High-Efficiency Particulate Air Filters for Preventing Wildfire-related Asthma Complications: A Cost-Effectiveness Study.

Rationale: Air pollution caused by wildfire smoke is linked to adverse health outcomes, especially for people living with asthma. Objectives: To evaluate whether government rebates for high-efficiency particulate air (HEPA) filters, which reduce concentrations of smoke particles indoors, are cost effective in managing asthma and preventing exacerbations in British Columbia (BC), Canada. Methods: We used a Markov model to analyze health states for asthma control, exacerbation severity, and death over a retrospective time horizon of 5 years (2018-2022). Concentrations of wildfire smoke-derived particulate matter with an aerodynamic diameter ⩽2.5 µm (PM2.5) from the Canadian Optimized Statistical Smoke Exposure Model and relevant literature informed the model. The base-case analysis assumed continuous use of a HEPA filter. Costs and quality-adjusted life-years (QALYs) resulting from varying rebates were computed for each Health Service Delivery Area (HSDA). Measurements and Main Results: In the base-case analysis, HEPA filter use resulted in increased costs of $83.34 (SE, $1.03) and increased QALYs of 0.0011 (SE, 0.0001) per person. The average incremental cost-effectiveness ratio among BC HSDAs was $74,652/QALY (SE, $3,517), with incremental cost-effectiveness ratios ranging from $40,509 to $89,206 per QALY in HSDAs. Across the province, the intervention was projected to prevent 4,418 exacerbations requiring systemic corticosteroids, 643 emergency department visits, and 425 hospitalizations during the 5-year time horizon. A full rebate was cost effective in 1 of the 16 HSDAs across BC. The probability of cost-effectiveness ranged from 0.1% to 74.8% across HSDAs. A $100 rebate was cost effective in most HSDAs. Conclusions: The cost-effectiveness of HEPA filters in managing wildfire smoke-related asthma issues in BC varies by region. Government rebates up to two-thirds of the filter cost are generally cost effective, with a full rebate being cost effective only in Kootenay Boundary.

Residential exposure to Aspergillus spp. is associated with exacerbations in COPD.

BACKGROUND: Sensitisation to Aspergillus fumigatus is linked to worse outcomes in patients with chronic obstructive pulmonary disease (COPD), however, its prevalence and clinical implications in domestic (residential) settings remains unknown. METHODS: Individuals with COPD (n=43) recruited in Singapore had their residences prospectively sampled and assessed by shotgun metagenomic sequencing including indoor air, outdoor air, and touch surfaces (total: 126 specimens). The abundance of environmental A. fumigatus and the occurrence of A. fumigatus (Asp f) allergens in the environment were determined and immunological responses to A. fumigatus allergens determined in association with clinical outcomes including exacerbation frequency. Findings were validated in 12 individuals (31 specimens) with COPD in Vancouver, Canada, a climatically different region. RESULTS: 157 metagenomes from 43 homes were assessed. Eleven and nine separate Aspergillus spp. were identified in Singapore and Vancouver respectively. Despite climatic, temperature, and humidity variation, A. fumigatus was detectable in the environment from both locations. The relative abundance of environmental A. fumigatus was significantly associated with exacerbation frequency in both Singapore (r=0.27, p=0.003) and Vancouver (r=0.49, p=0.01) and individuals with higher Asp f 3 sensitisation responses lived in homes with a greater abundance of environmental Asp f 3 allergens (p=0.037). Patients exposed and sensitised to Asp f 3 allergens demonstrated a higher rate of COPD exacerbations at 1-year follow-up (p=0.021). CONCLUSION: Environmental A. fumigatus exposure in the home environment including air and surfaces with resulting sensitisation carries pathogenic potential in individuals with COPD. Targeting domestic A. fumigatus abundance may reduce COPD exacerbations.

Air pollution, weather and positive airway pressure treatment adherence in adults with sleep apnea: a retrospective community-based repeated-measures longitudinal study.

