Publications by authors named "Carolyn S Calfee"

205 Publications

Phenotyping in acute respiratory distress syndrome: state of the art and clinical implications.

Curr Opin Crit Care 2021 Oct 19. Epub 2021 Oct 19.

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

Purpose Of Review: Decades of research in acute respiratory distress syndrome (ARDS) have led to few interventions that impact clinical outcomes. The pandemic of patients with ARDS due to the novel SARS-CoV-2 infection has stressed the need for more effective therapies in ARDS. Phenotyping may enable successful trials and precision therapeutics in this patient population.

Recent Findings: Clinical phenotypes that group patients by shared cause, time-course or radiographic presentation are of prognostic value, but their use is limited by misclassification. Physiological phenotypes, including the P/F ratio, ventilatory ratio and dead space fraction, predict poor outcomes but can rapidly change, making them unstable over time. Biologic phenotypes have prognostic value with composite clinical and biomarker sub-phenotypes additionally impacting treatment response but are yet to be prospectively validated.

Summary: Although much progress has been made in ARDS phenotyping, implementation of precision medicine practices will depend on conducting phenotype-aware trials using rapid point of care assays or machine learning algorithms. Omics studies will enhance our understanding of biologic determinants of clinical outcomes in ARDS sub-phenotypes. Whether biologic ARDS sub-phenotypes are specific to this syndrome or rather more broadly identify endotypes of critical illness remains to be determined.
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http://dx.doi.org/10.1097/MCC.0000000000000903DOI Listing
October 2021

Metabolic signatures of ARDS and ARDS heterogeneity.

Am J Physiol Lung Cell Mol Physiol 2021 Oct 20. Epub 2021 Oct 20.

Department of Medicine, University of California, San Francisco, San Francisco, California, United States.

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http://dx.doi.org/10.1152/ajplung.00218.2021DOI Listing
October 2021

A Research Agenda for Precision Medicine in Sepsis and Acute Respiratory Distress Syndrome: An Official American Thoracic Society Research Statement.

Am J Respir Crit Care Med 2021 Oct;204(8):891-901

Precision medicine focuses on the identification of therapeutic strategies that are effective for a group of patients based on similar unifying characteristics. The recent success of precision medicine in non-critical care settings has resulted from the confluence of large clinical and biospecimen repositories, innovative bioinformatics, and novel trial designs. Similar advances for precision medicine in sepsis and in the acute respiratory distress syndrome (ARDS) are possible but will require further investigation and significant investment in infrastructure. This project was funded by the American Thoracic Society Board of Directors. A multidisciplinary and diverse working group reviewed the available literature, established a conceptual framework, and iteratively developed recommendations for the Precision Medicine Research Agenda for Sepsis and ARDS. The following six priority recommendations were developed by the working group: ) the creation of large richly phenotyped and harmonized knowledge networks of clinical, imaging, and multianalyte molecular data for sepsis and ARDS; ) the implementation of novel trial designs, including adaptive designs, and embedding trial procedures in the electronic health record; ) continued innovation in the data science and engineering methods required to identify heterogeneity of treatment effect; ) further development of the tools necessary for the real-time application of precision medicine approaches; ) work to ensure that precision medicine strategies are applicable and available to a broad range of patients varying across differing racial, ethnic, socioeconomic, and demographic groups; and ) the securement and maintenance of adequate and sustainable funding for precision medicine efforts. Precision medicine approaches that incorporate variability in genomic, biologic, and environmental factors may provide a path forward for better individualizing the delivery of therapies and improving care for patients with sepsis and ARDS.
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http://dx.doi.org/10.1164/rccm.202108-1908STDOI Listing
October 2021

Prognostic factors for development of acute respiratory distress syndrome following traumatic injury - a systematic review and meta-analysis.

Eur Respir J 2021 Oct 8. Epub 2021 Oct 8.

Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada.

Purpose: To summarise the prognostic associations between various clinical risk factors and the development of the acute respiratory distress syndrome (ARDS) following traumatic injury.

