Publications by authors named "Carolyn Calfee"

191 Publications

Sepsis Subclasses: A Framework for Development and Interpretation.

Crit Care Med 2021 Feb 15. Epub 2021 Feb 15.

Department of Critical Care Medicine, The Clinical Research, Investigation, and Systems Modeling of Acute illness (CRISMA) Center, University of Pittsburgh School of Medicine, Pittsburgh, PA. Anaesthesia, Critical Care, and Pain Medicine, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom. Division of Pulmonary and Critical Care Medicine, University of California San Francisco, San Francisco, CA. Division of Pediatric Critical Care Medicine, Department of Critical Care Medicine, Children's Hospital of Pittsburgh, Pittsburgh, PA. Department of Medicine, University of Pittsburgh, Pittsburgh, PA. Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA. Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Michigan, Ann Arbor, MI. Division of Anaesthetics, Pain Medicine, and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom. Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom. Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN. Kaiser Permanente Division of Research, Oakland, CA. Keenan Research Centre for Biomedical Science, St Michael's Hospital, Toronto, ON, Canada. Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Boston, MA. Center for Experimental and Molecular Medicine, Amsterdam University Medical Centers, Location Academic Medical Center, University of Amsterdam, Amsterdam, NL. Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam University Medical Centers, location Academic Medical Center, University of Amsterdam, Amsterdam, NL. Guy's and St Thomas' NHS Foundation Trust, ICU support Offices, St Thomas' Hospital, London, United Kingdom. School of Immunology and Microbial Sciences, Kings College London, London, United Kingdom. Department of Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA. Inflammatix, Burlingame, CA. Department of Intensive Care Medicine, Nepean Hospital, Sydney, AU. Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA. Department of Medicine, Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, Durham, NC. Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, Cincinnati, OH. Department of Critical Care Medicine, Peking University People's Hospital, Beijing, China.

Sepsis is defined as a dysregulated host response to infection that leads to life-threatening acute organ dysfunction. It afflicts approximately 50 million people worldwide annually and is often deadly, even when evidence-based guidelines are applied promptly. Many randomized trials tested therapies for sepsis over the past 2 decades, but most have not proven beneficial. This may be because sepsis is a heterogeneous syndrome, characterized by a vast set of clinical and biologic features. Combinations of these features, however, may identify previously unrecognized groups, or "subclasses" with different risks of outcome and response to a given treatment. As efforts to identify sepsis subclasses become more common, many unanswered questions and challenges arise. These include: 1) the semantic underpinning of sepsis subclasses, 2) the conceptual goal of subclasses, 3) considerations about study design, data sources, and statistical methods, 4) the role of emerging data types, and 5) how to determine whether subclasses represent "truth." We discuss these challenges and present a framework for the broader study of sepsis subclasses. This framework is intended to aid in the understanding and interpretation of sepsis subclasses, provide a mechanism for explaining subclasses generated by different methodologic approaches, and guide clinicians in how to consider subclasses in bedside care.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/CCM.0000000000004842DOI Listing
February 2021

ARDS Subphenotypes Beyond the Syndrome: A Step Towards Treatable Traits?

Am J Respir Crit Care Med 2021 Feb 10. Epub 2021 Feb 10.

University of Belfast, Belfast, United Kingdom of Great Britain and Northern Ireland.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1164/rccm.202101-0218EDDOI Listing
February 2021

Precision medicine in acute respiratory distress syndrome: workshop report and recommendations for future research.

Eur Respir Rev 2021 Mar 2;30(159). Epub 2021 Feb 2.

Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Dept of Medicine, University of California, San Francisco, CA, USA.

Acute respiratory distress syndrome (ARDS) is a devastating critical illness that can be triggered by a wide range of insults and remains associated with a high mortality of around 40%. The search for targeted treatment for ARDS has been disappointing, possibly due to the enormous heterogeneity within the syndrome. In this perspective from the European Respiratory Society research seminar on "Precision medicine in ARDS", we will summarise the current evidence for heterogeneity, explore the evidence in favour of precision medicine and provide a roadmap for further research in ARDS. There is evident variation in the presentation of ARDS on three distinct levels: 1) aetiological; 2) physiological and 3) biological, which leads us to the conclusion that there is no typical ARDS. The lack of a common presentation implies that intervention studies in patients with ARDS need to be phenotype aware and apply a precision medicine approach in order to avoid the lack of success in therapeutic trials that we faced in recent decades. Deeper phenotyping and integrative analysis of the sources of variation might result in identification of additional treatable traits that represent specific pathobiological mechanisms, or so-called endotypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1183/16000617.0317-2020DOI Listing
March 2021

Global absence and targeting of protective immune states in severe COVID-19.

Nature 2021 03 25;591(7848):124-130. Epub 2021 Jan 25.

Department of Pathology, University of California San Francisco, San Francisco, CA, USA.

Although infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has pleiotropic and systemic effects in some individuals, many others experience milder symptoms. Here, to gain a more comprehensive understanding of the distinction between severe and mild phenotypes in the pathology of coronavirus disease 2019 (COVID-19) and its origins, we performed a whole-blood-preserving single-cell analysis protocol to integrate contributions from all major immune cell types of the blood-including neutrophils, monocytes, platelets, lymphocytes and the contents of the serum. Patients with mild COVID-19 exhibit a coordinated pattern of expression of interferon-stimulated genes (ISGs) across every cell population, whereas these ISG-expressing cells are systemically absent in patients with severe disease. Paradoxically, individuals with severe COVID-19 produce very high titres of anti-SARS-CoV-2 antibodies and have a lower viral load compared to individuals with mild disease. Examination of the serum from patients with severe COVID-19 shows that these patients uniquely produce antibodies that functionally block the production of the ISG-expressing cells associated with mild disease, by activating conserved signalling circuits that dampen cellular responses to interferons. Overzealous antibody responses pit the immune system against itself in many patients with COVID-19, and perhaps also in individuals with other viral infections. Our findings reveal potential targets for immunotherapies in patients with severe COVID-19 to re-engage viral defence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-021-03234-7DOI Listing
March 2021

COVID-19 ARDS is characterized by a dysregulated host response that differs from cytokine storm and is modified by dexamethasone.

Res Sq 2021 Jan 14. Epub 2021 Jan 14.

We performed comparative lower respiratory tract transcriptional profiling of 52 critically ill patients with the acute respiratory distress syndrome (ARDS) from COVID-19 or from other etiologies, as well as controls without ARDS. In contrast to a cytokine storm, we observed reduced proinflammatory gene expression in COVID-19 ARDS when compared to ARDS due to other causes. COVID-19 ARDS was characterized by a dysregulated host response with increased PTEN signaling and elevated expression of genes with non-canonical roles in inflammation and immunity that were predicted to be modulated by dexamethasone and granulocyte colony stimulating factor. Compared to ARDS due to other types of viral pneumonia, COVID-19 was characterized by impaired interferon-stimulated gene expression (ISG). We found that the relationship between SARS-CoV-2 viral load and expression of ISGs was decoupled in patients with COVID-19 ARDS when compared to patients with mild COVID-19. In summary, assessment of host gene expression in the lower airways of patients with COVID-19 ARDS did not demonstrate cytokine storm but instead revealed a unique and dysregulated host response predicted to be modified by dexamethasone.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21203/rs.3.rs-141578/v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814832PMC
January 2021

Assessing the importance of interleukin-6 in COVID-19 - Authors' reply.

Lancet Respir Med 2021 02 15;9(2):e14-e15. Epub 2021 Jan 15.

Feinstein Institute for Medical Research, Manhasset, NY, USA; Department of Pediatrics, Cohen Children's Medical Center, New Hyde Park, NY, USA; Zucker School of Medicine at Hofstra-Northwell, New York, NY, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2213-2600(20)30603-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834405PMC
February 2021

A Neutrophil Subset Defined by Intracellular Olfactomedin 4 is Associated with Mortality in Sepsis.

Am J Physiol Lung Cell Mol Physiol 2020 Dec 23. Epub 2020 Dec 23.

Departments of Medicine and Anesthesiology and the Cardiovascular Research Institute, University of California, San Francisco, California.