We assessed the relation between air pollution, weather, and adherence to positive airway pressure (PAP) therapy in a retrospective community-based repeated-measures study of adults with obstructive sleep apnea who purchased PAP devices from a registered provider between 2013 and 2017 (Ottawa, Ontario, Canada) and had at least one day of data. Daily PAP-derived data, air pollution, and weather databases were linked using postal code. The exposures were mean nocturnal (8:00 p.m. to 8:00 a.m.) (i) residential concentrations of nitrogen dioxide (NO2 ), fine particulate matter <=2.5 µm (PM2.5 ), ozone (O3 ), and Air Quality Health Index (AQHI), and (ii) temperature, relative humidity, and barometric pressure. Covariates in the main model were demographics, season, exposure year, and PAP therapy mode. We analysed 8148 adults (median age of 54 years and 61% men) and 2,071,588 days of data. Based on daily data, the median (interquartile range) daily PAP usage was 416 (323-487) min. Using mixed-effect regression analyses to incorporate daily data and clustering by individuals, we found a statistically significant decrease in adherence for increased levels of NO2 , PM2.5 , and AQHI. The largest effect was for NO2 : a decrease in daily PAP use while comparing the highest versus lowest quartiles (Qs) was 3.4 (95% confidence interval [CI] 2.8-3.9) min. Decreased PAP adherence was also associated with increased temperature (Q4 versus Q1: 2.6 [95% CI: 1.5-3.7] min) and decreased barometric pressure (Q1 versus Q4: 2.0 [95% CI 1.5-2.5] min). We observed modest but statistically significant acute effects of air pollution and weather on daily PAP adherence.

Controlled human exposures: a review and comparison of the health effects of diesel exhaust and wood smoke.

One of the most pressing issues in global health is air pollution. Emissions from traffic-related air pollution and biomass burning are two of the most common sources of air pollution. Diesel exhaust (DE) and wood smoke (WS) have been used as models of these pollutant sources in controlled human exposure (CHE) experiments. The aim of this review was to compare the health effects of DE and WS using results obtained from CHE studies. A total of 119 CHE-DE publications and 25 CHE-WS publications were identified for review. CHE studies of DE generally involved shorter exposure durations and lower particulate matter concentrations, and demonstrated more potent dysfunctional outcomes than CHE studies of WS. In the airways, DE induces neutrophilic inflammation and increases airway hyperresponsiveness, but the effects of WS are unclear. There is strong evidence that DE provokes systemic oxidative stress and inflammation, but less evidence exists for WS. Exposure to DE was more prothrombotic than WS. DE generally increased cardiovascular dysfunction, but limited evidence is available for WS. Substantial heterogeneity in experimental methodology limited the comparison between studies. In many areas, outcomes of WS exposures tended to trend in similar directions to those of DE, suggesting that the effects of DE exposure may be useful for inferring possible responses to WS. However, several gaps in the literature were identified, predominantly pertaining to elucidating the effects of WS exposure. Future studies should strongly consider performing head-to-head comparisons between DE and WS using a CHE design to determine the differential effects of these exposures.

Ambient Ultrafine Particulate Matter and Clinical Outcomes in Fibrotic Interstitial Lung Disease.

RATIONALE: Particulate matter ≤2.5µm (PM2.5) is associated with adverse outcomes in fibrotic interstitial lung disease (fILD), but the impact of ultrafine particulates (UFPs; aerodynamic diameter ≤100nm) remains unknown. OBJECTIVE: To evaluate UFP associations with clinical outcomes in fILD. METHODS: Multicenter, prospective cohort study enrolling patients with fILD from the University of Pittsburgh Simmons Center and Pulmonary Fibrosis Foundation Patient Registry (PFF-PR). Using a national-scale UFP model, we linked exposures using three approaches in Simmons (residential address geocoordinates, zip centroid geocoordinates, zip average) and two in PFF-PR where only 5-digit zip code was available (zip centroid, zip average). We tested UFP associations with transplant-free survival using multivariable Cox, baseline percent predicted forced vital capacity (FVC) and diffusion capacity of the lung (DLCO) using multivariable linear regressions, and decline in FVC and DLCO using linear mixed models, adjusting for age, sex, smoking, race, socioeconomic status, site, PM2.5, and nitrogen dioxide. RESULTS: Annual mean outdoor UFP levels for 2017 were estimated for 1416 Simmons and 1919 PFF-PR patients. Increased UFP level was associated with transplant-free survival in fully-adjusted Simmons residential address models (HR=1.08 per 1000 particles/cm3, 95%CI 1.01-1.15, p=0.02), but not PFF-PR models, which used less precise linkage approaches. Higher UFP was associated with lower baseline FVC and more rapid FVC decline in Simmons. CONCLUSIONS: Increased UFP exposure was associated with transplant-free survival and lung function in the cohort with precise residential location linkage. This work highlights the need for more robust regulatory networks to study the health effects of UFPs nationwide.

