Circuits between infected macrophages and T cells in SARS-CoV-2 pneumonia

Grant, Rogan A.; Morales-Nebreda, Luisa; Markov, Nikolay S.; Swaminathan, Suchitra; Querrey, Melissa; Guzman, Estefany R.; Abbott, Darryl A.; Donnelly, Helen K.; Donayre, Alvaro; Goldberg, Isaac A.; Klug, Zasu M.; Borkowski, Nicole; Lu, Ziyan; Kihshen, Hermon; Politanska, Yuliya; Sichizya, Lango; Kang, Mengjia; Shilatifard, Ali; Qi, Chao; Lomasney, Jon W.; Argento, A. Christine; Kruser, Jacqueline M.; Malsin, Elizabeth S.; Pickens, Chiagozie O.; Smith, Sean B.; Walter, James M.; Pawlowski, Anna E.; Schneider, Daniel; Nannapaneni, Prasanth; Abdala-Valencia, Hiam; Bharat, Ankit; Gottardi, Cara J.; Budinger, GR Scott; Misharin, Alexander V.; Singer, Benjamin D.; Wunderink, Richard G.

doi:10.1038/s41586-020-03148-w

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Circuits between infected macrophages and T cells in SARS-CoV-2 pneumonia

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Author(s): Rogan A. Grant ¹ , Luisa Morales-Nebreda ¹ , Nikolay S. Markov ¹ , Suchitra Swaminathan ² ^, ³ , Melissa Querrey ⁴ , Estefany R. Guzman ³ , Darryl A. Abbott ³ , Helen K. Donnelly ¹ , Alvaro Donayre ¹ , Isaac A. Goldberg ¹ , Zasu M. Klug ¹ , Nicole Borkowski ¹ , Ziyan Lu ¹ , Hermon Kihshen ¹ , Yuliya Politanska ¹ , Lango Sichizya ¹ , Mengjia Kang ¹ , Ali Shilatifard ⁵ ^, ⁶ , Chao Qi ⁷ , Jon W. Lomasney ⁷ , A. Christine Argento ¹ , Jacqueline M. Kruser ¹ , Elizabeth S. Malsin ¹ , Chiagozie O. Pickens ¹ , Sean B. Smith ¹ , James M. Walter ¹ , Anna E. Pawlowski ⁸ , Daniel Schneider ⁸ , Prasanth Nannapaneni ⁸ , Hiam Abdala-Valencia ¹ , Ankit Bharat ¹ ^, ⁴ , Cara J. Gottardi ¹ , GR Scott Budinger ¹ ^, ^** , Alexander V. Misharin ¹ ^, ⁶ ^, ^** , Benjamin D. Singer ¹ ^, ⁵ ^, ⁶ ^, ^** , Richard G. Wunderink ¹ ^, ⁶ ^, ^** , The NU SCRIPT Study Investigators

Publication date (Electronic): 11 January 2021

Journal: Nature

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Abstract

Some patients infected with Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) develop severe pneumonia and the acute respiratory distress syndrome (ARDS) ¹. Distinct clinical features in these patients have led to speculation that the immune response to virus in the SARS-CoV-2-infected alveolus differs from other types of pneumonia ². We collected bronchoalveolar lavage fluid samples from 88 patients with SARS-CoV-2-induced respiratory failure and 211 patients with known or suspected pneumonia from other pathogens and subjected them to flow cytometry and bulk transcriptomic profiling. We performed single-cell RNA-seq on 10 bronchoalveolar lavage fluid samples collected from patients with severe COVID-19 within 48 hours of intubation. In the majority of patients with SARS-CoV-2 infection, the alveolar space was persistently enriched in T cells and monocytes. Bulk and single-cell transcriptomic profiling suggested that SARS-CoV-2 infects alveolar macrophages, which in turn respond by producing T cell chemoattractants. These T cells produce interferon-gamma to induce inflammatory cytokine release from alveolar macrophages and further promote T cell activation. Collectively, our results suggest that SARS-CoV-2 causes a slowly-unfolding, spatially limited alveolitis in which alveolar macrophages harboring SARS-CoV-2 and T cells form a positive feedback loop that drives persistent alveolar inflammation.