Methods: We conducted this review in accordance with the PRISMA and CHARMS guidelines. We searched six databases from inception through December 2020. We included English language studies describing the clinical risk factors associated with the development of post-traumatic ARDS, as defined by either the American-European Consensus Conference or the Berlin definition. We pooled adjusted odds ratios for prognostic factors using the random effects method. We assessed risk of bias using the QUIPS tool and certainty of findings using GRADE methodology.

Results: We included 39 studies involving 5 350 927 patients. We identified the amount of crystalloid resuscitation as a potentially modifiable prognostic factor associated with the development of post-traumatic ARDS (adjusted odds ratio [aOR] 1.19 for each additional liter of crystalloid administered within first 6 h after injury, 95% CI 1.15 to 1.24, high certainty). Non-modifiable prognostic factors with a moderate or high certainty of association with post-traumatic ARDS included increasing age, non-Hispanic white race, blunt mechanism of injury, presence of head injury, pulmonary contusion, or rib fracture; and increasing chest injury severity.

Conclusion: We identified one important modifiable factor, the amount of crystalloid resuscitation within the first 24 h of injury, and several non-modifiable factors associated with development of post-traumatic ARDS. This information should support the judicious use of crystalloid resuscitation in trauma patients and may inform the development of a risk-stratification tools.
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http://dx.doi.org/10.1183/13993003.00857-2021DOI Listing
October 2021

Single Nucleotide Variant in FAS Associates With Organ Failure and Soluble Fas Cell Surface Death Receptor in Critical Illness.

Crit Care Med 2021 Sep 29. Epub 2021 Sep 29.

Translational Immunology, Benaroya Research Institute, Seattle, WA. Division of Pulmonary, Critical Care and Sleep Medicine, University of Washington, Seattle, WA. Division of Nephrology, Vanderbilt University Medical Center, Nashville, TN. Disease Networks Research Unit, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland. Department of Epidemiology, Institute of Public Health Genetics, University of Washington, Seattle, WA. Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, University of California San Francisco, CA. Department of Medicine, St. Paul's Hospital, University of British Columbia, Vancouver, BC, Canada. Division of Pulmonary, Allergy, and Critical Care Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. Harvard University School of Public Health and Division of Pulmonary and Critical Care, Department of Epidemiology, Massachusetts General Hospital/Harvard Medical School, Boston, MA.

Objectives: Multiple organ failure in critically ill patients is associated with poor prognosis, but biomarkers contributory to pathogenesis are unknown. Previous studies support a role for Fas cell surface death receptor (Fas)-mediated apoptosis in organ dysfunction. Our objectives were to test for associations between soluble Fas and multiple organ failure, identify protein quantitative trait loci, and determine associations between genetic variants and multiple organ failure.

Design: Retrospective observational cohort study.

Setting: Four academic ICUs at U.S. hospitals.

Patients: Genetic analyses were completed in a discovery (n = 1,589) and validation set (n = 863). Fas gene expression and flow cytometry studies were completed in outpatient research participants (n = 250).

Interventions: None.

Measurements And Main Results: In discovery and validation sets of critically ill patients, we tested for associations between enrollment plasma soluble Fas concentrations and Sequential Organ Failure Assessment score on day 3. We conducted a genome-wide association study of plasma soluble Fas (discovery n = 1,042) and carried forward a single nucleotide variant in the FAS gene, rs982764, for validation (n = 863). We further tested whether the single nucleotide variant in FAS (rs982764) was associated with Sequential Organ Failure Assessment score, FAS transcriptional isoforms, and Fas cell surface expression. Higher plasma soluble Fas was associated with higher day 3 Sequential Organ Failure Assessment scores in both the discovery (β = 4.07; p < 0.001) and validation (β = 6.96; p < 0.001) sets. A single nucleotide variant in FAS (rs982764G) was associated with lower plasma soluble Fas concentrations and lower day 3 Sequential Organ Failure Assessment score in meta-analysis (-0.21; p = 0.02). Single nucleotide variant rs982764G was also associated with a lower relative expression of the transcript for soluble as opposed to transmembrane Fas and higher cell surface expression of Fas on CD4+ T cells.