Microbial dysbiosis and the host airway epithelial response: insights into HIV-associated COPD using multi'omics profiling.

BACKGROUND: People living with HIV (PLWH) are at increased risk of developing Chronic Obstructive Pulmonary Disease (COPD) independent of cigarette smoking. We hypothesized that dysbiosis in PLWH is associated with epigenetic and transcriptomic disruptions in the airway epithelium. METHODS: Airway epithelial brushings were collected from 18 COPD + HIV + , 16 COPD - HIV + , 22 COPD + HIV - and 20 COPD - HIV - subjects. The microbiome, methylome, and transcriptome were profiled using 16S sequencing, Illumina Infinium Methylation EPIC chip, and RNA sequencing, respectively. Multi 'omic integration was performed using Data Integration Analysis for Biomarker discovery using Latent cOmponents. A correlation > 0.7 was used to identify key interactions between the 'omes. RESULTS: The COPD + HIV -, COPD -HIV + , and COPD + HIV + groups had reduced Shannon Diversity (p = 0.004, p = 0.023, and p = 5.5e-06, respectively) compared to individuals with neither COPD nor HIV, with the COPD + HIV + group demonstrating the most reduced diversity. Microbial communities were significantly different between the four groups (p = 0.001). Multi 'omic integration identified correlations between Bacteroidetes Prevotella, genes FUZ, FASTKD3, and ACVR1B, and epigenetic features CpG-FUZ and CpG-PHLDB3. CONCLUSION: PLWH with COPD manifest decreased diversity and altered microbial communities in their airway epithelial microbiome. The reduction in Prevotella in this group was linked with epigenetic and transcriptomic disruptions in host genes including FUZ, FASTKD3, and ACVR1B.

Phase Behavior and Viscosity in Biomass Burning Organic Aerosol and Climatic Impacts.

Smoke particles generated by burning biomass consist mainly of organic aerosol termed biomass burning organic aerosol (BBOA). BBOA influences the climate by scattering and absorbing solar radiation or acting as nuclei for cloud formation. The viscosity and the phase behavior (i.e., the number and type of phases present in a particle) are properties of BBOA that are expected to impact several climate-relevant processes but remain highly uncertain. We studied the phase behavior of BBOA using fluorescence microscopy and showed that BBOA particles comprise two organic phases (a hydrophobic and a hydrophilic phase) across a wide range of atmospheric relative humidity (RH). We determined the viscosity of the two phases at room temperature using a photobleaching method and showed that the two phases possess different RH-dependent viscosities. The viscosity of the hydrophobic phase is largely independent of the RH from 0 to 95%. We use the Vogel-Fulcher-Tamman equation to extrapolate our results to colder and warmer temperatures, and based on the extrapolation, the hydrophobic phase is predicted to be glassy (viscosity >1012 Pa s) for temperatures less than 230 K and RHs below 95%, with possible implications for heterogeneous reaction kinetics and cloud formation in the atmosphere. Using a kinetic multilayer model (KM-GAP), we investigated the effect of two phases on the atmospheric lifetime of brown carbon within BBOA, which is a climate-warming agent. We showed that the presence of two phases can increase the lifetime of brown carbon in the planetary boundary layer and polar regions compared to previous modeling studies. Hence, the presence of two phases can lead to an increase in the predicted warming effect of BBOA on the climate.

Exposure to diesel exhaust alters the functional metagenomic composition of the airway microbiome in former smokers.

The lung microbiome plays a crucial role in airway homeostasis, yet we know little about the effects of exposures such as air pollution therein. We conducted a controlled human exposure study to assess the impact of diesel exhaust (DE) on the human airway microbiome. Twenty-four participants (former smokers with mild to moderate COPD (N = 9), healthy former smokers (N = 7), and control healthy never smokers (N = 8)) were exposed to DE (300 µg/m3 PM2.5) and filtered air (FA) for 2 h in a randomized order, separated by a 4-week washout. Endobronchial brushing samples were collected 24 h post-exposure and sequenced for the 16S microbiome, which was analyzed using QIIME2 and PICRUSt2 to examine diversity and metabolic functions, respectively. DE exposure altered airway microbiome metabolic functions in spite of statistically stable microbiome diversity. Affected functions included increases in: superpathway of purine deoxyribonucleosides degradation (pathway differential abundance 743.9, CI 95% 201.2 to 1286.6), thiazole biosynthesis I (668.5, CI 95% 139.9 to 1197.06), and L-lysine biosynthesis II (666.5, CI 95% 73.3 to 1257.7). There was an exposure-by-age effect, such that menaquinone biosynthesis superpathways were the most enriched function in the microbiome of participants aged >60, irrespective of smoking or health status. Moreover, exposure-by-phenotype analysis showed metabolic alterations in former smokers after DE exposure. These observations suggest that DE exposure induced substantial changes in the metabolic functions of the airway microbiome despite the absence of diversity changes.