Sepsis is a heterogeneous syndrome clinically and biologically but biomarkers of distinct host response pathways for early prognostic information and testing targeted treatments are lacking. We hypothesized that Olfactomedin 4 (OLFM4), a matrix glycoprotein of neutrophil specific granules defines a distinct neutrophil subset that may be an independent risk factor for poor outcomes in sepsis. In a single-center, prospective cohort study, we enrolled adults admitted to an academic medical center from the Emergency Department (ED) with suspected sepsis (identified by 2 or greater Systemic Inflammatory Response Syndrome [SIRS] criteria and antibiotic receipt) from March 2016 through December 2017, followed by sepsis adjudication according to Sepsis-3. We collected 200mL of whole blood within 24 hours of admission and stained for the neutrophil surface marker CD66b followed by intracellular staining for OLFM4 quantitated by flow cytometry. The predictor for 60-day mortality was the percentage of OLFM4+ neutrophils and at a cut-point of OLFM4+ ≥37.6% determined by the Youden Index. Of 120 enrolled patients with suspected sepsis, 97 had sepsis and 23 had non-sepsis SIRS. The mean percentage of OLFM4+ neutrophils was significantly increased in both sepsis and non-sepsis SIRS patients who died (P ≤ 0.01). Among sepsis patients with elevated OLFM4+(≥37.6%), 56% died compared to 18% with OLFM4+ <37.6% (P=0.001).The association between OLFM4+ and mortality withstood adjustment for demographics, co-morbidities and measures of severity of illness (P<0.03). In sepsis, OLFM4+ neutrophil percentage is independently associated with 60-day mortality and may represent a novel measure of the heterogeneity of host response to sepsis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajplung.00090.2020DOI Listing
December 2020

MSC extracellular vesicles rescue mitochondrial dysfunction and improve barrier integrity in clinically relevant models of ARDS.

Eur Respir J 2020 Dec 17. Epub 2020 Dec 17.

Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Sciences, Queen's University Belfast, Belfast, United Kingdom

Alveolar epithelial-capillary barrier disruption is a hallmark of Acute Respiratory Distress Syndrome (ARDS). Contribution of mitochondrial dysfunction to the compromised alveolar-capillary barrier in ARDS remains unclear. Mesenchymal stromal cells-derived extracellular vesicles (MSC EVs) are considered as a cell free therapy for ARDS. Mitochondrial transfer was shown to be important for the therapeutic effects of MSCs and MSC EVs. Here we investigated the contribution of mitochondrial dysfunction to the injury of alveolar epithelial and endothelial barriers in ARDS and the ability of MSC EVs to modulate alveolar-capillary barrier integrity through mitochondrial transfer.Primary human small airway epithelial and pulmonary microvascular endothelial cells and human precision cut lung slices (PCLSs) were stimulated with endotoxin or plasma samples from patients with ARDS and treated with MSC EVs, barrier properties and mitochondrial functions were evaluated. LPS-injured mice were treated with MSC EVs and degree of lung injury and mitochondrial respiration of the lung tissue were assessed.Inflammatory stimulation resulted in increased permeability coupled with pronounced mitochondrial dysfunction in both types of primary cells and PCLSs. EVs derived from normal MSCs restored barrier integrity and normal levels of oxidative phosphorylation while EV preparation which did not contain mitochondria was not effective. , presence of mitochondria was critical for EV ability to reduce lung injury and restore mitochondrial respiration in the lung tissue.In the ARDS environment MSC-EVs improve alveolar-capillary barrier properties through restoration of mitochondrial functions at least partially mitochondrial transfer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1183/13993003.02978-2020DOI Listing
December 2020

A manifesto for the future of ICU trials.

Crit Care 2020 12 9;24(1):686. Epub 2020 Dec 9.

The Clinical Research, Investigation, and Systems Modeling of Acute Illness (CRISMA) Center, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13054-020-03393-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724445PMC
December 2020

Alternative Tobacco Product Use in Critically Ill Patients.

Int J Environ Res Public Health 2020 11 24;17(23). Epub 2020 Nov 24.

Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of California, San Francisco, CA 94143, USA.

Alternative tobacco product (ATP) use has bee linked to critical illness, however, few studies have examined the use of these substances in critically ill populations. We sought to examine ATP use within critically ill patients and to define barriers in accurately assessing use within this population. We prospectively studied 533 consecutive patients from the Early Assessment of Renal and Lung Injury study, enrolled between 2013 and 2016 at a tertiary referral center and a safety-net hospital. ATP use information (electronic cigarettes, cigars, pipes, hookahs/waterpipes, and snus/chewing tobacco) was obtained from the patient or surrogate using a detailed survey. Reasons for non-completion of the survey were recorded, and differences between survey responders vs. non-responders, self- vs. surrogate responders, and ATP users vs. non-users were explored. Overall, 80% ( = 425) of subjects (56% male) completed a tobacco product use survey. Of these, 12.2% ( = 52) reported current ATP use, while 5.6% reported using multiple ATP products. When restricted to subjects who were self-responders, 17% reported ATP use, while 10% reported current cigarette smoking alone. The mean age of ATP users was 57 ± 17 years. Those who did not complete a survey were sicker and more likely to have died during admission. Subjects who completed the survey as self-responders reported higher levels of ATP use than ones with surrogate responders ( < 0.0001). ATP use is common among critically ill patients despite them being generally older than traditional users. Survey self-responders were more likely than surrogate responders to report use. These findings highlight the importance of improving our current methods of surveillance of ATP use in older adults in the outpatient setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijerph17238707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727672PMC
November 2020

Twenty-Four-Hour Cardiovascular Effects of Electronic Cigarettes Compared With Cigarette Smoking in Dual Users.

J Am Heart Assoc 2020 12 19;9(23):e017317. Epub 2020 Nov 19.

Clinical Pharmacology Research Program Division of Cardiology Department of Medicine University of California San Francisco CA.

Background Cardiovascular safety is an important consideration regarding the benefits versus risks of electronic cigarette use (EC) for public health. The single-use cardiovascular effects of EC have been well studied but may not reflect effects of ad libitum use throughout the day. We aimed to compare the circadian hemodynamic effects as well as 24-hour biomarkers of oxidative stress, and platelet aggregation and inflammation, with ad libitum cigarette smoking (CS) versus EC versus no tobacco product use. Methods and Results Thirty-six healthy dual CS and EC users participated in a crossover study in a confined research setting. Circadian heart rate, blood pressure and plasma nicotine levels, 24-hour urinary catecholamines, 8-isoprostane and 11-dehydro-thromboxane B2, and plasma interleukin-6 and interleukin-8 were compared in CS, EC, and no nicotine conditions. Over 24 hours, and during daytime, heart rate and blood pressure were higher in CS and EC compared with no tobacco product conditions (<0.01). Heart rate on average was higher with CS versus EC. Urinary catecholamines, 8-isoprostane, and 11-dehydro-thromboxane B2 were not significantly different, but plasma IL-6 and IL-8 were higher with both CS and EC compared with no tobacco product (<0.01). Conclusions CS and EC had similar 24-hour patterns of hemodynamic effects compared with no tobacco product, with a higher average heart rate with CS versus EC, and similar effects on biomarkers of inflammation. EC may pose some cardiovascular risk, particularly to smokers with underlying cardiovascular disease, but may also provide a harm reduction opportunity for smokers willing to switch entirely to EC. Registration URL: https://www.clinicaltrials.gov; Unique Identifier: NCT02470754.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/JAHA.120.017317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763797PMC
December 2020

Phenotypes and personalized medicine in the acute respiratory distress syndrome.

Intensive Care Med 2020 12 18;46(12):2136-2152. Epub 2020 Nov 18.

Department of Anesthesia, University of California San Francisco, San Francisco, CA, USA.

Although the acute respiratory distress syndrome (ARDS) is well defined by the development of acute hypoxemia, bilateral infiltrates and non-cardiogenic pulmonary edema, ARDS is heterogeneous in terms of clinical risk factors, physiology of lung injury, microbiology, and biology, potentially explaining why pharmacologic therapies have been mostly unsuccessful in treating ARDS. Identifying phenotypes of ARDS and integrating this information into patient selection for clinical trials may increase the chance for efficacy with new treatments. In this review, we focus on classifying ARDS by the associated clinical disorders, physiological data, and radiographic imaging. We consider biologic phenotypes, including plasma protein biomarkers, gene expression, and common causative microbiologic pathogens. We will also discuss the issue of focusing clinical trials on the patient's phase of lung injury, including prevention, administration of therapy during early acute lung injury, and treatment of established ARDS. A more in depth understanding of the interplay of these variables in ARDS should provide more success in designing and conducting clinical trials and achieving the goal of personalized medicine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00134-020-06296-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673253PMC
December 2020

Upper airway gene expression reveals suppressed immune responses to SARS-CoV-2 compared with other respiratory viruses.

Nat Commun 2020 11 17;11(1):5854. Epub 2020 Nov 17.

Division of Infectious Diseases, University of California, San Francisco, CA, USA.

SARS-CoV-2 infection is characterized by peak viral load in the upper airway prior to or at the time of symptom onset, an unusual feature that has enabled widespread transmission of the virus and precipitated a global pandemic. How SARS-CoV-2 is able to achieve high titer in the absence of symptoms remains unclear. Here, we examine the upper airway host transcriptional response in patients with COVID-19 (n = 93), other viral (n = 41) or non-viral (n = 100) acute respiratory illnesses (ARIs). Compared with other viral ARIs, COVID-19 is characterized by a pronounced interferon response but attenuated activation of other innate immune pathways, including toll-like receptor, interleukin and chemokine signaling. The IL-1 and NLRP3 inflammasome pathways are markedly less responsive to SARS-CoV-2, commensurate with a signature of diminished neutrophil and macrophage recruitment. This pattern resembles previously described distinctions between symptomatic and asymptomatic viral infections and may partly explain the propensity for pre-symptomatic transmission in COVID-19. We further use machine learning to build 27-, 10- and 3-gene classifiers that differentiate COVID-19 from other ARIs with AUROCs of 0.981, 0.954 and 0.885, respectively. Classifier performance is stable across a wide range of viral load, suggesting utility in mitigating false positive or false negative results of direct SARS-CoV-2 tests.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-19587-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673985PMC
November 2020

Fluid administration and monitoring in ARDS: which management?

