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2.
Preprint in English | medRxiv | ID: ppmedrxiv-22270208

ABSTRACT

The COVID-19 pandemic continues to challenge the capacities of hospital ICUs which currently lack the ability to identify prospectively those patients who may require extended management. In this study of 90 ICU COVID-19 patients, we evaluated serum levels of four cytokines (IL-1{beta}, IL-6, IL-10 and TNF) as well as standard clinical and laboratory measurements. On 42 of these patients (binned into Initial and Replication Cohorts), we further performed CyTOF-based deep immunophenotyping of peripheral blood mononuclear cells with a panel of 38 antibodies. All measurements and patient samples were taken at time of ICU admission and retrospectively linked to patient clinical outcomes through statistical approaches. These analyses resulted in the definition of a new measure of patient clinical outcome: patients who will recover after short ICU stays (< 6 days) and those who will subsequently die or recover after long ICU stays (> 6 days). Based on these clinical outcome categories, we identified blood prognostic biomarkers that, at time of ICU admission, prospectively distinguish, with 91% sensitivity and 91% specificity (positive likelihood ratio 10.1), patients in the two clinical outcome groups. This is achieved through a tiered evaluation of serum IL-10 and targeted immunophenotyping of monocyte subsets, specifically, CD11clow classical monocytes. Immunophenotyping revealed clear predictors of clinical outcome in COVID-19 providing a highly sensitive and specific prognostic test that could prove useful in guiding clinical resource allocation. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=62 SRC="FIGDIR/small/22270208v4_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@1d4ac2eorg.highwire.dtl.DTLVardef@174167dorg.highwire.dtl.DTLVardef@707492org.highwire.dtl.DTLVardef@f5415f_HPS_FORMAT_FIGEXP M_FIG C_FIG

3.
Curr Opin Pulm Med ; 28(2): 152-161, 2022 03 01.
Article in English | MEDLINE | ID: covidwho-1483669

ABSTRACT

PURPOSE OF REVIEW: Pulmonary rehabilitation improves clinical outcomes in patients with chronic obstructive pulmonary disease (COPD). Traditional centre-based (in-person) pulmonary rehabilitation was largely shut down in response to the COVID-19 pandemic, forcing many centres to rapidly shift to remote home-based programs in the form of telerehabilitation (tele-pulmonary rehabilitation). This review summarizes the recent evidence for the feasibility and effectiveness of remote pulmonary rehabilitation programs, and their implications for the delivery of pulmonary rehabilitation in a postpandemic world. RECENT FINDINGS: A number of innovative adaptations to pulmonary rehabilitation in response to COVID-19 have been reported, and the evidence supports tele-pulmonary rehabilitation as a viable alternative to traditional centre-based pulmonary rehabilitation. However, these studies also highlight the challenges that must be surmounted in order to see its widespread adoption. SUMMARY: There are outstanding questions regarding the optimal model for tele-pulmonary rehabilitation. In the post-COVID-19 world, a 'hybrid' model may be more desirable, with some components held in person and others via telehealth technology. This would be determined by the infrastructure and expertise of individual centres, and the needs of their patients. In order to achieve a truly patient-centred pulmonary rehabilitation program, high-quality studies addressing these outstanding questions, as well as multidisciplinary collaboration, are required.


Subject(s)
COVID-19 , Pulmonary Disease, Chronic Obstructive , Telerehabilitation , Feasibility Studies , Humans , Pandemics , SARS-CoV-2
5.
EClinicalMedicine ; 38: 101035, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1313066

