Pub Date : 2024-02-28DOI: 10.1101/2024.02.26.24302674
Firoozeh V.Gerayeli, Hye Yun Park, Stephen Milne, Xuan Li, Chen Xi Yang, Josie Tuong, Rachel Eddy, Elizabeth Guinto, Chung Y Cheung, Julia Shun-Wei Yang, Cassie Gilchrist, Dina Yehia, Tara Stach, Tawimas Shaipanich, Jonathon Leipsic, Graeme Koelwyn, Janice Leung, Don D Sin
To elucidate the important cellular and molecular drivers of pulmonary long COVID, we generated a single-cell transcriptomic map of the airway mucosa using bronchial brushings from patients with long COVID who reported persistent pulmonary symptoms. Adults with and without long COVID were recruited from the general community in greater Vancouver, Canada. The cohort was divided into those with pulmonary long COVID (PLC), which was defined as persons with new or worsening respiratory symptoms following at least one year from their initial acute SARS-CoV-2 infection (N=9); and control subjects defined as SARS-CoV-2 infected persons whose acute respiratory symptoms had fully resolved or individuals who had not experienced acute COVID-19 (N=9). These participants underwent bronchoscopy from which a single cell suspension was created from bronchial brush samples and then sequenced. A total of 56,906 cells were recovered for the downstream analysis, with 34,840 cells belonging to the PLC group. A dimensionality reduction plot shows a unique cluster of neutrophils in the PLC group (p<.05). Ingenuity Pathway Analysis revealed that neutrophil degranulation pathway was enriched across epithelial cells. Differential gene expression analysis between the PLC and control groups demonstrated upregulation of mucin genes in secretory cell clusters. A single-cell transcriptomic landscape of the small airways shows that the PLC airways harbors a dominant neutrophil cluster and an upregulation in the neutrophil-associated activation signature with increased expression of MUC genes in the secretory cells. Together, they suggest that pulmonary symptoms of long COVID may be driven by chronic small airway inflammation.
{"title":"Single cell sequencing reveals cellular landscape alterations in the airway mucosa of patients with pulmonary long COVID","authors":"Firoozeh V.Gerayeli, Hye Yun Park, Stephen Milne, Xuan Li, Chen Xi Yang, Josie Tuong, Rachel Eddy, Elizabeth Guinto, Chung Y Cheung, Julia Shun-Wei Yang, Cassie Gilchrist, Dina Yehia, Tara Stach, Tawimas Shaipanich, Jonathon Leipsic, Graeme Koelwyn, Janice Leung, Don D Sin","doi":"10.1101/2024.02.26.24302674","DOIUrl":"https://doi.org/10.1101/2024.02.26.24302674","url":null,"abstract":"To elucidate the important cellular and molecular drivers of pulmonary long COVID, we generated a single-cell transcriptomic map of the airway mucosa using bronchial brushings from patients with long COVID who\u0000reported persistent pulmonary symptoms. Adults with and without long COVID were recruited from the general community in greater Vancouver, Canada. The cohort was divided into those with pulmonary long COVID (PLC), which was defined as persons with new or worsening respiratory symptoms following at least one year from their initial acute SARS-CoV-2 infection (N=9); and control subjects defined as SARS-CoV-2 infected persons whose acute respiratory symptoms had fully resolved or individuals who had not experienced acute COVID-19 (N=9). These participants underwent bronchoscopy from which a single cell suspension was created from bronchial brush samples and then sequenced. A total of 56,906 cells were recovered for the downstream analysis, with 34,840 cells belonging to the PLC group. A dimensionality reduction plot shows a unique cluster of neutrophils in the PLC group (p<.05). Ingenuity Pathway Analysis revealed that neutrophil degranulation pathway was enriched across epithelial cells. Differential gene expression analysis between the PLC and control groups demonstrated upregulation of mucin genes in secretory cell clusters. A single-cell transcriptomic landscape of the small airways shows that the PLC airways harbors a dominant neutrophil cluster and an upregulation in the neutrophil-associated activation signature with increased expression of MUC genes in the secretory cells. Together, they suggest that pulmonary symptoms of long COVID may be driven by chronic small airway inflammation.","PeriodicalId":501074,"journal":{"name":"medRxiv - Respiratory Medicine","volume":"39 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140008510","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 : 2024-02-20DOI: 10.1101/2024.02.19.24303057
Anbesan Hoole, Ahsan Ilyas, Matthew Cant, Sunaina Munawar, Rizwan Hameed, Shahzad Gill, Joel Riaz, Issac Siddiq
Introduction While Post Tuberculous (TB) Bronchiectasis is the most common cause of Bronchiectasis in South Asia, there has been little research into its microbiology and clinical characteristics in Pakistan. This single centre retrospective cohort study at Bach Christian Hospital (BCH) in rural Northern Pakistan seeks to address this issue. Methods Demographic, Imaging, Aetiological and Microbiological data were obtained from 32 patients with Bronchiectasis at BCH from between January 2023 and December 2023. Results 76% (25/32) of all cases of Bronchiectasis were Post TB. TB infection was seen in 5 cases of Post TB Bronchiectasis, TB with bacterial or fungal co infections in 4, and single bacterial infections in 4. In post TB Bronchiectasis 4 patients had growth of a single bacterium. Drug sensitivities were obtained for bacterial isolates. One patient each with Post TB and Non-TB Bronchiectasis died from Type 2 Respiratory failure despite appropriate treatment. 2 patients with Post TB Bronchiectasis and destroyed lung syndrome improved but with ongoing significant respiratory impairment. All other patients improved with treatment. Discussion 1. The frequency of Post TB Bronchiectasis is very high even for South Asia. 2. A significant number (8/24) of Post TB Bronchiectasis had re-infection or failure to improve despite appropriate drug treatment. TB PCR (Polymerase Chain Reaction) on Bronchoalveolar lavage (BAL) was key in the management of these patients. 3. Among patients with Post TB Bronchiectasis, those with co-infection present a difficult treatment challenge. 4. Some patients with Post TB Bronchiectasis have significant complications such as destroyed lung syndrome which is difficult to manage. 5. Drug susceptible bacteria and NTM were less commonly isolated than in other studies. Conclusion Further research is needed particularly to manage Post TB Bronchiectasis patients with co-infections or complications such as significant structural lung disease.