Intensive Care Med 2020 Dec 9;46(12):2252-2264. Epub 2020 Nov 9.

SC Anestesia e Rianimazione, Ospedale San Paolo, Polo Universitario, ASST Santi Paolo e Carlo, Milan, Italy.

Modalities of fluid management in patients sustaining the acute respiratory distress syndrome (ARDS) are challenging and controversial. Optimal fluid management should provide adequate oxygen delivery to the body, while avoiding inadvertent increase in lung edema which further impairs gas exchange. In ARDS patients, positive fluid balance has been associated with prolonged mechanical ventilation, longer ICU and hospital stay, and higher mortality. Accordingly, a restrictive strategy has been compared to a more liberal approach in randomized controlled trials conducted in various clinical settings. Restrictive strategies included fluid restriction guided by the monitoring of extravascular lung water, pulmonary capillary wedge or central venous pressure, and furosemide targeted to diuresis and/or albumin replacement in hypoproteinemic patients. Overall, restrictive strategies improved oxygenation significantly and reduced duration of mechanical ventilation, but had no significant effect on mortality. Fluid management may require different approaches depending on the time course of ARDS (i.e., early vs. late period). The effects of fluid strategy management according to ARDS phenotypes remain to be evaluated. Since ARDS is frequently associated with sepsis-induced acute circulatory failure, the prediction of fluid responsiveness is crucial in these patients to avoid hemodynamically inefficient-hence respiratory detrimental-fluid administration. Specific hemodynamic indices of fluid responsiveness or mini-fluid challenges should be preferably used. Since the positive airway pressure contributes to positive fluid balance in ventilated ARDS patients, it should be kept as low as possible. As soon as the hemodynamic status is stabilized, correction of cumulated fluid retention may rely on diuretics administration or renal replacement therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00134-020-06310-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652045PMC
December 2020

Effect of Hydroxychloroquine on Clinical Status at 14 Days in Hospitalized Patients With COVID-19: A Randomized Clinical Trial.

Authors:
Wesley H Self Matthew W Semler Lindsay M Leither Jonathan D Casey Derek C Angus Roy G Brower Steven Y Chang Sean P Collins John C Eppensteiner Michael R Filbin D Clark Files Kevin W Gibbs Adit A Ginde Michelle N Gong Frank E Harrell Douglas L Hayden Catherine L Hough Nicholas J Johnson Akram Khan Christopher J Lindsell Michael A Matthay Marc Moss Pauline K Park Todd W Rice Bryce R H Robinson David A Schoenfeld Nathan I Shapiro Jay S Steingrub Christine A Ulysse Alexandra Weissman Donald M Yealy B Taylor Thompson Samuel M Brown Jay Steingrub Howard Smithline Bogdan Tiru Mark Tidswell Lori Kozikowski Sherell Thornton-Thompson Leslie De Souza Peter Hou Rebecca Baron Anthony Massaro Imoigele Aisiku Lauren Fredenburgh Raghu Seethala Lily Johnsky Richard Riker David Seder Teresa May Michael Baumann Ashley Eldridge Christine Lord Nathan Shapiro Daniel Talmor Thomas O’Mara Charlotte Kirk Kelly Harrison Lisa Kurt Margaret Schermerhorn Valerie Banner-Goodspeed Katherine Boyle Nicole Dubosh Michael Filbin Kathryn Hibbert Blair Parry Kendall Lavin-Parsons Natalie Pulido Brendan Lilley Carl Lodenstein Justin Margolin Kelsey Brait Alan Jones James Galbraith Rebekah Peacock Utsav Nandi Taylor Wachs Michael Matthay Kathleen Liu Kirsten Kangelaris Ralph Wang Carolyn Calfee Kimberly Yee Gregory Hendey Steven Chang George Lim Nida Qadir Andrea Tam Rebecca Beutler Joseph Levitt Jenny Wilson Angela Rogers Rosemary Vojnik Jonasel Roque Timothy Albertson James Chenoweth Jason Adams Skyler Pearson Maya Juarez Eyad Almasri Mohamed Fayed Alyssa Hughes Shelly Hillard Ryan Huebinger Henry Wang Elizabeth Vidales Bela Patel Adit Ginde Marc Moss Amiran Baduashvili Jeffrey McKeehan Lani Finck Carrie Higgins Michelle Howell Ivor Douglas Jason Haukoos Terra Hiller Carolynn Lyle Alicia Cupelo Emily Caruso Claudia Camacho Stephanie Gravitz James Finigan Christine Griesmer Pauline Park Robert Hyzy Kristine Nelson Kelli McDonough Norman Olbrich Mark Williams Raj Kapoor Jean Nash Meghan Willig Henry Ford Jayna Gardner-Gray Mayur Ramesh Montefiore Moses Michelle Ng Gong Michael Aboodi Ayesha Asghar Omowunmi Amosu Madeline Torres Savneet Kaur Jen-Ting Chen Aluko Hope Brenda Lopez Kathleen Rosales Jee Young You Jarrod Mosier Cameron Hypes Bhupinder Natt Bryan Borg Elizabeth Salvagio Campbell R Duncan Hite Kristin Hudock Autumn Cresie Faysal Alhasan Jose Gomez-Arroyo Abhijit Duggal Omar Mehkri Andrei Hastings Debasis Sahoo Francois Abi Fadel Susan Gole Valerie Shaner Allison Wimer Yvonne Meli Alexander King Thomas Terndrup Matthew Exline Sonal Pannu Emily Robart Sarah Karow Catherine Hough Bryce Robinson Nicholas Johnson Daniel Henning Monica Campo Stephanie Gundel Sakshi Seghal Sarah Katsandres Sarah Dean Akram Khan Olivia Krol Milad Jouzestani Peter Huynh Alexandra Weissman Donald Yealy Denise Scholl Peter Adams Bryan McVerry David Huang Derek Angus Jordan Schooler Steven Moore Clark Files Chadwick Miller Kevin Gibbs Mary LaRose Lori Flores Lauren Koehler Caryn Morse John Sanders Caitlyn Langford Kristen Nanney Masiku MdalaGausi Phyllis Yeboah Peter Morris Jamie Sturgill Sherif Seif Evan Cassity Sanjay Dhar Marjolein de Wit Jessica Mason Andrew Goodwin Greg Hall Abbey Grady Amy Chamberlain Samuel Brown Joseph Bledsoe Lindsay Leither Ithan Peltan Nathan Starr Melissa Fergus Valerie Aston Quinn Montgomery Rilee Smith Mardee Merrill Katie Brown Brent Armbruster Estelle Harris Elizabeth Middleton Robert Paine Stacy Johnson Macy Barrios John Eppensteiner Alexander Limkakeng Lauren McGowan Tedra Porter Andrew Bouffler J. Clancy Leahy Bennet deBoisblanc Matthew Lammi Kyle Happel Paula Lauto Wesley Self Jonathan Casey Matthew Semler Sean Collins Frank Harrell Christopher Lindsell Todd Rice William Stubblefield Christopher Gray Jakea Johnson Megan Roth Margaret Hays Donna Torr Arwa Zakaria David Schoenfeld Taylor Thompson Douglas Hayden Nancy Ringwood Cathryn Oldmixon Christine Ulysse Richard Morse Ariela Muzikansky Laura Fitzgerald Samuel Whitaker Adrian Lagakos Roy Brower Lora Reineck Neil Aggarwal Karen Bienstock Michelle Freemer Myron Maclawiw Gail Weinmann Laurie Morrison Mark Gillespie Richard Kryscio Daniel Brodie Wojciech Zareba Anne Rompalo Michael Boeckh Polly Parsons Jason Christie Jesse Hall Nicholas Horton Laurie Zoloth Neal Dickert Deborah Diercks

JAMA 2020 12;324(21):2165-2176

Division of Pulmonary and Critical Care Medicine, Intermountain Medical Center, Murray, Utah.

Importance: Data on the efficacy of hydroxychloroquine for the treatment of coronavirus disease 2019 (COVID-19) are needed.

Objective: To determine whether hydroxychloroquine is an efficacious treatment for adults hospitalized with COVID-19.

Design, Setting, And Participants: This was a multicenter, blinded, placebo-controlled randomized trial conducted at 34 hospitals in the US. Adults hospitalized with respiratory symptoms from severe acute respiratory syndrome coronavirus 2 infection were enrolled between April 2 and June 19, 2020, with the last outcome assessment on July 17, 2020. The planned sample size was 510 patients, with interim analyses planned after every 102 patients were enrolled. The trial was stopped at the fourth interim analysis for futility with a sample size of 479 patients.

