The CONCEPT trial: a 1-year, multicenter, randomized,double-blind, double-dummy comparison of a stable dosing regimen of salmeterol/fluticasone propionate with an adjustable maintenance dosing regimen of formoterol/budesonide in adults with persistent asthma.

Follows RM.

Respiratory Division, Vancouver General Hospital, Vancouver, BC, Canada. markf interchange.ubc.ca

BACKGROUND: A patient-driven, adjustable maintenance dosing (AMD) approach to asthma therapy, in which the dose is adjusted by patients according to the severity of their symptoms, has recently been compared with fixed-dose therapy in open-label studies. OBJECTIVE: This study used a double-blind, double-dummy design to compare the efficacy of 2 treatment approaches: stable dosing of salmeterol/fluticasone propionate (SAL/FP) and AMD of formoterol/budesonide (FOR/BUD). METHODS: This was a 1-year, multicenter, randomized, double-blind, double-dummy study in adult patients with symptomatic asthma that was not controlled by therapy with 200 to 500 microg/d inhaled corticosteroid (ICS) plus a long-acting beta2 agonist, or with >500 to 1000 microg/d ICS alone. Patients were randomized to receive 1 inhalation of SAL/FP 50/250 microg BID or 2 inhalations of FOR/BUD 6/200 microg BID, both delivered via dry powder inhaler devices. After 4 weeks of stable dosing in both groups, eligible patients continued the study for an additional 48 weeks, receiving either a stable dose of SAL/FP or AMD of FOR/BUD. According to the AMD treatment plan, patients initially halved their dose and subsequently stepped up or down as indicated by the presence or absence of nocturnal awakenings due to asthma, frequency of rescue medication use, and changes in morning peak expiratory flow (PEF). The primary end point was the percentage of symptom-free days. Other parameters included daily asthma symptom scores, morning PEF, percentage of days free of rescue medication use, daily rescue medication use, percentage of nighttime awakenings due to asthma, percentage of weeks with well-controlled asthma, and number of exacerbations requiring oral corticosteroids or emergency department (ED) visits/hospitalizations. Tolerability was assessed in terms of adverse events spontaneously reported or elicited at clinic visits. RESULTS: The intent-to-treat population comprised 688 patients (344 per treatment arm) with a mean age of 45 years and a mean baseline forced expiratory volume in 1 second 81% of the predicted normal value. After 4 weeks' stable dosing, 581 patients (295 SAL/FP, 286 FOR/BUD) continued beyond visit 3 into the remaining 48-week treatment period. Over weeks 1 through 52, patients receiving stable dosing of SAL/FP had a significantly greater percentage of symptom-free days compared with those receiving AMD of FOR/BUD (median, 58.8% vs 52.1%, respectively; P = 0.034). The incidence of asthma exacerbations requiring oral steroids or an ED visit/hospitalization was 47% lower with SAL/FP compared with FOR/BUD (adjusted annual mean rate, 0.18 vs 0.33; P = 0.008). During weeks 5 through 52, patients in the FOR/BUD AMD group used a mean of 1.8 inhalations/d (equivalent to BUD 360 microg/d), and 235 (82.2%) patients stepped down to 1 inhalation/d. Mean (SD) daily ICS exposure over 52 weeks was 463 (81) microg FP and 480 (238) microg BUD in the respective treatment arms. CONCLUSIONS: In this adult population with persistent asthma, stable dosing of SAL/FP 50/250 microg BID resulted in significantly greater increases in symptom-free days, days free of rescue medication, and morning PEE, as well as almost halving the exacerbation rate, compared with AMD of FOR/BUD 6/200 microg. The results suggest that there is a minimum daily amount of maintenance therapy necessary to prevent exacerbations in adults with persistent asthma.

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Endotoxin exposure in asthmatic children and matched healthy controls: results of IPEADAM study.

Niven RM.

North West Lung Centre, Wythenshawe Hospital, Manchester M23 9LT, UK. gael tavernier.info

Children spend increasing time indoors. Exposure to environmental factors may contribute to the development or exacerbation of the asthmatic phenotype. Inter-relationships between these factors might influence the manifestation of asthma. Endotoxin exposure has been shown to have pro-inflammatory and protective effects in different situations. We investigated the exposure to several indoor pollutants (endotoxin, Der p 1, damp, ETS, PM2.5) in asthmatic and healthy children. The children were recruited from two primary care centers according to their response to a validated questionnaire. Asthmatic children were matched for sex, age and sib-ship size with children living in asthma free households. Of 90 matched pairs, higher levels of endotoxin were found in the living room carpets, but not the bedroom carpet or mattresses of the asthma compared with the control homes (STATA analysis OR: 1.88 (1.11-3.18); P=0.018). Asthmatic children were also more likely to live as part of a single parent family, in a house where the parents self-reported the presence of damp, and where the living room had been redecorated in the 12 months prior to the sampling visits. This study suggests that endotoxin in urban homes is a risk factor for the development of asthma. Moreover, this study found that there were no statistically significant interactions between environmental factors. PRACTICAL IMPLICATIONS: This study has demonstrated that the home environments of English children (4-17) with asthma and without the disease do not differ greatly. With the exception of endotoxin, the parameters examined in this study, including house dust mite allergens, nitrogen dioxide, ETS and damp are unlikely to be related to the development of asthma. Avoidance of these pollutants may not be beneficial in preventing asthma in this age group.