Conclusions: We found that single nucleotide variant rs982764G was associated with lower plasma soluble Fas concentrations in a discovery and validation population, and single nucleotide variant rs982764G was also associated with lower organ dysfunction on day 3. These findings support further study of the Fas pathway as a potential mediator of organ dysfunction in critically ill patients.
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http://dx.doi.org/10.1097/CCM.0000000000005333DOI Listing
September 2021

Latent Class Analysis Reveals COVID-19-related ARDS Subgroups with Differential Responses to Corticosteroids.

Am J Respir Crit Care Med 2021 Sep 20. Epub 2021 Sep 20.

Columbia University, Medicine/Pulmonary and Critical Care, New York City, New York, United States.

Rationale Two distinct subphenotypes have been identified in acute respiratory distress syndrome (ARDS), but the presence of subgroups in ARDS associated with COVID-19 is unknown. The objective of this study was to identify clinically relevant, novel subgroups in COVID-19-related ARDS, and compare them to previously described ARDS subphenotypes. Methods Eligible participants were adults with COVID-19 and ARDS at Columbia University Irving Medical Center. Latent class analysis (LCA) was used to identify subgroups with baseline clinical, respiratory, and laboratory data serving as partitioning variables. A previously-developed machine learning model was used to classify patients as the hypoinflammatory and hyperinflammatory subphenotypes. Baseline characteristics and clinical outcomes were compared between subgroups. Heterogeneity of treatment effect (HTE) for corticosteroid-use in subgroups was tested. Measurements and Main Results From 3/2-4/30/2020, 483 patients with COVID-19-related ARDS met study criteria. A two-class LCA model best fit the population (p=0.0075). Class 2 (23%) had higher pro-inflammatory markers, troponin, creatinine and lactate, lower bicarbonate and lower blood pressure than Class 1 (77%). 90-day mortality was higher in Class 2 versus Class 1 (75% vs 48%; p<0.0001). Considerable overlap was observed between these subgroups and ARDS subphenotypes. SARS-CoV-2 RT-PCR cycle threshold was associated with mortality in the hypoinflammatory but not the hyperinflammatory phenotype. HTE to corticosteroids was observed (p=0.0295), with improved mortality in the hyperinflammatory phenotype and worse mortality in the hypoinflammatory phenotype, with the caveat that corticosteroid treatment was not randomized. Conclusions We identified two COVID-19-related ARDS subgroups with differential outcomes, similar to previously described ARDS subphenotypes. SARS-CoV-2 PCR cycle threshold had differential value for predicting mortality in the subphenotypes. The subphenotypes had differential treatment responses to corticosteroids. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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http://dx.doi.org/10.1164/rccm.202105-1302OCDOI Listing
September 2021

Increased risk of severe clinical course of COVID-19 in carriers of HLA-C*04:01.

EClinicalMedicine 2021 Sep 2:101099. Epub 2021 Sep 2.

Kantonsspital Baden AG, Department of Medicine, Baden, CH 5404, Switzerland.

Background: Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, there has been increasing urgency to identify pathophysiological characteristics leading to severe clinical course in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Human leukocyte antigen alleles (HLA) have been suggested as potential genetic host factors that affect individual immune response to SARS-CoV-2. We sought to evaluate this hypothesis by conducting a multicenter study using HLA sequencing.

Methods: We analyzed the association between COVID-19 severity and HLAs in 435 individuals from Germany ( = 135), Spain ( = 133), Switzerland ( = 20) and the United States ( = 147), who had been enrolled from March 2020 to August 2020. This study included patients older than 18 years, diagnosed with COVID-19 and representing the full spectrum of the disease. Finally, we tested our results by meta-analysing data from prior genome-wide association studies (GWAS).

