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1.
Health Technol Assess ; 23(37): 1-146, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31343402

RESUMO

BACKGROUND: Despite widespread use of therapies such as inhaled corticosteroids (ICSs), people with chronic obstructive pulmonary disease (COPD) continue to suffer, have reduced life expectancy and utilise considerable NHS resources. Laboratory investigations have demonstrated that at low plasma concentrations (1-5 mg/l) theophylline markedly enhances the anti-inflammatory effects of corticosteroids in COPD. OBJECTIVE: To determine the clinical effectiveness and cost-effectiveness of adding low-dose theophylline to a drug regimen containing ICSs in people with COPD at high risk of exacerbation. DESIGN: A multicentre, pragmatic, double-blind, randomised, placebo-controlled clinical trial. SETTING: The trial was conducted in 121 UK primary and secondary care sites. PARTICIPANTS: People with COPD [i.e. who have a forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) of < 0.7] currently on a drug regimen including ICSs with a history of two or more exacerbations treated with antibiotics and/or oral corticosteroids (OCSs) in the previous year. INTERVENTIONS: Participants were randomised (1 : 1) to receive either low-dose theophylline or placebo for 1 year. The dose of theophylline (200 mg once or twice a day) was determined by ideal body weight and smoking status. PRIMARY OUTCOME: The number of participant-reported exacerbations in the 1-year treatment period that were treated with antibiotics and/or OCSs. RESULTS: A total of 1578 people were randomised (60% from primary care): 791 to theophylline and 787 to placebo. There were 11 post-randomisation exclusions. Trial medication was prescribed to 1567 participants: 788 in the theophylline arm and 779 in the placebo arm. Participants in the trial arms were well balanced in terms of characteristics. The mean age was 68.4 [standard deviation (SD) 8.4] years, 54% were male, 32% smoked and mean FEV1 was 51.7% (SD 20.0%) predicted. Primary outcome data were available for 98% of participants: 772 in the theophylline arm and 764 in the placebo arm. There were 1489 person-years of follow-up data. The mean number of exacerbations was 2.24 (SD 1.99) for participants allocated to theophylline and 2.23 (SD 1.97) for participants allocated to placebo [adjusted incidence rate ratio (IRR) 0.99, 95% confidence interval (CI) 0.91 to 1.08]. Low-dose theophylline had no significant effects on lung function (i.e. FEV1), incidence of pneumonia, mortality, breathlessness or measures of quality of life or disease impact. Hospital admissions due to COPD exacerbation were less frequent with low-dose theophylline (adjusted IRR 0.72, 95% CI 0.55 to 0.94). However, 39 of the 51 excess hospital admissions in the placebo group were accounted for by 10 participants having three or more exacerbations. There were no differences in the reporting of theophylline side effects between the theophylline and placebo arms. LIMITATIONS: A higher than expected percentage of participants (26%) ceased trial medication; this was balanced between the theophylline and placebo arms and mitigated by over-recruitment (n = 154 additional participants were recruited) and the high rate of follow-up. The limitation of not using documented exacerbations is addressed by evidence that patient recall is highly reliable and the results of a small within-trial validation study. CONCLUSION: For people with COPD at high risk of exacerbation, the addition of low-dose oral theophylline to a drug regimen that includes ICSs confers no overall clinical or health economic benefit. This result was evident from the intention-to-treat and per-protocol analyses. FUTURE WORK: To promote consideration of the findings of this trial in national and international COPD guidelines. TRIAL REGISTRATION: Current Controlled Trials ISRCTN27066620. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 37. See the NIHR Journals Library website for further project information.

2.
Ann Am Thorac Soc ; 16(7): 868-876, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30888842

RESUMO

Rationale: Pooling data from multiple cohorts and extending the time frame across childhood should minimize study-specific effects, enabling better characterization of childhood wheezing. Objectives: To analyze wheezing patterns from early childhood to adolescence using combined data from five birth cohorts. Methods: We used latent class analysis to derive wheeze phenotypes among 7,719 participants from five birth cohorts with complete report of wheeze at five time periods. We tested the associations of derived phenotypes with late asthma outcomes and lung function, and investigated the uncertainty in phenotype assignment. Results: We identified five phenotypes: never/infrequent wheeze (52.1%), early onset preschool remitting (23.9%), early onset midchildhood remitting (9%), persistent (7.9%), and late-onset wheeze (7.1%). Compared with the never/infrequent wheeze, all phenotypes had higher odds of asthma and lower forced expiratory volume in 1 second and forced expiratory volume in 1 second/forced vital capacity in adolescence. The association with asthma was strongest for persistent wheeze (adjusted odds ratio, 56.54; 95% confidence interval, 43.75-73.06). We observed considerable within-class heterogeneity at the individual level, with 913 (12%) children having low membership probability (<0.60) of any phenotype. Class membership certainty was highest in persistent and never/infrequent, and lowest in late-onset wheeze (with 51% of participants having membership probabilities <0.80). Individual wheezing patterns were particularly heterogeneous in late-onset wheeze, whereas many children assigned to early onset preschool remitting class reported wheezing at later time points. Conclusions: All wheeze phenotypes had significantly diminished lung function in school-age children, suggesting that the notion that early life episodic wheeze has a benign prognosis may not be true for a proportion of transient wheezers. We observed considerable within-phenotype heterogeneity in individual wheezing patterns.