Interventions: Patients were randomly assigned to hydroxychloroquine (400 mg twice daily for 2 doses, then 200 mg twice daily for 8 doses) (n = 242) or placebo (n = 237).

Main Outcomes And Measures: The primary outcome was clinical status 14 days after randomization as assessed with a 7-category ordinal scale ranging from 1 (death) to 7 (discharged from the hospital and able to perform normal activities). The primary outcome was analyzed with a multivariable proportional odds model, with an adjusted odds ratio (aOR) greater than 1.0 indicating more favorable outcomes with hydroxychloroquine than placebo. The trial included 12 secondary outcomes, including 28-day mortality.

Results: Among 479 patients who were randomized (median age, 57 years; 44.3% female; 37.2% Hispanic/Latinx; 23.4% Black; 20.1% in the intensive care unit; 46.8% receiving supplemental oxygen without positive pressure; 11.5% receiving noninvasive ventilation or nasal high-flow oxygen; and 6.7% receiving invasive mechanical ventilation or extracorporeal membrane oxygenation), 433 (90.4%) completed the primary outcome assessment at 14 days and the remainder had clinical status imputed. The median duration of symptoms prior to randomization was 5 days (interquartile range [IQR], 3 to 7 days). Clinical status on the ordinal outcome scale at 14 days did not significantly differ between the hydroxychloroquine and placebo groups (median [IQR] score, 6 [4-7] vs 6 [4-7]; aOR, 1.02 [95% CI, 0.73 to 1.42]). None of the 12 secondary outcomes were significantly different between groups. At 28 days after randomization, 25 of 241 patients (10.4%) in the hydroxychloroquine group and 25 of 236 (10.6%) in the placebo group had died (absolute difference, -0.2% [95% CI, -5.7% to 5.3%]; aOR, 1.07 [95% CI, 0.54 to 2.09]).

Conclusions And Relevance: Among adults hospitalized with respiratory illness from COVID-19, treatment with hydroxychloroquine, compared with placebo, did not significantly improve clinical status at day 14. These findings do not support the use of hydroxychloroquine for treatment of COVID-19 among hospitalized adults.

Trial Registration: ClinicalTrials.gov: NCT04332991.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jama.2020.22240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653542PMC
December 2020

Practitioner's Guide to Latent Class Analysis: Methodological Considerations and Common Pitfalls.

Crit Care Med 2021 Jan;49(1):e63-e79

Department of Psychiatry, University of California, San Francisco, San Francisco, CA.

Latent class analysis is a probabilistic modeling algorithm that allows clustering of data and statistical inference. There has been a recent upsurge in the application of latent class analysis in the fields of critical care, respiratory medicine, and beyond. In this review, we present a brief overview of the principles behind latent class analysis. Furthermore, in a stepwise manner, we outline the key processes necessary to perform latent class analysis including some of the challenges and pitfalls faced at each of these steps. The review provides a one-stop shop for investigators seeking to apply latent class analysis to their data.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/CCM.0000000000004710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746621PMC
January 2021

Global Absence and Targeting of Protective Immune States in Severe COVID-19.

bioRxiv 2020 Oct 29. Epub 2020 Oct 29.

While SARS-CoV-2 infection has pleiotropic and systemic effects in some patients, many others experience milder symptoms. We sought a holistic understanding of the severe/mild distinction in COVID-19 pathology, and its origins. We performed a whole-blood preserving single-cell analysis protocol to integrate contributions from all major cell types including neutrophils, monocytes, platelets, lymphocytes and the contents of serum. Patients with mild COVID-19 disease display a coordinated pattern of interferon-stimulated gene (ISG) expression across every cell population and these cells are systemically absent in patients with severe disease. Severe COVID-19 patients also paradoxically produce very high anti-SARS-CoV-2 antibody titers and have lower viral load as compared to mild disease. Examination of the serum from severe patients demonstrates that they uniquely produce antibodies with multiple patterns of specificity against interferon-stimulated cells and that those antibodies functionally block the production of the mild disease-associated ISG-expressing cells. Overzealous and auto-directed antibody responses pit the immune system against itself in many COVID-19 patients and this defines targets for immunotherapies to allow immune systems to provide viral defense.

One Sentence Summary: In severe COVID-19 patients, the immune system fails to generate cells that define mild disease; antibodies in their serum actively prevents the successful production of those cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/2020.10.28.359935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605559PMC
October 2020

Global Absence and Targeting of Protective Immune States in Severe COVID-19.

Res Sq 2020 Oct 28. Epub 2020 Oct 28.

Department of Pathology, San Francisco, 513 Parnassus Ave, HSW512, San Francisco, CA 94143-0511, USA.

While SARS-CoV-2 infection has pleiotropic and systemic effects in some patients, many others experience milder symptoms. We sought a holistic understanding of the severe/mild distinction in COVID-19 pathology, and its origins. We performed a wholeblood preserving single-cell analysis protocol to integrate contributions from all major cell types including neutrophils, monocytes, platelets, lymphocytes and the contents of serum. Patients with mild COVID-19 disease display a coordinated pattern of interferonstimulated gene (ISG) expression across every cell population and these cells are systemically absent in patients with severe disease. Severe COVID-19 patients also paradoxically produce very high anti-SARS-CoV-2 antibody titers and have lower viral load as compared to mild disease. Examination of the serum from severe patients demonstrates that they uniquely produce antibodies with multiple patterns of specificity against interferon-stimulated cells and that those antibodies functionally block the production of the mild disease-associated ISG-expressing cells. Overzealous and autodirected antibody responses pit the immune system against itself in many COVID-19 patients and this defines targets for immunotherapies to allow immune systems to provide viral defense.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21203/rs.3.rs-97042/v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605560PMC
October 2020

Cytokine elevation in severe and critical COVID-19: a rapid systematic review, meta-analysis, and comparison with other inflammatory syndromes.

Lancet Respir Med 2020 12 16;8(12):1233-1244. Epub 2020 Oct 16.

Feinstein Institute for Medical Research, Manhasset, NY, USA; Department of Pediatrics, Cohen Children's Medical Center, New Hyde Park, NY, USA; Zucker School of Medicine at Hofstra-Northwell, Hempstead, NY, USA.

The description of a so-called cytokine storm in patients with COVID-19 has prompted consideration of anti-cytokine therapies, particularly interleukin-6 antagonists. However, direct systematic comparisons of COVID-19 with other critical illnesses associated with elevated cytokine concentrations have not been reported. In this Rapid Review, we report the results of a systematic review and meta-analysis of COVID-19 studies published or posted as preprints between Nov 1, 2019, and April 14, 2020, in which interleukin-6 concentrations in patients with severe or critical disease were recorded. 25 COVID-19 studies (n=1245 patients) were ultimately included. Comparator groups included four trials each in sepsis (n=5320), cytokine release syndrome (n=72), and acute respiratory distress syndrome unrelated to COVID-19 (n=2767). In patients with severe or critical COVID-19, the pooled mean serum interleukin-6 concentration was 36·7 pg/mL (95% CI 21·6-62·3 pg/mL; I=57·7%). Mean interleukin-6 concentrations were nearly 100 times higher in patients with cytokine release syndrome (3110·5 pg/mL, 632·3-15 302·9 pg/mL; p<0·0001), 27 times higher in patients with sepsis (983·6 pg/mL, 550·1-1758·4 pg/mL; p<0·0001), and 12 times higher in patients with acute respiratory distress syndrome unrelated to COVID-19 (460 pg/mL, 216·3-978·7 pg/mL; p<0·0001). Our findings question the role of a cytokine storm in COVID-19-induced organ dysfunction. Many questions remain about the immune features of COVID-19 and the potential role of anti-cytokine and immune-modulating treatments in patients with the disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2213-2600(20)30404-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567529PMC
December 2020

Using best subset regression to identify clinical characteristics and biomarkers associated with sepsis-associated acute kidney injury.

Am J Physiol Renal Physiol 2020 12 12;319(6):F979-F987. Epub 2020 Oct 12.

Division of Nephrology, Department of Medicine, University of California, San Francisco, California.

Sepsis-associated acute kidney injury (AKI) is a complex clinical disorder associated with inflammation, endothelial dysfunction, and dysregulated coagulation. With standard regression methods, collinearity among biomarkers may lead to the exclusion of important biological pathways in a single final model. Best subset regression is an analytic technique that identifies statistically equivalent models, allowing for more robust evaluation of correlated variables. Our objective was to identify common clinical characteristics and biomarkers associated with sepsis-associated AKI. We enrolled 453 septic adults within 24 h of intensive care unit admission. Using best subset regression, we evaluated for associations using a range of models consisting of 1-38 predictors (composed of clinical risk factors and plasma and urine biomarkers) with AKI as the outcome [defined as a serum creatinine (SCr) increase of ≥0.3 mg/dL within 48 h or ≥1.5× baseline SCr within 7 days]. Two hundred ninety-seven patients had AKI. Five-variable models were found to be of optimal complexity, as the best subset of five- and six-variable models were statistically equivalent. Within the subset of five-variable models, 46 permutations of predictors were noted to be statistically equivalent. The most common predictors in this subset included diabetes, baseline SCr, angiopoetin-2, IL-8, soluble tumor necrosis factor receptor-1, and urine neutrophil gelatinase-associated lipocalin. The models had a c-statistic of ∼0.70 (95% confidence interval: 0.65-0.75). In conclusion, using best subset regression, we identified common clinical characteristics and biomarkers associated with sepsis-associated AKI. These variables may be especially relevant in the pathogenesis of sepsis-associated AKI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajprenal.00281.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792692PMC
December 2020

Severe COVID-19 Infections-Knowledge Gained and Remaining Questions.