Post-COVID dyspnea: prevalence, predictors, and outcomes in a longitudinal, prospective cohort.

BACKGROUND: The pathophysiology, evolution, and associated outcomes of post-COVID dyspnea remain unknown. The aim of this study was to determine the prevalence, severity, and predictors of dyspnea 12 months following hospitalization for COVID-19, and to describe the respiratory, cardiac, and patient-reported outcomes in patients with post-COVID dyspnea. METHODS: We enrolled a prospective cohort of all adult patients admitted to 2 academic hospitals in Vancouver, Canada with PCR-confirmed SARS-CoV-2 during the first wave of COVID between March and June 2020. Dyspnea was measured 3, 6, and 12 months after initial symptom onset using the University of California San Diego Shortness of Breath Questionnaire. RESULTS: A total of 76 patients were included. Clinically meaningful dyspnea (baseline score > 10 points) was present in 49% of patients at 3 months and 46% at 12 months following COVID-19. Between 3 and 12 months post-COVID-19, 24% patients had a clinically meaningful worsening in their dyspnea, 49% had no meaningful change, and 28% had a clinically meaningful improvement in their dyspnea. There was worse sleep, mood, quality of life, and frailty in patients with clinically meaningful dyspnea at 12 months post-COVID infection compared to patients without dyspnea. There was no difference in PFT findings, troponin, or BNP comparing patients with and without clinically meaningful dyspnea at 12 months. Severity of dyspnea and depressive symptoms at 3 months predicted severity of dyspnea at 12 months. CONCLUSIONS: Post-COVID dyspnea is common, persistent, and negatively impacts quality of life. Mood abnormalities may play a causative role in post-COVID dyspnea in addition to potential cardiorespiratory abnormalities. Dyspnea and depression at initial follow-up predict longer-term post-COVID dyspnea, emphasizing that standardized dyspnea and mood assessment following COVID-19 may identify patients at high risk of post-COVID dyspnea and facilitating early and effective management.

An updated systematic review and meta-analysis on portable air cleaners and blood pressure: Recommendations for users and manufacturers.

Fine particulate matter (PM2.5) air pollution is a leading contributor to the global burden of cardiovascular disease (CVD). One important underlying mechanism is an increase in blood pressure (BP). A growing number of studies have reported a beneficial effect of portable air cleaners (PACs) on systolic and diastolic BP; SBP and DBP. We conducted an updated systematic review and meta-analysis of studies using true versus sham mode filtration reporting the effects on BP. Of 214 articles identified up to February 5, 2023, seventeen (from China, USA, Canada, South Korea and Denmark) enrolling approximately 880 participants (484 female) met the inclusion criteria for meta-analyses. Aside from studies conducted in China, research on PACs and BP has been conducted in relatively low pollution settings. Mean indoor PM2.5 concentrations during the active and sham mode purification were 15.9 and 41.2 µg/m3, respectively. The mean efficiency of PACs against indoor PM2.5 was 59.8 % (ranging from 23 % to 82 %). True mode filtration was associated with a pooled mean difference of - 2.35 mmHg (95 % confidence interval [CI]: - 4.5, - 0.2) and - 0.81 mmHg (95 % CI: - 1.86, 0.24) in SBP and DBP, respectively. After removing the studies with high risk of bias, the magnitude of the pooled benefits on SBP and DBP increased to - 3.62 mmHg (95 % CI: - 6.69, - 0.56) and - 1.35 mmHg (95 % CI: - 2.29, - 0.41), respectively. However, there are several barriers to the use of PACs, specifically in low- and middle-income countries (LMICs), such as the initial purchase cost and filter replacements. There may be several avenues to help overcome these economic burdens and improve cost effectiveness, such as implementing government or other subsidized programs to distribute PACs targeting vulnerable and higher-risk individuals. We propose that environmental health researchers and healthcare providers should be better trained to educate the public regarding the use of PACs to reduce the impacts of PM2.5 on cardiometabolic diseases globally.