ABSTRACT

BACKGROUND: Many countries have implemented lockdowns to reduce COVID-19 transmission. However, there is no consensus on the optimal timing of these lockdowns to control community spread of the disease. Here we evaluated the relationship between timing of lockdowns, along with other risk factors, and the growth trajectories of COVID-19 across 3,112 counties in the US. METHODS: We ascertained dates for lockdowns and implementation of various non-pharmaceutical interventions at a county level and merged these data with those of US census and county-specific COVID-19 daily cumulative case counts. We then applied a Functional Principal Component (FPC) analysis on this dataset to generate FPC scores, which were used as a surrogate variable to describe the trajectory of daily cumulative case counts for each county. We used machine learning methods to identify risk factors including the timing of lockdown that significantly influenced the FPC scores. FINDINGS: We found that the first eigen-function accounted for most (>92%) of the variations in the daily cumulative case counts. The impact of lockdown timing on the total daily case count of a county became significant beginning approximately 7 days prior to that county reporting at least 5 cumulative cases of COVID-19. Delays in lockdown implementation after this date led to a rapid acceleration of COVID-19 spread in the county over the first ~50 days from the date with at least 5 cumulative cases, and higher case counts across the entirety of the follow-up period. Other factors such as total population, median family income, Gini index, median age, and within-county mobility also had a substantial effect. When adjusted for all these factors, the timing of lockdowns was the most significant risk factor associated with the county-specific daily cumulative case counts. INTERPRETATION: Lockdowns are an effective way of controlling the spread of COVID-19 in communities. Significant delays in lockdown cause a dramatic increase in the cumulative case counts. Thus, the timing of the lockdown relative to the case count is an important consideration in controlling the pandemic in communities. FUNDING: The study period is from June 2020 to July 2021. Dr. Xuekui Zhang is a Tier 2 Canada Research Chairs (Grant No. 950231363) and funded by Natural Sciences and Engineering Research Council of Canada (Grant No. RGPIN201704722). Dr. Li Xing is funded by Natural Sciences and Engineering Research Council of Canada (Grant Number: RGPIN 202103530). This research was enabled in part by support provided by WestGrid (www.westgrid.ca) and Compute Canada (www.computecanada.ca). The computing resource is provided by Compute Canada Resource Allocation Competitions #3495 (PI: Xuekui Zhang) and #1551 (PI: Li Xing). Dr. Don Sin is a Tier 1 Canada Research Chair in COPD and holds the de Lazzari Family Chair at the Heart Lung Innovation, Vancouver, Canada.

7.
Am J Respir Cell Mol Biol ; 64(6): 647-649, 2021 06.
Article in English | MEDLINE | ID: covidwho-1158162
8.
EClinicalMedicine ; 33: 100789, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-1144585

ABSTRACT

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) are highly susceptible from respiratory exacerbations from viral respiratory tract infections. However, it is unclear whether they are at increased risk of COVID-19 pneumonia or COVID-19-related mortality. We aimed to determine whether COPD is a risk factor for adverse COVID-19 outcomes including hospitalization, severe COVID-19, or death. METHODS: Following the PRISMA guidelines, we performed a systematic review of COVID-19 clinical studies published between November 1st, 2019 and January 28th, 2021 (PROSPERO ID: CRD42020191491). We included studies that quantified the number of COPD patients, and reported at least one of the following outcomes stratified by COPD status: hospitalization; severe COVID-19; ICU admission; mechanical ventilation; acute respiratory distress syndrome; or mortality. We meta-analyzed the results of individual studies to determine the odds ratio (OR) of these outcomes in patients with COPD compared to those without COPD. FINDINGS: Fifty-nine studies met the inclusion criteria, and underwent data extraction. Most studies were retrospective cohort studies/case series of hospitalized patients. Only four studies examined the effects of COPD on COVID-19 outcomes as their primary endpoint. In aggregate, COPD was associated with increased odds of hospitalization (OR 4.23, 95% confidence interval [CI] 3.65-4.90), ICU admission (OR 1.35, 95% CI 1.02-1.78), and mortality (OR 2.47, 95% CI 2.18-2.79). INTERPRETATION: Having a clinical diagnosis of COPD significantly increases the odds of poor clinical outcomes in patients with COVID-19. COPD patients should thus be considered a high-risk group, and targeted for preventative measures and aggressive treatment for COVID-19 including vaccination.

9.
J Mol Diagn ; 23(6): 683-690, 2021 06.
Article in English | MEDLINE | ID: covidwho-1121530

ABSTRACT

Fast, accurate, and reliable diagnostic tests are critical for controlling the spread of the coronavirus disease 2019 (COVID-19) associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The current gold standard for testing is real-time PCR; however, during the current pandemic, supplies of testing kits and reagents have been limited. We report the validation of a rapid (30 minutes), user-friendly, and accurate microchip real-time PCR assay for detection of SARS-CoV-2 from nasopharyngeal swab RNA extracts. Microchips preloaded with COVID-19 primers and probes for the N gene accommodate 1.2-µL reaction volumes, lowering the required reagents by 10-fold compared with tube-based real-time PCR. We validated our assay using contrived reference samples and 21 clinical samples from patients in Canada, determining a limit of detection of 1 copy per reaction. The microchip real-time PCR provides a significantly lower resource alternative to the Centers for Disease Control and Prevention-approved real-time RT-PCR assays with comparable sensitivity, showing 100% positive and negative predictive agreement of clinical samples.


