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1.  Is Chronic Asthma Associated with Shorter Leukocyte Telomere Length at Midlife? 
Rationale: Asthma is prospectively associated with age-related chronic diseases and mortality, suggesting the hypothesis that asthma may relate to a general, multisystem phenotype of accelerated aging.
Objectives: To test whether chronic asthma is associated with a proposed biomarker of accelerated aging, leukocyte telomere length.
Methods: Asthma was ascertained prospectively in the Dunedin Multidisciplinary Health and Development Study cohort (n = 1,037) at nine in-person assessments spanning ages 9–38 years. Leukocyte telomere length was measured at ages 26 and 38 years. Asthma was classified as life-course-persistent, childhood-onset not meeting criteria for persistence, and adolescent/adult-onset. We tested associations between asthma and leukocyte telomere length using regression models. We tested for confounding of asthma-leukocyte telomere length associations using covariate adjustment. We tested serum C-reactive protein and white blood cell counts as potential mediators of asthma-leukocyte telomere length associations.
Measurements and Main Results: Study members with life-course-persistent asthma had shorter leukocyte telomere length as compared with sex- and age-matched peers with no reported asthma. In contrast, leukocyte telomere length in study members with childhood-onset and adolescent/adult-onset asthma was not different from leukocyte telomere length in peers with no reported asthma. Adjustment for life histories of obesity and smoking did not change results. Study members with life-course-persistent asthma had elevated blood eosinophil counts. Blood eosinophil count mediated 29% of the life-course-persistent asthma-leukocyte telomere length association.
Conclusions: Life-course-persistent asthma is related to a proposed biomarker of accelerated aging, possibly via systemic eosinophilic inflammation. Life histories of asthma can inform studies of aging.
PMCID: PMC4214127  PMID: 24956257
asthma; telomere; aging; longitudinal; developmental phenotype
2.  Childhood and Adolescent Television Viewing and Antisocial Behavior in Early Adulthood 
Pediatrics  2013;131(3):439-446.
To investigate whether excessive television viewing throughout childhood and adolescence is associated with increased antisocial behavior in early adulthood.
We assessed a birth cohort of 1037 individuals born in Dunedin, New Zealand, in 1972–1973, at regular intervals from birth to age 26 years. We used regression analysis to investigate the associations between television viewing hours from ages 5 to 15 years and criminal convictions, violent convictions, diagnosis of antisocial personality disorder, and aggressive personality traits in early adulthood.
Young adults who had spent more time watching television during childhood and adolescence were significantly more likely to have a criminal conviction, a diagnosis of antisocial personality disorder, and more aggressive personality traits compared with those who viewed less television. The associations were statistically significant after controlling for sex IQ, socioeconomic status, previous antisocial behavior, and parental control. The associations were similar for both sexes, indicating that the relationship between television viewing and antisocial behavior is similar for male and female viewers.
Excessive television viewing in childhood and adolescence is associated with increased antisocial behavior in early adulthood. The findings are consistent with a causal association and support the American Academy of Pediatrics recommendation that children should watch no more than 1 to 2 hours of television each day.
PMCID: PMC3581845  PMID: 23420910
television; antisocial behavior; media violence; longitudinal studies
3.  Fast-food consumption and body mass index in children and adolescents: an international cross-sectional study 
BMJ Open  2014;4(12):e005813.
To investigate whether reported fast-food consumption over the previous year is associated with higher childhood or adolescent body mass index (BMI).
Secondary analysis from a multicentre, multicountry cross-sectional study (International Study of Asthma and Allergies in Children (ISAAC) Phase Three).
Subjects and methods
Parents/guardians of children aged 6–7 completed questionnaires which included questions about their children's asthma and allergies, fast-food consumption, height and weight. Adolescents aged 13–14 completed the same questionnaire. The questionnaire asked “In the past 12 months, how often on average did you (your child) eat fast-food/burgers?” The responses were infrequent (never/only occasionally), frequent (once/twice a week) or very frequent (three or more times per week). A general linear mixed model was used to determine the association between BMI and fast-food consumption, adjusting for Gross National Income per capita by country, measurement type (whether heights/weights were reported or measured), age and sex.