Disparities in self-reported healthcare access for airways disease in British Columbia, Canada, during the COVID-19 pandemic. Insights from a survey co-developed with people living with asthma and chronic obstructive pulmonary disease.

Patients' perspectives on the impact of the COVID-19 pandemic on their access to asthma and COPD healthcare could inform better, more equitable care delivery. We demonstrate this topic using British Columbia (BC), Canada, where the impact of the pandemic has not been described. We co-designed a cross-sectional survey with patient partners and administered it to a convenience sample of people living with asthma and COPD in BC between September 2020 and March 2021. We aimed to understand how access to healthcare for these conditions was affected during the pandemic. The survey asked respondents to report their characteristics, access to healthcare for asthma and COPD, types of services they found disrupted and telehealth (telephone or video appointment) use during the pandemic. We analysed 433 responses and found that access to healthcare for asthma and COPD was lower during the pandemic than pre-pandemic (p < 0.001). Specialty care services were most frequently reported as disrupted, while primary care, home care and diagnostics were least disrupted. Multivariable logistic regression revealed that access during the pandemic was positively associated with self-assessed financial ability (OR = 22.0, 95% CI: 7.0 - 84.0, p < 0.001, reference is disagreeing with having financial ability) and living in medium-sized urban areas (OR = 2.3, 95% CI: 1.0 - 5.2, p = 0.04, reference is rural areas). These disparities in access should be validated post-pandemic to confirm whether they still persist. They also indicate the continued relevance of exploring approaches for more equitable healthcare.

Urinary Eicosanoid Levels Reflect Allergen and Diesel Exhaust Coexposure and Are Linked to Impaired Lung Function.

Eicosanoids are potent regulators of homeostasis and inflammation. Co-exposure to allergen and diesel exhaust (DE) have been shown to lead to eosinophilic inflammation, impaired airflow, and increased airway responsiveness. It is not clear whether eicosanoids mediate the mechanism by which these exposures impair lung function. We conducted a randomized, double-blinded, and four-arm crossover study. Fourteen allergen-sensitized participants were exposed to four conditions: negative control; allergen-alone exposure; DE and allergen coexposure; coexposure with particle-reducing technology applied. Quantitative metabolic profiling of urinary eicosanoids was performed using LC-MS/MS. As expected, allergen inhalation increased eicosanoids. The prostacyclin metabolite 2,3-dinor-6-keto-PGF1α (PGF1α, prostaglandin F1α) increased with coexposure, but particle depletion suppressed this pathway. Individuals with a high genetic risk score demonstrated a greater increase in isoprostane metabolites following coexposure. Causal mediation analyses showed that allergen induced airflow impairment was mediated via leukotriene E4 and tetranor-prostaglandin D metabolite. Overall, DE exposure did not augment the allergen's effect on urinary eicosanoids, except insofar as variant genotypes conferred susceptibility to the addition of DE in terms of isoprostane metabolites. These findings will add to the body of previous controlled human exposure studies and provide greater insight into how complex environmental exposures in urban air may influence individuals with sensitivity to aeroallergens.

Evaluating fatigue in patients recovering from COVID-19: validation of the fatigue severity scale and single item screening questions.

