Machine learning enabled detection of COVID-19 pneumonia using exhaled breath analysis: a proof-of-concept study.

Detection of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) relies on real-time-reverse-transcriptase polymerase chain reaction (RT-PCR) on nasopharyngeal swabs. The false-negative rate of RT-PCR can be high when viral burden and infection is localized distally in the lower airways and lung parenchyma. An alternate safe, simple and accessible method for sampling the lower airways is needed to aid in the early and rapid diagnosis of COVID-19 pneumonia. In a prospective unblinded observational study, patients admitted with a positive RT-PCR and symptoms of SARS-CoV-2 infection were enrolled from three hospitals in Ontario, Canada. Healthy individuals or hospitalized patients with negative RT-PCR and without respiratory symptoms were enrolled into the control group. Breath samples were collected and analyzed by laser absorption spectroscopy (LAS) for volatile organic compounds (VOCs) and classified by machine learning (ML) approaches to identify unique LAS-spectra patterns (breathprints) for SARS-CoV-2. Of the 135 patients enrolled, 115 patients provided analyzable breath samples. Using LAS-breathprints to train ML classifier models resulted in an accuracy of 72.2%-81.7% in differentiating between SARS-CoV2 positive and negative groups. The performance was consistent across subgroups of different age, sex, body mass index, SARS-CoV-2 variants, time of disease onset and oxygen requirement. The overall performance was higher than compared to VOC-trained classifier model, which had an accuracy of 63%-74.7%. This study demonstrates that a ML-based breathprint model using LAS analysis of exhaled breath may be a valuable non-invasive method for studying the lower airways and detecting SARS-CoV-2 and other respiratory pathogens. The technology and the ML approach can be easily deployed in any setting with minimal training. This will greatly improve access and scalability to meet surge capacity; allow early and rapid detection to inform therapy; and offers great versatility in developing new classifier models quickly for future outbreaks.

Risk factors for recognized and unrecognized SARS-CoV-2 infection: a seroepidemiologic analysis of the Prospective Urban Rural Epidemiology (PURE) study.

There are limited data on individual risk factors for SARS-CoV-2 infection (including unrecognized infection). In this seroepidemiologic substudy of an ongoing prospective cohort study of community-dwelling adults, participants were thoroughly characterized pre-pandemic. The SARS-CoV-2 infection was ascertained by serology. Among 8,719 participants from 11 high-, middle-, and low-income countries, 3,009 (35%) were seropositive for SARS-CoV-2. Characteristics independently associated with seropositivity were younger age (odds ratio, OR; 95% confidence interval, CI, per five-year increase: 0.95; 0.91-0.98) and body mass index >25 kg/m2 (OR, 95% CI: 1.16, 1.01-1.34). Smoking (as compared with never smoking, OR, 95% CI: 0.83, 0.70-0.97) and COVID-19 vaccination (OR, 95% CI: 0.70, 0.60-0.82) were associated with a reduced risk of seropositivity. Among seropositive participants, 83% were unaware of having been infected with SARS-CoV-2. Seropositivity and a lack of awareness of infection were more common in lower-income countries. The COVID-19 vaccination reduces the risk of SARS-CoV-2 infection (including recognized and unrecognized infections). Overweight or obesity is an independent risk factor for SARS-CoV-2 infection. Infection and lack of infection awareness are more common in lower-income countries.IMPORTANCEIn this large, international study, evidence of SARS-CoV-2 infection was obtained by testing blood specimens from 8,719 community-dwelling adults from 11 countries. The key findings are that (i) the large majority (83%) of community-dwelling adults from several high-, middle-, and low-income countries with blood test evidence of SARS-CoV-2 infection were unaware of this infection-especially in lower-income countries; and (ii) overweight/obesity predisposes to SARS-CoV-2 infection, while COVID-19 vaccination is associated with a reduced risk of SARS-CoV-2 infection. These observations are not attributable to other individual characteristics, highlighting the importance of the COVID-19 vaccination to prevent not only severe infection but possibly any infection. Further research is needed to understand the mechanisms by which overweight/obesity might increase the risk of SARS-CoV-2 infection.

Association between impaired lung function and carotid intima-media thickness in children.

Association between obstructive lung function impairment with higher cIMT is present in childhood after accounting for common risk factors. This suggests that a developmental link between obstructive lung diseases and CVD may have its origin in early life. https://bit.ly/4657s2b.

