Pub Date : 2024-05-09DOI: 10.1101/2024.05.08.24307019
Shivanthan Shanthikumar, Liam Gubbels, Karen Davies, Hannah Walker, Anson Tsz Chun Wong, Jovana Maksimovic, Alicia Oshlack, Richard Saffery, Eric Levi, Sarath C. Ranganathan, Melanie R. Neeland
Respiratory diseases are a common cause of morbidity and hospitalisation for children. Despite this, treatment options are limited and are often ineffective. The development of curative or disease-modifying treatments for children relies on a better understanding of underlying immunity in the early airway. To establish a flow cytometry reference for immune cells in the paediatric airway, we analysed 178 samples from 66 children aged between 1-15 years. This included five tissues of the upper (nasal brushings, palatine tonsils, adenotonsil) and lower (bronchial brushings, bronchoalveolar lavage (BAL)) airway, as well as whole blood for paired analysis of local and systemic immune response. Nasal, bronchial, and alveolar samples were analysed using a 17-plex antibody panel that captures cells of immune and epithelial lineage, while tonsil, adenoid, and blood samples were analysed using a 31-plex antibody panel that extensively phenotypes mononuclear immune cells. All protocols, panels, and data are openly available, to facilitate implementation in paediatric clinical laboratories. We provide age-specific cell reference data for infancy (0-2 years), preschool (3-5 years), childhood (6-10 years) and adolescence (11-15 years) for 37 cell populations. We show tissue-specific maturation of the airway immune system across childhood, further highlighting the importance of developing age-specific references of the paediatric airway. Intra-individual, cross-tissue analysis of paired samples revealed marked correlation in immune cell proportions between paired nasal-bronchial samples, paired tonsil-adenoid samples, and paired adenoid-blood samples, which may have implications for clinical testing. Our study advances knowledge of airway immunity from infancy through to adolescence and provides an openly available control dataset to aid in interpretation of clinical findings in samples obtained from children with respiratory diseases.
{"title":"A cross-tissue, age-specific flow cytometry reference for immune cells in the airways and blood of children","authors":"Shivanthan Shanthikumar, Liam Gubbels, Karen Davies, Hannah Walker, Anson Tsz Chun Wong, Jovana Maksimovic, Alicia Oshlack, Richard Saffery, Eric Levi, Sarath C. Ranganathan, Melanie R. Neeland","doi":"10.1101/2024.05.08.24307019","DOIUrl":"https://doi.org/10.1101/2024.05.08.24307019","url":null,"abstract":"Respiratory diseases are a common cause of morbidity and hospitalisation for children. Despite this, treatment options are limited and are often ineffective. The development of curative or disease-modifying treatments for children relies on a better understanding of underlying immunity in the early airway. To establish a flow cytometry reference for immune cells in the paediatric airway, we analysed 178 samples from 66 children aged between 1-15 years. This included five tissues of the upper (nasal brushings, palatine tonsils, adenotonsil) and lower (bronchial brushings, bronchoalveolar lavage (BAL)) airway, as well as whole blood for paired analysis of local and systemic immune response. Nasal, bronchial, and alveolar samples were analysed using a 17-plex antibody panel that captures cells of immune and epithelial lineage, while tonsil, adenoid, and blood samples were analysed using a 31-plex antibody panel that extensively phenotypes mononuclear immune cells. All protocols, panels, and data are openly available, to facilitate implementation in paediatric clinical laboratories. We provide age-specific cell reference data for infancy (0-2 years), preschool (3-5 years), childhood (6-10 years) and adolescence (11-15 years) for 37 cell populations. We show tissue-specific maturation of the airway immune system across childhood, further highlighting the importance of developing age-specific references of the paediatric airway. Intra-individual, cross-tissue analysis of paired samples revealed marked correlation in immune cell proportions between paired nasal-bronchial samples, paired tonsil-adenoid samples, and paired adenoid-blood samples, which may have implications for clinical testing. Our study advances knowledge of airway immunity from infancy through to adolescence and provides an openly available control dataset to aid in interpretation of clinical findings in samples obtained from children with respiratory diseases.","PeriodicalId":501074,"journal":{"name":"medRxiv - Respiratory Medicine","volume":"25 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140939427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-06DOI: 10.1101/2024.04.30.24306656
Mauro Lago-Docampo, Ainhoa Iglesias-López, Carlos Vilariño, Adolfo Baloira, Joan Albert Barberá, Isabel Blanco, Diana Valverde
Background Pulmonary Arterial Hypertension (PAH) is a rare disease where the thickening of the precapillary pulmonary arteries ends up inducing right heart failure. Nowadays, obtaining an early diagnosis is challenging and typically delayed until undergoing right-heart catheterization.