3.
PLoS Med ; 16(2): e1002744, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30742624

RESUMO

BACKGROUND: Maternal obesity and excessive gestational weight gain may have persistent effects on offspring fat development. However, it remains unclear whether these effects differ by severity of obesity, and whether these effects are restricted to the extremes of maternal body mass index (BMI) and gestational weight gain. We aimed to assess the separate and combined associations of maternal BMI and gestational weight gain with the risk of overweight/obesity throughout childhood, and their population impact. METHODS AND FINDINGS: We conducted an individual participant data meta-analysis of data from 162,129 mothers and their children from 37 pregnancy and birth cohort studies from Europe, North America, and Australia. We assessed the individual and combined associations of maternal pre-pregnancy BMI and gestational weight gain, both in clinical categories and across their full ranges, with the risks of overweight/obesity in early (2.0-5.0 years), mid (5.0-10.0 years) and late childhood (10.0-18.0 years), using multilevel binary logistic regression models with a random intercept at cohort level adjusted for maternal sociodemographic and lifestyle-related characteristics. We observed that higher maternal pre-pregnancy BMI and gestational weight gain both in clinical categories and across their full ranges were associated with higher risks of childhood overweight/obesity, with the strongest effects in late childhood (odds ratios [ORs] for overweight/obesity in early, mid, and late childhood, respectively: OR 1.66 [95% CI: 1.56, 1.78], OR 1.91 [95% CI: 1.85, 1.98], and OR 2.28 [95% CI: 2.08, 2.50] for maternal overweight; OR 2.43 [95% CI: 2.24, 2.64], OR 3.12 [95% CI: 2.98, 3.27], and OR 4.47 [95% CI: 3.99, 5.23] for maternal obesity; and OR 1.39 [95% CI: 1.30, 1.49], OR 1.55 [95% CI: 1.49, 1.60], and OR 1.72 [95% CI: 1.56, 1.91] for excessive gestational weight gain). The proportions of childhood overweight/obesity prevalence attributable to maternal overweight, maternal obesity, and excessive gestational weight gain ranged from 10.2% to 21.6%. Relative to the effect of maternal BMI, excessive gestational weight gain only slightly increased the risk of childhood overweight/obesity within each clinical BMI category (p-values for interactions of maternal BMI with gestational weight gain: p = 0.038, p < 0.001, and p = 0.637 in early, mid, and late childhood, respectively). Limitations of this study include the self-report of maternal BMI and gestational weight gain for some of the cohorts, and the potential of residual confounding. Also, as this study only included participants from Europe, North America, and Australia, results need to be interpreted with caution with respect to other populations. CONCLUSIONS: In this study, higher maternal pre-pregnancy BMI and gestational weight gain were associated with an increased risk of childhood overweight/obesity, with the strongest effects at later ages. The additional effect of gestational weight gain in women who are overweight or obese before pregnancy is small. Given the large population impact, future intervention trials aiming to reduce the prevalence of childhood overweight and obesity should focus on maternal weight status before pregnancy, in addition to weight gain during pregnancy.


Assuntos
Índice de Massa Corporal , Análise de Dados , Ganho de Peso na Gestação/fisiologia , Obesidade Pediátrica/epidemiologia , Austrália/epidemiologia , Estudos de Coortes , Europa (Continente)/epidemiologia , Feminino , Humanos , América do Norte/epidemiologia , Sobrepeso/diagnóstico , Sobrepeso/epidemiologia , Obesidade Pediátrica/diagnóstico , Gravidez , Fatores de Risco
4.
Health Technol Assess ; 22(70): 1-82, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30520413

