Humoral and cellular response to the COVID-19 vaccine in immunocompromised children.

BACKGROUND: A suboptimal response to the 2-dose COVID-19 vaccine series in the immunocompromised population prompted recommendations for a 3rd primary dose. We aimed to determine the humoral and cellular immune response to the 3rd COVID-19 vaccine in immunocompromised children. METHODS: Prospective cohort study of immunocompromised participants, 5-21 years old, who received 2 prior doses of an mRNA COVID-19 vaccine. Humoral and CD4/CD8 T-cell responses were measured to SARS-CoV-2 spike antigens prior to receiving the 3rd vaccine dose and 3-4 weeks after the 3rd dose was given. RESULTS: Of the 37 participants, approximately half were solid organ transplant recipients. The majority (86.5%) had a detectable humoral response after the 2nd and 3rd vaccine doses, with a significant increase in antibody levels after the 3rd dose. Positive T-cell responses increased from being present in 86.5% to 100% of the cohort after the 3rd dose. CONCLUSIONS: Most immunocompromised children mount a humoral and cellular immune response to the 2-dose COVID-19 vaccine series, which is significantly augmented after receiving the 3rd vaccine dose. This supports the utility of the 3rd vaccine dose and the rationale for ongoing emphasis for vaccination against COVID-19 in this population. IMPACT: Most immunocompromised children mount a humoral and cellular immune response to the 2-dose COVID-19 vaccine series, which is significantly augmented after receiving the 3rd vaccine dose. This is the first prospective cohort study to analyze both the humoral and T-cell immune response to the 3rd COVID-19 primary vaccine dose in children who are immunocompromised. The results of this study support the utility of the 3rd vaccine dose and the rationale for ongoing emphasis for vaccination against COVID-19 in the immunosuppressed pediatric population.

Occupational exposure to solvents and lung function decline: A population based study.

RATIONALE: While cross-sectional studies have shown associations between certain occupational exposures and lower levels of lung function, there was little evidence from population-based studies with repeated lung function measurements. OBJECTIVES: We aimed to investigate the associations between occupational exposures and longitudinal lung function decline in the population-based Tasmanian Longitudinal Health Study. METHODS: Lung function decline between ages 45 years and 50 years was assessed using data from 767 participants. Using lifetime work history calendars completed at age 45 years, exposures were assigned according to the ALOHA plus Job Exposure Matrix. Occupational exposures were defined as ever exposed and cumulative exposure -unit- years. We investigated effect modification by sex, smoking and asthma status. RESULTS: Compared with those without exposure, ever exposures to aromatic solvents and metals were associated with a greater decline in FEV1 (aromatic solvents 15.5 mL/year (95% CI -24.8 to 6.3); metals 11.3 mL/year (95% CI -21.9 to - 0.7)) and FVC (aromatic solvents 14.1 mL/year 95% CI -28.8 to - 0.7; metals 17.5 mL/year (95% CI -34.3 to - 0.8)). Cumulative exposure (unit years) to aromatic solvents was also associated with greater decline in FEV1 and FVC. Women had lower cumulative exposure years to aromatic solvents than men (mean (SD) 9.6 (15.5) vs 16.6 (14.6)), but greater lung function decline than men. We also found association between ever exposures to gases/fumes or mineral dust and greater decline in lung function. CONCLUSIONS: Exposures to aromatic solvents and metals were associated with greater lung function decline. The effect of aromatic solvents was strongest in women. Preventive strategies should be implemented to reduce these exposures in the workplace.

Childhood measles contributes to post-bronchodilator airflow obstruction in middle-aged adults: A cohort study.