{"title":"Overexpression of miR-3168 impairs angiogenesis in Pulmonary Arterial Hypertension: Insights from circulating miRNA analysis","authors":"Mauro Lago-Docampo, Ainhoa Iglesias-López, Carlos Vilariño, Adolfo Baloira, Joan Albert Barberá, Isabel Blanco, Diana Valverde","doi":"10.1101/2024.04.30.24306656","DOIUrl":"https://doi.org/10.1101/2024.04.30.24306656","url":null,"abstract":"<strong>Background</strong> Pulmonary Arterial Hypertension (PAH) is a rare disease where the thickening of the precapillary pulmonary arteries ends up inducing right heart failure. Nowadays, obtaining an early diagnosis is challenging and typically delayed until undergoing right-heart catheterization.","PeriodicalId":501074,"journal":{"name":"medRxiv - Respiratory Medicine","volume":"34 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140939409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-01DOI: 10.1101/2024.04.30.24306497
Grant Stalker, Rosarie Tudas, Alpana Garg, Lauren Graham, Andrew L. Thurman, R. Todd Wiblin, Nabeel Hamzeh, Robert J. Blount, Raul Villacreses, Joseph Zabner, Alejandro Comellas, Josalyn L. Cho, Alejandro Pezzulo
Background Many of those infected with COVID-19 experience long-term disability due to persistent symptoms known as Long-COVID, which include ongoing respiratory issues, loss of taste and smell, and impaired daily functioning.
{"title":"Long-COVID improves in 50% of patients after a year in a Midwestern cohort","authors":"Grant Stalker, Rosarie Tudas, Alpana Garg, Lauren Graham, Andrew L. Thurman, R. Todd Wiblin, Nabeel Hamzeh, Robert J. Blount, Raul Villacreses, Joseph Zabner, Alejandro Comellas, Josalyn L. Cho, Alejandro Pezzulo","doi":"10.1101/2024.04.30.24306497","DOIUrl":"https://doi.org/10.1101/2024.04.30.24306497","url":null,"abstract":"<strong>Background</strong> Many of those infected with COVID-19 experience long-term disability due to persistent symptoms known as Long-COVID, which include ongoing respiratory issues, loss of taste and smell, and impaired daily functioning.","PeriodicalId":501074,"journal":{"name":"medRxiv - Respiratory Medicine","volume":"16 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140882184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-17DOI: 10.1101/2024.04.16.24305906
Christopher J Yarnell, Arviy Paranthaman, Peter Reardon, Federico Angriman, Thiago Bassi, Giacomo Bellani, Laurent Brochard, Harm Jan De Grooth, Laura Dragoi, Ewan C Goligher, Kimberley Lewis, Baoli Li, Hashim Kareemi, Bharath Kumar Tirupakuzhi Vijayaraghavan, Sangeeta Mehta, Ricard Mellado-Artigas, Julie Moore, Idunn Morris, Georgiana Roman-Sarita, Tai Pham, Jariya Sereeyotin, George Tomlinson, Hannah Wozniak, Takeshi Yoshida, Rob Fowler, Canadian Critical Care Trials Group
Purpose Intubation is a common procedure in acute hypoxemic respiratory failure (AHRF), with minimal evidence to guide decision-making. We conducted a survey of when to intubate patients with AHRF to measure the influence of clinical variables on intubation decision-making and quantify variability.