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Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Fei Zhou, Ting Yu, Ronghui Du … (2020)

Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p<0·0001), and d-dimer greater than 1 μg/mL (18·42, 2·64–128·55; p=0·0033) on admission. Median duration of viral shedding was 20·0 days (IQR 17·0–24·0) in survivors, but SARS-CoV-2 was detectable until death in non-survivors. The longest observed duration of viral shedding in survivors was 37 days. Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.

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Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study

Xiaobo Yang, Yuan Yu, Jiqian Xu … (2020)

Summary Background An ongoing outbreak of pneumonia associated with the severe acute respiratory coronavirus 2 (SARS-CoV-2) started in December, 2019, in Wuhan, China. Information about critically ill patients with SARS-CoV-2 infection is scarce. We aimed to describe the clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia. Methods In this single-centered, retrospective, observational study, we enrolled 52 critically ill adult patients with SARS-CoV-2 pneumonia who were admitted to the intensive care unit (ICU) of Wuhan Jin Yin-tan hospital (Wuhan, China) between late December, 2019, and Jan 26, 2020. Demographic data, symptoms, laboratory values, comorbidities, treatments, and clinical outcomes were all collected. Data were compared between survivors and non-survivors. The primary outcome was 28-day mortality, as of Feb 9, 2020. Secondary outcomes included incidence of SARS-CoV-2-related acute respiratory distress syndrome (ARDS) and the proportion of patients requiring mechanical ventilation. Findings Of 710 patients with SARS-CoV-2 pneumonia, 52 critically ill adult patients were included. The mean age of the 52 patients was 59·7 (SD 13·3) years, 35 (67%) were men, 21 (40%) had chronic illness, 51 (98%) had fever. 32 (61·5%) patients had died at 28 days, and the median duration from admission to the intensive care unit (ICU) to death was 7 (IQR 3–11) days for non-survivors. Compared with survivors, non-survivors were older (64·6 years [11·2] vs 51·9 years [12·9]), more likely to develop ARDS (26 [81%] patients vs 9 [45%] patients), and more likely to receive mechanical ventilation (30 [94%] patients vs 7 [35%] patients), either invasively or non-invasively. Most patients had organ function damage, including 35 (67%) with ARDS, 15 (29%) with acute kidney injury, 12 (23%) with cardiac injury, 15 (29%) with liver dysfunction, and one (2%) with pneumothorax. 37 (71%) patients required mechanical ventilation. Hospital-acquired infection occurred in seven (13·5%) patients. Interpretation The mortality of critically ill patients with SARS-CoV-2 pneumonia is considerable. The survival time of the non-survivors is likely to be within 1–2 weeks after ICU admission. Older patients (>65 years) with comorbidities and ARDS are at increased risk of death. The severity of SARS-CoV-2 pneumonia poses great strain on critical care resources in hospitals, especially if they are not adequately staffed or resourced. Funding None.

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Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report

Mark Peters (2021)

Abstract Background Coronavirus disease 2019 (Covid-19) is associated with diffuse lung damage. Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death. Methods In this controlled, open-label trial comparing a range of possible treatments in patients who were hospitalized with Covid-19, we randomly assigned patients to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. The primary outcome was 28-day mortality. Here, we report the preliminary results of this comparison. Results A total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care. Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (age-adjusted rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P<0.001). The proportional and absolute between-group differences in mortality varied considerably according to the level of respiratory support that the patients were receiving at the time of randomization. In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51 to 0.81) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%; rate ratio, 0.82; 95% CI, 0.72 to 0.94) but not among those who were receiving no respiratory support at randomization (17.8% vs. 14.0%; rate ratio, 1.19; 95% CI, 0.91 to 1.55). Conclusions In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support. (Funded by the Medical Research Council and National Institute for Health Research and others; RECOVERY ClinicalTrials.gov number, NCT04381936; ISRCTN number, 50189673.)