RESUMO

BACKGROUND: Asthma exacerbations affect the quality of life of patients with asthma and have a major effect on the overall costs of asthma care. An asthma self-management plan that advises the temporary quadrupling of inhaled corticosteroid dose may prevent asthma exacerbations, but this needs to be confirmed before being adopted widely. OBJECTIVES: To compare the clinical effectiveness and cost-effectiveness of an asthma self-management plan that advises patients to temporarily quadruple the dose of inhaled corticosteroid when asthma control starts to deteriorate with a standard self-management plan. DESIGN: A multicentre, parallel-group, pragmatic randomised trial, with follow-up for 12 months. SETTING: Primary and secondary care across 207 sites in the UK. PARTICIPANTS: Asthma patients aged ≥ 16 years treated with an inhaled corticosteroid who had experienced at least one exacerbation in the previous 12 months. INTERVENTIONS: Participants were randomised (1 : 1) to a usual-care self-management plan or to a modified self-management plan that advised a temporary quadrupling of the inhaled corticosteroid at the point of asthma deterioration, both of which were actively implemented and supported by local research staff. PRIMARY OUTCOME: The primary outcome of 'time to first asthma exacerbation' was defined as the need for systemic corticosteroids (for at least 3 consecutive days) and/or unscheduled health-care consultations for asthma (i.e. reaching zone 3 or 4 of the Asthma UK self-management plan). RESULTS: A total of 1922 participants were randomised: the primary analysis included 938 participants (97%) in the usual-care group and 933 participants (97%) in the modified self-management group. The number of participants having at least one exacerbation of asthma in the year after randomisation was 484 (51.6%) in the usual-care group and 420 (45.0%) in the modified self-management group [adjusted hazard ratio 0.81, 95% confidence interval (CI) 0.71 to 0.92; p = 0.002]. There were fewer serious adverse events reported in the modified self-management group than in the usual-care group (11 vs. 32, respectively). Eight and six events of pneumonia, lower respiratory tract infections or influenza were reported in the usual-care group and the modified self-management group, respectively. Health-care-related costs were lower in the modified self-management group. The modified self-management group was £24 (bootstrapped 95% CI -£122 to £71) less costly than usual care, with a greater quality-adjusted life-year gain of 0.02 (bootstrapped 95% CI -0.005 to 0.04). Therefore, the modified self-management group was 'dominant', with a 94-95% probability of being cost-effective at the £20,000-30,000 threshold. LIMITATIONS: As the Fourfold Asthma STudy (FAST) was an open-label pragmatic trial, the possibility of treatment bias that may have affected the participants in the modified self-management group cannot be ruled out. Poorer than expected completion of participant diary cards, particularly within the usual-care self-management group, could have led to a null bias, underestimating the true effect of the intervention. CONCLUSIONS: An asthma self-management plan that advises patients to temporarily quadruple their dose of inhaled corticosteroid at the point of asthma symptoms worsening does reduce clinically important asthma exacerbations. In addition, the plan is cost-effective compared with the usual-care self-management plan. FUTURE WORK: To effectively implement asthma self-management plans that advise a temporary quadrupling of inhaled steroid at asthma deterioration into routine practice. TRIAL REGISTRATION: Current Controlled Trials ISRCTN15441965. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 70. See the NIHR Journals Library website for further project information.

5.
Pediatr Pulmonol ; 2018 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-30426718

RESUMO

This study investigated whether the previously reported associations in this birth cohort between maternal vitamin D and E intakes during pregnancy and childhood wheeze/asthma outcomes at age 5 and 10 years are still evident at age 15 years. In a prospective study of 1924 children recruited in utero, maternal vitamin D and E intakes during pregnancy were assessed by food frequency questionnaire and the children completed raespiratory questionnaire at age 15 years. Treatment for asthma at age 15 was also ascertained using healthcare data. Maternal vitamin D and E intakes were also related to combined childhood asthma data collected at 1, 2, 5, 10, and 15 years of age. Symptom data were available for 747 (39%) 15-year olds and healthcare data for 1689 (88%). There were no associations between maternal vitamin D and E intakes and childhood wheeze and asthma at age 15. Analysis of combined data collected between 1 and 15 years of age demonstrated that higher maternal vitamin D and E intakes during pregnancy were associated with a reduced likelihood of being diagnosed with asthma in the first 15 years: hazard ratio (95%CI) per quartile increase in vitamin intake of 0.87 (0.78,0.98) and 0.88 (0.78,0.98), respectively. Lower maternal vitamin D and E intakes during pregnancy are associated with increased risk of children wheezing and being diagnosed with asthma in the first 10 years but not after puberty, suggesting that post-natal exposures predominate in the etiology of incident asthma as children transition through puberty into adulthood.