{"title":"Post Tuberculosis (TB) Bronchiectasis versus Non-TB Bronchiectasis in Northern Pakistan: A single centre retrospective cohort study on frequency, demographics, microbiology, and complications","authors":"Anbesan Hoole, Ahsan Ilyas, Matthew Cant, Sunaina Munawar, Rizwan Hameed, Shahzad Gill, Joel Riaz, Issac Siddiq","doi":"10.1101/2024.02.19.24303057","DOIUrl":"https://doi.org/10.1101/2024.02.19.24303057","url":null,"abstract":"Introduction\u0000While Post Tuberculous (TB) Bronchiectasis is the most common cause of Bronchiectasis in South Asia, there has been little research into its microbiology and clinical characteristics in Pakistan. This single centre retrospective cohort study at Bach Christian Hospital (BCH) in rural Northern Pakistan seeks to address this issue. Methods\u0000Demographic, Imaging, Aetiological and Microbiological data were obtained from 32 patients with Bronchiectasis at BCH from between January 2023 and December 2023. Results\u000076% (25/32) of all cases of Bronchiectasis were Post TB. TB infection was seen in 5 cases of Post TB Bronchiectasis, TB with bacterial or fungal co infections in 4, and single bacterial infections in 4. In post TB Bronchiectasis 4 patients had growth of a single bacterium. Drug sensitivities were obtained for bacterial isolates. One patient each with Post TB and Non-TB Bronchiectasis died from Type 2 Respiratory failure despite appropriate treatment. 2 patients with Post TB Bronchiectasis and destroyed lung syndrome improved but with ongoing significant respiratory impairment. All other patients improved with treatment. Discussion\u00001.\tThe frequency of Post TB Bronchiectasis is very high even for South Asia.\u00002.\tA significant number (8/24) of Post TB Bronchiectasis had re-infection or failure to improve despite appropriate drug treatment. TB PCR (Polymerase Chain Reaction) on Bronchoalveolar lavage (BAL) was key in the management of these patients.\u00003.\tAmong patients with Post TB Bronchiectasis, those with co-infection present a difficult treatment challenge.\u00004.\tSome patients with Post TB Bronchiectasis have significant complications such as destroyed lung syndrome which is difficult to manage. 5.\tDrug susceptible bacteria and NTM were less commonly isolated than in other studies. Conclusion\u0000Further research is needed particularly to manage Post TB Bronchiectasis patients with co-infections or complications such as significant structural lung disease.","PeriodicalId":501074,"journal":{"name":"medRxiv - Respiratory Medicine","volume":"23 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139910087","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 : 2024-02-18DOI: 10.1101/2024.02.16.24302743
Deena Osama Al Chaar, mudar Al Chaar, hussam Al bardan, Adele Al Chaar
Background To explore whether the use of cigarettes affects the prevalence of obstructive sleep apnea (OSA) in adults. Methods A questionnaire-based cross- sectional study was conducted among 233 participants. The questionnaire link was published on November 13, 2023 on social media sites and the Internet.The adults were divided into four groups: noncurrent smokers, current electronic cigarettes (e-cigarette) users only, current conventional cigarettes (c-cigarette) users only, and dual users. OSA was assessed by three main signs and symptoms from the questionnaire. Multivariable logistic regression after adjusting for covariates was conducted to investigate the association of OSA with different smoking patterns. The sample size was calculated as 233 to a population of 12,900000 with a margin error of 5% and a confidence interval of 95% using a sample size calculator. Conclusion Our study found that 68% of sleep apnea patients were smokers, with 24% passive smoking, 36% smoking regular cigarettes, 24% smoking hookah, and 8% smoking electronic cigarettes, which confirmed that sleep apnea is more related to smoking regular cigarettes than Electronic cigarettes
{"title":"STUDY ABOUT THE EFFECTS OF SMOKING ON SLEEP APNEA IN A SAMPLE OF SYRIAN SOCIETY","authors":"Deena Osama Al Chaar, mudar Al Chaar, hussam Al bardan, Adele Al Chaar","doi":"10.1101/2024.02.16.24302743","DOIUrl":"https://doi.org/10.1101/2024.02.16.24302743","url":null,"abstract":"Background\u0000To explore whether the use of cigarettes affects the prevalence of obstructive sleep apnea (OSA) in adults.\u0000Methods\u0000A questionnaire-based cross- sectional study was conducted among 233 participants.\u0000The questionnaire link was published on November 13, 2023 on social media sites and the Internet.The adults were divided into four groups: noncurrent smokers, current electronic cigarettes (e-cigarette) users only, current conventional cigarettes (c-cigarette) users only, and dual users. OSA was assessed by three main signs and symptoms from the questionnaire. Multivariable logistic regression after adjusting for covariates was conducted to investigate the association of OSA with different smoking patterns.\u0000The sample size was calculated as 233 to a population of 12,900000 with a margin error of 5% and a confidence interval of 95% using a sample size calculator. Conclusion\u0000Our study found that 68% of sleep apnea patients were smokers, with 24% passive smoking, 36% smoking regular cigarettes, 24% smoking hookah, and 8% smoking electronic cigarettes, which confirmed that sleep apnea is more related to smoking regular cigarettes than Electronic cigarettes","PeriodicalId":501074,"journal":{"name":"medRxiv - Respiratory Medicine","volume":"256 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139903015","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 : 2024-02-15DOI: 10.1101/2024.02.14.24302812
