and salmeterol treatment (median 2.5%, IQR 8.5) compared with placebo (median 12.5%, IQR 27.9). Compared with placebo, both fluticasone and salmeterol attenuated allergen-induced change in nasal potential (mean change from baseline -18.5, +0.4 and -7.2% respectively) and the increase in nasal albumin (median 154, 119 and 130 ng/ml respectively). Combination treatment did not have any additional benefits over the individual therapies. CONCLUSIONS: Although salmeterol has anti-inflammatory properties, intranasal salmeterol or its combination with fluticasone do not offer any added benefit over intranasal fluticasone alone for allergen-induced nasal responses.

Administration, Inhalation↗
PubMed2006

Anti-inflammatory effects of once daily low dose inhaled ciclesonide in mild to moderate asthmatic patients.

BACKGROUND: Ciclesonide exhibits clinical efficacy at 160 microg (ex-actuator) once daily but the anti-inflammatory effects at this dose are not known. We wished to know whether 4 weeks therapy with ciclesonide pMDI 160 microg once daily in the morning exhibited significant anti-inflammatory effects. METHODS: Seventeen patients with mild persistent asthma (FEV(1) 3.35 l) were recruited into a double-blind placebo-controlled randomized crossover study. Measurements were made after ciclesonide and placebo treatment as well as after run-in and washout periods, for adenosine monophosphate (AMP) bronchial challenge (primary variable), exhaled nitric oxide (NO) and induced sputum (in a subgroup). RESULTS: The mean (SEM) AMP bronchial challenge PC(20) following ciclesonide (140 (63) mg/ml) was significantly (P < 0.001) increased compared with placebo (17 (8) mg/ml), run-in (13 (5) mg/ml) and washout (9 (3) mg/ml) periods. This amounted to an eightfold (CI: 5.3-12.0) for ciclesonide vs placebo. Likewise, there were significant improvements in exhaled NO levels and a significant reduction in induced sputum eosinophil cell counts. CONCLUSION: We have shown that inhaled ciclesonide given at 160 microg once daily in the morning exhibits significant anti-inflammatory effects that are in keeping with the previously described clinical effects.

Administration, Inhalation↗
PubMed2005

The links between allergen skin test sensitivity, airway responsiveness and airway response to allergen.

BACKGROUND: The allergen-induced early asthmatic response [provocation concentration (PC)20, the concentration causing a 20% forced expiratory volume in 1 s (FEV)1 fall] depends on the level of IgE sensitivity and the degree of nonallergic airway hyperresponsiveness (AHR) and can be predicted from histamine PC20 and allergen skin test endpoint. OBJECTIVES: We examined the relationships between allergen PC20, methacholine PC20, and allergen skin test endpoint and assessed the accuracy of both the histamine PC20-based prediction of allergen PC20 (using methacholine) and a new methacholine PC20-based prediction equation. METHODS: From 158 allergen challenges, the allergen PC20, the methacholine PC20, and the skin test endpoint were recorded and relationships between these three were sought. We compared the measured allergen PC20 to that predicted from the previous histamine PC20-based and the new methacholine-based formulae. RESULTS: In single regressions, allergen PC20 correlated with both methacholine PC20 (r=0.25, P=0.0015) and skin test endpoint (r=0.52, P <0.00005). The relationship was improved by multiple regression of log-allergen PC20vs. log-methacholine PC20 and log-endpoint (r=0.61, P <0.00005). The histamine-based formula predicted allergen PC20 to within 2 doubling concentrations in 80% and within 3 in 92%. The new methacholine-based formula to within 2 and 3 concentrations in 81% and 94%, respectively; only nine of 158 subjects were outside the 3 concentrations. CONCLUSIONS: We have confirmed the dependence of the allergen-induced early asthmatic response upon the level of allergic sensitivity and the degree of AHR, the latter as assessed by methacholine challenge. The allergen PC20 can be predicted to within 3 doubling concentrations in 94% of cases.

Adult↗
PubMed2004

Relationship between quality of life and clinical status in asthma: a factor analysis.