JAMA Intern Med 2021 01;181(1):9-11

Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, University of California, San Francisco.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamainternmed.2020.6047DOI Listing
January 2021

The ABO histo-blood group, endothelial activation, and acute respiratory distress syndrome risk in critical illness.

J Clin Invest 2021 Jan;131(1)

Division of Pulmonary, Allergy, and Critical Care.

BACKGROUNDThe ABO histo-blood group is defined by carbohydrate modifications and is associated with risk for multiple diseases, including acute respiratory distress syndrome (ARDS). We hypothesized that genetically determined blood subtype A1 is associated with increased risk of ARDS and markers of microvascular dysfunction and coagulation.METHODSWe conducted analyses in 3 cohorts of critically ill trauma and sepsis patients (n = 3710) genotyped on genome-wide platforms to determine the association of the A1 blood type genotype with ARDS risk. We subsequently determined whether associations were present in FUT2-defined nonsecretors who lack ABO antigens on epithelium, but not endothelium. In a patient subgroup, we determined the associations of blood type with plasma levels of endothelial glycoproteins and disseminated intravascular coagulation (DIC). Lastly, we tested whether blood type A was associated with less donor lung injury recovery during human ex vivo lung perfusion (EVLP).RESULTSThe A1 genotype was associated with a higher risk of moderate to severe ARDS relative to type O in all 3 populations. In sepsis, this relationship was strongest in nonpulmonary infections. The association persisted in nonsecretors, suggesting a vascular mechanism. The A1 genotype was also associated with higher DIC risk as well as concentrations of thrombomodulin and von Willebrand factor, which in turn were associated with ARDS risk. Blood type A was also associated with less lung injury recovery during EVLP.CONCLUSIONWe identified a replicable association between ABO blood type A1 and risk of ARDS among the critically ill, possibly mediated through microvascular dysfunction and coagulation.FUNDINGNIH HL122075, HL125723, HL137006, HL137915, DK097307, HL115354, HL101779, and the University of Pennsylvania McCabe Fund Fellowship Award.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI139700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773362PMC
January 2021

A living WHO guideline on drugs for covid-19.

BMJ 2020 09 4;370:m3379. Epub 2020 Sep 4.

Department of Health Economics and Health Management, Institute for Health and Society, University of Oslo, Oslo, Norway

Clinical Question: What is the role of drug interventions in the treatment and prevention of covid-19?

New Recommendation: The latest version of this WHO living guidance provides strong recommendations against the use of hydroxychloroquine and lopinavir-ritonavir in patients with covid-19 regardless of disease severity. These recommendations follow the publication of results from the WHO SOLIDARITY trial

Recommendations: This guidance adds to recommendations for corticosteroids and remdesivir published in the previous versions, with no changes made in this update: (a) a strong recommendation for systemic corticosteroids in patients with severe and critical covid-19, (b) a conditional recommendation against systemic corticosteroids in patients with non-severe covid-19, (c) a conditional recommendation against remdesivir in hospitalised patients with covid-19.

How This Guideline Was Created: WHO has partnered with the non-profit Magic Evidence Ecosystem Foundation (MAGIC) for methodologic support, to develop and disseminate living guidance for covid-19 drug treatments, based on a living systematic review and network analysis. An international standing Guideline Development Group (GDG) of content experts, clinicians, patients, and methodologists produced recommendations following standards for trustworthy guideline development using the GRADE approach. No competing interests were identified for any panel member.

Understanding The New Recommendation: When moving from the to the strong recommendations against the use of hydroxychloroquine and lopinavir-ritonavir in patients with covid-19, the panel was informed by a living systematic review and network meta-analysis of 30 trials with 10 921 participants for hydroxychloroquine and seven trials with 7429 participants for lopinavir-ritonavir. The trials for both drugs included inpatients and outpatients. Moderate certainty evidence for both drugs demonstrated no reduction in mortality or need for mechanical ventilation. There was also low certainty of evidence for harm with both drugs, including diarrhoea and nausea/vomiting. The panel did not anticipate important variability when it comes to patient values and preferences. In addition, the panel decided that contextual factors such as resources, feasibility, acceptability, and equity for countries and health care systems did not alter the recommendation.

Updates: This is a living guideline. It replaces earlier versions (4 September and 20 November 2020) and supersedes the BMJ Rapid Recommendations on remdesivir published on 2 July 2020. The previous versions can be found as data supplements. New recommendations will be published as updates to this guideline.

Readers' Note: This is the third version (update 2) of the living guideline (BMJ 2020;370:m3379). When citing this article, please consider adding the update number and date of access for clarity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmj.m3379DOI Listing
September 2020