Imran Howell, Freda Yang, Vanessa Brown, Jennifer Cane, Emanuele Marchi, Adnan Azim, John Busby, Pamela Jane McDowell, Sarah Diver, Catherine Borg, Liam Heaney, Ian Pavord, Chris Brightling, Rekha Chaudhuri, Timothy SC Hinks
Mepolizumab is an anti-interleukin-5 monoclonal antibody treatment for severe eosinophilic asthma (SEA) that reduces asthma exacerbations. Residual airway inflammation on mepolizumab may lead to persistent exacerbations. Oral corticosteroids have broad anti-inflammatory effects and remain the main treatment for these residual exacerbations. Our study aimed to explore the nature and corticosteroid-responsiveness of airway inflammation after mepolizumab treatment to find potentially treatable inflammatory mechanisms. The MAPLE trial was a multi-centre, randomized, double-blind, placebo-controlled, crossover study of 2 weeks of high-dose oral prednisolone treatment at stable state in patients treated with mepolizumab for SEA. We analysed sputum and plasma samples from the MAPLE trial using high-throughput Olink proteomics. We also analysed plasma microRNA, sputum proteins using ELISA, and nasal mucosal bulk RNA sequencing. In patients receiving mepolizumab, prednisolone significantly downregulated sputum proteins related to type-2 inflammation and chemotaxis including IL-4, IL-5, IL-13, CCL24, CCL26, EDN, CCL17, CCL22, OX40 receptor, FCER2, and the ST2 receptor. Prednisolone also downregulated cell adhesion molecules, prostaglandin synthases, mast cell tryptases, MMP1, MMP12, and neuroimmune mediators. Tissue repair and neutrophilic pathways were upregulated. Type-2 proteins were also downregulated in plasma, combined with IL-12, IFN-γ, and IP-10. IL-10 and amphiregulin were upregulated. In the nasal transcriptome, prednisolone suppressed genes involved in leucocyte chemotaxis, mast cell tryptase, 15-lipoxygenase and MMP12. By contrast, mepolizumab differentially regulated only Galectin-10 in plasma and no sputum proteins, and in nasal tissue affected genes related to cilia, keratinisation, extracellular matrix formation, and IL-4/13 signalling. At stable state, prednisolone has broad anti-inflammatory effects on top of mepolizumab.
{"title":"Anti-inflammatory effects of oral prednisolone at stable state in people treated with mepolizumab: a proteomic and bulk transcriptomics analysis","authors":"Imran Howell, Freda Yang, Vanessa Brown, Jennifer Cane, Emanuele Marchi, Adnan Azim, John Busby, Pamela Jane McDowell, Sarah Diver, Catherine Borg, Liam Heaney, Ian Pavord, Chris Brightling, Rekha Chaudhuri, Timothy SC Hinks","doi":"10.1101/2024.02.14.24302812","DOIUrl":"https://doi.org/10.1101/2024.02.14.24302812","url":null,"abstract":"Mepolizumab is an anti-interleukin-5 monoclonal antibody treatment for severe eosinophilic asthma (SEA) that reduces asthma exacerbations. Residual airway inflammation on mepolizumab may lead to persistent exacerbations. Oral corticosteroids have broad anti-inflammatory effects and remain the main treatment for these residual exacerbations. Our study aimed to explore the nature and corticosteroid-responsiveness of airway inflammation after mepolizumab treatment to find potentially treatable inflammatory mechanisms. The MAPLE trial was a multi-centre, randomized, double-blind, placebo-controlled, crossover study of 2 weeks of high-dose oral prednisolone treatment at stable state in patients treated with mepolizumab for SEA. We analysed sputum and plasma samples from the MAPLE trial using high-throughput Olink proteomics. We also analysed plasma microRNA, sputum proteins using ELISA, and nasal mucosal bulk RNA sequencing. In patients receiving mepolizumab, prednisolone significantly downregulated sputum proteins related to type-2 inflammation and chemotaxis including IL-4, IL-5, IL-13, CCL24, CCL26, EDN, CCL17, CCL22, OX40 receptor, FCER2, and the ST2 receptor. Prednisolone also downregulated cell adhesion molecules, prostaglandin synthases, mast cell tryptases, MMP1, MMP12, and neuroimmune mediators. Tissue repair and neutrophilic pathways were upregulated. Type-2 proteins were also downregulated in plasma, combined with IL-12, IFN-γ, and IP-10. IL-10 and amphiregulin were upregulated. In the nasal transcriptome, prednisolone suppressed genes involved in leucocyte chemotaxis, mast cell tryptase, 15-lipoxygenase and MMP12. By contrast, mepolizumab differentially regulated only Galectin-10 in plasma and no sputum proteins, and in nasal tissue affected genes related to cilia, keratinisation, extracellular matrix formation, and IL-4/13 signalling. At stable state, prednisolone has broad anti-inflammatory effects on top of mepolizumab.","PeriodicalId":501074,"journal":{"name":"medRxiv - Respiratory Medicine","volume":"105 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139770531","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 : 2024-02-13DOI: 10.1101/2024.02.12.24302675
Caroline Beese, Lea Bayer, Bennet Huebbe, Jennifer Riedel, Sima Melnik, Gordon Brestrich, Christof Von Eiff, Tobias Tenenbaum