6.
JAMA ; 320(15): 1548-1559, 2018 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-30326124

RESUMO

Importance: Chronic obstructive pulmonary disease (COPD) is a major global health issue and theophylline is used extensively. Preclinical investigations have demonstrated that low plasma concentrations (1-5 mg/L) of theophylline enhance antiinflammatory effects of corticosteroids in COPD. Objective: To investigate the effectiveness of adding low-dose theophylline to inhaled corticosteroids in COPD. Design, Setting, and Participants: The TWICS (theophylline with inhaled corticosteroids) trial was a pragmatic, double-blind, placebo-controlled, randomized clinical trial that enrolled patients with COPD between February 6, 2014, and August 31, 2016. Final follow-up ended on August 31, 2017. Participants had a ratio of forced expiratory volume in the first second to forced vital capacity (FEV1/FVC) of less than 0.7 with at least 2 exacerbations (treated with antibiotics, oral corticosteroids, or both) in the previous year and were using an inhaled corticosteroid. This study included 1578 participants in 121 UK primary and secondary care sites. Interventions: Participants were randomized to receive low-dose theophylline (200 mg once or twice per day) to provide plasma concentrations of 1 to 5 mg/L (determined by ideal body weight and smoking status) (n = 791) or placebo (n = 787). Main Outcomes and Measures: The number of participant-reported moderate or severe exacerbations treated with antibiotics, oral corticosteroids, or both over the 1-year treatment period. Results: Of the 1567 participants analyzed, mean (SD) age was 68.4 (8.4) years and 54% (843) were men. Data for evaluation of the primary outcome were available for 1536 participants (98%) (772 in the theophylline group; 764 in the placebo group). In total, there were 3430 exacerbations: 1727 in the theophylline group (mean, 2.24 [95% CI, 2.10-2.38] exacerbations per year) vs 1703 in the placebo group (mean, 2.23 [95% CI, 2.09-2.37] exacerbations per year); unadjusted mean difference, 0.01 (95% CI, -0.19 to 0.21) and adjusted incidence rate ratio, 0.99 (95% CI, 0.91-1.08). Serious adverse events in the theophylline and placebo groups included cardiac, 2.4% vs 3.4%; gastrointestinal, 2.7% vs 1.3%; and adverse reactions such as nausea (10.9% vs 7.9%) and headaches (9.0% vs 7.9%). Conclusions and Relevance: Among adults with COPD at high risk of exacerbation treated with inhaled corticosteroids, the addition of low-dose theophylline, compared with placebo, did not reduce the number COPD exacerbations over a 1-year period. The findings do not support the use of low-dose theophylline as adjunctive therapy to inhaled corticosteroids for the prevention of COPD exacerbations. Trial Registration: isrctn.org Identifier: ISRCTN27066620.


Assuntos
Corticosteroides/administração & dosagem , Broncodilatadores/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Teofilina/administração & dosagem , Administração por Inalação , Idoso , Broncodilatadores/efeitos adversos , Broncodilatadores/sangue , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/mortalidade , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Teofilina/efeitos adversos , Teofilina/sangue , Falha de Tratamento , Capacidade Vital/efeitos dos fármacos
7.
Environ Int ; 119: 429-437, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30029097

RESUMO

Household Air Pollution (HAP) from burning biomass fuels is a major cause of mortality and morbidity in low-income settings worldwide. Little is known about the differences in objective personal HAP exposure by age and gender. We measured personal exposure to HAP across six groups defined by age and gender (young children, young males, young females, adult males, adult females, and elderly) in rural households in two sub-Saharan African countries. Data on 24-hour personal exposure to HAP were collected from 215 participants from 85 households in Uganda and Ethiopia. HAP exposure was assessed by measuring carbon monoxide (CO) and/or fine particulate matter (PM2.5) concentrations using five types of devices. 24 h PM2.5 personal exposure was highest among adult females with Geometric Mean (GM) and Geometric Standard Deviation (GSD) concentrations of 205 µg/m3 (1.67) in Ethiopia; 177 µg/m3 (1.61 GSD) in Uganda. The lowest PM2.5 exposures were recorded among young males GM (GSD) 30.2 µg/m3 (1.89) in Ethiopia; 26.3 µg/m3 (1.48) in Uganda. Young females had exposures about two-thirds of the adult female group. Adult males, young children and the elderly experienced lower exposures reflecting their limited involvement in cooking. There was a similar pattern of exposure by age and gender in both countries and when assessed by CO measurement. There are substantial differences in exposure to HAP depending on age and gender in sub-Saharan Africa rural households reflecting differences in household cooking activity and time spent indoors. Future work should consider these differences when implementing exposure reduction interventions. There was a strong agreement between optical and gravimetric devices measurements although optical devices tended to overestimate exposure. There is need to calibrate optical devices against a gravimetric standard prior to quantifying exposure.

8.
Int J Obes (Lond) ; 42(7): 1249-1264, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29717267

RESUMO

BACKGROUND/OBJECTIVES: A number of meta-analyses suggest an association between any maternal smoking in pregnancy and offspring overweight obesity. Whether there is a dose-response relationship across number of cigarettes and whether this differs by sex remains unclear. SUBJECT/METHODS: Studies reporting number of cigarettes smoked during pregnancy and offspring BMI published up to May 2015 were searched. An individual patient data meta-analysis of association between the number of cigarettes smoked during pregnancy and offspring overweight (defined according to the International Obesity Task Force reference) was computed using a generalized additive mixed model with non-linear effects and adjustment for confounders (maternal weight status, breastfeeding, and maternal education) and stratification for sex. RESULTS: Of 26 identified studies, 16 authors provided data on a total of 238,340 mother-child-pairs. A linear positive association was observed between the number of cigarettes smoked and offspring overweight for up to 15 cigarettes per day with an OR increase per cigarette of 1.03, 95% CI = [1.02-1.03]. The OR flattened with higher cigarette use. Associations were similar in males and females. Sensitivity analyses supported these results. CONCLUSIONS: A linear dose-response relationship of maternal smoking was observed in the range of 1-15 cigarettes per day equally in boys and girls with no further risk increase for doses above 15 cigarettes.