Gene Polymorphisms of Epithelial Cell-Derived Alarmins and Their Effects on Protein Levels and Disease Severity in Patients with COVID-19.

BACKGROUND: The immune response in COVID-19 is characterized by the release of alarmin cytokines, which play crucial roles in immune activation and inflammation. The interplay between these cytokines and genetic variations may influence disease severity and outcomes, while sex differences might further contribute to variations in the immune response. METHODS: We measured the levels of alarmin cytokines in a cohort of COVID-19 and non-COVID-19 patients using a sensitive Meso Scale Discovery system. Additionally, we conducted an SNP analysis to identify genetic variations within the IL-33 and TSLP genes. The association between these genetic variations, cytokine production, and COVID-19 severity was examined. RESULTS: Our findings revealed elevated levels of IL-33 and IL-25 in COVID-19-positive patients compared to COVID-19-negative patients (p < 0.05), indicating their potential as therapeutic targets for disease modulation. Moreover, a minor allele within the IL-33 gene (rs3939286) was found to be associated with a protective effect against severe COVID-19 (p < 0.05), and minor alleles of the TSLP gene (rs2289276 and rs13806933) were found to significantly reduce TSLP protein levels in serum (p < 0.05). Sex-specific effects of TSLP and IL-33 SNPs were observed, suggesting a potential influence of sex hormones and genetic variations on the regulation of cytokine production. CONCLUSION: The present study highlights the importance of alarmin cytokines and genetic variations in COVID-19 severity, providing valuable insights into personalized treatment approaches. Our results suggest that targeting alarmin cytokines may offer potential therapeutic benefits in managing COVID-19. Furthermore, the sex-specific effects of genetic variations emphasize the need to consider individual genetic profiles and sex differences when designing targeted interventions.

Household Air Pollution and Adult Lung Function Change, Respiratory Disease, and Mortality across Eleven Low- and Middle-Income Countries from the PURE Study.

BACKGROUND: Globally, household air pollution (HAP) is a major environmental hazard that affects respiratory health. However, few studies have examined associations between HAP and lung function decline and respiratory disease and mortality. METHODS: We used data from the Prospective Urban and Rural Epidemiology study and examined adults residing in 240 rural communities in 11 low- and middle-income countries where HAP from cooking with solid fuels is common. Spirometry was conducted for 28,574 individuals at baseline and 12,489 individuals during follow-up (mean of 8 y between spirometry measures). In cross-sectional analyses, we compared lung function measurements [forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and FEV1/FVC ratio] in those who used solid fuels for cooking in comparison with clean fuels. Using repeated measurements of lung function, we examined the percent change in lung function measures per year, comparing individuals by baseline fuel type and individuals who used solid fuels at baseline but switched to clean fuels during follow-up. We also examined associations with prospective health events (any respiratory diseases, respiratory disease hospitalizations, and all-cause mortality). RESULTS: In adjusted cross-sectional models, use of solid fuel in comparison with clean fuels was associated with lower FEV1 of -17.5mL (95% CI: -32.7, -2.3) and FVC of -14.4mL (95% CI: -32.0, 3.2), but not FEV1/FVC. In longitudinal analyses, individuals who switched from solid fuels to clean cooking fuels during follow-up (n=3,901, 46% of those using solid fuel at baseline), showed no differences in the annual rate of change in FEV1 or FVC, but had small improvements in FEV1/FVC change (0.2% per year, 95% CI: 0.03, 0.3). Individuals who switched from solid to clean fuels had a decreased hazard ratio for respiratory events of 0.76 (95% CI: 0.57, 1.00) in comparison with persistent solid fuel users, which was not attenuated by lung function measures. CONCLUSION: We observed modest associations between HAP exposure and lung function, lung function change, and respiratory disease and mortality. https://doi.org/10.1289/EHP11179.

Prediction of Lung Function Status Using Handgrip Strength and Anthropometry among the Healthy Malay Population in Malaysia.

