Soo Cheng

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

Abstract 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 GlaxoWellcomes internal clinical study registers. Main outcome measures: FEV1, morning and evening peak expiratory flow, night awakenings, β agonist use, and major exacerbations. Results: Eight studies, with 2324 adolescents and adults with asthma, met the inclusion criteria. Data on doses of >500 µg/day were limited. The dose-response curve for the raw data began to reach a plateau at around 100-200 µg/day and peaked by 500 µg/day. A negative exponential model for the data, without meta-analysis, indicated that 80% of the benefit at 1000 µg/day was achieved at doses of 70-170 µg/day and 90% by 100-250 µg/day. A quadratic meta-regression showed that the maximum achievable efficacy was obtained by doses of around 500 µg/day. The odds ratio for patients remaining in a study at a dose of 200 µg/day, compared with higher doses, was 0.73 (95% confidence interval 0.49 to 1.08). Comparison of the standardised difference in FEV1 for an inhaled dose of 200 µg/day against higher doses showed a difference in FEV1 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 µg, and the maximum effect is achieved with a dose of around 500 µg/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 µg/day. What is already known on this topic Inhaled corticosteroids are recommended for most patients with asthma, with the dose being increased as required to obtain control A therapeutic dose range of fluticasone propionate of 200-2000 µg/day is recommended in the British National Formulary for adults with asthma What this study adds Published data are insufficient to determine with confidence the dose-response relation of inhaled fluticasone at doses of >500 µg/day The dose-response curve for inhaled fluticasone in moderate to severe asthma in adolescents and adults, for all major clinical outcome measures, including exacerbations, begins to plateau at 100-200 µg/day and peaks at around 500 µg/day This study partially explains why adding a long acting β agonist to inhaled corticosteroids is more efficacious than increasing the dose of inhaled steroid beyond this dose range

International patterns of tuberculosis and the prevalence of symptoms of asthma, rhinitis, and eczema

BACKGROUND An ecological analysis was conducted of the relationship between tuberculosis notification rates and the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema in 85 centres from 23 countries in which standardised data are available. These essentially comprised countries in Europe as well as the USA, Canada, Australia, and New Zealand. METHODS Tuberculosis notification rates were obtained from the World Health Organization. Data on the prevalence of symptoms of asthma, rhinitis, and eczema in 235 477 children aged 13–14 years were based on the responses to the written and video questionnaires from the International Study of Asthma and Allergies in Childhood (ISAAC). The analysis was adjusted for gross national product (GNP) as an estimate of the level of affluence. RESULTS Tuberculosis notification rates were significantly inversely associated with the lifetime prevalence of wheeze and asthma and the 12 month period prevalence of wheeze at rest as assessed by the video questionnaire. An increase in the tuberculosis notification rates of 25 per 100 000 was associated with an absolute decrease in the prevalence of wheeze ever of 4.7%. Symptoms of allergic rhinoconjunctivitis in the past 12 months were inversely associated with tuberculosis notification rates, but there were no other significant associations with other ISAAC questions on allergic rhinoconjunctivitis or atopic eczema. CONCLUSIONS These findings are consistent with recent experimental evidence which suggests that exposure to Mycobacterium tuberculosis may reduce the risk of developing asthma.

Infections, medication use, and the prevalence of symptoms of asthma, rhinitis, and eczema in childhood

Background: The “hygiene hypothesis” postulates that infections during infancy may protect against asthma and atopy. There is also some evidence that antibiotic and/or paracetamol use may increase the risk of asthma. Methods: The study measured the association between infections, and medication use early in life and the risk of asthma at age 6–7 years. It involved 1584 children who had been notified to public health services with serious infections at age 0–4 years, and 2539 children sampled from the general population. For both groups, postal questionnaires were completed by parents. Results: There was little difference in the prevalence of current wheezing between the childhood infections group (prevalence  =  23.5%) and the general population group (prevalence  =  24.3%). There was also little difference whether the major site of infection was gastrointestinal (prevalence  =  24.1%), invasive (prevalence  =  24.6%) or respiratory (prevalence  =  21.1%). However, in both groups, there were associations with antibiotic (OR = 1.78, 95% CI 1.49 to 2.14) or paracetamol (OR = 1.38, 95% CI 1.04 to 1.83) use in the first year of life or recent paracetamol use (OR = 2.10, 95% CI 1.78 to 2.49) and current wheezing. There was a weak protective effect of childhood infections in children who had not used antibiotics in the first year of life (OR = 0.78, 95% CI 0.55 to 1.10). Conclusions: These findings are consistent with other evidence that antibiotic use early in life may increase the risk of asthma. They are also consistent with some preliminary evidence associating paracetamol use with an increased risk of asthma. Any protective effect of notifiable childhood infections was weak.