BACKGROUND AND OBJECTIVE: Chronic obstructive pulmonary disease (COPD) has potential origins in childhood but an association between childhood measles and post-bronchodilator (BD) airflow obstruction (AO) has not yet been shown. We investigated whether childhood measles contributed to post-BD AO through interactions with asthma and/or smoking in a non-immunized middle-aged population. METHODS: The population-based Tasmanian Longitudinal Health Study (TAHS) cohort born in 1961 (n = 8583) underwent spirometry in 1968 before immunization was introduced. A history of childhood measles infection was obtained from school medical records. During the fifth decade follow-up (n = 5729 responses), a subgroup underwent further lung function measurements (n = 1389). Relevant main associations and interactions by asthma and/or smoking on post-BD forced expiratory volume in 1 s/forced vital capacity (FEV1 /FVC; continuous variable) and AO (FEV1 /FVC < lower limit of normal) were estimated by multiple regression. RESULTS: Sixty-nine percent (n = 950) had a history of childhood measles. Childhood measles augmented the combined adverse effect of current clinical asthma and smoking at least 10 pack-years on post-BD FEV1 /FVC ratio in middle age (z-score: -0.70 (95% CI: -1.1 to -0.3) vs -1.36 (-1.6 to -1.1), three-way interaction: P = 0.009), especially for those with childhood-onset asthma. For never- and ever-smokers of <10 pack-years who had current asthma symptoms, compared with those without childhood measles, paradoxically, the odds for post-BD AO was not significant in the presence of childhood measles (OR: 12.0 (95% CI: 3.4-42) vs 2.17 (0.9-5.3)). CONCLUSION: Childhood measles infection appears to compound the associations between smoking, current asthma and post-BD AO. Differences between asthma subgroups provide further insight into the complex aetiology of obstructive lung diseases for middle-aged adults.

Childhood Lung Function Predicts Adult Chronic Obstructive Pulmonary Disease and Asthma-Chronic Obstructive Pulmonary Disease Overlap Syndrome.

RATIONALE: The burden of chronic obstructive pulmonary disease (COPD) is increasing, yet there are limited data on early life risk factors. OBJECTIVES: To investigate the role of childhood lung function in adult COPD phenotypes. METHODS: Prebronchodilator spirometry was performed for a cohort of 7-year-old Tasmanian children (n = 8,583) in 1968 who were resurveyed at 45 years, and a selected subsample (n = 1,389) underwent prebronchodilator and post-bronchodilator spirometry. For this analysis, COPD was spirometrically defined as a post-bronchodilator FEV1/FVC less than the lower limit of normal. Asthma-COPD overlap syndrome (ACOS) was defined as the coexistence of both COPD and current asthma. Associations between childhood lung function and asthma/COPD/ACOS were examined using multinomial regression. MEASUREMENTS AND MAIN RESULTS: At 45 years, 959 participants had neither current asthma nor COPD (unaffected), 269 had current asthma alone, 59 had COPD alone, and 68 had ACOS. The reweighted prevalence of asthma alone was 13.5%, COPD alone 4.1%, and ACOS 2.9%. The lowest quartile of FEV1 at 7 years was associated with ACOS (odds ratio, 2.93; 95% confidence interval, 1.32-6.52), but not COPD or asthma alone. The lowest quartile of FEV1/FVC ratio at 7 years was associated with ACOS (odds ratio, 16.3; 95% confidence interval, 4.7-55.9) and COPD (odds ratio, 5.76; 95% confidence interval, 1.9-17.4), but not asthma alone. CONCLUSIONS: Being in the lowest quartile for lung function at age 7 may have long-term consequences for the development of COPD and ACOS by middle age. Screening of lung function in school age children may identify a high-risk group that could be targeted for intervention. Further research is needed to understand possible modifiers of these associations and develop interventions for children with impaired lung function.

Traffic-related air pollution exposure is associated with allergic sensitization, asthma, and poor lung function in middle age.