9.
ERJ Open Res ; 4(2)2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29651422

RESUMO

Aspergillus fumigatus infects up to 50% of cystic fibrosis (CF) patients and may play a role in progressive lung disease. As cystic fibrosis transmembrane conductance regulator is expressed in cells of the innate immune system, we hypothesised that impaired antifungal immune responses play a role in CF-related Aspergillus lung disease. Peripheral blood mononuclear cells, polymorphonuclear cells (PMN) and monocytes were isolated from blood samples taken from CF patients and healthy volunteers. Live-cell imaging and colorimetric assays were used to assess antifungal activity in vitro. Production of reactive oxygen species (ROS) was measured using luminol-induced chemiluminescence and was related to clinical metrics as collected by case report forms. CF phagocytes are as effective as those from healthy controls with regards to phagocytosis, killing and restricting germination of A. fumigatus conidia. ROS production by CF phagocytes was up to four-fold greater than healthy controls (p<0.05). This effect could not be replicated in healthy phagocytes by priming with lipopolysaccharide or serum from CF donors. Increased production of ROS against A. fumigatus by CF PMN was associated with an increased number of clinical exacerbations in the previous year (p=0.007) and reduced lung function (by forced expiratory volume in 1 s) (p=0.014). CF phagocytes mount an intrinsic exaggerated release of ROS upon A. fumigatus stimulation which is associated with clinical disease severity.

10.
N Engl J Med ; 378(10): 902-910, 2018 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-29504499

RESUMO

BACKGROUND: Asthma exacerbations are frightening for patients and are occasionally fatal. We tested the concept that a plan for patients to manage their asthma (self-management plan), which included a temporary quadrupling of the dose of inhaled glucocorticoids when asthma control started to deteriorate, would reduce the incidence of severe asthma exacerbations among adults and adolescents with asthma. METHODS: We conducted a pragmatic, unblinded, randomized trial involving adults and adolescents with asthma who were receiving inhaled glucocorticoids, with or without add-on therapy, and who had had at least one exacerbation in the previous 12 months. We compared a self-management plan that included an increase in the dose of inhaled glucocorticoids by a factor of 4 (quadrupling group) with the same plan without such an increase (non-quadrupling group), over a period of 12 months. The primary outcome was the time to a first severe asthma exacerbation, defined as treatment with systemic glucocorticoids or an unscheduled health care consultation for asthma. RESULTS: A total of 1922 participants underwent randomization, of whom 1871 were included in the primary analysis. The number of participants who had a severe asthma exacerbation in the year after randomization was 420 (45%) in the quadrupling group as compared with 484 (52%) in the non-quadrupling group, with an adjusted hazard ratio for the time to a first severe exacerbation of 0.81 (95% confidence interval, 0.71 to 0.92; P=0.002). The rate of adverse effects, which were related primarily to local effects of inhaled glucocorticoids, was higher in the quadrupling group than in the non-quadrupling group. CONCLUSIONS: In this trial involving adults and adolescents with asthma, a personalized self-management plan that included a temporary quadrupling of the dose of inhaled glucocorticoids when asthma control started to deteriorate resulted in fewer severe asthma exacerbations than a plan in which the dose was not increased. (Funded by the Health Technology Assessment Programme of the National Institute for Health Research; Current Controlled Trials number, ISRCTN15441965 .).


Assuntos
Antiasmáticos/administração & dosagem , Asma/prevenção & controle , Fluticasona/administração & dosagem , Autogestão , Administração por Inalação , Adolescente , Adulto , Antiasmáticos/efeitos adversos , Asma/terapia , Relação Dose-Resposta a Droga , Feminino , Fluticasona/efeitos adversos , Humanos , Estimativa de Kaplan-Meier , Masculino , Modelos de Riscos Proporcionais
11.
Eur Respir J ; 51(2)2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29386348

RESUMO

There is increasing evidence that antenatal factors predispose to childhood asthma. We tested the hypothesis that reduced first trimester fetal size is associated with increased risk for asthma at 15 years of age.Fetal size in the first and second trimester was ascertained by ultrasound scan. The primary outcome of being dispensed one or more asthma medications by the family doctor in the year before the 15th birthday was determined from routinely acquired dispensing data.Dispensing data were available for 1699 (88% of the original cohort) participants at 15 years of age and questionnaire data for 750 (39%). Each reduction in z-score for first trimester size was associated with increased odds for dispensed asthma medication at 15 years of age (OR 1.26, 95% CI 1.03-1.54) and self-reported use of asthma medications (OR 1.55, 95% CI 1.16-2.08). Overall, first and second trimester size and forced expiratory volume in 1 s at ages 5, 10 and 15 years were reduced for those dispensed asthma medications compared with those not dispensed asthma medications (p=0.003).Antenatal factors that are active by the first trimester may contribute to respiratory well-being throughout childhood. Dropout from a birth cohort study can overestimate of the magnitude of any true association.