{"title":"An international factorial vignette-based survey of intubation decisions in acute hypoxemic respiratory failure","authors":"Christopher J Yarnell, Arviy Paranthaman, Peter Reardon, Federico Angriman, Thiago Bassi, Giacomo Bellani, Laurent Brochard, Harm Jan De Grooth, Laura Dragoi, Ewan C Goligher, Kimberley Lewis, Baoli Li, Hashim Kareemi, Bharath Kumar Tirupakuzhi Vijayaraghavan, Sangeeta Mehta, Ricard Mellado-Artigas, Julie Moore, Idunn Morris, Georgiana Roman-Sarita, Tai Pham, Jariya Sereeyotin, George Tomlinson, Hannah Wozniak, Takeshi Yoshida, Rob Fowler, Canadian Critical Care Trials Group","doi":"10.1101/2024.04.16.24305906","DOIUrl":"https://doi.org/10.1101/2024.04.16.24305906","url":null,"abstract":"<strong>Purpose</strong> Intubation is a common procedure in acute hypoxemic respiratory failure (AHRF), with minimal evidence to guide decision-making. We conducted a survey of when to intubate patients with AHRF to measure the influence of clinical variables on intubation decision-making and quantify variability.","PeriodicalId":501074,"journal":{"name":"medRxiv - Respiratory Medicine","volume":"94 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140629690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-12DOI: 10.1101/2024.04.11.24305702
Charlotte Levey, Maureen Manthe, Anna Taylor, Maryam Sahibqran, Eve Walker, Grace McDowell, Eric Livingston, Adam V. Benjafield, Chris Carlin
Introduction Use of home non-invasive ventilation (NIV) to treat persistent hypercapnic respiratory failure in patients with stable chronic obstructive pulmonary disease (COPD) effectively reduces readmission rates and mortality compared with standard therapy. Traditional workflows around the initiation and management of NIV include elective admission for therapy initiation and frequent face-to-face clinic visits for follow-up, but use of telemedicine offers an alternative approach.
{"title":"Impact of remote-monitored home non-invasive ventilation on patient outcomes: a retrospective cohort study","authors":"Charlotte Levey, Maureen Manthe, Anna Taylor, Maryam Sahibqran, Eve Walker, Grace McDowell, Eric Livingston, Adam V. Benjafield, Chris Carlin","doi":"10.1101/2024.04.11.24305702","DOIUrl":"https://doi.org/10.1101/2024.04.11.24305702","url":null,"abstract":"<strong>Introduction</strong> Use of home non-invasive ventilation (NIV) to treat persistent hypercapnic respiratory failure in patients with stable chronic obstructive pulmonary disease (COPD) effectively reduces readmission rates and mortality compared with standard therapy. Traditional workflows around the initiation and management of NIV include elective admission for therapy initiation and frequent face-to-face clinic visits for follow-up, but use of telemedicine offers an alternative approach.","PeriodicalId":501074,"journal":{"name":"medRxiv - Respiratory Medicine","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140591730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-12DOI: 10.1101/2024.04.10.24305440
Praveen Weeratunga, Bethany Hunter, Martin Sergeant, Joshua Bull, Colin Clelland, Laura Denney, Chaitanya Vuppusetty, Rachel Burgoyne, Jeongmin Woo, Tian Hu, Lee Borthwick, James Shaw, Agne Antanaciuvete, Andrew Filby, Helen Byrne, Andrew Fisher, Ling-Pei Ho
Healthy repair of the alveoli requires alveolar stem cells to differentiate into cells designed for gas exchange. In chronic lung fibrotic disease like idiopathic pulmonary fibrosis (IPF), alveolar epithelial cells regenerate abnormally. The cause of this is unknown but its highly cellular, inflamed and structurally altered regenerating niche is likely to be relevant. Here, in unique sets of human lung tissues capturing advancing fibrosis, and with a 33-plex single cell imaging mass cytometry (IMC), we provide a high resolution and comprehensive temporo-spatial cell atlas of the regenerating alveolar niches. Using a suite of mathematical tools, we expose an organized immune network and identify CD206hi alveolar macrophages as a central immune cell in the immune-alveolar epithelial interactome. A spatially-directed receptor-ligand analysis offers an in-silico mechanism by which these macrophages influenced alveolar regeneration. Our study unravels a complex cellular environment and identifies key interactions that influence alveolar regeneration in a fibrotic lung.