BACKGROUND: Traffic-related air pollution (TRAP) exposure is associated with allergic airway diseases and reduced lung function in children, but evidence concerning adults, especially in low-pollution settings, is scarce and inconsistent. OBJECTIVES: We sought to determine whether exposure to TRAP in middle age is associated with allergic sensitization, current asthma, and reduced lung function in adults, and whether these associations are modified by variants in Glutathione S-Transferase genes. METHODS: The study sample comprised the proband 2002 laboratory study of the Tasmanian Longitudinal Health Study. Mean annual residential nitrogen dioxide (NO2) exposure was estimated for current residential addresses using a validated land-use regression model. Associations between TRAP exposure and allergic sensitization, lung function, current wheeze, and asthma (n = 1405) were investigated using regression models. RESULTS: Increased mean annual NO2 exposure was associated with increased risk of atopy (adjusted odds ratio [aOR], 1.14; 95% CI, 1.02-1.28 per 1 interquartile range increase in NO2 [2.2 ppb]) and current wheeze (aOR, 1.14; 1.02-1.28). Similarly, living less than 200 m from a major road was associated with current wheeze (aOR, 1.38; 95% CI, 1.06-1.80) and atopy (aOR, 1.26; 95% CI, 0.99-1.62), and was also associated with having significantly lower prebronchodilator and postbronchodilator FEV1 and prebronchodilator forced expiratory flow at 25% to 75% of forced vital capacity. We found evidence of interactions between living less than 200 m from a major road and GSTT1 polymorphism for atopy, asthma, and atopic asthma. Overall, carriers of the GSTT1 null genotype had an increased risk of asthma and allergic outcomes if exposed to TRAP. CONCLUSIONS: Even relatively low TRAP exposures confer an increased risk of adverse respiratory and allergic outcomes in genetically susceptible individuals.

Occupational exposure to pesticides are associated with fixed airflow obstruction in middle-age.

RATIONALE: Population-based studies have found evidence of a relationship between occupational exposures and Chronic Obstructive Pulmonary Disease (COPD), but these studies are limited by the use of prebronchodilator spirometry. Establishing this link using postbronchodilator is critical, because occupational exposures are a modifiable risk factor for COPD. OBJECTIVES: To investigate the associations between occupational exposures and fixed airflow obstruction using postbronchodilator spirometry. METHODS: One thousand three hundred and thirty-five participants were included from 2002 to 2008 follow-up of the Tasmanian Longitudinal Health Study (TAHS). Spirometry was performed and lifetime work history calendars were used to collect occupational history. ALOHA plus Job Exposure Matrix was used to assign occupational exposure, and defined as ever exposed and cumulative exposure unit (EU)-years. Fixed airflow obstruction was defined by postbronchodilator FEV1/FVC <0.7 and the lower limit of normal (LLN). Multinomial logistic regressions were used to investigate potential associations while controlling for possible confounders. RESULTS: Ever exposure to biological dust (relative risk (RR)=1.58, 95% CI 1.01 to 2.48), pesticides (RR=1.74,95% CI 1.00 to 3.07) and herbicides (RR=2.09,95% CI 1.18 to 3.70) were associated with fixed airflow obstruction. Cumulative EU-years to all pesticides (RR=1.11,95% CI 1.00 to 1.25) and herbicides (RR=1.15,95% CI 1.00 to 1.32) were also associated with fixed airflow obstruction. In addition, all pesticides exposure was consistently associated with chronic bronchitis and symptoms that are consistent with airflow obstruction. Ever exposure to mineral dust, gases/fumes and vapours, gases, dust or fumes were only associated with fixed airflow obstruction in non-asthmatics only. CONCLUSIONS: Pesticides and herbicides exposures were associated with fixed airflow obstruction and chronic bronchitis. Biological dust exposure was also associated with fixed airflow obstruction in non-asthmatics. Minimising occupational exposure to these agents may help to reduce the burden of COPD.

Bronchial hyperresponsiveness and obesity in middle age: insights from an Australian cohort.

The association between obesity and bronchial hyperresponsiveness (BHR) is incompletely characterised. Using the 2006 follow-up of the Tasmanian Longitudinal Health Study, we measured the association between obesity and BHR and whether it was mediated by small airway closure or modified by asthma and sex of the patient.A methacholine challenge measured BHR. Multivariable logistic regression measured associations between body mass index (BMI) and BHR, adjusting for sex, asthma, smoking, corticosteroid use, family history and lung function. Mediation by airway closure was also measured.Each increase in BMI of 1 kg·m-2 was associated with a 5% increase in the odds of BHR (OR 1.05, 95% CI 1.01-1.09) and 43% of this association was mediated by airway closure. In a multivariable model, BMI (OR 1.06, 95% CI 1.00-1.16) was associated with BHR independent of female sex (OR 3.26, 95% CI 1.95-5.45), atopy (OR 2.30, 95% CI 1.34-3.94), current asthma (OR 5.74, 95% CI 2.79-11.82), remitted asthma (OR 2.35, 95% CI 1.27-4.35), low socioeconomic status (OR 2.11, 95% CI 1.03-4.31) and forced expiratory volume in 1 s/forced vital capacity (OR 0.86, 95% CI 0.82-0.91). Asthma modified the association with an increasing probability of BHR as BMI increased, only in those with no or remitted asthma.An important fraction of the BMI/BHR association was mediated via airway closure. Conflicting findings in previous studies could be explained by failure to consider this intermediate step.