12.
Pediatr Pulmonol ; 53(1): 10-16, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29136347

RESUMO

BACKGROUND: Airway epithelial cell (AEC) function differs between children with and without asthma. Here, we associated neonatal AEC function with asthma symptoms at 4 years of age. METHODS: Nasal AEC were collected from neonates within 48 h of birth. Cells were cultured and stimulated with tumor necrosis factor alpha/interleukin-1 beta (TNFα/IL-1ß), lipopolysaccharide (LPS), or house dust mite (HDM). Absolute concentrations of pro-inflammatory mediators in the culture supernatant were quantified and expressed as median [interquartile range] in pg/mg protein. A parent-completed respiratory questionnaire was returned when the child was 4 years old. RESULTS: AEC were successfully cultured in 139 neonates, of whom 120 were contacted at 4 years and 91 (76%) questionnaires were returned. Sixteen children had wheezed ever and 11 had recent wheeze. At birth, when compared to those with no recent wheeze, supernatants from cultured neonatal AEC from the children with recent wheeze had reduced median IL-8 (CXCL8) release after treatment with culture medium alone (P = 0.049), with TNFα/IL-1ß (P < 0.001) and LPS (P = 0.004). Additionally, and when compared to those with no recent wheeze, 4 year olds with recent wheeze had reduced neonatal AEC release of IL-6 (P = 0.013), GMCSF (P = 0.012), and ICAM-1 (P = 0.017) after treatment with TNFα/IL-1ß and reduced release of ICAM-1 (P = 0.038) and RANTES (P = 0.042) after treatment with HDM. CONCLUSIONS: Abnormalities in AEC function are present at birth before the onset of childhood wheeze. The relationship between reduced AEC function at birth and wheeze at 4 years was not exclusive, suggesting that post-natal factors are required for the AEC abnormality to translate into symptoms.


Assuntos
Asma/imunologia , Citocinas/imunologia , Células Epiteliais/imunologia , Mucosa Respiratória/citologia , Sons Respiratórios/imunologia , Animais , Células Cultivadas , Pré-Escolar , Citocinas/farmacologia , Feminino , Humanos , Recém-Nascido , Lipopolissacarídeos/farmacologia , Masculino , Pyroglyphidae/imunologia
13.
14.
Pediatr Allergy Immunol ; 28(5): 430-437, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28423467

RESUMO

BACKGROUND: The use of antibiotic therapy early in life might influence the risk of developing asthma. Studies assessing the influence of early life antibiotic use on the risk of asthma exacerbations are limited, and the results are inconsistent. Therefore, the aim of this study was to assess the association between use of antibiotic during the first 3 years of life and the risk of developing childhood asthma and the occurrence of asthma exacerbations. METHODS: Data from four large childhood cohorts were used; two population-based cohorts to study the risk of developing asthma: Generation R (n=7393, The Netherlands) and SEATON (n=891, Scotland, UK), and two asthma cohorts to assess the risk of asthma exacerbations: PACMAN (n=668, The Netherlands) and BREATHE (n=806, Scotland, UK). Odds ratios (ORs) were derived from logistic regression analysis within each database followed by pooling the results using a fixed- or random-effect model. RESULTS: Antibiotic use in early life was associated with an increased risk of asthma in a meta-analysis of the Generation R and SEATON data (OR: 2.18, 95% CI: 1.04-4.60; I2 : 76.3%). There was no association between antibiotic use in early life and risk of asthma exacerbations later in life in a meta-analysis of the PACMAN and BREATHE data (OR: 0.93, 95% CI: 0.65-1.32; I2 : 0.0%). CONCLUSION: Children treated with antibiotic in the first 3 years of life are more likely to develop asthma, but there is no evidence that the exposure to antibiotic is associated with increased risk of asthma exacerbations.


Assuntos
Antibacterianos/efeitos adversos , Asma/induzido quimicamente , Adolescente , Criança , Pré-Escolar , Progressão da Doença , Feminino , Humanos , Lactente , Recém-Nascido , Modelos Logísticos , Masculino , Razão de Chances , Fatores de Risco , Adulto Jovem
15.
PLoS One ; 12(2): e0170946, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28231292