72 900 children (17 countries) and 199 135 adolescents (36 countries) provided data. Frequent and very frequent fast-food consumption was reported in 23% and 4% of children, and 39% and 13% of adolescents, respectively. Children in the frequent and very frequent groups had a BMI that was 0.15 and 0.22 kg/m2 higher than those in the infrequent group (p<0.001). Male adolescents in the frequent and very frequent groups had a BMI that was 0.14 and 0.28 kg/m2 lower than those in the infrequent group (p<0.001). Female adolescents in the frequent and very frequent groups had a BMI that was 0.19 kg/m2 lower than those in the infrequent group (p<0.001).
Reported fast-food consumption is high in childhood and increases in adolescence. Compared with infrequent fast-food consumption, frequent and very frequent consumption is associated with a higher BMI in children. Owing to residual confounding, reverse causation and likely misreporting, the reverse association observed in adolescents should be interpreted with caution.
PMCID: PMC4265088  PMID: 25488096
BMI; Fast food consumption; International; Childhood obesity; Childhood overweight
4.  Systemic inflammation and lung function in young adults 
Thorax  2007;62(12):1064-1068.
Impaired lung function is associated with systemic inflammation and is a risk factor for cardiovascular disease in older adults. It is unknown when these associations emerge and to what extent they are mediated by smoking, chronic airways disease, and/or established atherosclerosis. We explored the association between the forced expiratory volume in one second (FEV1) and the systemic inflammatory marker C‐reactive protein (CRP) in young adults.
Associations between spirometric lung function and blood CRP were assessed in a population based birth cohort of approximately 1000 New Zealanders at ages 26 and 32 years. Analyses adjusted for height and sex to account for differences in predicted lung function and excluded pregnant women.
There were significant inverse associations between FEV1 and CRP at both ages. Similar results were found for the forced vital capacity. These associations were similar in men and women and were independent of smoking, asthma, and body mass index.
Reduced lung function is associated with systemic inflammation in young adults. This association is not related to smoking, asthma, or obesity. The reasons for the association are unexplained, but the findings indicate that the association between lower lung function and increased inflammation predates the development of either chronic lung disease or clinically significant atherosclerosis. The association between poor lung function and cardiovascular disease may be mediated by an inflammatory mechanism.
PMCID: PMC2094275  PMID: 17604302
inflammation; C‐reactive protein; spirometry; cohort studies
5.  The Worldwide Association between Television Viewing and Obesity in Children and Adolescents: Cross Sectional Study 
PLoS ONE  2013;8(9):e74263.
Studies exploring the effect of television viewing on obesity throughout childhood are conflicting. Most studies have been confined to single high-income countries. Our aim was to examine the association between television viewing habits and Body Mass Index (BMI) in adolescents and children in a multicentre worldwide sample.
In the International Study of Asthma and Allergies in Children Phase Three, adolescents aged between 12 and 15 years completed questionnaires which included questions on television viewing habits, height and weight. Parents/guardians of children aged between 5 and 8 years completed the same questionnaire on behalf of their children. The questionnaire asked “During a normal week, how many hours a day (24 hours) do you (does your child) watch television?” Responses were categorised as; “short” (<1 hour), “moderate” (1 to ≤3 hours), “long” (3 to ≤5 hours) and “prolonged” (>5 hours).
207,672 adolescents from 37 countries and 77,003 children from 18 countries provided data. Daily television viewing in excess of one hour was reported in 89% of adolescents and 79% of children. Compared with adolescents in the short viewing group, those in the moderate, long and prolonged groups had BMIs that were 0.14 kg/m2, 0.21 kg/m2, 0.30 kg/m2 and 0.08 kg/m2, 0.16 kg/m2 and 0.17 kg/m2 larger for females and males respectively (both P<0.001). Compared with children in the short viewing group, those in the moderate, long and prolonged groups had BMIs that were 0.24 kg/m2, 0.34 kg/m2, 0.36 kg/m2 and 0.19 kg/m2, 0.32 kg/m2 and 0.36 kg/m2 larger for females and males respectively (both P<0.001).
Increased television viewing hours were positively associated with BMI in both adolescents and children with an apparent dose response effect. These findings extend the evidence that television viewing contributes to increased BMI in childhood.
PMCID: PMC3783429  PMID: 24086327
6.  Accelerated decline in lung function in cigarette smokers is associated with TP53/HDM2 polymorphisms 
Human genetics  2009;126(4):559-565.