Lung function depends primarily on the strength of the intercostal muscles and the diaphragm, which is indirectly related to handgrip strength (HGS). This study aims to determine the predictability of lung functions using HGS among healthy adults of Malay ethnicity in Malaysia. This study also aims to compare the equation using HGS with equations without HGS, such as the Global Lung Initiative (GLI). This study was carried out among adults between 35 to 70 years of age residing in urban and rural Malaysia. A series of standardized questionnaires were used to collect socio-demographic information. Lung functions were measured using a portable spirometer and HGS was measured using a Jamar dynamometer. The predictability of lung function indices (FEV1 and FVC) using HGS, age, and height was determined using multiple linear regression (MLR). Prediction of lung function indices was also generated using models without HGS for comparison with the equation that used HGS from this study. Pearson correlation analysis showed that both dominant (r = 0.49; p < 0.001) and non-dominant (r = 0.58; p < 0.001) HGS had a moderate significant correlation with lung function. In the MLR model, HGS was a significant (p < 0.001) predictor of lung function indices (FEV1 and FVC). The correlation of the predicted and measured lung indices using the equation generated in this study, which includes HGS, was higher compared with other lung function test equations that do not include HGS. The equations from MLR could be used to predict lung function indices among healthy Malay adults. The measurement of HGS may be used as a screening tool for lung function status when spirometry is unavailable.

Comparison of three dosing intervals for the primary vaccination of the SARS-CoV-2 mRNA Vaccine (BNT162b2) on magnitude, neutralization capacity and durability of the humoral immune response in health care workers: A prospective cohort study.

OBJECTIVES: The dosing interval of a primary vaccination series can significantly impact on vaccine immunogenicity and efficacy. The current study compared 3 dosing intervals for the primary vaccination series of the BNT162b2 mRNA COVID-19 vaccine, on humoral immune response and durability against SARS-CoV-2 ancestral and Beta variants up to 9 months post immunization. METHODS: Three groups of age- and sex-matched healthcare workers (HCW) who received 2 primary doses of BNT162b2 separated by 35-days, 35-42 days or >42-days were enrolled. Vaccine induced antibody titers at 3 weeks, 3 and 6-9 months post-second dose were assessed. RESULTS: There were 309 age- and sex-matched HCW (mean age 43 [sd 13], 58% females) enrolled. Anti-SARS-CoV-2 binding (IgG, IgM, IgA) and neutralizing antibody titers showed significant waning in levels beyond 35 days post first dose. The second dose induced a significant rise in antibody titers, which peaked at 3 weeks and then declined at variable rates across groups. The magnitude, consistency and durability of response was greater for anti-Spike than anti-RBD antibodies; and for IgG than IgA or IgM. Compared to the shorter schedules, a longer interval of >42 days offered the highest binding and neutralizing antibody titers against SARS-CoV-2 ancestral and Beta (B1.351) variants beyond 3 months post-vaccination. CONCLUSIONS: This is the first comprehensive study to compare 3 dosing intervals for the primary vaccination of BNT162b2 mRNA COVID-19 vaccine implemented in the real world. These findings suggest that delaying the second dose beyond 42 days can potentiate and prolong the humoral response against ancestral and Beta variants of SARS-CoV-2 up to 9 months post-vaccination.

Three-dimensional MR Neurography of the Brachial Plexus: Vascular Suppression with Low-dose Ferumoxytol.

Background The efficacy of ferumoxytol, an ultrasmall superparamagnetic iron oxide particle for three-dimensional (3D) MR neurography, has yet to be evaluated. Purpose To evaluate the effects of low-dose ferumoxytol for vascular suppression and nerve visualization in 3D brachial plexus MR neurography as a pilot study. Materials and Methods Volunteers without anemia were prospectively enrolled in July 2021. Brachial plexus MR neurography was performed 30 minutes following infusion of 25% of the standard (510 mg of iron) therapeutic ferumoxytol dose with use of a 3D short-tau inversion recovery T2-weighted fast spin-echo sequence. The 3D fast spin-echo was acquired with and without the use of additional flow suppression techniques. Two musculoskeletal radiologists qualitatively evaluated examinations for the degree of vascular suppression (0-3, none to complete), nerve visualization (0-2, none to full), and motion artifact (0-4, none to severe). Nerve-to-fat, muscle, or vessel contrast ratios were calculated with use of manually drawn regions of interests. Comparisons of the proportion of scans with adequate image quality (vascular suppression, 3; nerve visualization, 1, 2; motion artifacts, 0, 1) were made with use of the McNemar test. Comparisons of quantitative contrast ratios were performed with use of Wilcoxon signed rank tests. P < .05 was deemed statistically significant. Results There were 12 volunteers (mean age, 25 years ± 3; six women) evaluated. The scans with adequate vascular suppression increased from 0% to 98% with and without ferumoxytol, respectively (P < .001). All individual nerve assessments of adequate nerve visualization increased from 4%-63% to 36%-100% without and with ferumoxytol, respectively (P < .001-.010), while motion artifacts were unchanged (from 33% to 52%, P = .212). Quantitatively, nerve-to-vessel contrast ratios increased from 0.6 without to 7.6 with ferumoxytol (P < .001). The addition of flow suppression did not change nerve-to-vessel contrast ratio quantitatively (from 7.5 to 8.4, P > .99) following ferumoxytol. Conclusion Low-dose ferumoxytol improved vascular suppression and nerve visualization in three-dimensional MR neurography of the brachial plexus compared to imaging without ferumoxytol. © RSNA, 2022.