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Author and article information

Journal

Journal ID (nlm-journal-id): 0410462

Journal ID (pubmed-jr-id): 6011

Journal ID (nlm-ta): Nature

Journal ID (iso-abbrev): Nature

Title: Nature

ISSN (Print): 0028-0836

ISSN (Electronic): 1476-4687

Publication date Nihms-submitted: 28 December 2020

Publication date (Electronic): 11 January 2021

Publication date (Print): February 2021

Publication date PMC-release: 11 July 2021

Volume: 590

Issue: 7847

Pages: 635-641

Affiliations

[1 ]Division of Pulmonary and Critical Care Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University

[2 ]Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University

[3 ]Robert H Lurie Comprehensive Cancer Research Center, Feinberg School of Medicine, Northwestern University

[4 ]Division of Thoracic Surgery, Department of Surgery, Feinberg School of Medicine, Northwestern University

[5 ]Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University

[6 ]Simpson Querrey Institute for Epigenetics, Feinberg School of Medicine, Northwestern University

[7 ]Department of Pathology, Feinberg School of Medicine, Northwestern University

[8 ]Clinical and Translational Sciences Institute, Feinberg School of Medicine, Northwestern University

Author notes

[*]

These authors contributed equally to this work and will list themselves first on their CVs.

Consortia: The NU SCRIPT Study Investigators:

Rogan A. Grant ¹, Luisa Morales-Nebreda ¹, Nikolay S. Markov ¹, Suchitra Swaminathan ^2,3, Melissa Querrey ⁴, Estefany R. Guzman ³, Darryl A. Abbott ³, Helen K. Donnelly ¹, Alvaro Donayre ¹, Isaac A. Goldberg ¹, Zasu M. Klug ¹, Nicole Borkowski ¹, Ziyan Lu ¹, Hermon Kihshen ¹, Yuliya Politanska ¹, Lango Sichizya ¹, Mengjia Kang ¹, Ali Shilatifard ^5,6, Chao Qi ⁷, Jon W. Lomasney ⁷, A. Christine Argento ¹, Jacqueline M. Kruser ¹, Elizabeth S. Malsin ¹, Chiagozie O. Pickens ¹, Sean B. Smith ¹, James M. Walter ¹, Anna E. Pawlowski ⁸, Daniel Schneider ⁸, Prasanth Nannapaneni ⁸, Hiam Abdala-Valencia ¹, Ankit Bharat ^1,4, Cara J. Gottardi ¹, GR Scott Budinger ¹, Alexander V. Misharin ^1,6, Benjamin D. Singer ^1,5,6, Richard G. Wunderink ^1,6, Ajay A. Wagh ¹, Alan R. Hauser ⁹, Alexis Rose Wolfe ¹, Anjali Thakrar ², Anjana V. Yeldandi ⁷, Ann A. Wang ¹, Anne R. Levenson ¹, Anthony M. Joudi ¹, Betty Tran ¹, Catherine A. Gao ¹, Chitaru Kurihara ⁴, Clara J. Schroedl ¹, Curt M. Horvath ^9,10, Daniel Meza ¹, David D. Odell ⁴, David W. Kamp ¹, Deborah R. Winter ², Egon A. Ozer ⁹, Elisheva D. Shanes ⁷, Elizabeth T. Bartom ^5,6, Emily J. Rendleman ⁵, Emily M. Leibenguth ¹, Firas Wehbe ⁸, Gabrielle Y. Liu ¹, Gaurav T. Gadhvi ², Heliodoro Tejedor Navarro ¹¹, Jacob I. Sznajder ¹, Jane E. Dematte ¹, Jasmine Le ¹, Jason M. Arnold ¹, Joanne C. Du ¹, John Coleman ¹, Joseph I. Bailey ¹, Joseph S. Deters ¹, Justin A. Fiala ¹, Justin Starren ⁸, Karen M. Ridge ¹, Katharine Secunda ¹, Kathleen Aren ², Khalilah L. Gates ¹, Kristy Todd ¹, Lindsey D. Gradone ¹, Lindsey N. Textor ¹, Lisa F. Wolfe ¹, Lorenzo L. Pesce ⁴, Luís A. Nunes Amaral ¹¹, Madeline L. Rosenbaum ¹, Manoj Kandpal ⁸, Manu Jain ¹, Marc A. Sala ¹, Mark Saine ⁴, Mary Carns ², Michael J. Alexander ¹, Michael J. Cuttica ¹, Michelle H. Prickett ¹, Nabiha H. Khan ⁵, Navdeep S. Chandel ^1,6, Nicholas D. Soulakis ⁸, Orlyn R. Rivas ¹, Patrick C. Seed ¹², Paul A. Reyfman ¹, Pearl D. Go ⁸, Peter H. S. Sporn ¹, Phillip R. Cooper ¹, Rade Tomic ¹, Radhika Patel ¹, Rafael Garza-Castillon ⁴, Ravi Kalhan ¹, Richard I. Morimoto ¹⁰, Ruben J. Mylvaganam ¹, Samuel S. Kim ⁴, Samuel W.M. Gatesy ¹³, Sanket Thakkar ⁴, Sarah Ben Maamar ⁸, SeungHye Han ¹, Sharon R. Rosenberg ¹, Sophia Nozick ⁹, Stefan J. Green ¹⁴, Susan R. Russell ¹, Taylor A. Poor ¹, Taylor J. Zak ⁷, Theresa A. Lombardo ⁸, Thomas Stoeger ¹¹, Todd Shamaly ⁸, Ziyou Ren ¹.