{"title":"Temporo-spatial cellular atlas of the regenerating alveolar niche in idiopathic pulmonary fibrosis","authors":"Praveen Weeratunga, Bethany Hunter, Martin Sergeant, Joshua Bull, Colin Clelland, Laura Denney, Chaitanya Vuppusetty, Rachel Burgoyne, Jeongmin Woo, Tian Hu, Lee Borthwick, James Shaw, Agne Antanaciuvete, Andrew Filby, Helen Byrne, Andrew Fisher, Ling-Pei Ho","doi":"10.1101/2024.04.10.24305440","DOIUrl":"https://doi.org/10.1101/2024.04.10.24305440","url":null,"abstract":"Healthy repair of the alveoli requires alveolar stem cells to differentiate into cells designed for gas exchange. In chronic lung fibrotic disease like idiopathic pulmonary fibrosis (IPF), alveolar epithelial cells regenerate abnormally. The cause of this is unknown but its highly cellular, inflamed and structurally altered regenerating niche is likely to be relevant. Here, in unique sets of human lung tissues capturing advancing fibrosis, and with a 33-plex single cell imaging mass cytometry (IMC), we provide a high resolution and comprehensive temporo-spatial cell atlas of the regenerating alveolar niches. Using a suite of mathematical tools, we expose an organized immune network and identify CD206<sup>hi</sup> alveolar macrophages as a central immune cell in the immune-alveolar epithelial interactome. A spatially-directed receptor-ligand analysis offers an in-silico mechanism by which these macrophages influenced alveolar regeneration. Our study unravels a complex cellular environment and identifies key interactions that influence alveolar regeneration in a fibrotic lung.","PeriodicalId":501074,"journal":{"name":"medRxiv - Respiratory Medicine","volume":"87 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140591833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-05DOI: 10.1101/2024.04.03.24304240
David G Hancock, Elizabeth Kicic-Starcevich, Thijs Sondag, Rael Rivers, Kate McGee, Yuliya V Karpievitch, Nina D’Vaz, Patricia Agudelo-Romero, Jose A Caparros-Martin, Thomas Iosifidis, Anthony Kicic, Stephen M Stick
Background and Objectives Cohort studies investigating respiratory disease pathogenesis aim to pair mechanistic investigations with longitudinal virus detection but are limited by the burden of methods tracking illness over time. In this study, we explored the utility of a smartphone app to robustly identify symptomatic respiratory illnesses, while reducing burden and facilitating real-time data collection and adherence monitoring.
{"title":"REAL TIME MONITORING OF RESPIRATORY VIRAL INFECTIONS IN COHORT STUDIES USING A SMARTPHONE APP","authors":"David G Hancock, Elizabeth Kicic-Starcevich, Thijs Sondag, Rael Rivers, Kate McGee, Yuliya V Karpievitch, Nina D’Vaz, Patricia Agudelo-Romero, Jose A Caparros-Martin, Thomas Iosifidis, Anthony Kicic, Stephen M Stick","doi":"10.1101/2024.04.03.24304240","DOIUrl":"https://doi.org/10.1101/2024.04.03.24304240","url":null,"abstract":"<strong>Background and Objectives</strong> Cohort studies investigating respiratory disease pathogenesis aim to pair mechanistic investigations with longitudinal virus detection but are limited by the burden of methods tracking illness over time. In this study, we explored the utility of a smartphone app to robustly identify symptomatic respiratory illnesses, while reducing burden and facilitating real-time data collection and adherence monitoring.","PeriodicalId":501074,"journal":{"name":"medRxiv - Respiratory Medicine","volume":"54 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140591930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-28DOI: 10.1101/2024.03.27.24304989
Pavel Pugach, Nazlie Latefi
