Randomized controlled trial of asthma risk with paracetamol use in infancy--a feasibility study.

BACKGROUND: There is non-experimental evidence that paracetamol (acetaminophen) use may increase the risk of developing asthma. However, numerous methodological issues need to be resolved before undertaking a randomized controlled trial to investigate this hypothesis. OBJECTIVE: To establish the feasibility of a randomized controlled trial of liberal paracetamol as usually given by parents/guardians vs. a comparator (restricted paracetamol in accordance with WHO guidelines, ibuprofen or placebo), and childhood asthma risk. METHODS: Questionnaires were completed by parents/guardians of infants admitted to Wellington Hospital with bronchiolitis to assess views about comparator treatments. Subsequently, infants of parents/guardians who provided informed consent were randomized to restricted or liberal paracetamol use for 3 months with paracetamol use recorded. RESULTS: Of 120 eligible participants, 72 (60%) parents/guardians completed the questionnaire. Ibuprofen, restricted paracetamol and placebo were acceptable to 42 (58%), 29 (40%) and 9 (12%) parents/guardians, respectively. 36 (30%) infants were randomized to restricted or liberal paracetamol. Paracetamol use was greater for the liberal vs. restricted group for reported [Hodges-Lehmann estimator of difference 0.94 mg/kg/day (95% CI 0.2-3.52), P = 0.02] and measured use [Hodges-Lehmann estimator of difference 2.11 mg/kg/day (95% CI 0.9-4.18), P = 0.004]. The median reported and measured use of paracetamol was 2.0-fold and 3.5-fold greater in the liberal vs. restricted group. CONCLUSIONS AND CLINICAL RELEVANCE: Although separation in paracetamol dosing is likely to be achieved with a liberal vs. restricted paracetamol regime, ibuprofen is the preferred comparator treatment in the proposed RCT of paracetamol use and risk of asthma in childhood.

Childhood asthma and GOLD-defined chronic obstructive pulmonary disease.

BACKGROUND: Current understanding of chronic obstructive pulmonary disease (COPD) is that it results from an interaction of genetic and environmental factors. This study aimed to investigate the strength of association of various known risk factors for COPD. METHODS: Detailed written questionnaires, full pulmonary function tests and atopy testing were completed in 749 people, aged 25-75 years, recruited from a random population sample. COPD was defined, using Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, as a post-bronchodilator forced expiratory volume in 1 s/forced vital capacity (FEV(1) /FVC) ratio <0.7. RESULTS: The prevalence of COPD was higher in men (OR 1.7 (95% CI 1.1-2.7)) and increased with increasing age (OR per decade older 2.1 (95% CI 1.7-2.7)). COPD was more frequent in current and ex-smokers and increased with increasing pack years (OR per 10 pack years 1.3 (95% CI 1.1-1.5)). On a logit scale, a diagnosis of asthma as a child conferred a similar risk as an increase in age of 22 years or 62 pack years of cigarette smoking. CONCLUSION: Childhood asthma emerged with the strongest association for GOLD-defined COPD. Possible explanations for this are suggested, including limitations of the current GOLD spirometric definition of COPD, a chance observation because of the high prevalence of both disorders in this population, or alternatively childhood asthma is a risk factor for COPD.

Quality of life measured by the St George's Respiratory Questionnaire and spirometry.