Regional differences in the contribution of smoking, dietary and cooking behaviours to airflow obstruction in China: A population-based case-control study.

BACKGROUND AND OBJECTIVE: The major contributing risk factors to airflow obstruction (AO) in China remain largely unknown. We examined the environmental and lifestyle risk factors of unrecognized AO in the baseline of a population-based cohort drawn from 115 urban and rural communities across 12 provinces in China. METHODS: Amongst 46,285 adults recruited from 2005 to 2009, 3686 were identified with AO on spirometry (defined by the ratio of forced expiratory volume in the first second to forced vital capacity <0.7) and without known chronic lung disease. These cases were age- and sex-matched to 11,129 controls with normal spirometry and no chronic lung disease from the same community. Conditional multivariable adjusted OR and population attributable fraction (PAF) were calculated for each identified risk factor and their combined effect. RESULTS: Compared to controls, smoking initiation age <20 years (OR 1.22 [95% CI 1.01-1.48]), smoking duration ≥40 years (OR 1.82 [1.50-2.22]), low vegetables (OR 1.86 [1.67-2.07]) and fruits (OR 1.14 [1.02-1.29]) intake, cooking with biomass fuels (OR 2.54 [2.32-2.78]) and poor kitchen ventilation (OR 1.37 [1.19-1.58]) were significantly associated with elevated risks of unrecognized AO. The combined effect of these lifestyle factors significantly elevated the odds by 25 fold (18.6-34.3). The addition of prior tuberculosis and low socioeconomic status further increased the odds to 40.1 (28.2-57.0) and the PAF to 66.7% (51.1-78.1). CONCLUSION: Smoking, unhealthy diet, biomass cooking fuels and low socioeconomic status are strongly associated with AO. Addressing these risk factors could substantially reduce the burden of AO in China.

Hospitalised COVID-19 outcomes are predicted by hypoxaemia and pneumonia phenotype irrespective of the timing of their emergence.

Despite the known clinical importance of hypoxemia and pneumonia, there is a paucity of evidence for these variables with respect to risk of mortality and short-term outcomes among those hospitalised with COVID-19. OBJECTIVE: Describe the prevalence and clinical course of patients hospitalised with COVID-19 based on oxygenation and pneumonia status at presentation and determine the incidence of emergent hypoxaemia or radiographic pneumonia during admission. METHODS: A retrospective study was conducted using a Canadian regional registry. Patients were stratified according to hypoxaemia/pneumonia phenotype and prevalence. Clinical parameters were compared between phenotypes using χ2 and one-way Analysis of variance (ANOVA). Cox analysis estimated adjusted Hazard Ratios (HR) for associations between disease outcomes and phenotypes. RESULTS: At emergency department (ED) admission, the prevalence of pneumonia and hypoxaemia was 43% and 50%, respectively, and when stratified to phenotypes: 28.2% hypoxaemia+/pneumonia+, 22.2% hypoxaemia+/pneumonia-, 14.5% hypoxaemia-/pneumonia+ and 35.1% hypoxaemia-/pneumonia-. Mortality was 31.1% in the hypoxaemia+/pneumonia- group and 26.3% in the hypoxaemia+/pneumonia+ group. Hypoxaemia with pneumonia and without pneumonia predicted higher probability of death. Hypoxaemia either <24 hours or ≥24 hours after hospitalisation predicted higher mortality and need for home oxygen compared with those without hypoxaemia. Patients with early hypoxaemia had higher probability of Intensive care unit (ICU) admission compared with those with late hypoxaemia. CONCLUSION: Mortality in COVID-19 infection is predicted by hypoxaemia with or without pneumonia and was greatest in patients who initially presented with hypoxaemia. The emergence of hypoxaemia was predicted by radiographic pneumonia. Patients with early and emergent hypoxaemia had similar mortality but were less likely to be admitted to ICU. There may be delayed identification of hypoxaemia, which prevents timely escalation of care.