In vitro studies have shown that p53 mediates a protective response against DNA damage by causing either cell-cycle arrest and DNA repair, or apoptosis. These responses have not yet been demonstrated in humans. A common source of DNA damage in humans is cigarette smoke, which should activate p53 repair mechanisms. The level of p53 is regulated by HDM2, which targets p53 for degradation. The G-allele of a polymorphism in intron 1 of HDM2 (rs2279744:G/T) results in higher HDM2 levels, and should be associated with a reduced p53 response and hence more DNA damage and corresponding tissue destruction. Similarly, the alleles of a polymorphism (rs1042522) in TP53 that encode arginine (G-allele) or proline (C-allele) at codon 72 cause increased pro-apoptotic (G-allele) or cell-cycle arrest activities (C-allele), respectively, and may moderate p53's ability to prevent DNA damage. To test these hypotheses we examined lung function in relation to cumulative history of smoking in a population-based cohort. The G-alleles in HDM2 and TP53 were found to be associated with accelerated smoking-related decline in lung function. These data support the hypothesis that p53 protects from DNA damage in humans and provides a potential explanation for variation in lung function impairment amongst smokers.
PMCID: PMC3740961  PMID: 19521721
7.  Biomarkers of Cardiac Dysfunction and Mortality from Community-Acquired Pneumonia in Adults 
PLoS ONE  2013;8(5):e62612.
Cardiac dysfunction is common in acute respiratory diseases and may influence prognosis. We hypothesised that blood levels of N-terminal B-type natriuretic peptide (NT-proBNP) and high-sensitivity Troponin T would predict mortality in adults with community-acquired pneumonia.
Methods and Findings
A prospective cohort of 474 consecutive patients admitted with community-acquired pneumonia to two New Zealand hospitals over one year. Blood taken on admission was available for 453 patients and was analysed for NT-proBNP and Troponin T. Elevated levels of NT-proBNP (>220 pmol/L) were present in 148 (33%) and 86 (19%) of these patients respectively. Among the 26 patients who died within 30 days of admission, 23 (89%) had a raised NT-proBNP and 14 (53%) had a raised Troponin T level on admission compared to 125 (29%) and 72 (17%) of the 427 who survived (p values<0.001). Both NT-proBNP and Troponin T predicted 30-day mortality in age-adjusted analysis but after mutual adjustment for the other cardiac biomarker and the Pneumonia Severity Index, a raised N-terminal pro-brain natriuretic peptide remained a predictor of 30-day mortality (OR = 5.3, 95% CI 1.4–19.8, p = 0.013) but Troponin T did not (OR = 1.3, 95% CI 0.5–3.2, p = 0.630). The areas under the receiver-operating curves to predict 30-day mortality were similar for NT-proBNP (0.88) and the Pneumonia Severity Index (0.87).
Elevated N-terminal B-type natriuretic peptide is a strong predictor of mortality from community-acquired pneumonia independent of clinical prognostic indicators. The pathophysiological basis for this is unknown but suggests that cardiac involvement may be an under-recognised determinant of outcome in pneumonia and may require a different approach to treatment. In the meantime, measurement of B-type natriuretic peptides may help to assess prognosis.
PMCID: PMC3646835  PMID: 23667500
8.  Association between childhood and adolescent television viewing and unemployment in adulthood 
Preventive Medicine  2011;54(2):168-173.
To assess the long-term association between childhood television viewing and adult unemployment, and if this association is mediated by educational achievement.
Study members were a general-population birth cohort of 1037 participants born in New Zealand in 1972/1973. Hours of weekday television viewing were reported at ages 5–15. Since age 18, unemployment was assessed retrospectively using life-history calendars to age 32. Information on educational qualifications was collected at age 32.
Childhood and adolescent television viewing predicted adult unemployment. This association was significant for male study members only (β=0.20, p<0.0001). The association for male study members remained after further controlling for socioeconomic status, cognitive ability, and early indications of behaviour problems (p<0.0007). The association was only partially mediated by educational achievement and television viewing remained a predictor of unemployment after adjusting for this (p=0.0035). By logistic regression, each additional hour of daily television viewing was associated with an increased likelihood of spending at least 6 months in unemployment between ages 18–32 years (OR=1.36, 95%, CI=1.06, 1.76, p=0.0157).
Childhood and adolescent television viewing may have long-lasting consequences for adult unemployment for boys. This association is only partially explained by the association between television viewing and educational achievement.
PMCID: PMC3275436  PMID: 22178044
adolescence; child; cohort studies; television; workforce
9.  Correlation between measures of insulin resistance in fasting and non-fasting blood 
Epidemiological investigation of insulin resistance is difficult. Standard measures of insulin resistance require invasive investigations, which are impractical for large-scale studies. Surrogate measures using fasting blood samples have been developed, but even these are difficult to obtain in population-based studies. Measures of insulin resistance have not been validated in non-fasting blood samples. Our objective was to assess the correlations between fasting and non-fasting measures of insulin resistance/sensitivity.