The Dose-Response Association between Nitrogen Dioxide Exposure and Serum Interleukin-6 Concentrations.

Systemic inflammation is an integral part of chronic obstructive pulmonary disease (COPD), and air pollution is associated with cardiorespiratory mortality, yet the interrelationships are not fully defined. We examined associations between nitrogen dioxide (NO2) exposure (as a marker of traffic-related air pollution) and pro-inflammatory cytokines, and investigated effect modification and mediation by post-bronchodilator airflow obstruction (post-BD-AO) and cardiovascular risk. Data from middle-aged participants in the Tasmanian Longitudinal Health Study (TAHS, n = 1389) were analyzed by multivariable logistic regression, using serum interleukin (IL)-6, IL-8 and tumor necrosis factor-α (TNF-α) as the outcome. Mean annual NO2 exposure was estimated at residential addresses using a validated satellite-based land-use regression model. Post-BD-AO was defined by post-BD forced expiratory ratio (FEV1/FVC) < lower limit of normal, and cardiovascular risk by a history of either cerebrovascular or ischaemic heart disease. We found a positive association with increasing serum IL-6 concentration (geometric mean 1.20 (95% CI: 1.1 to 1.3, p = 0.001) per quartile increase in NO2). This was predominantly a direct relationship, with little evidence for either effect modification or mediation via post-BD-AO, or for the small subgroup who reported cardiovascular events. However, there was some evidence consistent with serum IL-6 being on the causal pathway between NO2 and cardiovascular risk. These findings raise the possibility that the interplay between air pollution and systemic inflammation may differ between post-BD airflow obstruction and cardiovascular diseases.

Clinical and functional differences between early-onset and late-onset adult asthma: a population-based Tasmanian Longitudinal Health Study.

BACKGROUND: Differences between early-onset and late-onset adult asthma have not been comprehensively described using prospective data. AIMS: To characterise the differences between early-onset and late-onset asthma in a longitudinal cohort study. METHODS: The Tasmanian Longitudinal Health Study (TAHS) is a population-based cohort. Respiratory histories and spirometry were first performed in 1968 when participants were aged 7 (n=8583). The cohort was traced and resurveyed from 2002 to 2005 (n=5729 responses) and a sample, enriched for asthma and bronchitis participated in a clinical study when aged 44 (n=1389). RESULTS: Of the entire TAHS cohort, 7.7% (95% CI 6.6% to 9.0%) had early-onset and 7.8% (95% CI 6.4% to 9.4%) late-onset asthma. Atopy and family history were more common in early-onset asthma while female gender, current smoking and low socioeconomic status were more common in late-onset asthma. The impact on lung function of early-onset asthma was significantly greater than for late-onset asthma (mean difference prebronchodilator (BD) FEV1/FVC -2.8% predicted (-5.3 to -0.3); post-BD FEV1FVC -2.6% predicted (-5.0 to -0.1)). However, asthma severity and asthma score did not significantly differ between groups. An interaction between asthma and smoking was identified and found to be associated with greater fixed airflow obstruction in adults with late-onset asthma. This interaction was not evident in adults with early-onset disease. CONCLUSIONS: Early-onset and late-onset adult asthma are equally prevalent in the middle-aged population. Major phenotypic differences occur with asthma age-of-onset; while both share similar clinical manifestations, the impact on adult lung function of early-onset asthma is greater than for late-onset asthma.

Mother's smoking and complex lung function of offspring in middle age: A cohort study from childhood.