Background: Clinical and economic burden of infections due to respiratory syntactical virus (RSV) in children <2 years of age in Germany is still underestimated. Methods: In a retrospective health claims analysis, we identified RSV inpatient and outpatient episodes based on year-round specific RSV ICD-10 diagnoses or unspecified lower respiratory tract infection diagnoses during the RSV-season. High-risk groups were defined by ICD-10 codes. Hospitalization costs per patient were incurred between the beginning and end of an RSV episode. All-cause costs were compared to a matched control group without RSV infections based on age, sex, and prematurity in the inpatient and outpatient sectors. Results The incidence of hospitalization due to RSV was substantially higher in infants (21/1,000) than in toddlers (5.4/1,000). Most hospitalizations occurred in the first six months of life; the highest hospitalization incidences were observed in the second month of life (46/1,000). Infants with risk factors had a 2.4 times higher risk for hospitalization than those without. The economic burden per episode was high in the first 3 months of life and especially for those with risk factors and/or prematurity. However, overall annual resource utilization for the healthcare system was higher for healthy children with no underlying risk factors than for those with risk factors. Conclusion: RSV in children <2 years of age causes a considerable burden for the German healthcare system, both clinically and economically. Newborns, premature infants, children with chronic underlying risk factors are at highest risk for severe outcomes, but the overall disease burden affects healthy infants.
{"title":"Clinical and economic burden of lower respiratory tract infection due to respiratory syncytial virus in young children in Germany","authors":"Caroline Beese, Lea Bayer, Bennet Huebbe, Jennifer Riedel, Sima Melnik, Gordon Brestrich, Christof Von Eiff, Tobias Tenenbaum","doi":"10.1101/2024.02.12.24302675","DOIUrl":"https://doi.org/10.1101/2024.02.12.24302675","url":null,"abstract":"Background: Clinical and economic burden of infections due to respiratory syntactical virus (RSV) in children <2 years of age in Germany is still underestimated. Methods: In a retrospective health claims analysis, we identified RSV inpatient and outpatient episodes based on year-round specific RSV ICD-10 diagnoses or unspecified lower respiratory tract infection diagnoses during the RSV-season. High-risk groups were defined by ICD-10 codes. Hospitalization costs per patient were incurred between the beginning and end of an RSV episode. All-cause costs were compared to a matched control group without RSV infections based on age, sex, and prematurity in the inpatient and outpatient sectors. Results The incidence of hospitalization due to RSV was substantially higher in infants (21/1,000) than in toddlers (5.4/1,000). Most hospitalizations occurred in the first six months of life; the highest hospitalization incidences were observed in the second month of life (46/1,000). Infants with risk factors had a 2.4 times higher risk for hospitalization than those without. The economic burden per episode was high in the first 3 months of life and especially for those with risk factors and/or prematurity. However, overall annual resource utilization for the healthcare system was higher for healthy children with no underlying risk factors than for those with risk factors. Conclusion: RSV in children <2 years of age causes a considerable burden for the German healthcare system, both clinically and economically. Newborns, premature infants, children with chronic underlying risk factors are at highest risk for severe outcomes, but the overall disease burden affects healthy infants.","PeriodicalId":501074,"journal":{"name":"medRxiv - Respiratory Medicine","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139770382","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 : 2024-02-08DOI: 10.1101/2024.02.07.24302414
Mateusz Kozinski, Doruk Oner, Jakub Gwizdala, Catherine Beigelman, Pascal Fua, Angela Koutsokera, Alessio Casutt, Michele De Palma, john-david Aubert, Horst Bischof, Christophe von Garnier, Sahand Rahi, Martin Urschler, Nahal Mansouri
Bronchiolitis Obliterans Syndrome (BOS), a fibrotic airway disease following lung transplantation, conventionally relies on pulmonary function tests (PFTs) for diagnosis due to limitations of CT images. Thus far, deep neural networks (DNNs) have not been used for BOS detection. We optimized a DNN for detection of BOS solely using CT scans by integrating an innovative co-training method for enhanced performance in low-data scenarios. The novel auxiliary task is to predict the temporal precedence of CT scans of BOS patients. We tested our method using CT scans at various stages of inspiration from 75 post-transplant patients, including 26 with BOS. The method achieved a ROC-AUC of 0.90 (95% CI: 0.840-0.953) in distinguishing BOS from non-BOS CT scans. Performance correlated with disease progression, reaching 0.88 ROC-AUC for stage I, 0.91 for stage II, and an outstanding 0.94 for stage III BOS. Importantly, performance parity existed between standard and high-resolution scans. Particularly noteworthy is the DNN's ability to predict BOS in at-risk patients (FEV1 between 80% and 90% of best FEV1) with a robust 0.87 ROC-AUC (CI: 0.735-0.974). Using techniques for visually interpreting the results of deep neural networks, we reveal that our method is especially sensitive to hyperlucent areas compatible with air-trapping or bronchiectasis. Our approach shows the potential to improve BOS diagnosis, enabling early detection and management. Detecting BOS from low-resolution scans reduces radiation exposure and using scans at any stage of respiration makes our method more accessible. Additionally, we demonstrate that techniques that limit overfitting are essential to unlocking the power of DNNs in scenarios with scarce training data. Our method may enable clinicians to use DNNs in studies where only a modest number of patients is available.