RESUMO

BACKGROUND: Maternal smoking during pregnancy is linked to reduced birth weight but the gestation at onset of this relationship is not certain. We present a systematic review of the literature describing associations between maternal smoking during pregnancy and ultrasound measurements of fetal size, together with an accompanying meta-analysis. METHODS: Studies were selected from electronic databases (OVID, EMBASE and Google Scholar) that examined associations between maternal smoking or smoke exposure and antenatal fetal ultrasound measurements. Outcome measures were first, second or third trimester fetal measurements. RESULTS: There were 284 abstracts identified, 16 papers were included in the review and the meta-analysis included data from eight populations. Maternal smoking was associated with reduced second trimester head size (mean reduction 0.09 standard deviation (SD) [95% CI 0.01, 0.16]) and femur length (0.06 [0.01, 0.10]) and reduced third trimester head size (0.18 SD [0.13, 0.23]), femur length (0.27 SD [0.21, 0.32]) and estimated fetal weight (0.18 SD [0.11, 0.24]). Higher maternal cigarette consumption was associated with a lower z score for head size in the second (mean difference 0.09 SD [0, 0.19]) and third (0.15 SD [0.03, 0.26]) trimesters compared to lower consumption. Fetal measurements were not reduced for those whose mothers quit before or after becoming pregnant compared to mothers who had never smoked. CONCLUSIONS: Maternal smoking during pregnancy is associated with reduced fetal measurements after the first trimester, particularly reduced head size and femur length. These effects may be attenuated if mothers quit or reduce cigarette consumption during pregnancy.


Assuntos
Desenvolvimento Fetal , Retardo do Crescimento Fetal/etiologia , Fumar/efeitos adversos , Poluição por Fumaça de Tabaco/efeitos adversos , Peso ao Nascer , Feminino , Cabeça/embriologia , Humanos , Gravidez , Primeiro Trimestre da Gravidez , Segundo Trimestre da Gravidez , Terceiro Trimestre da Gravidez
16.
Pediatr Allergy Immunol ; 28(2): 162-169, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27779796

RESUMO

BACKGROUND: Childhood asthma is a common condition whose prevalence is changing. We hypothesized that the relationship between asthma and associated risk factors has changed over a 50-year period. METHODS: An ecological study design was used. Children aged 8-13 attending schools in Aberdeen city were surveyed on seven occasions between 1964 and 2014. The following were determined: history of asthma, history of eczema, parental smoking, parental asthma, sex and socio-economic status. Analysis was by a structural change model with two knots. The outcome reported was the change in odds ratio between asthma and a given risk factor during a given period. RESULTS: There were 23,241 questionnaires distributed and 17,439 returned (75%). The odds ratio (OR) for a child with asthma to have eczema increased between 1989 and 1999 by 1.031 [95% CI 1.028, 1.035] and by 1.042 between 2004 and 2014 [1.038, 1.047]. The OR for a child with asthma to have a parent who smoked rose by 1.032 [1.028, 1.036] between 1989 and 1999 and by 1.043 [1.038, 1.047] between 2004 and 2014), and to have a parent with asthma (1.027 [1.022, 1.031] for 1994-99 and 1.042 [1.037, 1.048] for 2004-2014). The OR for a child with asthma being male, but not and being from the most deprived communities, rose between 1989-1999 and 2004-2014. CONCLUSIONS: The relationship between asthma prevalence and particular risk factors changed over the 50-year period of study, and this might reflect changes in children's environment and/or susceptibility.


Assuntos
Asma/epidemiologia , Eczema/epidemiologia , Fatores de Tempo , Adolescente , Criança , Fumar Cigarros , Feminino , Humanos , Masculino , Anamnese , Pais , Prevalência , Fatores de Risco , Inquéritos e Questionários , Reino Unido/epidemiologia
17.
Environ Res ; 153: 126-134, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27940105

RESUMO

BACKGROUND: Evidence from longitudinal population-based studies relating occupational exposure to the full range of different forms of airborne pollutants and lung function and airway obstruction is limited. OBJECTIVE: To relate self-reported COPD and lung function impairment to occupational exposure to different forms of airborne chemical pollutants in individuals who did not have childhood wheeze. METHODS: A prospective cohort study was randomly selected in 1964 at age 10-15 years and followed up in 1989, 1995, 2001 and 2014 (aged 58-64) by spirometry and respiratory questionnaire. Occupational histories were recorded in 2014 and occupational exposures assigned using an airborne chemical job exposure matrix. The risk of COPD and lung function impairment was analyzed in subjects, who did not have childhood wheeze, using logistic and linear regression and linear mixed effects models. RESULTS: 237 subjects without childhood wheeze (mean age 60.6 years, 47% male) were analyzed. There was no association between any respiratory outcomes and exposure to gases, fibers, mists or mineral dusts and no consistent associations with exposure to fumes. Reduced FEV1 was associated with longer duration (years) of exposure to any of the six main pollutant forms - vapors, gases, dusts, fumes, fibers and mists (VGDFFiM) with evidence of a dose-response relationship (p-trend=0.004). Exposure to biological dusts was associated with self-reported COPD and FEV1

Assuntos
Poluentes Ocupacionais do Ar/toxicidade , Pulmão/fisiologia , Exposição Ocupacional/efeitos adversos , Doença Pulmonar Obstrutiva Crônica/etiologia , Adolescente , Adulto , Criança , Estudos de Coortes , Estudos Transversais , Poeira , Feminino , Volume Expiratório Forçado , Humanos , Estudos Longitudinais , Pulmão/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Sons Respiratórios , Adulto Jovem
18.
Food Sci Nutr ; 4(6): 848-851, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27826434