The present authors aimed to determine if the criteria for the diagnosis of chronic obstructive pulmonary disease (COPD) and its classification by severity as recommended by the Global Initiative for Chronic Obstructive Lung Disease are supported by measurements of respiratory health-related quality of life. A community-based sample of adults aged 25-75 yrs had pre- and post-bronchodilator spirometry and completed the St George's Respiratory Questionnaire (SGRQ). Loess scatter plot smoothers of the SGRQ versus post-bronchodilator forced expiratory volume in one second (FEV(1))/forced vital capacity (FVC) ratio and post-bronchodilator FEV(1) % predicted together with receiver operating characteristic (ROC) curve analysis were used to determine the relationship between spirometric variables and clinically important differences in the SGRQ score. The scatter plot smoother and ROC curve analyses supported the value of 0.7 for post-bronchodilator FEV(1)/FVC ratio, which was approximately 4 units higher than the nadir of the SGRQ. To represent a distance of 8 units on the SGRQ, the cut-off points for post-bronchodilator FEV(1) that delimit COPD severity stages were 80, 60 and 40% pred for mild, moderate and severe COPD, respectively. To diagnose chronic obstructive pulmonary disease the use of post-bronchodilator forced expiratory volume in one second/forced vital capacity ratio of 0.7 is supported by health-related quality of life measurements. There may be advantages in using forced expiratory volume in one second cut-off points of 80, 60 and 40% predicted for the classification of mild, moderate and severe chronic obstructive pulmonary disease, respectively, similar to the approach recommended for asthma.

Distinct clinical phenotypes of airways disease defined by cluster analysis.

Airways disease is currently classified using diagnostic labels such as asthma, chronic bronchitis and emphysema. The current definitions of these classifications may not reflect the phenotypes of airways disease in the community, which may have differing disease processes, clinical features or responses to treatment. The aim of the present study was to use cluster analysis to explore clinical phenotypes in a community population with airways disease. A random population sample of 25-75-yr-old adults underwent detailed investigation, including a clinical questionnaire, pulmonary function tests, nitric oxide measurements, blood tests and chest computed tomography. Cluster analysis was performed on the subgroup with current respiratory symptoms or obstructive spirometric results. Subjects with a complete dataset (n = 175) were included in the cluster analysis. Five clusters were identified with the following characteristics: cluster 1: severe and markedly variable airflow obstruction with features of atopic asthma, chronic bronchitis and emphysema; cluster 2: features of emphysema alone; cluster 3: atopic asthma with eosinophilic airways inflammation; cluster 4: mild airflow obstruction without other dominant phenotypic features; and cluster 5: chronic bronchitis in nonsmokers. Five distinct clinical phenotypes of airflow obstruction were identified. If confirmed in other populations, these findings may form the basis of a modified taxonomy for the disorders of airways obstruction.

Proportional classifications of COPD phenotypes.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) encompasses a group of disorders characterised by the presence of incompletely reversible airflow obstruction with overlapping subsets of different phenotypes including chronic bronchitis, emphysema or asthma. The aim of this study was to determine the proportion of adult subjects aged >50 years within each phenotypic subgroup of COPD, defined as a post-bronchodilator ratio of forced expiratory volume in 1 s/forced vital capacity (FEV(1)/FVC) <0.7, in accordance with current international guidelines. METHODS: Adults aged >50 years derived from a random population-based survey undertook detailed questionnaires, pulmonary function tests and chest CT scans. The proportion of subjects in each of 16 distinct phenotypes was determined based on combinations of chronic bronchitis, emphysema and asthma, with and without incompletely reversible airflow obstruction defined by a post-bronchodilator FEV(1)/FVC ratio of 0.7. RESULTS: A total of 469 subjects completed the investigative modules, 96 of whom (20.5%) had COPD. Diagrams were constructed to demonstrate the relative proportions of the phenotypic subgroups in subjects with and without COPD. 18/96 subjects with COPD (19%) had the classical phenotypes of chronic bronchitis and/or emphysema but no asthma; asthma was the predominant COPD phenotype, being present in 53/96 (55%). When COPD was defined as a post-bronchodilator FEV(1)/FVC less than the lower limit of normal, there were one-third fewer subjects with COPD and a smaller proportion without a defined emphysema, chronic bronchitis or asthma phenotype. CONCLUSION: This study provides proportional classifications of the phenotypic subgroups of COPD which can be used as the basis for further research into the pathogenesis and treatment of this heterogeneous disorder.

Dose-response relation of inhaled fluticasone propionate in adolescents and adults with asthma: meta-analysis.