Fasting and non-fasting measurements of metabolic function were compared in 30 volunteers (15 male) aged 28 to 48 years. Participants provided a morning blood sample after an overnight fast and a second sample approximately 4 hours after lunch on the same day.
Non-fasting levels of the adipokines leptin, adiponectin, and leptin:adiponectin ratios were not significantly different and highly correlated with fasting values (r values 0.95, 0.96, and 0.95 respectively, P values < 0.001). There were moderate correlations between fasting and non-fasting estimates of insulin sensitivity using the McAuley (r = 0.60, P = 0.001) and QUICKI formulae (r = 0.39, P = 0.037). The HOMA-IR estimate of insulin resistance was also moderately correlated (r = 0.45, P = 0.016).
Semi-fasting measures of leptin, adiponectin, and leptin:adiponectin ratios correlate closely with fasting values and are likely to be sufficient for population-based research. Other measures of insulin resistance or sensitivity in semi-fasted blood samples are moderately correlated with values obtained after an overnight fast. These estimates of insulin resistance/sensitivity may also be adequate for many epidemiological studies and would avoid the difficulties of obtaining fasting blood samples.
PMCID: PMC3177770  PMID: 21899745
10.  Clinical and epidemiological profile of patients with severe H1N1/09 pandemic influenza in Australia and New Zealand: an observational cohort study 
BMJ Open  2011;1(1):e000100.
Pandemic influenza H1N1/09 emerged in April 2009 and spread widely in Australia and New Zealand. Although an unprecedented number of cases required intensive care, comparative community-based studies with seasonal influenza strains have not shown any significant differences in clinical symptoms or severity.
The authors performed active surveillance on confirmed influenza-related admissions and compared the clinical profile of patients with pandemic H1N1/09 influenza and patients with seasonal influenza at eight hospitals in Australia and one hospital in New Zealand.
During the 1 July and 30 November 2009, 560 patients with confirmed influenza were admitted, of which 478 had H1N1/09, and 82 had other seasonal strains. Patients with H1N1/09 influenza were younger, were more likely to have fever and were more likely to be pregnant but less likely to have chronic obstructive pulmonary disease and ischaemic heart disease than patients with seasonal strains. Other clinical features and comorbidities were reported in similar proportions. Admission to intensive care was required in 22% of patients with H1N1/09 influenza and 12% in patients with other strains. Hospital mortality was 5% in patients with H1N1 influenza.
The clinical features of H1N1/09 influenza and seasonal strains were similar in hospitalised patients. A higher proportion of patients had comorbidities than had been reported in community-based studies. Although the overall mortality was similar, the authors found evidence that H1N1/09 caused severe disease in a higher proportion of hospitalised patients.
Article summary
Article focus
We performed an observational study of patients with H1N1/09 and seasonal strains of influenza in 2009, based on active surveillance at nine sentinel hospitals.
We explored differences between patients with H1N1/09 influenza infection and those with seasonal influenza infections.
Key messages
This study found that the clinical features of H1N1/09 influenza were similar in hospitalised patients, similar to previous community-based studies.
The finding that H1N1/09 influenza was associated with more severe disease reconciles apparently contradictory data suggesting no differences in community studies, but unprecedented use of critical care services.
Strengths and limitations of this study
This surveillance system was rapidly established, and initial data collection was retrospective from the medical record where symptoms were not always well documented. Despite high levels of awareness in medical staff, clinical testing criteria were operating during the period of the study and were likely to bias the proportion of patients reporting fever and respiratory symptoms. Nucleic-acid detection using PCR is regarded as the gold standard for diagnosis, but our experience with discordant results on repeated testing suggested that it may not be completely sensitive. This study does not encompass the full duration of the epidemic which was waning in several states (notably Victoria and New South Wales) at the commencement of the study period. Although several hospitals provided maternity and paediatric services, these patient groups are likely to be under-represented in this series. The population served by the sentinel hospitals is not known, and thus we were not able to establish a disease incidence rate.
This large study captured all admissions with influenza at multiple hospitals across Australia and New Zealand. All cases were confirmed by nucleic acid detection with clinical details collected by research staff.