Many studies have shown that correlation between clinical asthma status and asthma-specific quality of life is only weak to moderate. However, this relationship has never been explored to determine whether the weakness is due to noise of measurement or whether quality of life is a distinct component of asthma health status. With a database from three clinical trials (n = 763), factor analysis was used to explore the relationships between quality of life, measured by the Asthma Quality of Life Questionnaire (AQLQ), and conventional measures of asthma clinical status (symptoms, airway calibre and rescue beta2-agonist use). The analysis revealed that although patients with severe, poorly controlled asthma tend to have worse quality of life than milder, well-controlled patients, overall asthma health status has four components (factors): asthma-specific quality of life; airway calibre; daytime symptoms and daytime beta2-agonist use, and night-time symptoms and night-time beta2-agonist use. The clean loading of all 21 outcomes onto four distinct and clinically identifiable factors suggests that, although some weakness of correlation between clinical indices and quality of life may be due to noise of measurement, it is mainly attributable to asthma health status being composed of distinct components.

Activities of Daily Living↗
PubMed2004

Extracellular matrix regulates human airway smooth muscle cell migration.

Extracellular matrix proteins regulate the survival and proliferation of smooth muscle cells. Their effect on airway smooth muscle cell migration is not known. Their role in leukotriene-primed (0.1 microM leukotriene E4) chemotaxis of cultured human airway smooth muscle cells towards platelet-derived growth factor BB (1 ng.mL(-1)) was investigated. Migration of cells was greater on membranes coated with collagens III and V and fibronectin compared to collagen I, elastin and laminin (all 10 microg.mL(-1)). Concentration-dependent promotion of migration was observed on collagen I (1,000>10 microg.mL(-1)), which was associated with increased phosphorylation of Src kinase. This was not observed on laminin or elastin. The role of Src kinase was further confirmed by demonstrating that its inhibitor, PP1 analogue (1 microM), inhibited chemotaxis. Collagen I itself was not a chemoattractant; however, haptokinesis was observed when cells were primed with leukotriene E4, and haptotaxis when cells were primed with platelet-derived growth factor. The priming effect of leukotrienes on chemotaxis was not elicited by promoting adhesion, increasing surface expression of beta1, alphav and alpha5 integrin, or Src kinase phosphorylation. These experiments demonstrate that the extracellular matrix, along with growth factors and cysteinyl leukotrienes, can regulate human airway smooth muscle cell migration. This may be relevant in the remodelling process in chronic airway diseases, such as asthma.

Bronchi↗
PubMed2002

The promise of and problems with evidence-based medicine for paediatric asthma management.

The concept of 'evidence-based medicine' has now been in widespread use in clinical practice for over a decade. There are different types of clinical study, which may provide evidence on which to base clinical decisions, but some are much less robust than others. In making decisions about treatment, one of the highest levels of evidence in primary research is the randomized controlled trial. This study design has been used in clinical research for over 50 years. Systematic reviews of randomized controlled trial are scientific studies that review, critically appraise and, where appropriate, aggregate results from a number of different randomized controlled trials. They are increasingly being used throughout health care to provide guidance about treatment. Under the auspices of The Cochrane Collaboration, systematic reviews of randomized controlled trials are being conducted across the whole of health care. One of the most active areas for this work is within the field of asthma and clinicians are now able to access a large number of different systematic reviews on The Cochrane Library. If used appropriately, they can aid the clinician in making decisions about individual patients and provide a sound evidence base from which clinical guidelines can be developed.

Asthma↗
PubMed2002

Rapid response of circulating myeloid dendritic cells to inhaled allergen in asthmatic subjects.

BACKGROUND: Dendritic cells (DC) are thought to play a key role in the initiation and maintenance of T cell immunity to inhaled antigens. While the density of DC within the bronchial mucosa is increased in stable asthma, there is little information currently available concerning the effects of allergen inhalation on DC in subjects with asthma. OBJECTIVES: To enumerate changes in the numbers of circulating CD33(+) myeloid DC in asthmatics, before and after allergen challenge. METHODS: Blood DC numbers were enumerated by flow cytometry before and at 3, 6 and 24 h after inhaled allergen and diluent in 10 mild, allergic asthmatic subjects. RESULTS: Blood DC numbers rapidly fell from 3.42 +/- 0.30 x 10(7)/L at baseline, to 2.10 +/- 0.17 x 10(7)/L by 3 h post-challenge (P < 0.01), and remained significantly below baseline values at both 6 and 24 h following allergen challenge. No such changes in DC numbers were noted after diluent challenge. A similar, early fall in circulating lymphocytes was also noted post-allergen challenge, whereas changes in circulating eosinophil and neutrophil numbers occurred more slowly. CONCLUSIONS: A significant proportion of myeloid DC rapidly 'disappear' from the circulation following allergen inhalation, suggesting that margination of circulating myeloid DC, and their recruitment into the airway mucosa, is an important feature of the immune response to inhaled allergen.