BACKGROUND: Fatigue is a common symptom in hospitalized and non-hospitalized patients recovering from COVID-19, but no fatigue measurement scales or questions have been validated in these populations. The objective of this study was to perform validity assessments of the fatigue severity scale (FSS) and two single-item screening questions (SISQs) for fatigue in patients recovering from COVID-19. METHODS: We examined patients ≥ 28 days after their first SARS-CoV-2 infection who were hospitalized for their acute illness, as well as non-hospitalized patients referred for persistent symptoms. Patients completed questionnaires through 1 of 4 Post COVID-19 Recovery Clinics in British Columbia, Canada. Construct validity was assessed by comparing FSS scores to quality of life and depression measures. Two SISQs were evaluated based on the ability to classify fatigue (FSS score ≥ 4). RESULTS: Questionnaires were returned in 548 hospitalized and 546 non-hospitalized patients, with scores computable in 96.4% and 98.2% of patients respectively. Cronbach's alpha was 0.96 in both groups. The mean ± SD FSS score was 4.4 ± 1.8 in the hospitalized and 5.2 ± 1.6 in the non-hospitalized group, with 62.5% hospitalized and 78.9% non-hospitalized patients classified as fatigued. Ceiling effects were 7.6% in the hospitalized and 16.1% in non-hospitalized patients. FSS scores negatively correlated with EQ-5D scores in both groups (Spearman's rho - 0.6 in both hospitalized and non-hospitalized; p < 0.001) and were higher among patients with a positive PHQ-2 depression screen (5.4 vs. 4.0 in hospitalized and 5.9 vs. 4.9 in non-hospitalized; p < 0.001). An SISQ asking whether there was "fatigue present" had a sensitivity of 70.6% in hospitalized and 83.2% in non-hospitalized patients; the "always feeling tired" SISQ, had a sensitivity of 70.5% and 89.6% respectively. CONCLUSIONS: Fatigue was common and severe in patients referred for post COVID-19 assessment. Overall, the FSS is suitable for measuring fatigue in these patients, as there was excellent data quality, strong internal consistency, and construct validity. However, ceiling effects may be a limitation in the non-hospitalized group. SISQs had good sensitivity for identifying clinically relevant fatigue in non-hospitalized patients but only moderate sensitivity in the hospitalized group, indicating that there were more false negatives.

Defining the effects of traffic-related air pollution on the human plasma proteome using an aptamer proteomic array: A dose-dependent increase in atherosclerosis-related proteins.

BACKGROUND: Traffic-related air pollution (TRAP) is a critical risk factor and major contributor to respiratory and cardiovascular disease (CVD). The effects of TRAP beyond the lungs can be related to changes in circulatory proteins. However, such TRAP-mediated changes have not been defined in an unbiased manner using a controlled human model. OBJECTIVE: To detail global protein changes (the proteome) in plasma following exposure to inhaled diesel exhaust (DE), a paradigm of TRAP, using controlled human exposures. METHODS: In one protocol, ex-smokers and never-smokers were exposed to filtered air (FA) and DE (300 µg PM2.5/m3), on order-randomized days, for 2 h. In a second protocol, independent never-smoking participants were exposed to lower concentrations of DE (20, 50 or 150 µg PM2.5/m3) and FA, for 4 h, on order-randomized days. Each exposure was separated by 4 weeks of washout. Plasma samples obtained 24 h post-exposure from ex-smokers (n = 6) were first probed using Slow off-rate modified aptamer proteomic array. Plasma from never-smokers (n = 11) was used for independent assessment of proteins selected from the proteomics study by immunoblotting. RESULTS: Proteomics analyses revealed that DE significantly altered 342 proteins in plasma of ex-smokers (n = 6). The top 20 proteins therein were primarily associated with inflammation and CVD. Plasma from never-smokers (n = 11) was used for independent assessment of 6 proteins, amongst the top 10 proteins increased by DE in the proteomics study, for immunoblotting. The abundance of all six proteins (fractalkine, apolipoproteins (APOB and APOM), IL18R1, MIP-3 and MMP-12) was significantly increased by DE in plasma of these never-smokers. DE-mediated increase was shown to be concentration-dependent for fractalkine, APOB and MMP-12, all biomarkers of atherosclerosis, which correlated with plasma levels of IL-6, a subclinical marker of CVD, in independent participants. CONCLUSION: This investigation details changes in the human plasma proteome due to TRAP. We identify specific atherosclerosis-related proteins that increase concentration-dependently across a range of TRAP levels applicable worldwide.

Controlled human exposure to diesel exhaust: results illuminate health effects of traffic-related air pollution and inform future directions.