Common cold viruses are leading triggers of asthma attacks, causing nearly two million hospitalizations per year and productivity losses approaching $40B. They also increase susceptibility to bacterial infections driving antibiotic use. Post-market clinical studies have questioned the efficacy of most over the counter (OTC) cough and cold ingredients against placebo in treating various symptoms. To our knowledge, only aspirin significantly improved overall illness severity compared to placebo and that was by about 25-30%. In this double-blind randomized placebo-controlled trial involving 157 participants, we sought to determine whether a throat spray containing a mucosal immune complex (MIC) (comprised of lysozyme, lactoferrin, and aloe) can increase the hereto reported efficacy of aspirin at reducing common cold symptoms. Previously published reports showed that the MIC can protect respiratory epithelia and lower inflammatory cytokines. Participants self-administered treatments (throat sprays every hour and tablets every four hours) and completed surveys at home over two days. Treatments included MIC spray mixed with 6mg aspirin + placebo tablet (Treatment 1), MIC spray + placebo tablet (Treatment 2), MIC spray + 325 mg aspirin tablet (Treatment 3). Participants included adult volunteers ages 21-66 (average 44), 54% female, 46% male, 46% African American, 8% Asian, 39% Caucasian, and 7% Hispanic, having common cold symptoms lasting less than two days. The main outcome measures included Sore Throat Pain Intensity (STPIS) 0-100 at 36 hours (primary endpoint) and Modified Jackson Score (MJS), a combination of eight cold symptoms (secondary endpoint). Both primary and secondary endpoints were met. Sore throat pain as measured by STPIS decreased 68-75% by 36 hours depending on treatment. Other symptoms such as nasal discharge, congestion, sneezing, cough, sore throat, and malaise as measured by MJS decreased 38-68% depending on treatment. In repeated measure within group analysis observing the same participants over multiple time points; STPIS mean change from baseline to 36 hours was as follows: Placebo (-7.84 (-14%) [95% CI -14.20 to -1.47]; p<0.0001), Treatment 1 (-42.41 (-75%)[95% CI -48.30 to -36.52]; p<0.0001), Treatment 2 (-38.60 (-68%)[95% CI -46.64 to -31.56]; p<0.0001), and Treatment 3 (-44.19 (-79%) [95% CI -52.11to -36.27]; p<0.0001). In repeated measure within group analysis all treatments significantly reduced cold symptom severity (MJS) from Days 1-2. Results were as follows: Treatment 1 (-2.26 (-38%) [95% CI -3.04 - -1.47] p<0.0001), Treatment 2 (-3.81 (-53%) [95% CI -4.82 - -2.80] p<0.0001), Treatment 3 (-4.49 (-69%) [95% CI -5.62- -3.57]; p<0.0001). As a result of this study, we conclude that supporting upper respiratory epithelia and reducing COX-mediated inflammation may be used to effectively treat common cold symptoms. Trial registration ClinicalTrials.gov Identifier: NCT06106880 Posted 30/10/2023
{"title":"Supporting Respiratory Epithelia and Lowering Inflammation to Effectively Treat Common Cold Symptoms: a Randomized Controlled Trial","authors":"Pavel Pugach, Nazlie Latefi","doi":"10.1101/2024.03.27.24304989","DOIUrl":"https://doi.org/10.1101/2024.03.27.24304989","url":null,"abstract":"Common cold viruses are leading triggers of asthma attacks, causing nearly two million hospitalizations per year and productivity losses approaching $40B. They also increase susceptibility to bacterial infections driving antibiotic use. Post-market clinical studies have questioned the efficacy of most over the counter (OTC) cough and cold ingredients against placebo in treating various symptoms. To our knowledge, only aspirin significantly improved overall illness severity compared to placebo and that was by about 25-30%. In this double-blind randomized placebo-controlled trial involving 157 participants, we sought to determine whether a throat spray containing a mucosal immune complex (MIC) (comprised of lysozyme, lactoferrin, and aloe) can increase the hereto reported efficacy of aspirin at reducing common cold symptoms. Previously published reports showed that the MIC can protect respiratory epithelia and lower inflammatory cytokines. Participants self-administered treatments (throat sprays every hour and tablets every four hours) and completed surveys at home over two days. Treatments included MIC spray mixed with 6mg aspirin + placebo tablet (Treatment 1), MIC spray + placebo tablet (Treatment 2), MIC spray + 325 mg aspirin tablet (Treatment 3). Participants included adult volunteers ages 21-66 (average 44), 54% female, 46% male, 46% African American, 8% Asian, 39% Caucasian, and 7% Hispanic, having common cold symptoms lasting less than two days. The main outcome measures included Sore Throat Pain Intensity (STPIS) 0-100 at 36 hours (primary endpoint) and Modified Jackson Score (MJS), a combination