⁹ Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University

¹⁰ Department of Molecular Biosciences, Weinberg College of Art and Sciences, Northwestern University

¹¹ Department of Chemical and Biological Engineering, McCormick School of Engineering, Northwestern University

¹² Division of Pediatric Infectious Diseases, Stanley Manne Research Institute, Ann and Robert H. Lurie Children’s Hospital

¹³ Division of Infectious Diseases, Department of Medicine, Feinberg School of Medicine, Northwestern University

¹⁴ Genome Research Core, University of Illinois at Chicago.

Authors contribution:

G.R.S.B., A.V.M., B.D.S. and R.G.W. conceived and designed the project and provided funding. R.A.G., L.M.-N., N.S.M., G.R.S.B., A.V.M., B.D.S. and R.G.W. curated and analyzed the data and wrote the manuscript. C.O.P., J.M.K., J.M.W., B.D.S. and R.G.W. performed adjudication of clinical outcomes. A.D., H.K.D., I.A.G., N.B. and Z.M.K. recruited patients into the study and coordinated interactions between clinical and research teams. A.C.A., A.B., B.D.S., C.O.P., E.S.M., G.R.S.B., J.M.K., J.M.W., L.M.-N., R.G.W. and S.B.S. performed BAL procedures and sample collection. A.S. contributed equipment. C.Q. performed clinical microbiological assessment of BAL fluid. J.W.L. performed autopsies on patients who died from COVID-19 and provided biological materials. M.Q. performed RNAscope assay, imaging and analysis. A.E.P., D.S., M.K., P.N., performed programmatic extraction of clinical data and data curation. C.J.G. and E.S.M. coordinated and performed sample collection from healthy volunteers and provided biological materials. D.A.A., E.R.G., A.V.M. and S.S. processed BAL fluid samples and performed flow cytometry and cell sorting. D.A.A., H.K., L.S., R.A.G. and Z.L. performed post-sorting sample processing including RNA isolation for RNA-seq. B.D.S., A.V.M. and S.S. analyzed flow cytometry data. A.V.M. and Z.L. performed single-cell RNA-seq. H.A.-V. and Y.P. performed bulk RNA-seq. All authors provided edits and feedback on the manuscript.

[** ]These corresponding authors jointly supervised this work and are listed in alphabetical order.

Article

Manuscript ID: NIHMS1656482

DOI: 10.1038/s41586-020-03148-w

PMC ID: 7987233

PubMed ID: 33429418

SO-VID: 9aade119-9557-4919-91b9-3535ffa49ac9

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Circuits between infected macrophages and T cells in SARS-CoV-2 pneumonia

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Novel Coronavirus Disease COVID-19

Most cited references 43

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study

Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report

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