{"title":"Harnessing Deep Learning to Detect Bronchiolitis Obliterans Syndrome from Chest CT","authors":"Mateusz Kozinski, Doruk Oner, Jakub Gwizdala, Catherine Beigelman, Pascal Fua, Angela Koutsokera, Alessio Casutt, Michele De Palma, john-david Aubert, Horst Bischof, Christophe von Garnier, Sahand Rahi, Martin Urschler, Nahal Mansouri","doi":"10.1101/2024.02.07.24302414","DOIUrl":"https://doi.org/10.1101/2024.02.07.24302414","url":null,"abstract":"Bronchiolitis Obliterans Syndrome (BOS), a fibrotic airway disease following lung transplantation, conventionally relies on pulmonary function tests (PFTs) for diagnosis due to limitations of CT images. Thus far, deep neural networks (DNNs)\u0000have not been used for BOS detection. We optimized a DNN for detection of BOS solely using CT scans by integrating an innovative co-training method for enhanced performance in low-data scenarios. The novel auxiliary task is to predict the temporal precedence of CT scans of BOS patients. We tested our method using CT scans at various stages of inspiration from 75 post-transplant patients, including 26 with BOS. The method achieved a ROC-AUC of 0.90 (95% CI: 0.840-0.953) in distinguishing BOS from non-BOS CT scans. Performance correlated with disease progression, reaching 0.88 ROC-AUC for stage I, 0.91 for stage II, and an outstanding 0.94 for stage III BOS. Importantly, performance parity\u0000existed between standard and high-resolution scans. Particularly noteworthy is the DNN's ability to predict BOS in at-risk patients (FEV1 between 80% and 90% of best FEV1) with a robust 0.87 ROC-AUC (CI: 0.735-0.974). Using techniques for visually interpreting the results of deep neural networks, we reveal that our method is especially sensitive to\u0000hyperlucent areas compatible with air-trapping or bronchiectasis. Our approach shows the potential to improve BOS diagnosis, enabling early detection and management. Detecting BOS from low-resolution scans reduces radiation exposure and using scans at any stage of respiration makes our method more accessible. Additionally, we demonstrate that\u0000techniques that limit overfitting are essential to unlocking the power of DNNs in scenarios with scarce training data. Our method may enable clinicians to use DNNs in studies where only a modest number of patients is available.","PeriodicalId":501074,"journal":{"name":"medRxiv - Respiratory Medicine","volume":"308 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139770384","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 : 2024-02-03DOI: 10.1101/2024.01.31.24302108
Cinthya Pena-Orbea, David Bruckman, Jarrod E. Dalton, J Darryl Thornton, Jay L Alberts, Catherine M Heinzinger, Nancy Foldvary-Schaefer, Reena Mehra
Background The association between neighborhood socioeconomic disadvantage and poor cardiovascular outcomes is well established; however, less is known about its interplay with obstructive sleep apnea. Methods Adult cardiovascular disease-naïve patients who underwent sleep testing at Cleveland Clinic in Ohio from August of 1998 to August of 2021 were included in this cohort. The primary exposure was Area Deprivation Index (ADI) calculated by national rank, i.e. 25th, 50th, and 75th percentiles; higher quartiles reflecting greater deprivation (ADI-Q1-4) with Q1 as reference. Cox proportional hazard models were used to determine the hazard of composite outcome of major adverse cardiovascular events (MACE), i.e. including heart failure, stroke, atrial fibrillation and coronary artery disease or death, adjusted for demographics, comorbidities, cardiac medications and objective OSA-related measures including of Apnea Hypopnea Index (AHI) and sleep-related hypoxia (percentage of sleep time spent<90%SaO2,T90). Linear models were used to examine the relationship between ADI and OSA-related measures. Interaction terms were tested between ADI and OSA-related measures. Results: Of 72,443 adults age was 50.4±14.2 years, 50.5% were men, and 18.4% Black individuals. The median AHI was 14.3[5.8, 33.3] with a median follow-up of 4.39 [IQR,1.76-7.92] years. The relative incidence of initial MACE in the presence of competing risk of death was 17% higher (HR,1.17[95%CI 1.09-1.27],p<.001) for those living in ADI-Q4. Greater levels of area deprivation were associated with sleep-related hypoxia measures including higher degree of T90(p<.001); lower mean SaO2(p<.001), and lower minimum SaO2(p<.001). Significant interactions between T90 and ADI were observed with the risk of MACE(p=0.002) or death(p=0.005). T90 conferred a 37% increased risk of MACE(HR, 1.37[95%CI:1.23-1.53]) for those living in ADI-Q1; and a 26% increased risk(HR, 1.26[95%CI:1.14-1.38%]) among patients living in ADI-Q4. For individuals living in ADI-Q2 and Q3, T90 conferred a respective 56% and 51% increased risk of death (HR,1.56[95%CI:1.23 - 1.96]; HR, 1.51[95%CI:1.21-1.88]), respectively. Conclusions: Neighborhood disadvantage was associated with an increased risk for MACE or death in this clinical cohort and this association was modified by sleep-related hypoxia. Further research is needed to identify neighborhood-specific social determinants contributing to sleep-cardiovascular health disparities to develop neighborhood-specific interventions.