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A systematic review to examine the impact of psycho-educational interventions on health outcomes and costs in adults and children with difficult asthma.

Harvey I.

School of Medicine, Health Policy and Practice, University of East Anglia, Norwich, UK.

OBJECTIVES: Prior research has highlighted the importance of psychosocial factors in 'difficult' asthma. This study aimed to review the content, effectiveness and cost-effectiveness of psycho-educational interventions designed to address these factors in patients with severe and difficult asthma. DATA SOURCES: Thirty-two electronic databases and other sources were searched for studies of educational, self-management, psychosocial and multifaceted interventions. REVIEW METHODS: Abstracts were screened in duplicate, against prior definitions, to identify eligible interventions targeted to patients with forms of or risk factors for difficult asthma. Studies were classified by patient group (child, adult) and graded along two dimensions related to study design and relevance in terms of the degree to which they were judged to have targeted difficult asthma. Detailed data were extracted from studies meeting a minimum design and relevance threshold. Characteristics of studies were tabulated and results qualitatively synthesised. Where sufficiently similar studies reported adequate data about comparable outcomes, quantitative syntheses of results were undertaken using a random effects approach to calculate pooled relative risks (RR) or standardised mean differences (SMD), with 95% confidence intervals (CI). RESULTS: Searches identified over 23,000 citations. After initial screening and removal of duplicates, 4240 possibly relevant abstracts were assessed. Papers associated with 188 studies were initially obtained and classified. Fifty-seven studies including control groups and those that were judged to have at least 'possible' targeting of difficult asthma (35 in children, 21 in adults, 1 in both) were selected for in-depth review. The delivery, setting, timing and content of interventions varied considerably even within broad types. Reporting of interventions and methodological quality was often poor, but studies demonstrated some success in targeting and following up at-risk patients. Studies reporting data suitable for calculation of summary statistics were of higher quality than those that did not. There was evidence from these that, compared to usual or non-psycho-educational care, psycho-educational interventions reduced admissions when data from the latest follow-ups reported were pooled across nine studies in children (RR = 0.64, CI = 0.46-0.89) and six studies with possible targeting of difficult asthma in adults (RR = 0.57, CI = 0.34-0.93). In children, the greatest and only significant effects were confined to individual studies with limited targeting of difficult asthma and no long-term follow-up. Limited data in adults also suggested effects may not extend to those most at risk. There was no evidence of pooled effects of psycho-educational interventions on emergency attendances from eight studies in children (RR = 0.97, CI = 0.78-1.21) and four in adults (RR = 1.03, CI = 0.82-1.29). There were overall significant reductions in symptoms, similar in different sub-groups of difficult asthma, across four paediatric studies that could be combined (SMD = -0.45, CI = -0.68 to -0.22), but mixed results across individual adult studies. A few individual studies in children showed mainly positive effects on measures of self-care behaviour, but with respect to all other outcomes in adults and children, studies showed mixed results or suggested limited effectiveness of psycho-educational interventions. No studies of psychosocial interventions were included in any quantitative syntheses and it was not possible to draw clear conclusions regarding the relative effectiveness of educational, self-management and multifaceted programmes. Data on costs were very limited. Of the two well-designed economic evaluations identified, both of multifaceted interventions, one in children suggested an additional cost of achieving health gain in terms of symptom-free days. Provisional data from the other study suggested that in adults the significantly increased costs of providing an intervention were not offset by any short-term savings in use of healthcare resources or associated with improvements in health outcomes. CONCLUSIONS: There was some evidence of overall positive effects of psycho-educational interventions on hospital admissions in adults and children, and on symptoms in children, but limited evidence of effects on other outcomes. The majority of research and greatest effects, especially in adults, were confined to patients with severe disease but who lacked other characteristics indicative of difficult asthma or likely to put them at risk. A lack of good-quality research limited conclusions about cost-effectiveness. Although psycho-educational interventions may be of some benefit to patients with severe disease, there is currently a lack of evidence to warrant significant changes in clinical practice with regard to the care of patients with more difficult asthma. Further research is needed to: (1) standardise reporting of complex interventions; (2) extend and update this review; (3) improve identification of patients at risk from their asthma; (4) develop and test appropriate outcome measures for this group; and (5) design and evaluate, via the conduct of high-quality pragmatic RCTs, more powerful psycho-educational interventions that are conceptualised in terms of the ways in which psychosocial factors and asthma interact.