Subject(s)
COVID-19 Nucleic Acid Testing/standards , COVID-19/diagnosis , Lab-On-A-Chip Devices , RNA, Viral/genetics , Real-Time Polymerase Chain Reaction/standards , SARS-CoV-2/genetics , Benchmarking , COVID-19/epidemiology , COVID-19 Nucleic Acid Testing/instrumentation , COVID-19 Nucleic Acid Testing/methods , Canada/epidemiology , Humans , Limit of Detection , Nasopharynx/virology , Point-of-Care Testing , Reagent Kits, Diagnostic/supply & distribution
10.
Int J Chron Obstruct Pulmon Dis ; 16: 379-391, 2021.
Article in English | MEDLINE | ID: covidwho-1110155

ABSTRACT

Pulmonary rehabilitation (PR) is effective in reducing symptoms and improving health status, and exercise tolerance of patients with chronic obstructive pulmonary disease (COPD). The coronavirus disease 19 (COVID-19) pandemic has greatly impacted PR programs and their delivery to patients. Owing to fears of viral transmission and resultant outbreaks of COVID-19, institution-based PR programs have been forced to significantly reduce enrolment or in some cases completely shut down during the pandemic. As a majority of COPD patients are elderly and have multiple co-morbidities including cardiovascular disease and diabetes, they are notably susceptible to severe complications of COVID-19. As such, patients have been advised to stay at home and avoid social contact to the maximum extent possible. This has increased patients' vulnerability to physical deconditioning, depression, and social isolation. To address this major gap in care, some traditional hospital or clinic-centered PR programs have converted some or all of their learning contents to home-based telerehabilitation during the pandemic. There are, however, some significant barriers to this approach that have impeded its implementation in the community. These include variable access and use of technology (by patients), a lack of standardization of methods and tools for evaluation of the program, and inadequate training and resources for health professionals in optimally delivering telerehabilitation to patients. There is a pressing need for high-quality studies on these modalities of PR to enable the successful implementation of PR at home and via teleconferencing technologies. Here, we highlight the importance of telerehabilitation of patients with COPD in the post-COVID world and discuss various strategies for clinical implementation.


Subject(s)
COVID-19 , Pulmonary Disease, Chronic Obstructive/rehabilitation , Telerehabilitation , COVID-19/epidemiology , COVID-19/prevention & control , Communicable Disease Control/methods , Humans , Pulmonary Disease, Chronic Obstructive/epidemiology , Quality Improvement , SARS-CoV-2 , Telerehabilitation/methods , Telerehabilitation/organization & administration , Telerehabilitation/standards
11.
Hum Genet ; 140(6): 969-979, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1092066

ABSTRACT

SARS-CoV-2 is responsible for the coronavirus disease 2019 (COVID-19) and the current health crisis. Despite intensive research efforts, the genes and pathways that contribute to COVID-19 remain poorly understood. We, therefore, used an integrative genomics (IG) approach to identify candidate genes responsible for COVID-19 and its severity. We used Bayesian colocalization (COLOC) and summary-based Mendelian randomization to combine gene expression quantitative trait loci (eQTLs) from the Lung eQTL (n = 1,038) and eQTLGen (n = 31,784) studies with published COVID-19 genome-wide association study (GWAS) data from the COVID-19 Host Genetics Initiative. Additionally, we used COLOC to integrate plasma protein quantitative trait loci (pQTL) from the INTERVAL study (n = 3,301) with COVID-19 loci. Finally, we determined any causal associations between plasma proteins and COVID-19 using multi-variable two-sample Mendelian randomization (MR). The expression of 18 genes in lung and/or blood co-localized with COVID-19 loci. Of these, 12 genes were in suggestive loci (PGWAS < 5 × 10-05). LZTFL1, SLC6A20, ABO, IL10RB and IFNAR2 and OAS1 had been previously associated with a heightened risk of COVID-19 (PGWAS < 5 × 10-08). We identified a causal association between OAS1 and COVID-19 GWAS. Plasma ABO protein, which is associated with blood type in humans, demonstrated a significant causal relationship with COVID-19 in the MR analysis; increased plasma levels were associated with an increased risk of COVID-19 and, in particular, severe COVID-19. In summary, our study identified genes associated with COVID-19 that may be prioritized for future investigations. Importantly, this is the first study to demonstrate a causal association between plasma ABO protein and COVID-19.