BACKGROUND AND OBJECTIVE: Existing evidence that supports maternal smoking to be a potential risk factor for chronic obstructive pulmonary disease (COPD) for adult offspring has barely been mentioned in major guideline documents, suggesting a need for more robust and consistent data. We aimed to examine whether such early life exposure can predispose to COPD in middle age, possibly through its interaction with personal smoking. METHODS: The fifth-decade follow-up of the Tasmanian Longitudinal Health Study cohort, which was first studied in 1968 (n = 8583), included a 2004 postal survey (n = 5729 responses) and subsequent laboratory attendance (n = 1389) for comprehensive lung function testing between 2006 and 2008. Multivariable linear and logistic regression models included sampling weights. RESULTS: Post-bronchodilator airflow obstruction (less than fifth percentile) was detected for 9.3% (n = 123) of middle-aged offspring. Its association with heavy maternal smoking (>20 cigarettes/day) during childhood was 2.7-fold higher than for those without exposure (95% confidence interval [1.3, 5.7] P = 0.009). Maternal smoking per se approximately doubled the adverse effect of personal smoking on gas transfer factor (z-score -0.46 [-0.6 to -0.3] vs -0.25 [-0.4 to -0.1], P[interaction] = 0.048) and was paradoxically associated with reduced residual volumes for non-smokers. CONCLUSIONS: Heavy maternal smoking during childhood appears to predispose to spirometrically defined COPD. The interplay between maternal and personal smoking on gas transfer factor suggests that early life exposure increases an individual's susceptibility to adult smoking exposure. These findings provide further evidence to suggest that maternal smoking might be a risk factor for COPD and reinforce the public health message advocating smoking abstinence.

The interplay between the effects of lifetime asthma, smoking, and atopy on fixed airflow obstruction in middle age.

RATIONALE: The contribution by asthma to the development of fixed airflow obstruction (AO) and the nature of its effect combined with active smoking and atopy remain unclear. OBJECTIVES: To investigate the prevalence and relative influence of lifetime asthma, active smoking, and atopy on fixed AO in middle age. METHODS: The population-based Tasmanian Longitudinal Health Study cohort born in 1961 (n = 8,583) and studied with prebronchodilator spirometry in 1968 was retraced (n = 7,312) and resurveyed (n = 5,729 responses) from 2002 to 2005. A sample enriched for asthma and chronic bronchitis underwent a further questionnaire, pre- and post-bronchodilator spirometry (n = 1,389), skin prick testing, lung volumes, and diffusing capacity measurements. Prevalence estimates were reweighted for sampling fractions. Multiple linear and logistic regression were used to assess the relevant associations. MEASUREMENTS AND MAIN RESULTS: Main effects and interactions between lifetime asthma, active smoking, and atopy as they relate to fixed AO were measured. The prevalence of fixed AO was 6.0% (95% confidence interval [CI], 4.5-7.5%). Its association with early-onset current clinical asthma was equivalent to a 33 pack-year history of smoking (odds ratio, 3.7; 95% CI, 1.5-9.3; P = 0.005), compared with a 24 pack-year history for late-onset current clinical asthma (odds ratio, 2.6; 95% CI, 1.03-6.5; P = 0.042). An interaction (multiplicative effect) was present between asthma and active smoking as it relates to the ratio of post-bronchodilator FEV(1)/FVC, but only among those with atopic sensitization. CONCLUSIONS: Active smoking and current clinical asthma both contribute substantially to fixed AO in middle age, especially among those with atopy. The interaction between these factors provides another compelling reason for atopic individuals with current asthma who smoke to quit.

Association between latitude and allergic diseases: a longitudinal study from childhood to middle-age.

BACKGROUND: Worldwide variations in allergy prevalence suggest that geographic factors may contribute to asthma. Ecologic studies have suggested that latitude, a marker of UV-B exposure and allergen exposures, may be related to clinical allergies. OBJECTIVE: To examine the relationship between latitude or UV-B based on self-reported geolocation and allergic sensitization and disease prevalence in Australia. METHODS: The Tasmanian Longitudinal Health Study is a population-based study of respiratory disease spanning childhood to adulthood. The most recent follow-up included a postal survey of 5,729 participants and a clinical substudy of 1,396 participants. Participants' residential addresses were coded for latitude and linked with the UV-B data from satellite-based observations of atmospheric ozone. Multivariable logistic regression analyses were performed to estimate the associations between latitude or UV-B and allergic diseases. RESULTS: Most northerly latitude, that is, latitude closest to the Equator, and high current UV-B exposure were associated with increased odds of hay fever, food allergy, and skin sensitization to house dust mites and molds. More northerly latitude and higher UV-B exposure were associated with increased odds of current asthma among atopic individuals contrasting with a reduced odds of current asthma among nonatopic individuals. CONCLUSION: This is the first study, to our knowledge, to demonstrate a differential effect of atopic status on the relationship between latitude and current asthma. Our study demonstrates in a genetically and culturally similar group of individuals that geographic factors may a play role in the development of allergic disease.