{"title":"Neighborhood Disadvantage Association with Sleep Apnea and Longitudinal Cardiovascular Events in a Large Clinical Cohort","authors":"Cinthya Pena-Orbea, David Bruckman, Jarrod E. Dalton, J Darryl Thornton, Jay L Alberts, Catherine M Heinzinger, Nancy Foldvary-Schaefer, Reena Mehra","doi":"10.1101/2024.01.31.24302108","DOIUrl":"https://doi.org/10.1101/2024.01.31.24302108","url":null,"abstract":"Background\u0000The association between neighborhood socioeconomic disadvantage and poor cardiovascular outcomes is well established; however, less is known about its interplay with obstructive sleep apnea.\u0000Methods Adult cardiovascular disease-naïve patients who underwent sleep testing at Cleveland Clinic in Ohio from August of 1998 to August of 2021 were included in this cohort. The primary exposure was Area Deprivation Index (ADI) calculated by national rank, i.e. 25th, 50th, and 75th percentiles; higher quartiles reflecting greater deprivation (ADI-Q1-4) with Q1 as reference. Cox proportional hazard models were used to determine the hazard of composite outcome of major adverse cardiovascular events (MACE), i.e. including heart failure, stroke, atrial fibrillation and coronary artery disease or death, adjusted for demographics, comorbidities, cardiac medications and objective OSA-related measures including of Apnea Hypopnea Index (AHI) and sleep-related hypoxia (percentage of sleep time spent<90%SaO2,T90). Linear models were used to examine the relationship between ADI and OSA-related measures. Interaction terms were tested between ADI and OSA-related measures.\u0000Results: Of 72,443 adults age was 50.4±14.2 years, 50.5% were men, and 18.4% Black individuals. The median AHI was 14.3[5.8, 33.3] with a median follow-up of 4.39 [IQR,1.76-7.92] years. The relative incidence of initial MACE in the presence of competing risk of death was 17% higher (HR,1.17[95%CI 1.09-1.27],p<.001) for those living in ADI-Q4. Greater levels of area deprivation were associated with sleep-related hypoxia measures including higher degree of T90(p<.001); lower mean SaO2(p<.001), and lower minimum SaO2(p<.001). Significant interactions between T90 and ADI were observed with the risk of MACE(p=0.002) or death(p=0.005). T90 conferred a 37% increased risk of MACE(HR, 1.37[95%CI:1.23-1.53]) for those living in ADI-Q1; and a 26% increased risk(HR, 1.26[95%CI:1.14-1.38%]) among patients living in ADI-Q4. For individuals living in ADI-Q2 and Q3, T90 conferred a respective 56% and 51% increased risk of death (HR,1.56[95%CI:1.23 - 1.96]; HR, 1.51[95%CI:1.21-1.88]), respectively.\u0000Conclusions: Neighborhood disadvantage was associated with an increased risk for MACE or death in this clinical cohort and this association was modified by sleep-related hypoxia. Further research is needed to identify neighborhood-specific social determinants contributing to sleep-cardiovascular health disparities to develop neighborhood-specific interventions.","PeriodicalId":501074,"journal":{"name":"medRxiv - Respiratory Medicine","volume":"38 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139661457","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 : 2024-02-03DOI: 10.1101/2024.02.02.24302197
Ann-Marcia Comfort Tukpah, Jonathan Rose, Diane Seger, Gary Matt Hunninghake, David W Bates
Rationale: Racial and ethnic differences in presentation and outcomes have been reported in systemic sclerosis (SSc) and SSc-interstitial lung disease (ILD). However, diverse cohorts and additional modeling can improve understanding of risk features and outcomes, which is important for reducing associated disparities. Objective(s): To determine if there are racial/ethnic differences associated with SSc-ILD risk and age; time intervals between SSc and ILD, and with emergency department (ED) visit or hospitalization rates. Methods: A retrospective cohort study using electronic health record data from an integrated health system, over a 5.5 year period was conducted using clinical and sociodemographic variables, models were generated with sequential adjustments for these variables. Logistic regression models were used to examine the association of covariates with ILD and age at SSc-ILD. Healthcare outcomes were analyzed with complementary log-log regression models. Results: The cohort included 756 adults (83.6% female, 80.3% non-Hispanic White) with SSc with a mean age of 59 years. Overall, 33.7% of patients in the cohort had an ILD code, with increased odds for Asian (odds ratio [OR], 2.59; 95% confidence interval [CI], 1.29, 5.18; P=.007) compared to White patients. The age in years of patients with SSc-ILD was younger for Hispanic (mean difference, -6.5; 95% CI, -13 , -0.21; P = 0.04) and Black/African American patients (-10; 95% CI -16 , -4.9; P <0.001) compared to White patients. Black/African American patients were more likely to have an ILD code before an SSc code (59% compared to 20.6% of White patients), and had the shortest interval from SSc to ILD (3 months). Black/African American (HR, 2.59; 95% CI 1.47, 4.49; P=0.001) and Hispanic patients (HR 2.29; 95% CI 1.37, 3.82; P=0.002) had higher rates of an ED visit. Conclusion: In this study, SSc-ILD presentation and outcomes differed by racial/ethnic group (increased odds of SSc-ILD, younger age at SSc-ILD, and preceding diagnosis with respect to SSc, rates of ED visit), some of which was attenuated with adjustment for clinical and sociodemographic characteristics. Differing presentation may be driven by social drivers of health (SDOH), autoantibody profiles, or other key unmeasured factors contributing to susceptibility and severity.