Air pollution is an issue of increasing interest due to its globally relevant impacts on morbidity and mortality. Controlled human exposure (CHE) studies are often employed to investigate the impacts of pollution on human health, with diesel exhaust (DE) commonly used as a surrogate of traffic related air pollution (TRAP). This paper will review the results derived from 104 publications of CHE to DE (CHE-DE) with respect to health outcomes. CHE-DE studies have provided mechanistic evidence supporting TRAP's detrimental effects on related to the cardiovascular system (e.g., vasomotor dysfunction, inhibition of fibrinolysis, and impaired cardiac function) and respiratory system (e.g., airway inflammation, increased airway responsiveness, and clinical symptoms of asthma). Oxidative stress is thought to be the primary mechanism of TRAP-induced effects and has been supported by several CHE-DE studies. A historical limitation of some air pollution research is consideration of TRAP (or its components) in isolation, limiting insight into the interactions between TRAP and other environmental factors often encountered in tandem. CHE-DE studies can help to shed light on complex conditions, and several have included co-exposure to common elements such as allergens, ozone, and activity level. The ability of filters to mitigate the adverse effects of DE, by limiting exposure to the particulate fraction of polluted aerosols, has also been examined. While various biomarkers of DE exposure have been evaluated in CHE-DE studies, a definitive such endpoint has yet to be identified. In spite of the above advantages, this paradigm for TRAP is constrained to acute exposures and can only be indirectly applied to chronic exposures, despite the critical real-world impact of living long-term with TRAP. Those with significant medical conditions are often excluded from CHE-DE studies and so results derived from healthy individuals may not apply to more susceptible populations whose further study is needed to avoid potentially misleading conclusions. In spite of limitations, the contributions of CHE-DE studies have greatly advanced current understanding of the health impacts associated with TRAP exposure, especially regarding mechanisms therein, with important implications for regulation and policy.

Controlled human exposure to diesel exhaust: a method for understanding health effects of traffic-related air pollution.

Diesel exhaust (DE) is a major component of air pollution in urban centers. Controlled human exposure (CHE) experiments are commonly used to investigate the acute effects of DE inhalation specifically and also as a paradigm for investigating responses to traffic-related air pollution (TRAP) more generally. Given the critical role this model plays in our understanding of TRAP's health effects mechanistically and in support of associated policy and regulation, we review the methodology of CHE to DE (CHE-DE) in detail to distill critical elements so that the results of these studies can be understood in context. From 104 eligible publications, we identified 79 CHE-DE studies and extracted information on DE generation, exposure session characteristics, pollutant and particulate composition of exposures, and participant demographics. Virtually all studies had a crossover design, and most studies involved a single DE exposure per participant. Exposure sessions were typically 1 or 2 h in duration, with participants alternating between exercise and rest. Most CHE-DE targeted a PM concentration of 300 µg/m3. There was a wide range in commonly measured co-pollutants including nitrogen oxides, carbon monoxide, and total organic compounds. Reporting of detailed parameters of aerosol composition, including particle diameter, was inconsistent between studies, and older studies from a given lab were often cited in lieu of repeating measurements for new experiments. There was a male predominance in participants, and over half of studies involved healthy participants only. Other populations studied include those with asthma, atopy, or metabolic syndrome. Standardization in reporting exposure conditions, potentially using current versions of engines with modern emissions control technology, will allow for more valid comparisons between studies of CHE-DE, while recognizing that diesel engines in much of the world remain old and heterogeneous. Inclusion of female participants as well as populations more susceptible to TRAP will broaden the applicability of results from CHE-DE studies.

Concentration-dependent increase in symptoms due to diesel exhaust in a controlled human exposure study.

BACKGROUND: Traffic-related air pollution (TRAP) exposure causes adverse effects on wellbeing and quality of life, which can be studied non-invasively using self-reported symptoms. However, little is known about the effects of different TRAP concentrations on symptoms following controlled exposures, where acute responses can be studied with limited confounding. We investigated the concentration-response relationship between diesel exhaust (DE) exposure, as a model TRAP, and self-reported symptoms. METHODS: We recruited 17 healthy non-smokers into a double-blind crossover study where they were exposed to filtered air (FA) and DE standardized to 20, 50, 150 µg/m3 PM2.5 for 4 h, with a ≥ 4-week washout between exposures. Immediately before, and at 4 h and 24 h from the beginning of the exposure, we administered visual analog scale (VAS) questionnaires and grouped responses into chest, constitutional, eye, neurological, and nasal categories. Additionally, we assessed how the symptom response was related to exposure perception and airway function. RESULTS: An increase in DE concentration raised total (ß ± standard error = 0.05 ± 0.03, P = 0.04), constitutional (0.01 ± 0.01, P = 0.03) and eye (0.02 ± 0.01, P = 0.05) symptoms at 4 h, modified by perception of temperature, noise, and anxiety. These symptoms were also correlated with airway inflammation. Compared to FA, symptoms were significantly increased at 150 µg/m3 for the total (8.45 ± 3.92, P = 0.04) and eye (3.18 ± 1.55, P = 0.05) categories, with trends towards higher values in the constitutional (1.49 ± 0.86, P = 0.09) and nasal (1.71 ± 0.96, P = 0.08) categories. CONCLUSION: DE exposure induced a concentration-dependent increase in symptoms, primarily in the eyes and body, that was modified by environmental perception. These observations emphasize the inflammatory and sensory effects of TRAP, with a potential threshold below 150 µg/m3 PM2.5. We demonstrate VAS questionnaires as a useful tool for health monitoring and provide insight into the TRAP concentration-response at exposure levels relevant to public health policy.