of eight cold symptoms (secondary endpoint). Both primary and secondary endpoints were met. Sore throat pain as measured by STPIS decreased 68-75% by 36 hours depending on treatment. Other symptoms such as nasal discharge, congestion, sneezing, cough, sore throat, and malaise as measured by MJS decreased 38-68% depending on treatment. In repeated measure within group analysis observing the same participants over multiple time points; STPIS mean change from baseline to 36 hours was as follows: Placebo (-7.84 (-14%) [95% CI -14.20 to -1.47]; p<0.0001), Treatment 1 (-42.41 (-75%)[95% CI -48.30 to -36.52]; p<0.0001), Treatment 2 (-38.60 (-68%)[95% CI -46.64 to -31.56]; p<0.0001), and Treatment 3 (-44.19 (-79%) [95% CI -52.11to -36.27]; p<0.0001). In repeated measure within group analysis all treatments significantly reduced cold symptom severity (MJS) from Days 1-2. Results were as follows: Treatment 1 (-2.26 (-38%) [95% CI -3.04 - -1.47] p<0.0001), Treatment 2 (-3.81 (-53%) [95% CI -4.82 - -2.80] p<0.0001), Treatment 3 (-4.49 (-69%) [95% CI -5.62- -3.57]; p<0.0001). As a result of this study, we conclude that supporting upper respiratory epithelia and reducing COX-mediated inflammation may be used to effectively treat common cold symptoms. Trial registration ClinicalTrials.gov Identifier: NCT06106880 Posted 30/10/2023","PeriodicalId":501074,"journal":{"name":"medRxiv - Respiratory Medicine","volume":"90 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140324556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-27DOI: 10.1101/2024.03.26.24304775
Min Hyung Ryu, Jeong H Yun, Kangjin Kim, Michele Gentili, Auyon Ghosh, Frank Sciurba, Andrew Limper, Gerard Criner, Kevin K Brown, Robert Wise, Fernando J Martinez, Kevin R Flaherty, Michael H Cho, Peter J Castaldi, Dawn L DeMeo, Edwin K Silverman, Craig P Hersh, Jarrett D Morrow
Rationale: Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are debilitating diseases associated with divergent histopathological changes in the lungs. At present, due to cost and technical limitations, profiling cell types is not practical in large epidemiology cohorts (n>1000). Here, we used computational deconvolution to identify cell types in COPD and IPF lungs whose abundances and cell type-specific gene expression are associated with disease diagnosis and severity. Methods: We analyzed lung tissue RNA-seq data from 1026 subjects (COPD, n=465; IPF, n=213; control, n=348) from the Lung Tissue Research Consortium. We performed RNA-seq deconvolution, querying thirty-eight discrete cell-type varieties in the lungs. We tested whether deconvoluted cell-type abundance and cell type-specific gene expression were associated with disease severity. Results: The abundance score of twenty cell types significantly differed between IPF and control lungs. In IPF subjects, eleven and nine cell types were significantly associated with forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO), respectively. Aberrant basaloid cells, a rare cells found in fibrotic lungs, were associated with worse FVC and DLCO in IPF subjects, indicating that this aberrant epithelial population increased with disease severity. Alveolar type 1 and vascular endothelial (VE) capillary A were decreased in COPD lungs compared to controls. An increase in macrophages and classical monocytes was associated with lower DLCO in IPF and COPD subjects. In both diseases, lower non-classical monocytes and VE capillary A cells were associated with increased disease severity. Alveolar type 2 cells and alveolar macrophages had the highest number of genes with cell type-specific differential expression by disease severity in COPD and IPF. In IPF, genes implicated in the pathogenesis of IPF, such as matrix metallopeptidase 7, growth differentiation factor 15, and eph receptor B2, were associated with disease severity in a cell type-specific manner. Conclusion: Utilization of RNA-seq deconvolution enabled us to pinpoint cell types present in the lungs that are associated with the severity of COPD and IPF. This knowledge offers valuable insight into the alterations within tissues in more advanced illness, ultimately providing a better understanding of the underlying pathological processes that drive disease progression.