Subject(s)
Blood Proteins/metabolism , COVID-19/epidemiology , Genetic Predisposition to Disease , Lung/metabolism , Polymorphism, Single Nucleotide , Quantitative Trait Loci , SARS-CoV-2/isolation & purification , ABO Blood-Group System/metabolism , COVID-19/metabolism , COVID-19/virology , Cohort Studies , Genome-Wide Association Study , Humans , Mendelian Randomization Analysis , Risk Factors
12.
R Soc Open Sci ; 7(11): 200958, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-1005759

ABSTRACT

Angiotensin-converting enzyme 2 (ACE2) and serine protease TMPRSS2 have been implicated in cell entry for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19). The expression of ACE2 and TMPRSS2 in the lung epithelium might have implications for the risk of SARS-CoV-2 infection and severity of COVID-19. We use human genetic variants that proxy angiotensin-converting enzyme (ACE) inhibitor drug effects and cardiovascular risk factors to investigate whether these exposures affect lung ACE2 and TMPRSS2 gene expression and circulating ACE2 levels. We observed no consistent evidence of an association of genetically predicted serum ACE levels with any of our outcomes. There was weak evidence for an association of genetically predicted serum ACE levels with ACE2 gene expression in the Lung eQTL Consortium (p = 0.014), but this finding did not replicate. There was evidence of a positive association of genetic liability to type 2 diabetes mellitus with lung ACE2 gene expression in the Gene-Tissue Expression (GTEx) study (p = 4 × 10-4) and with circulating plasma ACE2 levels in the INTERVAL study (p = 0.03), but not with lung ACE2 expression in the Lung eQTL Consortium study (p = 0.68). There were no associations of genetically proxied liability to the other cardiometabolic traits with any outcome. This study does not provide consistent evidence to support an effect of serum ACE levels (as a proxy for ACE inhibitors) or cardiometabolic risk factors on lung ACE2 and TMPRSS2 expression or plasma ACE2 levels.

13.
Sci Rep ; 10(1): 21863, 2020 12 14.
Article in English | MEDLINE | ID: covidwho-977274

ABSTRACT

Cell entry of SARS-CoV-2, the novel coronavirus causing COVID-19, is facilitated by host cell angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2). We aimed to identify and characterize genes that are co-expressed with ACE2 and TMPRSS2, and to further explore their biological functions and potential as druggable targets. Using the gene expression profiles of 1,038 lung tissue samples, we performed a weighted gene correlation network analysis (WGCNA) to identify modules of co-expressed genes. We explored the biology of co-expressed genes using bioinformatics databases, and identified known drug-gene interactions. ACE2 was in a module of 681 co-expressed genes; 10 genes with moderate-high correlation with ACE2 (r > 0.3, FDR < 0.05) had known interactions with existing drug compounds. TMPRSS2 was in a module of 1,086 co-expressed genes; 31 of these genes were enriched in the gene ontology biologic process 'receptor-mediated endocytosis', and 52 TMPRSS2-correlated genes had known interactions with drug compounds. Dozens of genes are co-expressed with ACE2 and TMPRSS2, many of which have plausible links to COVID-19 pathophysiology. Many of the co-expressed genes are potentially targetable with existing drugs, which may accelerate the development of COVID-19 therapeutics.


Subject(s)
COVID-19/metabolism , Lung/metabolism , Receptors, Coronavirus/metabolism , Transcriptome , Adult , Aged , Angiotensin-Converting Enzyme 2/metabolism , Cohort Studies , Databases, Chemical , Female , Humans , Lung/pathology , Male , Middle Aged , Serine Endopeptidases/metabolism
14.
Preprint in English | medRxiv | ID: ppmedrxiv-20207118