Findings: We describe a potential association of HLA-C*04:01 with severe clinical course of COVID-19. Carriers of HLA-C*04:01 had twice the risk of intubation when infected with SARS-CoV-2 (risk ratio 1.5 [95% CI 1.1-2.1], odds ratio 3.5 [95% CI 1.9-6.6], adjusted -value = 0.0074). These findings are based on data from four countries and corroborated by independent results from GWAS. Our findings are biologically plausible, as HLA-C*04:01 has fewer predicted bindings sites for relevant SARS-CoV-2 peptides compared to other HLA alleles.

Interpretation: HLA-C*04:01 carrier state is associated with severe clinical course in SARS-CoV-2. Our findings suggest that HLA class I alleles have a relevant role in immune defense against SARS-CoV-2.

Funding: Funded by Roche Sequencing Solutions, Inc.
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http://dx.doi.org/10.1016/j.eclinm.2021.101099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410317PMC
September 2021

Titrating Oxygen Therapy in Critically Ill Patients.

JAMA 2021 09;326(10):911-913

Interdepartmental Division of Critical Care Medicine and the Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada.

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http://dx.doi.org/10.1001/jama.2021.9843DOI Listing
September 2021

Tracheal aspirate RNA sequencing identifies distinct immunological features of COVID-19 ARDS.

Nat Commun 2021 08 26;12(1):5152. Epub 2021 Aug 26.

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

The immunological features that distinguish COVID-19-associated acute respiratory distress syndrome (ARDS) from other causes of ARDS are incompletely understood. Here, we report the results of comparative lower respiratory tract transcriptional profiling of tracheal aspirate from 52 critically ill patients with ARDS from COVID-19 or from other etiologies, as well as controls without ARDS. In contrast to a "cytokine storm," we observe reduced proinflammatory gene expression in COVID-19 ARDS when compared to ARDS due to other causes. COVID-19 ARDS is characterized by a dysregulated host response with increased PTEN signaling and elevated expression of genes with non-canonical roles in inflammation and immunity. In silico analysis of gene expression identifies several candidate drugs that may modulate gene expression in COVID-19 ARDS, including dexamethasone and granulocyte colony stimulating factor. Compared to ARDS due to other types of viral pneumonia, COVID-19 is characterized by impaired interferon-stimulated gene (ISG) expression. The relationship between SARS-CoV-2 viral load and expression of ISGs is 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 reveals distinct immunological features of COVID-19 ARDS.
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http://dx.doi.org/10.1038/s41467-021-25040-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8390461PMC
August 2021

Plasma Metabolites in Early Sepsis Identify Distinct Clusters Defined by Plasma Lipids.

Crit Care Explor 2021 Aug 29;3(8):e0478. Epub 2021 Jul 29.

Departments of Medicine and Anesthesia, Cardiovascular Research Institute, University of California, San Francisco, CA.

Unbiased global metabolomic profiling has not been used to identify distinct subclasses in patients with early sepsis and sepsis-associated acute respiratory distress syndrome. In this study, we examined whether the plasma metabolome reflects systemic illness in early sepsis and in acute respiratory distress syndrome.

Design: Plasma metabolites were measured in subjects with early sepsis.

Setting: Patients were admitted from the emergency department to the ICU in a plasma sample collected within 24 hours of ICU admission. Metabolic profiling of 970 metabolites was performed by Metabolon (Durham, NC). Hierarchical clustering and partial least squares discriminant clustering were used to identify distinct clusters among patients with early sepsis and sepsis-associated acute respiratory distress syndrome.

Interventions: None.