Ambient wood smoke, traffic pollution and adult asthma prevalence and severity.

BACKGROUND AND OBJECTIVE: The impact of ambient wood smoke and traffic-related air pollution on adult asthma has not been well studied. This paper aims to investigate associations between exposure to ambient wood smoke, traffic-related air pollution and current asthma/asthma severity in middle age, and whether any associations are modified by atopic status. METHODS: Using data from the Tasmanian Longitudinal Health Study, associations between ambient wood smoke and two indices of traffic-related air pollution (frequency of heavy vehicles near the home and frequency of intense traffic noise) and current asthma/asthma severity were investigated. Unconditional logistic regression to examine current asthma and ordinal logistic regression to examine asthma severity was used. RESULTS: For asthmatics, both exposure to ambient wood smoke (odds ratio 1.11; 95% confidence interval 1.02-1.20) and being frequently exposed to heavy vehicles (odds ratio 1.80; 95% confidence interval 1.09-2.96) were associated with increased asthma severity. Neither association varied by atopic status. CONCLUSIONS: In middle-aged adults, ambient wood smoke and traffic pollution were associated with increased asthma severity. These findings suggest that avoiding or limiting exposure to traffic pollution and wood smoke may help to reduce asthma. Future studies to replicate this finding are recommended and should examine specific biological mechanisms for this effect.

Childhood eczema and rhinitis predict atopic but not nonatopic adult asthma: a prospective cohort study over 4 decades.

BACKGROUND: The evidence on whether the atopic march observed in childhood (ie, the progression from eczema to allergic rhinitis and asthma) extends to adulthood is sparse, and there is no evidence on whether the progression leads to a specific phenotype of asthma. OBJECTIVE: We sought to assess whether childhood eczema and rhinitis are risk factors for specific phenotypes of adult asthma. METHODS: Participants of the Tasmanian Longitudinal Health Study recruited in 1968 (age range, 6.0-7.0 years) were followed up at age 44 years. The risk of current atopic or nonatopic asthma in middle age characterized by sensitization to aeroallergens given childhood eczema, rhinitis, or both was calculated by using multinomial logistic regression. RESULTS: No association was found between childhood eczema or rhinitis and nonatopic adult asthma. In contrast, childhood eczema and rhinitis in combination predicted both new-onset atopic asthma by middle age (adjusted multinomial odds ratio [aMOR], 6.3; 95% CI, 1.7-23.2) and the persistence of childhood asthma to adult atopic asthma (aMOR, 11.7; 95% CI, 3.6-37.9). Participants with childhood eczema alone were at increased risk of new-onset atopic asthma (aMOR, 4.1; 95% CI, 1.9-8.8), whereas rhinitis alone predicted the persistence of childhood asthma to atopic asthma (aMOR, 2.7; 95% CI, 1.3-5.6). Of all asthma, 29.7% of persistent atopic asthma and 18.1% of new-onset atopic asthma could be attributed to having childhood eczema and rhinitis. CONCLUSION: Childhood eczema and rhinitis are strongly associated with the incidence and persistence of adult atopic asthma.

Use of respiratory function tests to predict survival in amyotrophic lateral sclerosis.

Respiratory function tests (RFTs) are commonly used as a measure of progression in ALS. This study assessed the ability of various RFTs to predict survival in ALS patients. Subjects with ALS had one or more measurements of seated and supine FVC, maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP). Kaplan-Meier (KM) analysis was used to determine whether patients with abnormal RFTs had shorter survival than those with normal RFTs. The sensitivity and specificity of RFTs as predictors of two-year survival were calculated from receiver operating characteristic (ROC) curves. With KM analysis, subjects with abnormal values of seated FVC, supine FVC, MIP and MEP had significantly reduced survival compared to subjects with normal values. With ROC curves, a normal supine FVC was highly predictive for two-year survival and had superior sensitivity over seated FVC. Slower rates of decline in seated or supine FVC were strong predictors of two-year survival. Our study demonstrates that respiratory function measurements are useful to predict survival in ALS patients. We show that measurements of FVC in the supine position are worth including in the assessment of respiratory function in ALS.