OBJECTIVE: To examine the dose-response relation of inhaled fluticasone propionate in adolescents and adults with asthma. DESIGN: Meta-analysis of placebo controlled, randomised clinical trials that presented data on at least one outcome measure of asthma and that used at least two different doses of fluticasone. SETTING: Medline, Embase, and GlaxoWellcome's internal clinical study registers. MAIN OUTCOME MEASURES: FEV(1), morning and evening peak expiratory flow, night awakenings, beta agonist use, and major exacerbations. RESULTS: Eight studies, with 2324 adolescents and adults with asthma, met the inclusion criteria. Data on doses of >500 microg/day were limited. The dose-response curve for the raw data began to reach a plateau at around 100-200 microg/day and peaked by 500 microg/day. A negative exponential model for the data, without meta-analysis, indicated that 80% of the benefit at 1000 microg/day was achieved at doses of 70-170 microg/day and 90% by 100-250 microg/day. A quadratic meta-regression showed that the maximum achievable efficacy was obtained by doses of around 500 microg/day. The odds ratio for patients remaining in a study at a dose of 200 microg/day, compared with higher doses, was 0.73 (95% confidence interval 0.49 to 1.08). Comparison of the standardised difference in FEV(1 )for an inhaled dose of 200 microg/day against higher doses showed a difference in FEV(1) of 0.13 of a standard deviation (-0.02 to 0.29). CONCLUSIONS: In adolescent and adult patients with asthma, most of the therapeutic benefit of inhaled fluticasone is achieved with a total daily dose of 100-250 microg, and the maximum effect is achieved with a dose of around 500 microg/day. However, these findings were limited by the lack of data on individual patients and by the paucity of dose-response studies that included doses of >500 microg/day.

COPD prevalence in a random population survey: a matter of definition.

A recent American Thoracic Society and European Respiratory Society joint Task Force report recommends using a lower limit of normal (LLN) of forced expiratory volume in one second/forced vital capacity as opposed to a fixed ratio of <0.7 to diagnose airflow obstruction, in order to reduce false positive diagnoses of chronic obstructive pulmonary disease (COPD) as defined by the Global Initiative for Obstructive Lung Disease (GOLD). To date, there is no reliable spirometry-based prevalence data for COPD in New Zealand and the effect of different definitions of airflow obstruction based on post-bronchodilator spirometry is not known. Detailed written questionnaires, full pulmonary function tests (including pre- and post-bronchodilator flow-volume loops) and atopy testing were completed in 749 subjects recruited from a random population sample. The GOLD-defined, age-adjusted prevalence (95% confidence interval) for adults aged >or=40 yrs was 14.2 (11.0-17.0)% compared with an LLN-defined, age-adjusted, post-bronchodilator prevalence in the same group of 9.0 (6.7-11.3)%. The prevalence of chronic obstructive pulmonary disease varied markedly depending on the definition used. Further research using longitudinal rather than cross-sectional data will help decide the preferred approach in chronic obstructive pulmonary disease prevalence surveys.

Inhaled fluticasone propionate and adrenal effects in adult asthma: systematic review and meta-analysis.

The dose-response relationship of inhaled fluticasone propionate (FP) for adrenal suppression in adults with asthma is not clear. The current authors carried out a systematic review and meta-analysis of placebo-controlled randomised dose-response studies of >or=4 weeks' duration, which assessed the adrenal effects of FP by cosyntropin stimulation tests in adult asthma. The main outcome measure was the proportion of subjects with adrenal function below the lower limit of the normal range. Five studies, with a total of 732 subjects with asthma, met the inclusion criteria. Data on daily doses >1,000 mug were limited to one study. The proportion of subjects with adrenal function below the lower limit of the normal range on placebo was 3.9%; for a 500-microg per day increase in FP dose the odds of an abnormality increased by 1.38 (95% confidence interval 1.01-1.59). The continuous secondary outcome measures showed an inverse linear relationship with the FP dose up to 2,000 microg.day(-1). In conclusion, for routine prescribing within the established therapeutic dose-response range (50-500 microg.day(-1)), fluticasone propionate has minimal effects on adrenal function. This conclusion is limited by the paucity of long-term studies of daily doses of fluticasone propionate >1,000 mug and by the considerable individual variability in the response.