Farm exposure in utero may protect against asthma, hay fever and eczema

The aim of the present study was to assess which factors contribute to the lower prevalence of allergic diseases in farmers’ children, and the importance of timing of exposure. In a cross-sectional questionnaire survey, asthma symptoms, hay fever and eczema were assessed, as well as current, early and prenatal farm-related exposures in 1,333 farmers’ children and 566 reference children aged 5–17 yrs. Farmers’ children had a lower incidence of asthma symptoms and eczema. Current and maternal exposure during pregnancy to animals and/or grain and hay reduced the risk of asthma symptoms, hay fever and eczema. The exposure–response association for maternal exposure was nonlinear for most outcomes. After mutual adjustment, the effects of prenatal exposure remained unchanged whereas current exposure remained protective only for asthma medication, asthma ever and hay fever. Exposure during the first 2 yrs was not associated with symptoms, after controlling for prenatal exposure. A combination of prenatal and current exposure was most strongly associated with wheeze (odds ratio (OR) 0.48, 95% confidence interval (CI) 0.28–0.80), asthma medication (OR 0.50, 95% CI 0.30–0.82), asthma ever (OR 0.50, 95% CI 0.33–0.76), hay fever (OR 0.47, 95% CI 0.30–0.73) and eczema (OR 0.46, 95% CI 0.30–0.70). Prenatal exposure may contribute to the low prevalence of asthma, hay fever and eczema in farmers’ children, but continued exposure may be required to maintain optimal protection.

Lifelong farm exposure may strongly reduce the risk of asthma in adults.

Background:  Farm exposures may protect against childhood asthma, hay fever and eczema. Whether farm exposures also confer protection in adult farmers remains unclear. Moreover, little is known about the role of timing of exposure. We assessed the effects of current and childhood farm exposures on asthma, hay fever and eczema in farmers and a rural nonfarming control population.

Pollen counts in relation to the prevalence of allergic rhinoconjunctivitis, asthma and atopic eczema in the International Study of Asthma and Allergies in Childhood (ISAAC)

Background Although pollens are major allergens associated with allergic rhinoconjunctivitis and asthma, there is little information about the relative prevalence of these conditions in populations with different pollen exposures.

Mortality in New Zealand workers exposed to phenoxy herbicides and dioxins.

Aims: To evaluate mortality in New Zealand phenoxy herbicide producers and sprayers exposed to dioxins. Methods: Phenoxy herbicide producers (n = 1025) and sprayers (n = 703) were followed up from 1 January 1969 and 1 January 1973 respectively to 31 December 2000. A total of 813 producers and 699 sprayers were classified as exposed to dioxin and phenoxy herbicides. Standardised mortality ratios (SMR) were calculated using national mortality rates. Results: At the end of follow up, 164 producers and 91 sprayers had died. Cancer mortality was reduced for sprayers (SMR = 0.82, 95% CI 0.57 to 1.14) and increased in exposed production workers (SMR = 1.24, 95% CI 0.90 to 1.67), especially for synthesis workers (SMR = 1.69), formulation and lab workers (SMR = 1.64), and maintenance/waste treatment/cleaning workers (SMR = 1.46). Lymphohaematopoietic cancer mortality was increased in exposed production workers (SMR = 1.65, 95% CI 0.53 to 3.85), especially for multiple myeloma (SMR = 5.51, 95% CI 1.14 to 16.1). Among sprayers, colon cancer (SMR = 1.94, 95% CI 0.84 to 3.83) showed increased mortality. Conclusions: Results showed 24% non-significant excess cancer mortality in phenoxy herbicide producers, with a significant excess for multiple myeloma. Associations were stronger for those exposed to multiple agents including dioxin during production. Overall cancer mortality was not increased for producers and sprayers mainly handling final technical products, although they were likely to have been exposed to TCDD levels far higher than those currently in the general New Zealand population.