Lifetime Risk Factors for Pre- and Post-Bronchodilator Lung Function Decline. A Population-based Study.

Rationale: Interactions between early life and adult insults on lung function decline are not well understood, with most studies investigating prebronchodilator (pre-BD) FEV1 decline.Objectives: To investigate relationships between adult risk factors and pre- and post-BD lung function decline and their potential effect modification by early life and genetic factors.Methods: Multiple regression was used to examine associations between adult exposures (asthma, smoking, occupational exposures, traffic pollution, and obesity) and decline in both pre- and post-BD spirometry (forced expiratory volume in 1 s [FEV1], forced vital capacity [FVC], and FEV1/FVC) between ages 45 and 53 years in the Tasmanian Longitudinal Health Study (n = 857). Effect modification of these relationships by childhood respiratory risk factors, including low childhood lung function and GST (glutathione S-transferase) gene polymorphisms, was investigated.Results: Baseline asthma, smoking, occupational exposure to vapors/gases/dusts/fumes, and living close to traffic were associated with accelerated decline in both pre- and post-BD FEV1. These factors were also associated with FEV1/FVC decline. Occupational exposure to aromatic solvents was associated with pre-BD but not post-BD FEV1 decline. Maternal smoking accentuated the effect of personal smoking on pre- and post-BD FEV1 decline. Lower childhood lung function and having the GSTM1 null allele accentuated the effect of occupational exposure to vapors/gases/dusts/fumes and personal smoking on post-BD FEV1 decline. Incident obesity was associated with accelerated decline in FEV1 and more pronounced in FVC.Conclusions: This study provides new evidence for accentuation of individual susceptibility to adult risk factors by low childhood lung function, GSTM1 genotype, and maternal smoking.

Tailoring Polyethers for Post-polymerization Functionalization by Cross Metathesis.

Olefin cross metathesis is reported for the first time to attach small molecules to a range of novel polyethers with a poly(ethylene glycol) backbone and pendent alkene groups, allowing for a loading of up to one compound per monomer unit. These polymers are tailored to prevent the occurrence of self metathesis (reaction of the polymer with itself) by varying the substitution on the pendent alkenes, thus steering their reactivity toward olefin cross metathesis. Efficient functionalization has been observed for a range of coupling partners as a proof of concept for the use of olefin metathesis to graft small and larger molecules to polyethers for drug delivery. This approach also paves the way for the use of olefin cross metathesis as an efficient method to functionalize a wide variety of polymers with pendent olefin groups.

Expiratory reactance abnormalities in patients with expiratory dynamic airway collapse: a new application of impulse oscillometry.

Expiratory dynamic airways collapse (EDAC) is a condition that affects the central airways; it is not well characterised physiologically, with relatively few studies. We sought to characterise impulse oscillometry (IOS) features of EDAC in patients with normal spirometry. Expiratory data were hypothesised to be the most revealing. In addition, we compared IOS findings in chronic obstructive pulmonary disease (COPD) patients with and without EDAC. EDAC was identified at bronchoscopy as 75-100% expiratory closure at the carina or bilateral main bronchi. Four patient groups were compared: controls with no EDAC and normal lung function; lone EDAC with normal lung function; COPD-only patients; and COPD patients with EDAC. 38 patients were studied. Mean IOS data z-scores for EDAC compared to controls showed significantly higher reactance (X) values including X at 5 Hz, resonance frequency and area under the reactance curve (AX). EDAC showed significantly greater expiratory/inspiratory differences in all IOS data compared to controls. Stepwise logistic regression showed that resonant frequency best discriminated between EDAC and normal control, whereas classification and regression tree analysis found AX ≥3.523 to be highly predictive for EDAC in cases with normal lung function (14 out of 15 cases, and none out of eight controls). These data show a new utility of IOS: detecting EDAC in patients with normal lung function.