Effect of repeated intradermal injections of heat-inactivated Mycobacterium bovis bacillus Calmette-Guérin in adult asthma.

BACKGROUND: There are a number of reports in the Chinese medical literature from the last 30 years regarding the efficacy of repeated doses of heat-inactivated bacillus Calmette-Guérin (BCG) in established asthma. There is also epidemiological and experimental evidence that exposure to mycobacteria has the potential to suppress the development of asthma/atopy. METHODS: Thirty-one Mantoux-negative adults with stable moderately severe asthma who were skin prick test positive to house dust mite were randomized to receive one injection (0.1 mL) a week for 4 weeks of heat-inactivated BCG or normal saline. Markers of asthma severity (including peak flow, forced expiratory volume in 1 s, major and minor exacerbations, symptom scores and beta-agonist use), blood eosinophil and IgE levels were monitored for 3 months. RESULTS: There were no statistically significant differences between the treatment group and placebo for any of the outcome variables. The recruitment to the trial was halted early and the number of injections reduced in a number of patients due to excessive local reactions to BCG. CONCLUSIONS: In addition to the lack of efficacy of repeated heat-inactivated BCG injections, the occurrence of severe local reactions will limit the therapeutic application of this approach in asthma.

Don't forget dengue! Clinical features of dengue fever in returning travellers.

BACKGROUND: Dengue virus infection is an increasingly important cause of imported fever, but many cases remain unrecognised. This study reviews the clinical features of dengue fever in patients seen at a regional department of infection and tropical medicine. SUBJECTS: All patients with dengue fever presenting to the Department of Infection and Tropical Medicine in Leicester over a three year period. RESULTS: The diagnosis of dengue fever was confirmed in 15 patients. The age range of patients was 19-61 years, and 80% were immigrants returning from a visit to their country of origin. In 11 (73%) patients, infection was associated with travel to India; others had gone to South-east Asia, Barbados and Uganda. All patients presented within three weeks of their return to the United Kingdom. The clinical manifestations of infection were often non-specific. They included fever, nausea, headache, cough and diarrhoea; 5 (33%) patients had a macular rash. Thrombocytopenia was seen in 7 (47%) patients, but only one had evidence of dengue haemorrhagic fever. Dengue infection was confirmed by serology in 14 (93%) patients. In one, dengue virus type 1 was identified by polymerase chain reaction, and the virus was subsequently isolated in tissue culture. CONCLUSIONS: Dengue virus infection should be considered in all febrile travellers who have recently returned from areas where the disease is endemic and in whom tests for malaria are negative.

The effect of delipidated deglycolipidated (DDMV) and heat-killed Mycobacterium vaccae in asthma.

Experimental and epidemiological evidence supports the hypothesis that exposure to mycobacteria has the potential to suppress the development of asthma and/or atopy and there are reports in the Chinese medical literature of repeated vaccination with inactivated BCG being effective in the management of asthma. Forty-three patients with stable moderately severe asthma who were skin prick test positive to house dust mite were randomized to receive two intradermal injections of either phosphate-buffered saline (placebo), heat-killed Mycobacterium vaccae (0.5 mg), or delipidated deglycolipidated Mycobacterium vaccae (DDMV) (0.05 mg). Markers of asthma severity were measured for 3 mo and blood eosinophil, IgE levels, and the T cell proliferative and cytokine responses were monitored. There were no significant differences between either treatment group and the placebo group for any of the outcome variables. There was also no difference between the treatment groups and placebo for eosinophil, IgE levels, or the T cell proliferative and cytokine response. The results indicate no effect of low dose intradermal DDMV or M. vaccae on asthma severity in patients with established asthma.