Prevalence and burden of COPD misclassification in the Canadian Longitudinal Study on Aging (CLSA).

INTRODUCTION: To examine the prevalence of chronic obstructive pulmonary disease (COPD) misclassification and the associated burden of symptoms, healthcare utilisation and physical performance status in the Canadian general population. This information is presently lacking from large population-based studies with high-quality spirometry data that can be generalised to the general population. METHODS: The prevalence of self-reported physician-diagnosed COPD and the concordance with spirometry airflow obstruction (AO) were assessed in a cross-sectional cohort of Canadian older adults. The associations between confirmed COPD, under-diagnosis and over-diagnosis with self-reported respiratory symptoms, healthcare utilisation and physical performance (timed up and go, handgrip strength and 4 metres walk test) were assessed, adjusting for baseline characteristics using multivariable linear and logistic models. RESULTS: A total of 21 242 participants (mean age 64 (SD 10) years; 42% men) with high quality spirometry were included. Physician-diagnosed COPD was reported in (n=973) 5% of the participants. Only (n=217) 1% of the entire cohort had confirmed COPD supported by spirometry AO. Discordance between self-reported COPD and spirometry findings was observed in (n=1565) 8%: with 4% representing under-diagnosis cases (no self-reported COPD but AO) and 4% representing over-diagnosis cases (self-reported COPD but no AO). Compared with normals (no self-reported COPD and normal spirometry), those with confirmed, under-diagnosed or over-diagnosed COPD showed higher risks for respiratory symptoms (adjusted OR (aOR) 2.1 (95% CI: 1.6 to 2.7); aOR 1.8 (95% CI: 1.6 to 2.1]; aOR 1.6 (95% CI: 1.4 to 1.9)); healthcare utilisation in the prior 12 months (ß coefficient 0.8 (95% CI: 0.2 to 2.6); ß 0.9 (95% CI: 0.5 to 1.5); ß 1.6 (95% CI: 0.7 to 4.0)). Mood disorders were higher in confirmed and over-diagnosed COPD (aOR 1.7 (95% CI: 1.3 to 2.4); 1.7 (95% CI: 1.4 to 2.0), respectively). Physical performance was lower for COPD groups. CONCLUSIONS: The prevalence of COPD misclassification is high in the general population of older adults. These were associated with significantly high burden of respiratory symptoms, healthcare utilisation and low physical performance compared with the general population with normal spirometry and no self-reported COPD. These findings highlight the high burden of COPD misclassification, which may be substantially reduced with greater accessibility to spirometry measurements in the community.

Associations between lung function and physical and cognitive health in the Canadian Longitudinal Study on Aging (CLSA): A cross-sectional study from a multicenter national cohort.