Administration, Inhalation↗
PubMed2002

Distribution of intranasal instillations in mice: effects of volume, time, body position, and anesthesia.

Intranasal instillation techniques are used to deliver various substances to the upper and lower respiratory tract (URT and LRT) in mice. Here, we quantify the relative distribution achieved with intranasal delivery of a nonabsorbable tracer, (99m)Tc-labeled sulfide-colloid. Relative distribution was determined by killing mice after instillation and quantifying the radioactivity in dissected tissues using gamma scintigraphy. A significant effect of delivery volume on relative distribution was observed when animals were killed 5 min after instillation delivered under gas anesthesia. With a delivery volume of 5 microl, no radiation was detected in the LRT; this increased to a maximum of 55.7 +/- 2.5% distribution to the LRT when 50 microl were delivered. The majority of radiation not detected in the LRT was found in the URT. Over the course of the following 1 h, radiation in the LRT remained constant, while that in the URT decreased and appeared in the gastrointestinal tract. Instillation of 25 microl into anesthetized mice resulted in 30.1 +/- 6.9% distribution to the LRT, while only 5.3 +/- 1.5% (P < 0.05) of the same volume was detected in the LRT of awake mice. Varying the body position of mice did not affect relative distribution. When using intranasal instillation, the relative distribution between the URT and LRT and the gastrointestinal tract is heavily influenced by delivery volume and level of anesthesia.

Administration, Intranasal↗
PubMed2001

Inhaled leukotriene E(4), but not leukotriene D(4), increased airway inflammatory cells in subjects with atopic asthma.

Allergen-induced late airway responses are associated with increased numbers of airway eosinophils and basophils. The purpose of this study was to compare and contrast the effects of inhaled cysteinyl leukotrienes LTD(4) and LTE(4), which are released during allergen- induced airway responses, and allergen, on airway inflammatory cells. Fifteen subjects with atopic, mild asthma inhaled diluent, LTD(4), LTE(4), and allergen. Spirometry was performed for 7 h, and sputum inflammatory cells were measured before, 7 h, and 24 h after challenges. The maximum early percent fall in FEV(1) was 23.6 +/- 1.4%, 21.6 +/- 2.3%, 29.3 +/- 2.4%, and 4.0 +/- 1.1% after LTD(4), LTE(4), allergen, and diluent, respectively. Only inhaled LTE(4) and allergen significantly increased sputum eosinophils at 7 h and 24 h, and sputum basophils at 7 h. Six additional subjects underwent airway biopsies 4 h after inhalation. There were significantly more eosinophils in the lamina propria after inhalation of LTE(4) compared with LTD(4) and diluent (p < 0.05). These results suggest cysteinyl leukotrienes play a role in eosinophil migration into the airways in allergic asthma, and for the same degree of bronchoconstriction, inhaled LTE(4) causes more tissue and airway eosinophilia than LTD(4).

Administration, Inhalation↗
PubMed2001

Low dose inhaled budesonide and formoterol in mild persistent asthma: the OPTIMA randomized trial.

The optimal treatment for mild asthma is uncertain. We assessed the effects of adding a long-acting inhaled beta-agonist, formoterol, to low doses of an inhaled corticosteroid, budesonide, for 1 yr in subjects with mild asthma, receiving no or only a small dose of inhaled corticosteroid. The 698 corticosteroid free patients (Group A) were assigned to twice daily treatment with 100 microg budesonide, 100 microg budesonide plus 4.5 microg formoterol, or placebo. The 1,272 corticosteroid-treated patients (Group B) were assigned to twice daily treatment with 100 microg budesonide, 100 microg budesonide plus 4.5 microg formoterol, 200 microg budesonide, or 200 microg budesonide plus 4.5 microg formoterol. The main outcome variables were time to the first severe asthma exacerbation and poorly controlled asthma days. In Group A, budesonide alone reduced the risk for severe exacerbations by 60% and poorly controlled days by 48%; adding formoterol increased lung function with no change in other end points. By contrast, in Group B, adding formoterol reduced the risk for the first severe exacerbation and for poorly controlled days by 43 and 30%, respectively. Thus, in corticosteroid-free patients, low dose inhaled budesonide alone reduced severe exacerbations and improved asthma control, and in patients already receiving inhaled corticosteroid, adding formoterol was more effective than doubling the corticosteroid dose.

Administration, Inhalation↗
PubMed2001

Dose-dependent effects of inhaled mometasone furoate on airway function and inflammation after allergen inhalation challenge.