RESUMO

Low maternal vitamin E intake during pregnancy is associated with childhood asthma and a trial is required to test whether increasing maternal vitamin E intake reduces childhood asthma. This study investigated whether such a trial is possible using food to increase vitamin E intake. Three soup varieties with enhanced vitamin E content (16-19 mg/can) from food ingredients were developed. Near identical retail versions (vitamin E 1-4 mg/can) acted as placebo. In a pilot double-blind randomized controlled trial, pregnant women were randomized 1:1 to enhanced or placebo soups (three tins/week) from 12 weeks gestation to delivery. Vitamin E intake was quantified at 12, 20, and 34 weeks gestation. Qualitative interviews were conducted. 59 women were randomized (29 enhanced, 30 placebo), 28 completed the trial, (15 enhanced, 13 placebo). In women completing the trial, vitamin E intake of the placebo group remained unchanged; 7.09 mg/d (95% CI 5.41-8.77) at 12 weeks, 6.41 mg/d (5.07-7.75) at 20 weeks, and 6.67 mg/d (5.38-7.96) at 34 weeks gestation; vitamin E intake of the enhanced group increased from 6.50 mg/d (5.21-7.79) at 12 weeks to 14.9 mg/d (13.3-16.4) at 20 weeks and 15.2 mg/d (12.9-17.5) at 34 weeks, P < 0.001. Qualitative interviewing provided clear guidance on improving adherence. Although 31 women withdrew at median 19 weeks gestation (interquartile range 16-25), the intervention was consumed by women for 80% of weeks between 12 and 34 weeks gestation and for 63% of weeks between 12 weeks gestation and delivery. In a pilot double-blind randomized controlled trial (RCT) it is possible to increase maternal vitamin E intake using food ingredients, a further food product is required to improve adherence.

20.
Trials ; 17(1): 499, 2016 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-27737713

RESUMO

BACKGROUND: Asthma is one of the commonest chronic diseases in the UK. Acute exacerbations of asthma are unpredictable, disruptive and frightening. They cause considerable morbidity and account for a large component of the health service costs of asthma. The widespread use of an asthma self-management plan, designed to encourage disease monitoring and timely intervention, can reduce exacerbations and is, therefore, recommended for all patients with asthma. Unfortunately, the majority of patients are not provided with such a plan. There are a variety of reasons for this but uncertainty about what to include in the plan when asthma control is deteriorating, but before the need for orally administered corticosteroids, is a contributing factor. The aim of this trial is to determine whether an asthma self-management plan, which includes a temporary quadrupling of the dose of inhaled corticosteroid when asthma control starts to deteriorate, reduces asthma exacerbations requiring orally administered corticosteroids or unscheduled health care consultation for asthma. METHODS: A multicentre, pragmatic, randomised trial in adults aged over 16 years with a clinical diagnosis of asthma, treated with a licensed dose of inhaled corticosteroid and at least one exacerbation in the previous 12 months requiring treatment with systemic corticosteroids. Participants will be randomised to either a self-management plan, which includes a temporary (maximum of 14 days) fourfold increase in inhaled corticosteroid or the same plan without an increase in inhaled corticosteroid. Participants will be followed up at 6 and 12 months and will attend the clinic for an additional visit if their asthma control deteriorates. The primary outcome is time to first asthma exacerbation, defined as the need for systemic corticosteroids and/or unscheduled health care consultation for asthma. The estimated sample size is 1800 participants. DISCUSSION: The FAST trial is an independent study that has been prioritised and commissioned by the National Institute for Health Research (NIHR) in the United Kingdom. It will provide high-quality evidence to inform clinical decision-making on the role of an asthma self-management plan, which includes a temporary fourfold increase of inhaled corticosteroid, when asthma control starts to deteriorate. The first participant was randomised on 17th May 2013 and recruitment will close on 31 January 2016 with the last patient last visit taking place in January 2017. TRIAL REGISTRATION: ISRCTN: 15441965 , registered on 25 April 2013.


Assuntos
Corticosteroides/administração & dosagem , Corticosteroides/economia , Antiasmáticos/administração & dosagem , Antiasmáticos/economia , Asma/tratamento farmacológico , Asma/economia , Custos de Medicamentos , Pulmão/efeitos dos fármacos , Administração por Inalação , Administração Oral , Adolescente , Corticosteroides/efeitos adversos , Adulto , Antiasmáticos/efeitos adversos , Asma/diagnóstico , Asma/fisiopatologia , Protocolos Clínicos , Análise Custo-Benefício , Progressão da Doença , Feminino , Humanos , Pulmão/fisiopatologia , Masculino , Projetos de Pesquisa , Autocuidado , Fatores de Tempo , Resultado do Tratamento , Reino Unido , Adulto Jovem
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