ABSTRACT

SARS-CoV-2 is responsible for the coronavirus disease 2019 (COVID-19) and the current health crisis. Despite intensive research efforts, the genes and pathways that contribute to COVID-19 remain poorly understood. We therefore used an integrative genomics (IG) approach to identify candidate genes responsible for COVID-19 and its severity. We used Bayesian colocalization (COLOC) and summary-based Mendelian randomization to combine gene expression quantitative trait loci (eQTLs) from the Lung eQTL (n=1,038) and eQTLGen (n=31,784) studies with published COVID-19 genome-wide association study (GWAS) data from the COVID-19 Host Genetics Initiative. Additionally, we used COLOC to integrate plasma protein quantitative trait loci (pQTL) from the INTERVAL study (n=3,301) with COVID-19-associated loci. Finally, we determined any causal associations between plasma proteins and COVID-19 using multi-variable two-sample Mendelian randomization (MR). We found that the expression of 20 genes in lung and 31 genes in blood was associated with COVID-19. Of these genes, only three (LZTFL1, SLC6A20 and ABO) had been previously linked with COVID-19 in GWAS. The novel loci included genes involved in interferon pathways (IL10RB, IFNAR2 and OAS1). Plasma ABO protein, which is associated with blood type in humans, demonstrated a significant causal relationship with COVID-19 in MR analysis; increased plasma levels were associated with an increased risk of having COVID-19 and risk of severe COVID-19. In summary, our study identified genes associated with COVID-19 that may be prioritized for future investigation. Importantly, this is the first study to demonstrate a causal association between plasma ABO protein and COVID-19.

15.
Am J Respir Crit Care Med ; 202(5): 642-644, 2020 09 01.
Article in English | MEDLINE | ID: covidwho-788318
16.
EClinicalMedicine ; 26: 100546, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-785512
18.
Biomicrofluidics ; 14(4): 044117, 2020 Jul.
Article in English | MEDLINE | ID: covidwho-733467

ABSTRACT

The effect of air-borne nanoparticles (NPs) on human health is an active area of research, with clinical relevance evidenced by the current COVID-19 pandemic. As in vitro models for such studies, lung-on-a-chip (LOAC) devices can represent key physical and physiological aspects of alveolar tissues. However, widespread adoption of the LOAC device for NP testing has been hampered by low intra-laboratory and inter-laboratory reproducibility. To complement ongoing experimental work, we carried out finite-element simulations of the deposition of NPs on the epithelial layer of a well-established LOAC design. We solved the Navier-Stokes equations for the fluid flow in a three-dimensional domain and studied the particle transport using Eulerian advection-diffusion for fine NPs and Lagrangian particle tracking for coarse NPs. Using Langmuir and Frumkin kinetics for surface adsorption and desorption, we investigated NP adsorption under different exercise and breath-holding patterns. Conditions mimicking physical exercise, through changes in air-flow volume and breathing frequency, enhance particle deposition. Puff profiles typical of smoking, with breath-holding between inhalation and exhalation, also increase particle deposition per breathing cycle. Lagrangian particle tracking shows Brownian motion and gravitational settling to be two key factors, which may cooperate or compete with each other for different particle sizes. Comparisons are made with experimental data where possible and they show qualitative and semi-quantitative agreement. These results suggest that computer simulations can potentially inform and accelerate the design and application of LOAC devices for analyzing particulate- and microbe-alveolar interactions.

19.
Preprint in English | medRxiv | ID: ppmedrxiv-20178368

ABSTRACT

RationaleChronic obstructive pulmonary disease (COPD) is a risk factor for severe COVID-19. Inhaled corticosteroids (ICS) are commonly prescribed for the prevention of acute exacerbations in people with COPD, but their use is associated with increased risk of respiratory infections. The effects of ICS on SARS-CoV-2 susceptibility or COVID-19 severity are currently unknown. ObjectivesTo determine the effects of ICS treatment on the bronchial epithelial cell expression of key SARS-CoV-2-related genes in volunteers with COPD. MethodsWe performed a randomized, open-label, parallel treatment trial of 12 weeks treatment with ICS in combination with long-acting beta-agonist (formoterol/budesonide 12/400 {micro}g twice daily or salmeterol/fluticasone propionate 25/250 {micro}g twice daily), or treatment with LABA only (formoterol 12 {micro}g twice daily), in volunteers with mild to very severe COPD. We obtained bronchial epithelial cell samples via bronchoscopy before and after treatment, and determined transcriptome-wide gene expression by RNA sequencing. Main Results63 volunteers were randomized to receive treatment. Compared to formoterol alone, formoterol/budesonide treatment decreased the expression of the SARS-CoV-2 receptor gene ACE2 and the host cell protease gene ADAM17. These genes were highly co-expressed with innate immune response genes, particularly those of the type I interferon and anti-viral response pathways, which also tended to decrease following ICS treatment. ConclusionsThis is the first randomized controlled trial to show that ICS affect the expression of key SARS-CoV-2-related genes in COPD. Their relation to important anti-viral response genes may have critical implications for SARS-CoV-2 susceptibility or COVID-19 severity in this vulnerable population.

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