Gender differences in occupational exposure patterns

Objectives The authors conducted a population-based survey to examine gender differences in occupational exposure patterns and to investigate whether any observed differences are due to: (a) gender differences in occupational distribution; and/or (b) gender differences in tasks within occupations. Methods Men and women aged 20–64 years were randomly selected from the Electoral Roll and invited to take part in a telephone interview, which collected information on self-reported occupational exposure to specific dusts and chemicals, physical exposures and organisational factors. The authors used logistic regression to calculate prevalence ORs and 95% CIs comparing the exposure prevalence of males (n=1431) and females (n=1572), adjusting for age. To investigate whether men and women in the same occupation were equally exposed, the authors also matched males to females on current occupation using the five-digit code (n=1208) and conducted conditional logistic regression adjusting for age. Results Overall, male workers were two to four times more likely to report exposure to dust and chemical substances, loud noise, irregular hours, night shifts and vibrating tools. Women were 30% more likely to report repetitive tasks and working at high speed, and more likely to report exposure to disinfectants, hair dyes and textile dust. When men were compared with women with the same occupation, gender differences were attenuated. However, males remained significantly more likely to report exposure to welding fumes, herbicides, wood dust, solvents, tools that vibrate, irregular hours and night-shift work. Women remained more likely to report repetitive tasks and working at high speed, and in addition were more likely to report awkward or tiring positions compared with men with the same occupation. Conclusion This population-based study showed substantial differences in occupational exposure patterns between men and women, even within the same occupation. Thus, the influence of gender should not be overlooked in occupational health research.

Two year follow up of pulmonary function values among welders in New Zealand

OBJECTIVES: To examine whether welding is a risk factor for an accelerated decline in pulmonary function. METHODS: 2 Year follow up of pulmonary function and respiratory symptoms among 54 welders and 38 non-welders in eight New Zealand welding sites. RESULTS: There were no significant differences in age, height, smoking habits, ethnicity, or total time in industrial work between welders and non-welders. No overall differences were noted in the changes of pulmonary function variables between the two study groups. However, when the comparison was restricted to smokers, welders had a significantly greater (p = 0.02) annual decline (88.8 ml) in FEV1 than non-welders, who had a slight non-significant annual increase (34.2 ml). Also, welders without respiratory protection or local exhaust ventilation while welding had a greater annual decline both in forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) than welders with protection (p = 0.001 and 0.04, respectively). Among welders a significant association was found between the acute across shift change and the annual decline in FEV1. Chronic bronchitis was more common among welders (24%) than non-welders (5%). Only one welder (2%) but eight non-welders (21%) reported having asthma. CONCLUSIONS: Welders who smoked and welders working without local exhaust ventilation or respiratory protection have an increased risk of accelerated decline in FEV1.

Case-control study of high risk occupations for bladder cancer in New Zealand

We conducted a nationwide case‐control study of bladder cancer in adult New Zealanders to identify occupations that may contribute to the risk of bladder cancer in the New Zealand population. A total of 213 incident cases of bladder cancer (age 25–70 years) notified to the New Zealand Cancer Registry during 2003 and 2004, and 471 population controls, were interviewed face‐to‐face. The questionnaire collected demographic information and a full occupational history. The relative risks for bladder cancer associated with ever being employed in particular occupations and industries were calculated by unconditional logistic regression adjusting for age, sex, smoking and socio‐economic status. Estimates were subsequently semi‐Bayes adjusted to account for the large number of occupations and industries being considered. An elevated bladder cancer risk was observed for hairdressers (odds ratio (OR) 9.15 95% Confidence Interval (95%CI) 1.60–62.22), and sewing machinists (OR 3.07 95%CI 1.35–6.96). Significantly increased risks were not observed for several other occupations that have been reported in previous studies, including sales assistants (OR 1.03 95%CI 0.64–1.67), painters and paperhangers (OR 1.42 95%CI 0.56–3.60), sheet metal workers (OR 0.39, 95%CI 0.15–1.00), printing trades workers (OR 1.11 95%CI 0.41–3.05) and truck drivers (OR 1.36 95%CI 0.60–3.09), although the elevated odds ratios for painters, printers and truck drivers are consistent with excesses observed in other studies. Nonsignificantly increased risks were observed for tailors and dressmakers (OR 2.84 95%CI 0.62–13.05), rubber and plastics products machine operators (OR 2.82 95%CI 0.75–10.67), building workers (OR 2.15, 95%CI 0.68–6.73), and female market farmers and crop growers (OR 2.05 95%CI 0.72–5.83). In conclusion, this study has confirmed that hairdressers and sewing machinists are high risk occupations for bladder cancer in New Zealand, and has identified several other occupations and industries of high bladder cancer risk that merit further study.