{"title":"Computational Deconvolution of Cell Type-Specific Gene Expression in COPD and IPF Lungs Reveals Disease Severity Associations","authors":"Min Hyung Ryu, Jeong H Yun, Kangjin Kim, Michele Gentili, Auyon Ghosh, Frank Sciurba, Andrew Limper, Gerard Criner, Kevin K Brown, Robert Wise, Fernando J Martinez, Kevin R Flaherty, Michael H Cho, Peter J Castaldi, Dawn L DeMeo, Edwin K Silverman, Craig P Hersh, Jarrett D Morrow","doi":"10.1101/2024.03.26.24304775","DOIUrl":"https://doi.org/10.1101/2024.03.26.24304775","url":null,"abstract":"Rationale: Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are debilitating diseases associated with divergent histopathological changes in the lungs. At present, due to cost and technical limitations, profiling cell types is not practical in large epidemiology cohorts (n>1000). Here, we used computational deconvolution to identify cell types in COPD and IPF lungs whose abundances and cell type-specific gene expression are associated with disease diagnosis and severity. Methods: We analyzed lung tissue RNA-seq data from 1026 subjects (COPD, n=465; IPF, n=213; control, n=348) from the Lung Tissue Research Consortium. We performed RNA-seq deconvolution, querying thirty-eight discrete cell-type varieties in the lungs. We tested whether deconvoluted cell-type abundance and cell type-specific gene expression were associated with disease severity. Results: The abundance score of twenty cell types significantly differed between IPF and control lungs. In IPF subjects, eleven and nine cell types were significantly associated with forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO), respectively. Aberrant basaloid cells, a rare cells found in fibrotic lungs, were associated with worse FVC and DLCO in IPF subjects, indicating that this aberrant epithelial population increased with disease severity. Alveolar type 1 and vascular endothelial (VE) capillary A were decreased in COPD lungs compared to controls. An increase in macrophages and classical monocytes was associated with lower DLCO in IPF and COPD subjects. In both diseases, lower non-classical monocytes and VE capillary A cells were associated with increased disease severity. Alveolar type 2 cells and alveolar macrophages had the highest number of genes with cell type-specific differential expression by disease severity in COPD and IPF. In IPF, genes implicated in the pathogenesis of IPF, such as matrix metallopeptidase 7, growth differentiation factor 15, and eph receptor B2, were associated with disease severity in a cell type-specific manner. Conclusion: Utilization of RNA-seq deconvolution enabled us to pinpoint cell types present in the lungs that are associated with the severity of COPD and IPF. This knowledge offers valuable insight into the alterations within tissues in more advanced illness, ultimately providing a better understanding of the underlying pathological processes that drive disease progression.","PeriodicalId":501074,"journal":{"name":"medRxiv - Respiratory Medicine","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140313343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-26DOI: 10.1101/2024.03.25.24304837
Sibel T Savas, Stefan A. Tschanz, Philipp Latzin, Carmen Casaulta, Loretta Muller
Rationale: Primary ciliary dyskinesia is a rare genetic disease affecting ciliary motility and causing respiratory symptoms. Diagnosis can be done by high-speed-videomicroscopy using nasal epithelial cells (NECs) obtained via brushings. This procedure can be painful, especially for children. The use of lidocaine is proposed to reduce this pain; however, it is not clear whether lidocaine changes ciliary beating frequency (CBF) or pattern (CBP) in the subsequent high-speed-videomicroscopy. Objective: The aim of this study was to analyse the effect of lidocaine on the CBF and the CBP of differentiated, air-liquid-interface cultured NECs. Methods: NECs from healthy volunteers were obtained via brushings and cultured at the air-liquid-interface. After differentiation, lidocaine or isotonic saline (IS, control) were added apically for 1 or 5 min each and CBF (in top view of whole inserts and side views of scratched cells) and CBP (only side view) were assessed and recorded up to 150 min. CBF was computed and CBP was analysed semiquantitatively. Results: Lidocaine as well as IS increased the CBF in the top view approach significantly compared to baseline. However, we found no significant differences between lidocaine and IS (control) treatment. Additionally, no effect of lidocaine on CBF, CBP, amplitude, inter- and intracellular coordination or transport was seen in the side view approach. Conclusion: We conclude that the observed CBF increase is related to the addition of liquid on the mucus layer and not by the lidocaine itself. Therefore, it seems possible to use lidocaine for nasal analgesia without impact on subsequent analysis of the ciliary motility.
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