BACKGROUND: Low lung function is associated with high mortality and adverse cardiopulmonary outcomes. Less is known of its association with broader health indices such as self-reported respiratory symptoms, perceived general health, and cognitive and physical performance. The present study seeks to address the association between forced expiratory volume in 1 second (FEV1), an indicator of lung function, with broad markers of general health, relevant to aging trajectory in the general population. METHODS AND FINDINGS: From the Canadian general population, 22,822 adults (58% females, mean age 58.8 years [standard deviation (SD) 9.6]) were enrolled from the community between June 2012 and April 2015 from 11 Canadian cities and 7 provinces. Mixed effects regression was used to assess the cross-sectional relationship between FEV1 with self-reported respiratory symptoms, perceived poor general health, and cognitive and physical performance. All associations were adjusted for age, sex, body mass index (BMI), education, smoking status, and self-reported comorbidities and expressed as adjusted odds ratios (aORs). Based on the Global Lung Function Initiative (GLI) reference values, 38% (n = 8,626) had normal FEV1 (z-scores >0), 37% (n = 8,514) mild (z-score 0 to > -1 SD), 19% (n = 4,353) moderate (z-score -1 to > -2 SD), and 6% (n = 1,329) severely low FEV1 (z-score = < -2 SD). There was a graded association between lower FEV1 with higher aOR [95% CI] of self-reported moderate to severe respiratory symptoms (mild FEV1 1.09 [0.99 to 1.20] p = 0.08, moderate 1.45 [1.28 to 1.63] p < 0.001, and severe 2.67 [2.21 to 3.23] p < 0.001]), perceived poor health (mild 1.07 [0.9 to 1.27] p = 0.45, moderate 1.48 [1.24 to 1.78] p = <0.001, and severe 1.82 [1.42 to 2.33] p < 0.001]), and impaired cognitive performance (mild 1.03 [0.95 to 1.12] p = 0.41, moderate 1.16 [1.04 to 1.28] p < 0.001, and severe 1.40 [1.19 to 1.64] p < 0.001]). Similar graded association was observed between lower FEV1 with lower physical performance on gait speed, Timed Up and Go (TUG) test, standing balance, and handgrip strength. These associations were consistent across different strata by age, sex, tobacco smoking, obstructive, and nonobstructive impairment on spirometry. A limitation of the current study is the observational nature of these findings and that causality cannot be inferred. CONCLUSIONS: We observed graded associations between lower FEV1 with higher odds of disabling respiratory symptoms, perceived poor general health, and lower cognitive and physical performance. These findings support the broader implications of measured lung function on general health and aging trajectory.

Variations in risks from smoking between high-income, middle-income, and low-income countries: an analysis of data from 179 000 participants from 63 countries.

BACKGROUND: Separate studies suggest that the risks from smoking might vary between high-income (HICs), middle-income (MICs), and low-income (LICs) countries, but this has not yet been systematically examined within a single study using standardised approaches. We examined the variations in risks from smoking across different country income groups and some of their potential reasons. METHODS: We analysed data from 134 909 participants from 21 countries followed up for a median of 11·3 years in the Prospective Urban Rural Epidemiology (PURE) cohort study; 9711 participants with myocardial infarction and 11 362 controls from 52 countries in the INTERHEART case-control study; and 11 580 participants with stroke and 11 331 controls from 32 countries in the INTERSTROKE case-control study. In PURE, all-cause mortality, major cardiovascular disease, cancers, respiratory diseases, and their composite were the primary outcomes for this analysis. Biochemical verification of urinary total nicotine equivalent was done in a substudy of 1000 participants in PURE. FINDINGS: In PURE, the adjusted hazard ratio (HR) for the composite outcome in current smokers (vs never smokers) was higher in HICs (HR 1·87, 95% CI 1·65-2·12) than in MICs (1·41, 1·34-1·49) and LICs (1·35, 1·25-1·46; interaction p<0·0001). Similar patterns were observed for each component of the composite outcome in PURE, myocardial infarction in INTERHEART, and stroke in INTERSTROKE. The median levels of tar, nicotine, and carbon monoxide displayed on the cigarette packs from PURE HICs were higher than those on the packs from MICs. In PURE, the proportion of never smokers reporting high second-hand smoke exposure (≥1 times/day) was 6·3% in HICs, 23·2% in MICs, and 14·0% in LICs. The adjusted geometric mean total nicotine equivalent was higher among current smokers in HICs (47·2 µM) than in MICs (31·1 µM) and LICs (25·2 µM; ANCOVA p<0·0001). By contrast, it was higher among never smokers in LICs (18·8 µM) and MICs (11·3 µM) than in HICs (5·0 µM; ANCOVA p=0·0001). INTERPRETATION: The variations in risks from smoking between country income groups are probably related to the higher exposure of tobacco-derived toxicants among smokers in HICs and higher rates of high second-hand smoke exposure among never smokers in MICs and LICs. FUNDING: Full funding sources are listed at the end of the paper (see Acknowledgments).

Differences and agreement between two portable hand-held spirometers across diverse community-based populations in the Prospective Urban Rural Epidemiology (PURE) study.