Childhood predictors of lung function trajectories and future COPD risk: a prospective cohort study from the first to the sixth decade of life.

BACKGROUND: Lifetime lung function is related to quality of life and longevity. Over the lifespan, individuals follow different lung function trajectories. Identification of these trajectories, their determinants, and outcomes is important, but no study has done this beyond the fourth decade. METHODS: We used six waves of the Tasmanian Longitudinal Health Study (TAHS) to model lung function trajectories measured at 7, 13, 18, 45, 50, and 53 years. We analysed pre-bronchodilator FEV1 z-scores at the six timepoints using group-based trajectory modelling to identify distinct subgroups of individuals whose measurements followed a similar pattern over time. We related the trajectories identified to childhood factors and risk of chronic obstructive pulmonary disease (COPD) using logistic regression, and estimated population-attributable fractions of COPD. FINDINGS: Of the 8583 participants in the original cohort, 2438 had at least two waves of lung function data at age 7 years and 53 years and comprised the study population. We identified six trajectories: early below average, accelerated decline (97 [4%] participants); persistently low (136 [6%] participants); early low, accelerated growth, normal decline (196 [8%] participants); persistently high (293 [12%] participants); below average (772 [32%] participants); and average (944 [39%] participants). The three trajectories early below average, accelerated decline; persistently low; and below average had increased risk of COPD at age 53 years compared with the average group (early below average, accelerated decline: odds ratio 35·0, 95% CI 19·5-64·0; persistently low: 9·5, 4·5-20·6; and below average: 3·7, 1·9-6·9). Early-life predictors of the three trajectories included childhood asthma, bronchitis, pneumonia, allergic rhinitis, eczema, parental asthma, and maternal smoking. Personal smoking and active adult asthma increased the impact of maternal smoking and childhood asthma, respectively, on the early below average, accelerated decline trajectory. INTERPRETATION: We identified six potential FEV1 trajectories, two of which were novel. Three trajectories contributed 75% of COPD burden and were associated with modifiable early-life exposures whose impact was aggravated by adult factors. We postulate that reducing maternal smoking, encouraging immunisation, and avoiding personal smoking, especially in those with smoking parents or low childhood lung function, might minimise COPD risk. Clinicians and patients with asthma should be made aware of the potential long-term implications of non-optimal asthma control for lung function trajectory throughout life, and the role and benefit of optimal asthma control on improving lung function should be investigated in future intervention trials. FUNDING: National Health and Medical Research Council of Australia; European Union's Horizon 2020; The University of Melbourne; Clifford Craig Medical Research Trust of Tasmania; The Victorian, Queensland & Tasmanian Asthma Foundations; The Royal Hobart Hospital; Helen MacPherson Smith Trust; and GlaxoSmithKline.

The interaction between farming/rural environment and TLR2, TLR4, TLR6 and CD14 genetic polymorphisms in relation to early- and late-onset asthma.

Asthma phenotypes based on age-of-onset may be differently influenced by the interaction between variation in toll-like receptor (TLR)/CD14 genes and environmental microbes. We examined the associations between single-nucleotide polymorphisms (SNP) in the TLR/CD14 genes and asthma, and their interaction with proxies of microbial exposure (childhood farm exposure and childhood rural environment). Ten SNPs in four genes (TLR2, TLR4, TLR6, CD14) were genotyped for 1,116 participants from the Tasmanian Longitudinal Health Study (TAHS). Using prospectively collected information, asthma was classified as never, early- (before 13 years) or late-onset (after 13 years). Information on childhood farm exposure/childhood rural environment was collected at baseline. Those with early-onset asthma were more likely to be males, had a family history of allergy and a personal history of childhood atopy. We found significant interaction between TLR6 SNPs and childhood farm exposure. For those with childhood farm exposure, carriers of the TLR6-rs1039559 T-allele (p-interaction = 0.009) and TLR6-rs5743810 C-allele (p-interaction = 0.02) were associated with lower risk of early-onset asthma. We suggest the findings to be interpreted as hypothesis-generating as the interaction effect did not withstand correction for multiple testing. In this large, population-based longitudinal study, we found that the risk of early- and late-onset asthma is differently influenced by the interaction between childhood farming exposure and genetic variations.