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Authors:
Derek C Angus Lennie Derde Farah Al-Beidh Djillali Annane Yaseen Arabi Abigail Beane Wilma van Bentum-Puijk Lindsay Berry Zahra Bhimani Marc Bonten Charlotte Bradbury Frank Brunkhorst Meredith Buxton Adrian Buzgau Allen C Cheng Menno de Jong Michelle Detry Lise Estcourt Mark Fitzgerald Herman Goossens Cameron Green Rashan Haniffa Alisa M Higgins Christopher Horvat Sebastiaan J Hullegie Peter Kruger Francois Lamontagne Patrick R Lawler Kelsey Linstrum Edward Litton Elizabeth Lorenzi John Marshall Daniel McAuley Anna McGlothin Shay McGuinness Bryan McVerry Stephanie Montgomery Paul Mouncey Srinivas Murthy Alistair Nichol Rachael Parke Jane Parker Kathryn Rowan Ashish Sanil Marlene Santos Christina Saunders Christopher Seymour Anne Turner Frank van de Veerdonk Balasubramanian Venkatesh Ryan Zarychanski Scott Berry Roger J Lewis Colin McArthur Steven A Webb Anthony C Gordon Farah Al-Beidh Derek Angus Djillali Annane Yaseen Arabi Wilma van Bentum-Puijk Scott Berry Abigail Beane Zahra Bhimani Marc Bonten Charlotte Bradbury Frank Brunkhorst Meredith Buxton Allen Cheng Menno De Jong Lennie Derde Lise Estcourt Herman Goossens Anthony Gordon Cameron Green Rashan Haniffa Francois Lamontagne Patrick Lawler Edward Litton John Marshall Colin McArthur Daniel McAuley Shay McGuinness Bryan McVerry Stephanie Montgomery Paul Mouncey Srinivas Murthy Alistair Nichol Rachael Parke Kathryn Rowan Christopher Seymour Anne Turner Frank van de Veerdonk Steve Webb Ryan Zarychanski Lewis Campbell Andrew Forbes David Gattas Stephane Heritier Lisa Higgins Peter Kruger Sandra Peake Jeffrey Presneill Ian Seppelt Tony Trapani Paul Young Sean Bagshaw Nick Daneman Niall Ferguson Cheryl Misak Marlene Santos Sebastiaan Hullegie Mathias Pletz Gernot Rohde Kathy Rowan Brian Alexander Kim Basile Timothy Girard Christopher Horvat David Huang Kelsey Linstrum Jennifer Vates Richard Beasley Robert Fowler Steve McGloughlin Susan Morpeth David Paterson Bala Venkatesh Tim Uyeki Kenneth Baillie Eamon Duffy Rob Fowler Thomas Hills Katrina Orr Asad Patanwala Steve Tong Mihai Netea Shilesh Bihari Marc Carrier Dean Fergusson Ewan Goligher Ghady Haidar Beverley Hunt Anand Kumar Mike Laffan Patrick Lawless Sylvain Lother Peter McCallum Saskia Middeldopr Zoe McQuilten Matthew Neal John Pasi Roger Schutgens Simon Stanworth Alexis Turgeon Alexandra Weissman Neill Adhikari Matthew Anstey Emily Brant Angelique de Man Francois Lamonagne Marie-Helene Masse Andrew Udy Donald Arnold Phillipe Begin Richard Charlewood Michael Chasse Mark Coyne Jamie Cooper James Daly Iain Gosbell Heli Harvala-Simmonds Tom Hills Sheila MacLennan David Menon John McDyer Nicole Pridee David Roberts Manu Shankar-Hari Helen Thomas Alan Tinmouth Darrell Triulzi Tim Walsh Erica Wood Carolyn Calfee Cecilia O’Kane Murali Shyamsundar Pratik Sinha Taylor Thompson Ian Young Shailesh Bihari Carol Hodgson John Laffey Danny McAuley Neil Orford Ary Neto Michelle Detry Mark Fitzgerald Roger Lewis Anna McGlothlin Ashish Sanil Christina Saunders Lindsay Berry Elizabeth Lorenzi Eliza Miller Vanessa Singh Claire Zammit Wilma van Bentum Puijk Wietske Bouwman Yara Mangindaan Lorraine Parker Svenja Peters Ilse Rietveld Kik Raymakers Radhika Ganpat Nicole Brillinger Rene Markgraf Kate Ainscough Kathy Brickell Aisha Anjum Janis-Best Lane Alvin Richards-Belle Michelle Saull Daisy Wiley Julian Bion Jason Connor Simon Gates Victoria Manax Tom van der Poll John Reynolds Marloes van Beurden Evelien Effelaar Joost Schotsman Craig Boyd Cain Harland Audrey Shearer Jess Wren Giles Clermont William Garrard Kyle Kalchthaler Andrew King Daniel Ricketts Salim Malakoutis Oscar Marroquin Edvin Music Kevin Quinn Heidi Cate Karen Pearson Joanne Collins Jane Hanson Penny Williams Shane Jackson Adeeba Asghar Sarah Dyas Mihaela Sutu Sheenagh Murphy Dawn Williamson Nhlanhla Mguni Alison Potter David Porter Jayne Goodwin Clare Rook Susie Harrison Hannah Williams Hilary Campbell Kaatje Lomme James Williamson Jonathan Sheffield Willian van’t Hoff Phobe McCracken Meredith Young Jasmin Board Emma Mart Cameron Knott Julie Smith Catherine Boschert Julia Affleck Mahesh Ramanan Ramsy D’Souza Kelsey Pateman Arif Shakih Winston Cheung Mark Kol Helen Wong Asim Shah Atul Wagh Joanne Simpson Graeme Duke Peter Chan Brittney Cartner Stephanie Hunter Russell Laver Tapaswi Shrestha Adrian Regli Annamaria Pellicano James McCullough Mandy Tallott Nikhil Kumar Rakshit Panwar Gail Brinkerhoff Cassandra Koppen Federica Cazzola Matthew Brain Sarah Mineall Roy Fischer Vishwanath Biradar Natalie Soar Hayden White Kristen Estensen Lynette Morrison Joanne Smith Melanie Cooper Monash Health Yahya Shehabi Wisam Al-Bassam Amanda Hulley Christina Whitehead Julie Lowrey Rebecca Gresha James Walsham Jason Meyer Meg Harward Ellen Venz Patricia Williams Catherine Kurenda Kirsy Smith Margaret Smith Rebecca Garcia Deborah Barge Deborah Byrne Kathleen Byrne Alana Driscoll Louise Fortune Pierre Janin Elizabeth Yarad Naomi Hammond Frances Bass Angela Ashelford Sharon Waterson Steve Wedd Robert McNamara Heidi Buhr Jennifer Coles Sacha Schweikert Bradley Wibrow Rashmi Rauniyar Erina Myers Ed Fysh Ashlish Dawda Bhaumik Mevavala Ed Litton Janet Ferrier Priya Nair Hergen Buscher Claire Reynolds John Santamaria Leanne Barbazza Jennifer Homes Roger Smith Lauren Murray Jane Brailsford Loretta Forbes Teena Maguire Vasanth Mariappa Judith Smith Scott Simpson Matthew Maiden Allsion Bone Michelle Horton Tania Salerno Martin Sterba Wenli Geng Pieter Depuydt Jan De Waele Liesbet De Bus Jan Fierens Stephanie Bracke Brenda Reeve William Dechert Michaël Chassé François Martin Carrier Dounia Boumahni Fatna Benettaib Ali Ghamraoui David Bellemare Ève Cloutier Charles Francoeur François Lamontagne Frédérick D’Aragon Elaine Carbonneau Julie Leblond Gloria Vazquez-Grande Nicole Marten Maggie Wilson Martin Albert Karim Serri Alexandros Cavayas Mathilde Duplaix Virginie Williams Bram Rochwerg Tim Karachi Simon Oczkowski John Centofanti Tina Millen Erick Duan Jennifer Tsang Lisa Patterson Shane English Irene Watpool Rebecca Porteous Sydney Miezitis Lauralyn McIntyre Laurent Brochard Karen Burns Gyan Sandhu Imrana Khalid Alexandra Binnie Elizabeth Powell Alexandra McMillan Tracy Luk Noah Aref Zdravko Andric Sabina Cviljevic Renata Đimoti Marija Zapalac Gordan Mirković Bruno Baršić Marko Kutleša Viktor Kotarski Ana Vujaklija Brajković Jakša Babel Helena Sever Lidija Dragija Ira Kušan Suvi Vaara Leena Pettilä Jonna Heinonen Anne Kuitunen Sari Karlsson Annukka Vahtera Heikki Kiiski Sanna Ristimäki Amine Azaiz Cyril Charron Mathieu Godement Guillaume Geri Antoine Vieillard-Baron Franck Pourcine Mehran Monchi David Luis Romain Mercier Anne Sagnier Nathalie Verrier Cecile Caplin Shidasp Siami Christelle Aparicio Sarah Vautier Asma Jeblaoui Muriel Fartoukh Laura Courtin Vincent Labbe Cécile Leparco Grégoire Muller Mai-Anh Nay Toufik Kamel Dalila Benzekri Sophie Jacquier Emmanuelle Mercier Delphine Chartier Charlotte Salmon PierreFrançois Dequin Francis Schneider Guillaume Morel Sylvie L’Hotellier Julio Badie Fernando Daniel Berdaguer Sylvain Malfroy Chaouki Mezher Charlotte Bourgoin Bruno Megarbane Sebastian Voicu Nicolas Deye Isabelle Malissin Laetitia Sutterlin Christophe Guitton Cédric Darreau Mickaël Landais Nicolas Chudeau Alain Robert Pierre Moine Nicholas Heming Virginie Maxime Isabelle Bossard Tiphaine Barbarin Nicholier Gwenhael Colin Vanessa Zinzoni Natacham Maquigneau André Finn Gabriele Kreß Uwe Hoff Carl Friedrich Hinrichs Jens Nee Mathias Pletz Stefan Hagel Juliane Ankert Steffi Kolanos Frank Bloos Sirak Petros Bastian Pasieka Kevin Kunz Peter Appelt Bianka Schütze Stefan Kluge Axel Nierhaus Dominik Jarczak Kevin Roedl Dirk Weismann Anna Frey Vivantes Klinikum Neukölln Lorenz Reill Michael Distler Astrid Maselli János Bélteczki István Magyar Ágnes Fazekas Sándor Kovács Viktória Szőke Gábor Szigligeti János Leszkoven Daniel Collins Patrick Breen Stephen