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Categorizing Asthma Severity: An Overview of National Guidelines.

Colice GL.

Pulmonary, Critical Care and Respiratory Services, Washington Hospital Center, and The George Washington University School of Medicine, Washington, District of Columbia.

Asthma is an inflammatory disease of the airways associated with intermittent episodes of bronchospasm. Corticosteroids are the most effective anti-inflammatory class of medication currently available for the treatment of asthma. However, as higher doses of inhaled corticosteroids are used the risks of systemic exposure and side effects will correspondingly increase. Justification of the benefits from higher doses of inhaled corticosteroids can only be made if patients with more severe asthma can be identified. Methods to categorize asthma severity have been introduced in various national asthma management guidelines. Unfortunately, there are substantial conceptual and practical differences among these recommended approaches to asthma severity categorization. Furthermore, these recommended approaches suffer from a focus on features of asthma control, such as symptoms, short-acting beta-agonist use, and lung function rather than actual measures of asthma severity that would encompass markers of airway inflammation. Without the endpoints necessary to assess airway inflammation, current recommendations for asthma severity categorization may lead to systematic under dosing of appropriate anti-inflammatory therapy with subsequent perpetuation of the asthma exacerbation cycle.

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Paternal History of Asthma and Airway Responsiveness in Children with Asthma.

Weiss ST.

Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.

Rationale: Little is known regarding the relationship between parental history of asthma and subsequent airway hyperresponsiveness (AHR) in children with asthma. Objectives: We evaluated this relationship in 1,041 asthmatic children participating in a randomized trial of anti-inflammatory medications (the Childhood Asthma Management Program [CAMP]). Methods: Methacholine challenge testing was performed prior to treatment randomization and once per year over an average of 4.5 years post-randomization. Crosssectional and longitudinal repeated measures analyses were performed to model the relationship between PC20 (the methacholine concentration causing a 20% fall in forced expiratory volume in one second) with maternal, paternal and joint parental histories of asthma. Models were adjusted for potential confounders. Measurements and Main Results: At baseline, AHR was strongly associated with a paternal history of asthma. Children with a paternal history of asthma demonstrated significantly greater AHR than those without such history (median logePC20=0.84 vs. 1.13, p=.006). Although maternal history of asthma was not associated with AHR, children with two asthmatic parents had greater AHR than those with no asthmatic parents (median logePC20=0.52 vs. 1.17, p=.0008). Longitudinal multivariate analysis of the relation between paternal history of asthma and AHR using repeated PC20 measurements over 44 months post-randomization confirmed a significant association between paternal history of asthma and AHR among children in CAMP. Conclusions: Our findings suggest that the genetic contribution of the father is associated with AHR, an important determinant of disease severity among children with asthma.

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Childhood asthma: exhaled markers of airway inflammation, asthma control score, and lung function tests.

Jobsis Q.

Department of Pediatric Pulmonology, University Hospital Maastricht, The Netherlands. p.rosias orbisconcern.nl

Exhaled markers of airway inflammation become increasingly important in the management of childhood asthma. The aims of the present study are: 1) to compare exhaled markers of inflammation (nitric oxide, carbon monoxide, and acidity of breath condensate) with conventional asthma measures (lung function tests and asthma control score) in childhood asthma; and 2) to investigate the detectability of albumin, CRP, IL-6, IL-8, TNF-alpha, sICAM-1, and sTNF-R75 in the exhaled breath condensate (EBC) of asthmatic children. Thirty-two children with mild to moderate persistent asthma and healthy controls aged 6-12 years were studied. We measured exhaled NO and CO, and subsequently EBC was collected. Inflammatory mediators in EBC were measured using an enzyme-linked immunosorbent assay. Respiratory symptoms and asthma control were assessed using the asthma control questionnaire (ACQ) of Juniper et al. (Eur Respir J 1999;14:902-907). Exhaled NO showed a significant correlation with exhaled CO (r = 0.59, P < 0.05) and FEV1 (r = -0.59, P < 0.05), but not with ACQ score (r = 0.48, P = 0.06). Exhaled CO was correlated with prebronchodilator FEV1 (r = -0.45, P < 0.05), but not with asthma control (r = 0.18, P = 0.35). Acidity of EBC was significantly lower in asthmatic children than in healthy controls (P < 0.05), but did not correlate with any of the conventional asthma measures. We were not able to demonstrate the presence of CRP, IL-6, IL-8, TNF-alpha, sICAM-1, and sTNF-R75 in EBC. Albumin was found in two EBC samples of asthmatic children. We conclude that exhaled NO had a better correlation with lung function parameters and asthma control than exhaled CO and acidity of EBC, in mild to moderate persistent childhood asthma. However, exhaled NO, CO, and deaerated pH of EBC did not differ between asthmatic children and controls, possibly because of a too homogeneous and well-controlled study population. To further evaluate the clinical utility of exhaled markers in monitoring childhood asthma, more studies are required on a wider range of asthma severity, and preferably with repeated measurements of markers and of asthma control. Copyright 2004 Wiley-Liss, Inc.