{"title":"Racial and ethnic associations with interstitial lung disease and healthcare utilization in patients with systemic sclerosis","authors":"Ann-Marcia Comfort Tukpah, Jonathan Rose, Diane Seger, Gary Matt Hunninghake, David W Bates","doi":"10.1101/2024.02.02.24302197","DOIUrl":"https://doi.org/10.1101/2024.02.02.24302197","url":null,"abstract":"Rationale: Racial and ethnic differences in presentation and outcomes have been reported in systemic sclerosis (SSc) and SSc-interstitial lung disease (ILD). However, diverse cohorts and additional modeling can improve understanding of risk features and outcomes, which is important for reducing associated disparities. Objective(s): To determine if there are racial/ethnic differences associated with SSc-ILD risk and age; time intervals between SSc and ILD, and with emergency department (ED) visit or hospitalization rates. Methods: A retrospective cohort study using electronic health record data from an integrated health system, over a 5.5 year period was conducted using clinical and sociodemographic variables, models were generated with sequential adjustments for these variables. Logistic regression models were used to examine the association of covariates with ILD and age at SSc-ILD. Healthcare outcomes were analyzed with complementary log-log regression models. Results: The cohort included 756 adults (83.6% female, 80.3% non-Hispanic White) with SSc with a mean age of 59 years. Overall, 33.7% of patients in the cohort had an ILD code, with increased odds for Asian (odds ratio [OR], 2.59; 95% confidence interval [CI], 1.29, 5.18; P=.007) compared to White patients. The age in years of patients with SSc-ILD was younger for Hispanic (mean difference, -6.5; 95% CI, -13 , -0.21; P = 0.04) and Black/African American patients (-10; 95% CI -16 , -4.9; P <0.001) compared to White patients. Black/African American patients were more likely to have an ILD code before an SSc code (59% compared to 20.6% of White patients), and had the shortest interval from SSc to ILD (3 months). Black/African American (HR, 2.59; 95% CI 1.47, 4.49; P=0.001) and Hispanic patients (HR 2.29; 95% CI 1.37, 3.82; P=0.002) had higher rates of an ED visit. Conclusion: In this study, SSc-ILD presentation and outcomes differed by racial/ethnic group (increased odds of SSc-ILD, younger age at SSc-ILD, and preceding diagnosis with respect to SSc, rates of ED visit), some of which was attenuated with adjustment for clinical and sociodemographic characteristics. Differing presentation may be driven by social drivers of health (SDOH), autoantibody profiles, or other key unmeasured factors contributing to susceptibility and severity.","PeriodicalId":501074,"journal":{"name":"medRxiv - Respiratory Medicine","volume":"7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139678976","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 : 2024-02-02DOI: 10.1101/2024.01.30.24301935
Andrew Barros, Seung Wook Lee, J Randall Moorman
Objectives To elucidate the changes in cardiorespiratory dynamics during neuromuscular blockade and prone positioning and determine the associations between changes in cardiorespiratory dynamics following prone positioning and mortality. Design Single center retrospective cohort study of patients admitted to the medical ICU between June 1, 2020 and September 1, 2022 who received prone positioning while mechanically ventilated. Results Our final cohort consisted of 136 patients. Prone position was associated with an improvement in A-a gradient of 113 mmHg (95% CrI 78 - 149) between the pre-proning values and 10 hours post proning. Norepinephrine dose did not significantly change before and after prone positioning (Estimated difference: 0.04 mcg/min 95% CrI -1.00 - 1.07). For the outcome of 7-d mortality, there was a high probability that the baseline factors of increasing age, male sex, and higher baseline A-a gradient were associated with increased risk of death. Increased total vasopressor requirement and increased in PCO2 were associated with worse prognosis while a decrease in instantaneous heart rate and a decrease in heart rate variability were associated with improved prognosis. Conclusion The immediate changes in prone positioning primarily impact respiratory physiology, with limited influence on circulatory parameters. Predictors of short-term mortality after prone positioning include both respiratory and cardiovascular parameters suggesting that extrapulmonary effects, such as improvement in right ventricular heart function, might also contribute to the benefit of prone positioning.