INTRODUCTION: Portable spirometers are commonly used in longitudinal epidemiological studies to measure and track the forced expiratory volume in first second (FEV1) and forced vital capacity (FVC). During the course of the study, it may be necessary to replace spirometers with a different model. This raise questions regarding the comparability of measurements from different devices. We examined the correlation, mean differences and agreement between two different spirometers, across diverse populations and different participant characteristics. METHODS: From June 2015 to Jan 2018, a total of 4,603 adults were enrolled from 628 communities in 18 countries and 7 regions of the world. Each participant performed concurrent measurements from the MicroGP and EasyOne spirometer. Measurements were compared by the intra-class correlation coefficient (ICC) and Bland-Altman method. RESULTS: Approximately 65% of the participants achieved clinically acceptable quality measurements. Overall correlations between paired FEV1 (ICC 0.88 [95% CI 0.87, 0.88]) and FVC (ICC 0.84 [0.83, 0.85]) were high. Mean differences between paired FEV1 (-0.038 L [-0.053, -0.023]) and FVC (0.033 L [0.012, 0.054]) were small. The 95% limits of agreement were wide but unbiased (FEV1 984, -1060; FVC 1460, -1394). Similar findings were observed across regions. The source of variation between spirometers was mainly at the participant level. Older age, higher body mass index, tobacco smoking and known COPD/asthma did not adversely impact on the inter-device variability. Furthermore, there were small and acceptable mean differences between paired FEV1 and FVC z-scores using the Global Lung Initiative normative values, suggesting minimal impact on lung function interpretation. CONCLUSIONS: In this multicenter, diverse community-based cohort study, measurements from two portable spirometers provided good correlation, small and unbiased differences between measurements. These data support their interchangeable use across diverse populations to provide accurate trends in serial lung function measurements in epidemiological studies.

Functional recovery following hospitalisation of patients diagnosed with COVID-19: a protocol for a longitudinal cohort study.

INTRODUCTION: COVID-19 is an international public health crisis with more than 132 million infections worldwide. Beyond acute infection, emerging data indicate patients diagnosed with COVID-19 may experience persistent sequelae similar to survivors of sepsis or acute respiratory syndromes, including mobility limitations and fatigue. However, there is limited evidence on the trajectory of functional recovery in those hospitalised with COVID-19. The primary aim of the Coronavirus Registry Functional Recovery (COREG-FR) study is to understand the trajectory of functional recovery among individuals hospitalised for COVID-19 over the medium (up to 6 months) and longer term (6-12 months) that will guide clinical care and optimal management of serious COVID-19 illness and recovery. METHODS AND ANALYSIS: COREG-FR is a multicentre longitudinal cohort study. We will enrol a minimum of 211 adults age 18 years and older with COVID-19 from five hospitals. Participants will be followed from admission to hospital as an inpatient, to hospital discharge, and at 3-month, 6-month, 9-month and up to 12-month post-hospital discharge. We will conduct telephone interviews at ward admission and discharge, and telephone interviews plus in-person assessments of physical function and lung function at all remaining follow-ups. Our primary outcome is the Activity Measure for Post-Acute Care mobility scale measured at all time points. We will conduct linear mixed effects regression analyses to explore determinants of functional outcomes after COVID-19 illness. Subgroup analyses based on age (≤65 vs >65 years), frailty status (Clinical Frailty Scale score ≤4 vs >5) and variants of concern will be conducted. ETHICS AND DISSEMINATION: COREG-FR has been approved by Research Ethics Boards at participating sites. We will disseminate this work through peer-reviewed manuscripts, presentations at national and international meetings and through the established COREG website (www.coregontario.ca). COREG-FR is designed as a data platform for future studies evaluating COVID-19 recovery. TRIAL REGISTRATION NUMBER: NCT04602260; Pre-results.

Respiratory Symptoms Are Associated With Frailty in Older Adults With Normal Spirometry, Independent of Smoking, in the Canadian Longitudinal Study of Aging.