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Genome screen for asthma and bronchial hyperresponsiveness: interactions with passive smoke exposure.

Bleecker ER.

Center for Human Genomics, Department of Pediatrics, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA. dmeyers wfubmc.edu

BACKGROUND: Asthma is a common respiratory disease caused by the interaction of genetic susceptibility and exposure to various environmental factors. Passive smoke exposure, characterized by parental smoking, has been shown to be a risk factor for the development of atopy and asthma. OBJECTIVE: We sought to perform a genome-wide linkage screen for asthma and bronchial hyperresponsiveness (BHR) and to determine the influence of passive tobacco smoke exposure during childhood on the results of genetic linkage studies to investigate gene-environment interactions. METHODS: A genome-wide linkage screen for asthma and BHR was performed in 200 families ascertained through a parent with asthma. Analyses were performed separately for the entire sample and for the smoking-exposed and nonexposed families. RESULTS: For asthma and BHR, the strongest evidence for linkage was observed for chromosomes 3p and 5q. The families in which the children were exposed to passive smoking accounted for the evidence for linkage of BHR to 5q ( P < .001), but evidence for linkage to 3p was found in both sets of families. Similar results were observed for asthma. However, there was no observed difference in the frequency of asthma or BHR in the offspring from the smoke-exposed compared with the nonexposed families. CONCLUSION: The results from this study demonstrate that the influence of susceptibility genes for a common disease such as asthma might not be apparent unless there is the appropriate exposure to environmental stimuli, such as passive exposure to cigarette smoke. This approach should be useful for identification of asthma susceptibility genes.

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Factors associated with short-term clinical outcomes after acute treatment of asthma in a pediatric emergency department.

Mintegi-Raso S.

Division of Pediatric Emergency Medicine, Department of Pediatrics, Hospital de Cruces, Barakaldo, Bizkaia, Spain. jbenito hcru.osakidetza.net

Outcomes of emergency room treatment of children with asthma have not been well-documented. The purpose of this study was to describe the short-term clinical course of children aged 0-14 years after standard treatment for an acute asthma exacerbation in a pediatric emergency department, and to determine factors associated with follow-up morbidity. This was a prospective cohort study of a randomly selected sample of children with asthma who required treatment for an acute asthma exacerbation during the year 2002. A clinical chart was filled out by the attending pediatrician during the emergency department visit. Participants were interviewed by telephone at 7 and 15 days after the pediatric emergency visit. The study population included 258 children; 125 of them (48.4%) were <2 years old. Eighty-nine percent of children reported a visit with his/her primary asthma care provider during the first week after discharge from the emergency department. A total of 185 children missed 1 or more days of school, with a mean of 3.1 +/- 2.7 days (range, 1-23 days). Twenty-nine patients (11%) returned for medical care at the emergency department, 22 (8.5%) of them during the first week after discharge, and 4 (1.6%) required hospitalization. At the first follow-up control (day 7), 111 patients (43%) reported persistent symptoms and/or difficult breathing, and 157 (61%) were still using asthma medication. At the second follow-up control (day 15), 53 patients (20.5%) reported persistent respiratory symptoms, and 69 (26.7%) used asthma medication. In children >2 years of age, the percentage of patients with respiratory symptoms on day 7 was significantly lower among those who reported maintenance therapy with inhaled steroids (23.7% vs. 46%, P = 0.006). On day 7, asthma symptoms were more frequent in children <2 years of age compared to older children showed a higher percentage of asthma symptoms (50% vs. 36%, P = 0.014). Children <2 years old compared to older children also missed more days school or day nursery (4.48 +/- 4.62 days vs. 2.4 +/- 2.19 days). The short-term outcome of asthma children attended at the emergency department is worse than expected, according to rates of rehospitalization and return for medical care after discharge. Maintenance treatment with inhaled steroids favored a prompt recovery in children older than 2 years of age, whereas the short-term outcome of children aged <2 years was not influenced by any variable. Copyright 2004 Wiley-Liss, Inc.

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