{"title":"CARDIORESPIRATORY DYNAMICS DURING PRONE POSITIONING FOR SEVERE ARDS: A RETROSPECTIVE COHORT STUDY","authors":"Andrew Barros, Seung Wook Lee, J Randall Moorman","doi":"10.1101/2024.01.30.24301935","DOIUrl":"https://doi.org/10.1101/2024.01.30.24301935","url":null,"abstract":"Objectives\u0000To elucidate the changes in cardiorespiratory dynamics during neuromuscular blockade and prone positioning and determine the associations between changes in cardiorespiratory dynamics following prone positioning and mortality.\u0000Design\u0000Single center retrospective cohort study of patients admitted to the medical ICU between June 1, 2020 and September 1, 2022 who received prone positioning while mechanically ventilated.\u0000Results\u0000Our final cohort consisted of 136 patients. Prone position was associated with an improvement in A-a gradient of 113 mmHg (95% CrI 78 - 149) between the pre-proning values and 10 hours post proning. Norepinephrine dose did not significantly change before and after prone positioning (Estimated difference: 0.04 mcg/min 95% CrI -1.00 - 1.07). For the outcome of 7-d mortality, there was a high probability that the baseline factors of increasing age, male sex, and higher baseline A-a gradient were associated with increased risk of death. Increased total vasopressor requirement and increased in PCO2 were associated with worse prognosis while a decrease in instantaneous heart rate and a decrease in heart rate variability were associated with improved prognosis. Conclusion\u0000The immediate changes in prone positioning primarily impact respiratory physiology, with limited influence on circulatory parameters. Predictors of short-term mortality after prone positioning include both respiratory and cardiovascular parameters suggesting that extrapulmonary effects, such as improvement in right ventricular heart function, might also contribute to the benefit of prone positioning.","PeriodicalId":501074,"journal":{"name":"medRxiv - Respiratory Medicine","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139661199","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 : 2024-02-01DOI: 10.1101/2024.01.31.24301705
Tyler C. Lovelace, Min Hyung Ryu, Minxue Jia, Peter Castaldi, Frank C Sciurba, Craig P. Hersh, Panayiotis Benos
Chronic Obstructive Pulmonary Disease (COPD) is a leading cause of mortality. Predicting mortality risk in COPD patients can be important for disease management strategies. Although scores for all-cause mortality have been developed previously, there is limited research on factors that may directly affect COPD-specific mortality. We used probabilistic (causal) graphs to analyze clinical baseline COPDGene data, including demographics, spirometry, quantitative chest imaging, and symptom features, as well as gene expression data (from year-5). We identified factors linked to all-cause and COPD-specific mortality. Although many were similar, there were differences in certain comorbidities (all-cause mortality model only) and forced vital capacity (COPD-specific mortality model only). Using our results, we developed VAPORED, a 7-variable COPD-specific mortality risk score, which we validated using the ECLIPSE 3-yr mortality data. We showed that the new model is more accurate than the existing ADO, BODE, and updated BODE indices. Additionally, we identified biological signatures linked to all-cause mortality, including a plasma cell mediated component. Finally, we developed a web page to help clinicians calculate mortality risk using VAPORED, ADO, and BODE indices. Given the importance of predicting COPD-specific and all-cause mortality risk in COPD patients, we showed that probabilistic graphs can identify the features most directly affecting them, and be used to build new, more accurate models of mortality risk. Novel biological features affecting mortality were also identified. This is an important step towards improving our identification of high-risk patients and potential biological mechanisms that drive COPD mortality.
{"title":"Disentangling Predictors of COPD Mortality with Probabilistic Graphical Models","authors":"Tyler C. Lovelace, Min Hyung Ryu, Minxue Jia, Peter Castaldi, Frank C Sciurba, Craig P. Hersh, Panayiotis Benos","doi":"10.1101/2024.01.31.24301705","DOIUrl":"https://doi.org/10.1101/2024.01.31.24301705","url":null,"abstract":"Chronic Obstructive Pulmonary Disease (COPD) is a leading cause of mortality. Predicting mortality risk in COPD patients can be important for disease management strategies. Although scores for all-cause mortality have been developed previously, there is limited research on factors that may directly affect COPD-specific mortality. We used probabilistic (causal) graphs to analyze clinical baseline COPDGene data, including demographics, spirometry, quantitative chest imaging, and symptom features, as well as gene expression data (from year-5). We identified factors linked to all-cause and COPD-specific mortality. Although many were similar, there were differences in certain comorbidities (all-cause mortality model only) and forced vital capacity (COPD-specific mortality model only). Using our results, we developed VAPORED, a 7-variable COPD-specific mortality risk score, which we validated using the ECLIPSE 3-yr mortality data. We showed that the new model is more accurate than the existing ADO, BODE, and updated BODE indices. Additionally, we identified biological signatures linked to all-cause mortality, including a plasma cell mediated component. Finally, we developed a web page to help clinicians calculate mortality risk using VAPORED, ADO, and BODE indices.\u0000Given the importance of predicting COPD-specific and all-cause mortality risk in COPD patients, we showed that probabilistic graphs can identify the features most directly affecting them, and be used to build new, more accurate models of mortality risk. Novel biological features affecting mortality were also identified. This is an important step towards improving our identification of high-risk patients and potential biological mechanisms that drive COPD mortality.","PeriodicalId":501074,"journal":{"name":"medRxiv - Respiratory Medicine","volume":"242 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139661662","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}
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