Dibutyl phthalate exposure alters T-cell subsets in blood from allergen-sensitized volunteers.

Phthalates are ubiquitous environmental contaminants associated with allergic disease in epidemiological and animal studies. This investigation aims to support these associations by interrogating systemic immune effects in allergen-sensitized volunteers after controlled indoor air exposure to a known concentration of dibutyl phthalate (DBP). The phthalate-allergen immune response (PAIR) study enrolled 16 allergen-sensitized participants to a double-blinded, randomized, crossover exposure to two conditions (DBP or control air for 3 hr), each followed immediately by inhaled allergen challenge. Peripheral blood immune cell composition and activation along with inflammatory mediators were measured before and after exposure. DBP exposure prior to the inhaled allergen challenge increased the percentage of CD4+ T helper cells and decreased the percentage of regulatory T cells (3 hr and 20 hr post-exposure), while only modest overall effects were observed for inflammatory mediators. The cells and mediators affected by the phthalate exposure were generally not overlapping with the endpoints affected by allergen inhalation alone. Thus, in distinction to our previously published effects on lung function, DBP appears to alter endpoints in peripheral blood that are not necessarily enhanced by allergen alone. Further studies are needed to clarify the role of phthalate-induced systemic effects in disease pathogenesis.

A prospective study of 12-week respiratory outcomes in COVID-19-related hospitalisations.

The long-term respiratory morbidity of COVID-19 remains unclear. We describe the clinical, radiological and pulmonary function abnormalities that persist in previously hospitalised patients assessed 12 weeks after COVID-19 symptom onset, and identify clinical predictors of respiratory outcomes. At least one pulmonary function variable was abnormal in 58% of patients and 88% had abnormal imaging on chest CT. There was strong association between days on oxygen supplementation during the acute phase of COVID-19 and both DLCO-% (diffusion capacity of the lung for carbon monoxide) predicted and total CT score. These findings highlight the need to develop treatment strategies and the importance of long-term respiratory follow-up after hospitalisation for COVID-19.

Allergen inhalation generates pro-inflammatory oxidised phosphatidylcholine associated with airway dysfunction.

Oxidised phosphatidylcholines (OxPCs) are produced under conditions of elevated oxidative stress and can contribute to human disease pathobiology. However, their role in allergic asthma is unexplored. The aim of this study was to characterise the OxPC profile in the airways after allergen challenge of people with airway hyperresponsiveness (AHR) or mild asthma. The capacity of OxPCs to contribute to pathobiology associated with asthma was also to be determined.Using bronchoalveolar lavage fluid from two human cohorts, OxPC species were quantified using ultra-high performance liquid chromatography-tandem mass spectrometry. Murine thin-cut lung slices were used to measure airway narrowing caused by OxPCs. Human airway smooth muscle (HASM) cells were exposed to OxPCs to assess concentration-associated changes in inflammatory phenotype and activation of signalling networks.OxPC profiles in the airways were different between people with and without AHR and correlated with methacholine responsiveness. Exposing patients with mild asthma to allergens produced unique OxPC signatures that associated with the severity of the late asthma response. OxPCs dose-dependently induced 15% airway narrowing in murine thin-cut lung slices. In HASM cells, OxPCs dose-dependently increased the biosynthesis of cyclooxygenase-2, interleukin (IL)-6, IL-8, granulocyte-macrophage colony-stimulating factor and the production of oxylipins via protein kinase C-dependent pathways.Data from human cohorts and primary HASM cell culture show that OxPCs are present in the airways, increase after allergen challenge and correlate with metrics of airway dysfunction. Furthermore, OxPCs may contribute to asthma pathobiology by promoting airway narrowing and inducing a pro-inflammatory phenotype and contraction of airway smooth muscle. OxPCs represent a potential novel target for treating oxidative stress-associated pathobiology in asthma.