Frohlich Ruth Whelan Bairbre McNicholas Michael Scully Siobhan Casey Maeve Kernan Peter Doran Michael O’Dywer Michelle Smyth Leanne Hayes Oscar Hoiting Marco Peters Els Rengers Mirjam Evers Anton Prinssen Jeroen Bosch Ziekenhuis Koen Simons Wim Rozendaal F Polderman P de Jager M Moviat A Paling A Salet Emma Rademaker Anna Linda Peters E de Jonge J Wigbers E Guilder M Butler Keri-Anne Cowdrey Lynette Newby Yan Chen Catherine Simmonds Rachael McConnochie Jay Ritzema Carter Seton Henderson Kym Van Der Heyden Jan Mehrtens Tony Williams Alex Kazemi Rima Song Vivian Lai Dinu Girijadevi Robert Everitt Robert Russell Danielle Hacking Ulrike Buehner Erin Williams Troy Browne Kate Grimwade Jennifer Goodson Owen Keet Owen Callender Robert Martynoga Kara Trask Amelia Butler Livia Schischka Chelsea Young Eden Lesona Shaanti Olatunji Yvonne Robertson Nuno José Teodoro Amaro dos Santos Catorze Tiago Nuno Alfaro de Lima Pereira Lucilia Maria Neves Pessoa Ricardo Manuel Castro Ferreira Joana Margarida Pereira Sousa Bastos Simin Aysel Florescu Delia Stanciu Miahela Florentina Zaharia Alma Gabriela Kosa Daniel Codreanu Yaseen Marabi Eman Al Qasim Mohamned Moneer Hagazy Lolowa Al Swaidan Hatim Arishi Rosana Muñoz-Bermúdez Judith Marin-Corral Anna Salazar Degracia Francisco Parrilla Gómez Maria Isabel Mateo López Jorge Rodriguez Fernandez Sheila Cárcel Fernández Rosario Carmona Flores Rafael León López Carmen de la Fuente Martos Angela Allan Petra Polgarova Neda Farahi Stephen McWilliam Daniel Hawcutt Laura Rad Laura O’Malley Jennifer Whitbread Olivia Kelsall Laura Wild Jessica Thrush Hannah Wood Karen Austin Adrian Donnelly Martin Kelly Sinéad O’Kane Declan McClintock Majella Warnock Paul Johnston Linda Jude Gallagher Clare Mc Goldrick Moyra Mc Master Anna Strzelecka Rajeev Jha Michael Kalogirou Christine Ellis Vinodh Krishnamurthy Vashish Deelchand Jon Silversides Peter McGuigan Kathryn Ward Aisling O’Neill Stephanie Finn Barbara Phillips Dee Mullan Laura Oritz-Ruiz de Gordoa Matthew Thomas Katie Sweet Lisa Grimmer Rebekah Johnson Jez Pinnell Matt Robinson Lisa Gledhill Tracy Wood Matt Morgan Jade Cole Helen Hill Michelle Davies David Antcliffe Maie Templeton Roceld Rojo Phoebe Coghlan Joanna Smee Euan Mackay Jon Cort Amanda Whileman Thomas Spencer Nick Spittle Vidya Kasipandian Amit Patel Suzanne Allibone Roman Mary Genetu Mohamed Ramali Alison Ghosh Peter Bamford Emily London Kathryn Cawley Maria Faulkner Helen Jeffrey Tim Smith Chris Brewer Jane Gregory James Limb Amanda Cowton Julie O’Brien Nikitas Nikitas Colin Wells Liana Lankester Mark Pulletz Patricia Williams Jenny Birch Sophie Wiseman Sarah Horton Ana Alegria Salah Turki Tarek Elsefi Nikki Crisp Louise Allen Iain McCullagh Philip Robinson Carole Hays Maite Babio-Galan Hannah Stevenson Divya Khare Meredith Pinder Selvin Selvamoni Amitha Gopinath Richard Pugh Daniel Menzies Callum Mackay Elizabeth Allan Gwyneth Davies Kathryn Puxty Claire McCue Susanne Cathcart Naomi Hickey Jane Ireland Hakeem Yusuff Graziella Isgro Chris Brightling Michelle Bourne Michelle Craner Malcolm Watters Rachel Prout Louisa Davies Suzannah Pegler Lynsey Kyeremeh Gill Arbane Karen Wilson Linda Gomm Federica Francia Stephen Brett Sonia Sousa Arias Rebecca Elin Hall Joanna Budd Charlotte Small Janine Birch Emma Collins Jeremy Henning Stephen Bonner Keith Hugill Emanuel Cirstea Dean Wilkinson Michal Karlikowski Helen Sutherland Elva Wilhelmsen Jane Woods Julie North Dhinesh Sundaran Laszlo Hollos Susan Coburn Joanne Walsh Margaret Turns Phil Hopkins John Smith Harriet Noble Maria Theresa Depante Emma Clarey Shondipon Laha Mark Verlander Alexandra Williams Abby Huckle Andrew Hall Jill Cooke Caroline Gardiner-Hill Carolyn Maloney Hafiz Qureshi Neil Flint Sarah Nicholson Sara Southin Andrew Nicholson Barbara Borgatta Ian Turner-Bone Amie Reddy Laura Wilding Loku Chamara Warnapura Ronan Agno Sathianathan David Golden Ciaran Hart Jo Jones Jonathan Bannard-Smith Joanne Henry Katie Birchall Fiona Pomeroy Rachael Quayle Arystarch Makowski Beata Misztal Iram Ahmed Thyra KyereDiabour Kevin Naiker Richard Stewart Esther Mwaura Louise Mew Lynn Wren Felicity Willams Richard Innes Patricia Doble Joanne Hutter Charmaine Shovelton Benjamin Plumb Tamas Szakmany Vincent Hamlyn Nancy Hawkins Sarah Lewis Amanda Dell Shameer Gopal Saibal Ganguly Andrew Smallwood Nichola Harris Stella Metherell Juan Martin Lazaro Tabitha Newman Simon Fletcher Jurgens Nortje Deirdre Fottrell-Gould Georgina Randell Mohsin Zaman Einas Elmahi Andrea Jones Kathryn Hall Gary Mills Kim Ryalls Helen Bowler Jas Sall Richard Bourne Zoe Borrill Tracey Duncan Thomas Lamb Joanne Shaw Claire Fox Jeronimo Moreno Cuesta Kugan Xavier Dharam Purohit Munzir Elhassan Dhanalakshmi Bakthavatsalam Matthew Rowland Paula Hutton Archana Bashyal Neil Davidson Clare Hird Manish Chhablani Gunjan Phalod Amy Kirkby Simon Archer Kimberley Netherton Henrik Reschreiter Julie Camsooksai Sarah Patch Sarah Jenkins David Pogson Steve Rose Zoe Daly Lutece Brimfield Helen Claridge Dhruv Parekh Colin Bergin Michelle Bates Joanne Dasgin Christopher McGhee Malcolm Sim Sophie Kennedy Hay Steven Henderson Mandeep-Kaur Phull Abbas Zaidi Tatiana Pogreban Lace Paulyn Rosaroso Daniel Harvey Benjamin Lowe Megan Meredith Lucy Ryan Anil Hormis Rachel Walker Dawn Collier Sarah Kimpton Susan Oakley Kevin Rooney Natalie Rodden Emma Hughes Nicola Thomson Deborah McGlynn Andrew Walden Nicola Jacques Holly Coles Emma Tilney Emma Vowell Martin Schuster-Bruce Sally Pitts Rebecca Miln Laura Purandare Luke Vamplew Michael Spivey Sarah Bean Karen Burt Lorraine Moore Christopher Day Charly Gibson Elizabeth Gordon Letizia Zitter Samantha Keenan Evelyn Baker Shiney Cherian Sean Cutler Anna Roynon-Reed Kate Harrington Ajay Raithatha Kris Bauchmuller Norfaizan Ahmad Irina Grecu Dawn Trodd Jane Martin Caroline Wrey Brown Ana-Marie Arias Thomas Craven David Hope Jo Singleton Sarah Clark Nicola Rae Ingeborg Welters David Oliver Hamilton Karen Williams Victoria Waugh David Shaw Zudin Puthucheary Timothy Martin Filipa Santos Ruzena Uddin Alastair Somerville Kate Colette Tatham Shaman Jhanji Ethel Black Arnold Dela Rosa Ryan Howle Redmond Tully Andrew Drummond Joy Dearden Jennifer Philbin Sheila Munt Alain Vuylsteke Charles Chan Saji Victor Ramprasad Matsa Minerva Gellamucho Ben Creagh-Brown Joe Tooley Laura Montague Fiona De Beaux Laetitia Bullman Ian Kersiake Carrie Demetriou Sarah Mitchard Lidia Ramos Katie White Phil Donnison Maggie Johns Ruth Casey Lehentha Mattocks Sarah Salisbury Paul Dark Andrew Claxton Danielle McLachlan Kathryn Slevin Stephanie Lee Jonathan Hulme Sibet Joseph Fiona Kinney Ho Jan Senya Aneta Oborska Abdul Kayani Bernard Hadebe Rajalakshmi Orath Prabakaran Lesley Nichols Matt Thomas Ruth Worner Beverley Faulkner Emma Gendall Kati Hayes Colin Hamilton-Davies Carmen Chan Celina Mfuko Hakam Abbass Vineela Mandadapu Susannah Leaver Daniel Forton Kamal Patel Elankumaran Paramasivam Matthew Powell Richard Gould Elizabeth Wilby Clare Howcroft Dorota Banach Ziortza Fernández de Pinedo Artaraz Leilani Cabreros Ian White Maria Croft Nicky Holland Rita Pereira Ahmed Zaki David Johnson Matthew Jackson Hywel Garrard Vera Juhaz Alistair Roy Anthony Rostron Lindsey Woods Sarah Cornell Suresh Pillai Rachel Harford Tabitha Rees Helen Ivatt Ajay Sundara Raman Miriam Davey Kelvin Lee Russell Barber Manish Chablani Farooq Brohi Vijay Jagannathan Michele Clark Sarah Purvis Bill Wetherill Ahilanandan Dushianthan Rebecca Cusack Kim de Courcy-Golder Simon Smith Susan Jackson Ben Attwood Penny Parsons Valerie Page Xiao Bei Zhao Deepali Oza Jonathan Rhodes Tom Anderson Sheila Morris Charlotte Xia Le Tai Amy Thomas Alexandra Keen Stephen Digby Nicholas Cowley Laura Wild David Southern Harsha Reddy Andy Campbell Claire Watkins Sara Smuts Omar Touma Nicky Barnes Peter Alexander Tim Felton Susan Ferguson Katharine Sellers Joanne Bradley-Potts David Yates Isobel Birkinshaw Kay Kell Nicola Marshall Lisa Carr-Knott Charlotte Summers