Comparisons of the potency of different inhaled corticosteroids, delivery devices, and treatment regimens in the management of asthma can only be made when outcome measurements display a dose-dependent effect. These outcomes have been difficult to identify. In this study, we compared in a randomized, double-blind, crossover design, the effects of 6 d treatment with placebo and three doses (50, 100, and 400 microg, twice daily) of mometasone furoate delivered by dry powder inhaler (MF-DPI) on responses after allergen inhalation challenge. Twelve mild asthmatic subjects with dual responses after allergen inhalation were studied. Outcome measurements included early and late asthmatic responses, the change in methacholine airway responsiveness 24 h after challenge, and sputum eosinophilia measured 7 and 24 h after challenge. All three doses of MF-DPI demonstrated similar attenuation of early responses and allergen-induced airway hyperresponsiveness relative to placebo (p < 0.05). The late maximal %fall in FEV(1) after placebo treatment was 23.5% and was significantly reduced in a dose-dependent manner to 12.3%, 11.0%, and 5.9% for the 50-, 100-, and 400-microg twice-daily treatments (p = 0.007). The allergen-induced increase in sputum eosinophilia (x10(4) cells/ml) 24 h after challenge during placebo treatment was 60.2 and was significantly reduced to 24.0, 15.3, and 6.2 for the 50-, 100-, and 400-microg twice-daily treatments. MF-DPI is effective at attenuating allergen-induced early and late responses, airway hyperresponsiveness, and sputum eosinophilia, and dose-response effects exist for the attenuation of the late response.

Administration, Inhalation↗
PubMed2001

Th type 1-stimulating activity of lung macrophages inhibits Th2-mediated allergic airway inflammation by an IFN-gamma-dependent mechanism.

In the mucosal immune system, resident dendritic cells are specialized for priming Th2-polarized immunity, whereas the Ag-presenting activity of macrophages has been linked with the development of Th1 phenotype. As an immune switch toward Th1 can protect against Th2-mediated allergic response, this study investigated the capacity of lung macrophages to stimulate Th1 responses during the secondary exposure to inhaled allergen, thereby suppressing Th2-mediated allergic airway inflammation in a murine model of allergic asthma. Following airway macrophage depletion in OVA-sensitized mice, lung T cells defaulted to a phenotype that produced less Th1 (IFN-gamma) and more Th2 (IL-4 and IL-5) cytokines, leading to more severe airway hyperreactivity and inflammation after intranasal Ag challenge. After OVA pulsing and adoptive transfer, lung macrophages selectively promoted a Th1 response in Ag-sensitized recipients and did not induce pulmonary eosinophilia. By contrast, OVA pulsing and adoptive transfer of a lung cell preparation, consisting of dendritic cells, B cells, and macrophages, promoted a Th2 response with an associated inflammatory response that was suppressed when macrophages were present and pretreated with IFN-gamma, but exacerbated when macrophages were depleted before IFN-gamma treatment. In addition, Th1-promoting activity of lung macrophages was not related to the autocrine production of IL-12p40. These results suggest that the Th1-promoting APC activity may be an inherent property of the lung macrophage population, and may play an important role, upon stimulation by IFN-gamma, in antagonizing an ongoing Th2 immunity and Th2-dependent allergic responses.

Administration, Intranasal↗
PubMed2001

The inhaled Steroid Treatment as Regular Therapy in early asthma (START) study: rationale and design.

Although the beneficial effects of treatment with inhaled steroids in asthma are widely accepted, the role of early intervention in patients with mild asthma remains unsettled. Conventional efficacy trials are often of short duration and involve highly selected patient populations that exclude many patients typical of those encountered in routine clinical practice. Hence, a large "real-world" effectiveness study is needed to evaluate the benefits of early intervention with inhaled steroids in patients with mild, persistent asthma. In the START (inhaled Steroid Treatment As Regular Therapy in early asthma) study, patients ages 6-60 years, from 31 countries and districts worldwide with mild persistent asthma, have been randomized to once-daily treatment with budesonide, 200 microg (for patients < 11 years) or 400 microg (for patients > or = 11 years), or placebo via Turbuhaler for 3 years. The double-blind treatment period will be followed by a 2-year period of open budesonide treatment. Throughout the study, other asthma medication including glucocorticosteroids can be given as judged appropriate by the investigator. Lung function will be measured by spirometry using standardized techniques at 3-month intervals throughout the study, and bronchodilator reversibility will be measured annually. The primary outcome measures are the time to the first severe asthma-related event during the first 3 years of the study and the change in postbronchodilator forced expiratory volume in 1 second (FEV(1)) from baseline during the entire 5-year study period. These measures have been chosen to reflect the progression of mild asthma toward more severe asthma and the extent of irreversible airflow limitation, which should reflect the degree of airway remodeling.