BACKGROUND: Recent studies have demonstrated that even in the absence of lung impairment as determined by spirometry, smoking and respiratory symptoms are associated with poor overall health and well-being. However, this relationship is not well defined; and it remains unclear the degree to which symptoms are related to poor health, independent of smoking. This is of particular importance to older adults, as they are more likely to exhibit respiratory symptoms and are, therefore, at risk of not receiving appropriate treatment if they have never smoked and have normal spirometry. METHODS: We performed a cross-sectional analysis of data from the Canadian Longitudinal Study on Aging to delineate the associations of respiratory symptoms and smoking on the health of participants age 45-86 who exhibited normal spirometry. Participant health was estimated using a frailty index, a multidimensional measure of vulnerability to adverse outcomes that has been validated in numerous health settings. RESULTS: Of the 21,293 participants included in our analysis, 87% exhibited a normal FEV1, FVC, and FEV1/FVC; of those, 45% reported at least one respiratory symptom, and 50% were former or current smokers. Both respiratory symptoms and smoking were independently associated with frailty (median interquartile range [IQR] = 0.11 [0.07-0.15]), the most substantial associations observed for those having at least one respiratory symptom (adjusted ß 0.023, 95% CI 0.022-0.025) and current smokers with > 10 pack-year exposure (adjusted ß 0.014, 95% CI [0.010-0.019). Not only was the association between symptoms and frailty evident in never smokers, a significant proportion of the total effect of smoking on frailty was observed to be mediated by symptoms. CONCLUSIONS: Our data show that respiratory symptoms, regardless of smoking history, were a significant correlate of frailty in older adults with normal spirometry. Hence, they should not be simply regarded as a benign by-product of aging.

Impact of electronic cigarette ever use on lung function in adults aged 45-85: a cross-sectional analysis from the Canadian Longitudinal Study on Aging.

OBJECTIVE: To describe the sociodemographic characteristics associated with e-cigarette ever use and to examine the impact of e-cigarette ever use on lung function impairment in an ageing population. DESIGN: A cross-sectional analysis of data from the Canadian Longitudinal Study on Aging. SETTING: A national stratified sample of 44 817 adults living in Canadian provinces. PARTICIPANTS: Respondents included participants aged 45-85 and residing in the community in Canadian provinces. OUTCOME MEASURES: The Global Lung Function Initiative normative values for forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), forced expiratory ratio (FEV1/FVC) appropriate for age, sex, height and ethnicity were used to interpret the severity of lung function impairment. Multinomial logistic regression analysis was used to examine the impact of e-cigarette ever use on obstructive and restrictive lung function impairment. RESULTS: The prevalence of e-cigarette ever use was 6.5% and varied by sociodemographic factors including higher prevalence among individuals younger than 65 years, those with lower education attainment and those with lower annual household income. E-cigarette ever use was associated with 2.10 (95% CI 1.57 to 2.08) times higher odds of obstructive lung function impairment after adjusting for conventional cigarette smoking and other covariates. Individuals with exposure to e-cigarette ever use and 15 or more pack-years had 7.43 (95% CI 5.30 to 10.38) times higher odds for obstructive lung function impairment when compared with non-smokers and non-e-cigarette users after adjusting for covariates. Smokers with 15 or more pack-years had higher odds of restrictive lung function impairment irrespective of e-cigarette ever use. CONCLUSIONS: Ever use of e-cigarettes was found to be associated with obstructive lung function impairment after adjusting for covariates, suggesting that e-cigarette use may be adding to the respiratory and other chronic disease burden in the population.

External validation of the 4C mortality score among COVID-19 patients admitted to hospital in Ontario, Canada: a retrospective study.

Risk prediction scores are important tools to support clinical decision-making for patients with coronavirus disease (COVID-19). The objective of this paper was to validate the 4C mortality score, originally developed in the United Kingdom, for a Canadian population, and to examine its performance over time. We conducted an external validation study within a registry of COVID-19 positive hospital admissions in the Kitchener-Waterloo and Hamilton regions of southern Ontario between March 4, 2020 and June 13, 2021. We examined the validity of the 4C score to prognosticate in-hospital mortality using the area under the receiver operating characteristic curve (AUC) with 95% confidence intervals calculated via bootstrapping. The study included 959 individuals, of whom 224 (23.4%) died in-hospital. Median age was 72 years and 524 individuals (55%) were male. The AUC of the 4C score was 0.77, 95% confidence interval 0.79-0.87. Overall mortality rates across the pre-defined risk groups were 0% (Low), 8.0% (Intermediate), 27.2% (High), and 54.2% (Very High). Wave 1, 2 and 3 values of the AUC were 0.81 (0.76, 0.86), 0.74 (0.69, 0.80), and 0.76 (0.69, 0.83) respectively. The 4C score is a valid tool to prognosticate mortality from COVID-19 in Canadian hospitals and can be used to prioritize care and resources for patients at greatest risk of death.