JAMA 2020 10;324(13):1317-1329

Division of Anaesthetics, Pain Medicine and Intensive Care Medicine, Department of Surgery and Cancer, Imperial College London and Imperial College Healthcare NHS Trust, London, United Kingdom.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited.

Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19.

Design, Setting, And Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020.

Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108).

Main Outcomes And Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%).

Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively.

Conclusions And Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions.

Trial Registration: ClinicalTrials.gov Identifier: NCT02735707.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jama.2020.17022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489418PMC
October 2020

Prevalence of phenotypes of acute respiratory distress syndrome in critically ill patients with COVID-19: a prospective observational study.

Lancet Respir Med 2020 12 27;8(12):1209-1218. Epub 2020 Aug 27.

Critical Care Directorate, Royal Gwent Hospital, Newport, UK; Department of Anaesthesia, Intensive Care and Pain Medicine, Division of Population Medicine, Cardiff University, Cardiff, UK.

Background: In acute respiratory distress syndrome (ARDS) unrelated to COVID-19, two phenotypes, based on the severity of systemic inflammation (hyperinflammatory and hypoinflammatory), have been described. The hyperinflammatory phenotype is known to be associated with increased multiorgan failure and mortality. In this study, we aimed to identify these phenotypes in COVID-19-related ARDS.

Methods: In this prospective observational study done at two UK intensive care units, we recruited patients with ARDS due to COVID-19. Demographic, clinical, and laboratory data were collected at baseline. Plasma samples were analysed for interleukin-6 (IL-6) and soluble tumour necrosis factor receptor superfamily member 1A (TNFR1) using a novel point-of-care assay. A parsimonious regression classifier model was used to calculate the probability for the hyperinflammatory phenotype in COVID-19 using IL-6, soluble TNFR1, and bicarbonate levels. Data from this cohort was compared with patients with ARDS due to causes other than COVID-19 recruited to a previous UK multicentre, randomised controlled trial of simvastatin (HARP-2).

Findings: Between March 17 and April 25, 2020, 39 patients were recruited to the study. Median ratio of partial pressure of arterial oxygen to fractional concentration of oxygen in inspired air (PaO/FiO) was 18 kpa (IQR 15-21) and acute physiology and chronic health evaluation II score was 12 (10-16). 17 (44%) of 39 patients had died by day 28 of the study. Compared with survivors, patients who died were older and had lower PaO/FiO. The median probability for the hyperinflammatory phenotype was 0·03 (IQR 0·01-0·2). Depending on the probability cutoff used to assign class, the prevalence of the hyperinflammatory phenotype was between four (10%) and eight (21%) of 39, which is lower than the proportion of patients with the hyperinflammatory phenotype in HARP-2 (186 [35%] of 539). Using the Youden index cutoff (0·274) to classify phenotype, five (63%) of eight patients with the hyperinflammatory phenotype and 12 (39%) of 31 with the hypoinflammatory phenotype died. Compared with matched patients recruited to HARP-2, levels of IL-6 were similar in our cohort, whereas soluble TNFR1 was significantly lower in patients with COVID-19-associated ARDS.

Interpretation: In this exploratory analysis of 39 patients, ARDS due to COVID-19 was not associated with higher systemic inflammation and was associated with a lower prevalence of the hyperinflammatory phenotype than that observed in historical ARDS data. This finding suggests that the excess mortality observed in COVID-19-related ARDS is unlikely to be due to the upregulation of inflammatory pathways described by the parsimonious model.

Funding: US National Institutes of Health, Innovate UK, and Randox.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2213-2600(20)30366-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718296PMC
December 2020

Dose-Dependent Pulmonary Toxicity of Aerosolized Vitamin E Acetate.

Am J Respir Cell Mol Biol 2020 12;63(6):748-757

Department of Medicine and.

Electronic-cigarette, or vaping, product use-associated lung injury (EVALI) is a syndrome of acute respiratory failure characterized by monocytic and neutrophilic alveolar inflammation. Epidemiological and clinical evidence suggests a role of vitamin E acetate (VEA) in the development of EVALI, yet it remains unclear whether VEA has direct pulmonary toxicity. To test the hypotheses that aerosolized VEA causes lung injury in mice and directly injures human alveolar epithelial cells, we exposed adult mice and primary human alveolar epithelial type II (AT II) cells to an aerosol of VEA generated by a device designed for vaping oils. Outcome measures in mice included lung edema, BAL analysis, histology, and inflammatory cytokines; outcomes included cell death, cytokine release, cellular uptake of VEA, and gene-expression analysis. Comparison exposures in both models included the popular nicotine-containing JUUL aerosol. We discovered that VEA caused dose-dependent increases in lung water and BAL protein compared with control and JUUL-exposed mice in association with increased BAL neutrophils, oil-laden macrophages, multinucleated giant cells, and inflammatory cytokines. VEA aerosol was also toxic to AT II cells, causing increased cell death and the release of monocyte and neutrophil chemokines. VEA was directly absorbed by AT II cells, resulting in the differential gene expression of several inflammatory biological pathways. Given the epidemiological and clinical characteristics of the EVALI outbreak, these results suggest that VEA plays an important causal role.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1165/rcmb.2020-0209OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790140PMC
December 2020

COVID-19-associated acute respiratory distress syndrome: is a different approach to management warranted?

Lancet Respir Med 2020 08 6;8(8):816-821. Epub 2020 Jul 6.

Center for Acute Respiratory Failure, New York-Presbyterian Medical Center, New York, NY, USA; Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA.

The COVID-19 pandemic has seen a surge of patients with acute respiratory distress syndrome (ARDS) in intensive care units across the globe. As experience of managing patients with COVID-19-associated ARDS has grown, so too have efforts to classify patients according to respiratory system mechanics, with a view to optimising ventilatory management. Personalised lung-protective mechanical ventilation reduces mortality and has become the mainstay of treatment in ARDS. In this Viewpoint, we address ventilatory strategies in the context of recent discussions on phenotypic heterogeneity in patients with COVID-19-associated ARDS. Although early reports suggested that COVID-19-associated ARDS has distinctive features that set it apart from historical ARDS, emerging evidence indicates that the respiratory system mechanics of patients with ARDS, with or without COVID-19, are broadly similar. In the absence of evidence to support a shift away from the current paradigm of ventilatory management, we strongly recommend adherence to evidence-based management, informed by bedside physiology, as resources permit.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2213-2600(20)30304-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338016PMC
August 2020

Is a "Cytokine Storm" Relevant to COVID-19?

JAMA Intern Med 2020 09;180(9):1152-1154

Division of Pulmonary, Department of Medicine, Critical Care, Allergy and Sleep Medicine; University of California, San Francisco.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamainternmed.2020.3313DOI Listing
September 2020

Prone Positioning in Awake, Nonintubated Patients With COVID-19: Necessity Is the Mother of Invention.

JAMA Intern Med 2020 Jun 17. Epub 2020 Jun 17.

Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Department of Medicine, University of California, San Francisco.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamainternmed.2020.3027DOI Listing
June 2020

Cigarette Smoking and ARDS After Blunt Trauma: The Influence of Changing Smoking Patterns and Resuscitation Practices.

Chest 2020 Oct 20;158(4):1490-1498. Epub 2020 Jun 20.

Department of Medicine, University of California San Francisco, San Francisco, CA; Center for Tobacco Control Research and Education, University of California San Francisco, San Francisco, CA; Department of Anesthesia and the Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA.

Background: Cigarette smoking is associated with an increased risk of developing ARDS. However, whether changes in smoking patterns or processes of care impact this relationship is unclear.

Research Question: Are changes in smoking and resuscitation patterns associated with changes in the relationship between smoking and ARDS?

Study Design And Methods: We conducted a prospective cohort study of critically injured adults with blunt trauma from 2005 to 2015. Plasma cotinine, a tobacco biomarker, was measured to categorize patients by smoking status. We used regression to assess the relationship between smoking, resuscitation practices, and ARDS over time.

Results: In the overall cohort, active (OR, 1.9; 95% CI, 1.0-3.5; P = .046) and passive (OR, 2.6; 95% CI, 1.4-4.8; P = .002) smoking were associated with an increased risk of developing ARDS in multivariate analyses. In contrast to the dose-response relationship in patients enrolled from 2005 to 2008, passive cigarette smoke exposure was associated with the highest risk of developing ARDS in patients enrolled from 2009 to 2015, suggesting a threshold effect. Packed RBC (pRBC) and fresh frozen plasma (FFP) transfusions were associated with an increased risk of developing ARDS, particularly in active smokers (pRBC: OR, 5.6; P < .001; FFP: OR, 4.5; P < .001) compared with passive smokers or nonsmokers. Blood product transfusion and smoking patterns changed over time.

Interpretation: Despite changes in resuscitation and smoking patterns, cigarette smoking remains associated with an increased risk of developing ARDS. However, this relationship changed over time, with passive smokers at particularly increased risk of developing ARDS in later years, which may be related to changes in smoking patterns or transfusion practices over time. These findings highlight the need for additional mechanistic and epidemiologic studies of the effects of low levels of cigarette smoke exposure on lung health.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.chest.2020.05.603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545485PMC
October 2020