PMCID: PMC3191436  PMID: 22021761
Infectious diseases; epidemiology; infection control; emergency medicine; toxinology; prehospital; evenoming; anaphylaxis; asthma; television; respiratory; patient reported outcomes airways disease; COPD
11.  Cannabis Smoking and Periodontal Disease Among Young Adults 
Tobacco smoking is a recognized behavioral risk factor for periodontal disease (through its systemic effects), and cannabis smoking may contribute in a similar way.
To determine whether cannabis smoking is a risk factor for periodontal disease.
Design and Setting
Prospective cohort study of the general population, with cannabis use determined at ages 18, 21, 26, and 32 years and dental examinations conducted at ages 26 and 32 years. The most recent data collection (at age 32 years) was completed in June 2005.
A complete birth cohort born in 1972 and 1973 in Dunedin, New Zealand, and assessed periodically (with a 96% follow-up rate of the 1015 participants who survived to age 32 years). Complete data for this analysis were available from 903 participants (comprising 89.0% of the surviving birth cohort).
Main Outcome Measure
Periodontal disease status at age 32 years (and changes from ages 26 to 32 years) determined from periodontal combined attachment loss (CAL) measured at 3 sites per tooth.
Three cannabis exposure groups were determined: no exposure (293 individuals, or 32.3%), some exposure (428; 47.4%), and high exposure (182; 20.2%). At age 32 years, 265 participants (29.3%) had 1 or more sites with 4 mm or greater CAL, and 111 participants (12.3%) had 1 or more sites with 5 mm or greater CAL. Incident attachment loss between the ages of 26 and 32 years in the none, some, and high cannabis exposure groups was 6.5%, 11.2%, and 23.6%, respectively. After controlling for tobacco smoking (measured in pack-years), sex, irregular use of dental services, and dental plaque, the relative risk estimates for the highest cannabis exposure group were as follows: 1.6 (95% confidence interval [CI], 1.2–2.2) for having 1 or more sites with 4 mm or greater CAL; 3.1 (95% CI, 1.5–6.4) for having 1 or more sites with 5 mm or greater CAL; and 2.2 (95% CI, 1.2–3.9) for having incident attachment loss (in comparison with those who had never smoked cannabis). Tobacco smoking was strongly associated with periodontal disease experience, but there was no interaction between cannabis use and tobacco smoking in predicting the condition’s occurrence.
Cannabis smoking may be a risk factor for periodontal disease that is independent of the use of tobacco.
PMCID: PMC2823391  PMID: 18252882
12.  Factors affecting exhaled nitric oxide measurements: the effect of sex 
Respiratory Research  2007;8(1):82.
Exhaled nitric oxide (FENO) measurements are used as a surrogate marker for eosinophilic airway inflammation. However, many constitutional and environmental factors affect FENO, making it difficult to devise reference values. Our aim was to evaluate the relative importance of factors affecting FENO in a well characterised adult population.
Data were obtained from 895 members of the Dunedin Multidisciplinary Health and Development Study at age 32. The effects of sex, height, weight, lung function indices, smoking, atopy, asthma and rhinitis on FENO were explored by unadjusted and adjusted linear regression analyses.
The effect of sex on FENO was both statistically and clinically significant, with FENO levels approximately 25% less in females. Overall, current smoking reduced FENO up to 50%, but this effect occurred predominantly in those who smoked on the day of the FENO measurement. Atopy increased FENO by 60%. The sex-related differences in FENO remained significant (p < 0.001) after controlling for all other significant factors affecting FENO.
Even after adjustment, FENO values are significantly different in males and females. The derivation of reference values and the interpretation of FENO in the clinical setting should be stratified by sex. Other common factors such as current smoking and atopy also require to be taken into account.
PMCID: PMC2231356  PMID: 18005450
13.  Overcoming beta-agonist tolerance: high dose salbutamol and ipratropium bromide. Two randomised controlled trials 
Respiratory Research  2007;8(1):19.
Asthmatics treated with long-acting beta-agonists have a reduced bronchodilator response to moderate doses of inhaled short acting beta-agonists during acute bronchoconstriction. It is not known if the response to higher doses of nebulised beta-agonists or other bronchodilators is impaired. We assessed the effect of long-acting beta-agonist treatment on the response to 5 mg nebulised salbutamol and to ipratropium bromide.
Two double-blind, placebo-controlled, crossover studies of inhaled formoterol 12 μg twice daily in patients with asthma.