Acute Disease↗
PubMed2001

Measuring asthma control in group studies: do we need airway calibre and rescue beta2-agonist use?

Collection of airway calibre and beta2-agonist data in large clinical trials and epidemiological surveys is sometimes difficult and may be an inefficient use of resources. The aim of this study was to determine whether the omission of the forced expiratory volume in 1 sec (FEV1) and beta2-agonist questions from the seven-item Asthma Control Questionnaire (ACQ) alters its measurement properties and validity. In an observational study, 50 adults with symptomatic asthma attended the clinic at 0, 1, 5 and 9 weeks to complete the ACQ and other measures of asthma status. All patients completed the study and provided complete data sets. Omission of the FEV1 and beta2-agonist questions from the ACQ made minimal difference to the reliability, responsiveness, and both cross-sectional and longitudinal validity of the instrument. Omission of the FEV1 question significantly lowered the summary score (P<0.001) but omission of the beta2-agonist question did not alter it (P>0.05). In group studies, both the FEV1 and beta2-agonist questions may be omitted from the ACQ without changing the validity or the measurement properties of the instrument. Lowering of the summary score by the omission of the FEV1 question means that data from this abbreviated form cannot be combined with or compared to data collected using the full questionnaire.

Adolescent↗
PubMed2001

Adding formoterol to budesonide in moderate asthma--health economic results from the FACET study.

The FACET (Formoterol and Corticosteroid Establishing Therapy) study established that there is a clear clinical benefit in adding formoterol to budesonide therapy in patients who have persistent symptoms of asthma despite treatment with low to moderate doses of an inhaled corticosteroid. We combined the clinical results from the FACET study with an expert survey on average resource use in connection with mild and severe asthma exacerbations in the U.K., Sweden and Spain. The primary objective of this study was to assess the health economics of adding the inhaled long-acting beta2-agonist formoterol to the inhaled corticosteroid budesonide in the treatment of asthma. The extra costs of adding the inhaled beta2-agonist formoterol to the corticosteroid budesonide in asthmatic patients in Sweden were offset by savings from reduced use of resources for exacerbations. For Spain the picture was mixed. Adding formoterol to low dose budesonide generated savings, whereas for moderate doses of budesonide about 75% of the extra formoterol costs could be recouped. In the U.K., other savings offset about half of the extra cost of formoterol. All cost-effectiveness ratios are within accepted cost-effectiveness ranges reported from previous studies. If productivity losses were included, there were net savings in all three countries, ranging from Euro 267-1183 per patient per year. In conclusion, adding the inhaled, long-acting beta2-agonist formoterol to low-moderate doses of the inhaled corticosteroid budesonide generated significant gains in all outcome measures with partial or complete offset of costs. Adding formoterol to budesonide can thus be considered to be cost-effective.

Acute Disease↗
PubMed2001

The trials and tribulations of IL-5, eosinophils, and allergic asthma.

Eosinophils have been suggested to be part of the pathologic process that characterizes asthma, and their recruitment into the upper or lower airways appears to be essential for the clinical manifestations of allergen inhalation. IL-5 is a cytokine necessary for the development, differentiation, recruitment, activation, and survival of eosinophils. Allergen inhalation increases the production of IL-5 in the airways as measured in bronchoalveolar lavage cells and induced sputum. The relationship between IL-5 and the development of airway eosinophilia has been firmly established in IL-5 transgenic mice, with allergen challenge models in IL-5-deficient mice, and in mice treated with blocking anti-IL-5 antibodies. In addition, an accumulation of evidence suggests that treating mice with anti-IL-5 blocking antibodies prevents allergen-induced airway hyperresponsiveness. A recently reported study examined the effects of treatment with a humanized anti-IL-5 mAb (SB-240563) on allergen-induced airway responses and inflammation in atopic subjects. The authors of the study concluded that their results call into question the role of eosinophils in mediating the allergen-induced late asthmatic response and airway hyperresponsiveness; however, because of methodologic limitations, the study cannot be used either to support or to refute the concept of an important role for eosinophils in causing allergen-induced changes in airway function.

Animals↗