High-dose salbutamol: 36 hours after the last dose of 1 week of formoterol or placebo treatment, 11 subjects inhaled methacholine to produce a 20% fall in FEV1. Salbutamol 5 mg was then administered via nebuliser and the FEV1 was monitored for 20 minutes. Ipratropium: 36 hours after the last dose of 1 week of formoterol or placebo treatment, 11 subjects inhaled 4.5% saline to produce a 20% fall in FEV1. Salbutamol 200 μg or ipratropium bromide 40 μg was then inhaled and the FEV1 was monitored for 30 minutes. Four study arms compared the response to each bronchodilator after formoterol and placebo. Analyses compared the area under the bronchodilator response curves, adjusting for changes in pre-challenge FEV1, dose of provocational agent and FEV1 fall during the challenge procedure.
The response to nebulised salbutamol was 15% lower after formoterol therapy compared to placebo (95% confidence 5 to 25%, p = 0.008). The response to ipratropium was unchanged.
Long-acting beta-agonist treatment induces tolerance to the bronchodilator effect of beta-agonists, which is not overcome by higher dose nebulised salbutamol. However, the bronchodilator response to ipratropium bromide is unaffected.
PMCID: PMC1821019  PMID: 17341317
14.  Associations between respiratory symptoms, lung function and gastro-oesophageal reflux symptoms in a population-based birth cohort 
Respiratory Research  2006;7(1):142.
Several studies have reported an association between asthma and gastro-oesophageal reflux, but it is unclear which condition develops first. The role of obesity in mediating this association is also unclear. We explored the associations between respiratory symptoms, lung function, and gastro-oesophageal reflux symptoms in a birth cohort of approximately 1000 individuals.
Information on respiratory symptoms, asthma, atopy, lung function and airway responsiveness was obtained at multiple assessments from childhood to adulthood in an unselected birth cohort of 1037 individuals followed to age 26. Symptoms of gastro-oesophageal reflux and irritable bowel syndrome were recorded at age 26.
Heartburn and acid regurgitation symptoms that were at least "moderately bothersome" at age 26 were significantly associated with asthma (odds ratio = 3.2; 95% confidence interval = 1.6–6.4), wheeze (OR = 3.5; 95% CI = 1.7–7.2), and nocturnal cough (OR = 4.3; 95% CI = 2.1–8.7) independently of body mass index. In women reflux symptoms were also associated with airflow obstruction and a bronchodilator response to salbutamol. Persistent wheezing since childhood, persistence of asthma since teenage years, and airway hyperresponsiveness since age 11 were associated with a significantly increased risk of heartburn and acid regurgitation at age 26. There was no association between irritable bowel syndrome and respiratory symptoms.
Reflux symptoms are associated with respiratory symptoms in young adults independently of body mass index. The mechanism of these associations remains unclear.
PMCID: PMC1702357  PMID: 17147826
15.  Tolerance to bronchodilation during treatment with long-acting beta-agonists, a randomised controlled trial 
Respiratory Research  2005;6(1):107.
Regular use of beta-agonists leads to tolerance to their bronchodilator effects. This can be demonstrated by measuring the response to beta-agonist following bronchoconstriction using methacholine. However most studies have demonstrated tolerance after a period of beta-agonist withdrawal, which is not typical of their use in clinical practice. This study assessed tolerance to the bronchodilator action of salbutamol during ongoing treatment with long-acting beta-agonist.
Random-order, double-blind, placebo-controlled, crossover trial. After 1 week without beta-agonists, 13 asthmatic subjects inhaled formoterol 12 μg twice daily or matching placebo for 1 week. Eight hours after the first and last doses subjects inhaled methacholine to produce a 20% fall in FEV1. Salbutamol 100, 200 and 400 μg (cumulative dose) was then given at 5-minute intervals and FEV1 was measured 5 minutes after each dose. After a 1 week washout subjects crossed over to the other treatment. Unscheduled use of beta-agonists was not allowed during the study. The main outcome variable was the area under the salbutamol response curve.
The analysis showed a significant time by treatment interaction indicating that the response to salbutamol fell during formoterol therapy compared to placebo. After 1 week of formoterol the area under the salbutamol response curve was 48% (95% confidence interval 28 to 68%) lower than placebo. This reduction in response remained significant when the analyses were adjusted for changes in the pre-challenge FEV1 and dose of methacholine given (p = 0.001).
The bronchodilator response to salbutamol is significantly reduced in patients taking formoterol. Clinically relevant tolerance to rescue beta-agonist treatment is likely to occur in patients treated with long-acting beta-agonists.
PMCID: PMC1266400  PMID: 16168062

Results 1-15 (15)