Measurements And Main Results: Among critically ill patients with early sepsis ( = 197), three metabolically distinct subgroups were identified, with metabolic subtype driven by plasma lipids. Group 1, with 45 subjects (23% of cohort), had increased 60-day mortality (odds ratio, 2; 95% CI, 0.99-4.0; = 0.04 for group 1 vs all others). This group also had higher rates of vasopressor-dependent shock, acute kidney injury, and met Berlin acute respiratory distress syndrome criteria more often (all < 0.05). Conversely, metabolic group 3, with 76 subjects (39% of cohort), had the lowest risk of 60-day mortality (odds ratio, 0.44; 95% CI, 0.22-0.86; = 0.01) and lower rates of organ dysfunction as reflected in a lower Simplified Acute Physiology Score II ( < 0.001). In contrast, global metabolomic profiling did not separate patient with early sepsis with moderate-to-severe acute respiratory distress syndrome ( = 78) from those with sepsis without acute respiratory distress syndrome ( = 75).

Conclusions: Plasma metabolomic profiling in patients with early sepsis identified three metabolically distinct groups that were characterized by different plasma lipid profiles, distinct clinical phenotypes, and 60-day mortality. Plasma metabolites did not distinguish patients with early sepsis who developed acute respiratory distress syndrome from those who did not.
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http://dx.doi.org/10.1097/CCE.0000000000000478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323800PMC
August 2021

Advancing precision medicine for acute respiratory distress syndrome.

Lancet Respir Med 2021 Jul 23. Epub 2021 Jul 23.

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

Acute respiratory distress syndrome (ARDS) is a heterogeneous clinical syndrome. Understanding of the complex pathways involved in lung injury pathogenesis, resolution, and repair has grown considerably in recent decades. Nevertheless, to date, only therapies targeting ventilation-induced lung injury have consistently proven beneficial, and despite these gains, ARDS morbidity and mortality remain high. Many candidate therapies with promise in preclinical studies have been ineffective in human trials, probably at least in part due to clinical and biological heterogeneity that modifies treatment responsiveness in human ARDS. A precision medicine approach to ARDS seeks to better account for this heterogeneity by matching therapies to subgroups of patients that are anticipated to be most likely to benefit, which initially might be identified in part by assessing for heterogeneity of treatment effect in clinical trials. In October 2019, the US National Heart, Lung, and Blood Institute convened a workshop of multidisciplinary experts to explore research opportunities and challenges for accelerating precision medicine in ARDS. Topics of discussion included the rationale and challenges for a precision medicine approach in ARDS, the roles of preclinical ARDS models in precision medicine, essential features of cohort studies to advance precision medicine, and novel approaches to clinical trials to support development and validation of a precision medicine strategy. In this Position Paper, we summarise workshop discussions, recommendations, and unresolved questions for advancing precision medicine in ARDS. Although the workshop took place before the COVID-19 pandemic began, the pandemic has highlighted the urgent need for precision therapies for ARDS as the global scientific community grapples with many of the key concepts, innovations, and challenges discussed at this workshop.
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http://dx.doi.org/10.1016/S2213-2600(21)00157-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8302189PMC
July 2021

Latent class analysis-derived subphenotypes are generalisable to observational cohorts of acute respiratory distress syndrome: a prospective study.

Thorax 2021 Jul 12. Epub 2021 Jul 12.

Department of Anesthesiology, University of California San Francisco, San Francisco, California, USA.

Rationale: Using latent class analysis (LCA), two subphenotypes of acute respiratory distress syndrome (ARDS) have consistently been identified in five randomised controlled trials (RCTs), with distinct biological characteristics, divergent outcomes and differential treatment responses to randomised interventions. Their existence in unselected populations of ARDS remains unknown. We sought to identify subphenotypes in observational cohorts of ARDS using LCA.

Methods: LCA was independently applied to patients with ARDS from two prospective observational cohorts of patients admitted to the intensive care unit, derived from the Validating Acute Lung Injury markers for Diagnosis (VALID) (n=624) and Early Assessment of Renal and Lung Injury (EARLI) (n=335) studies. Clinical and biological data were used as class-defining variables. To test for concordance with prior ARDS subphenotypes, the performance metrics of parsimonious classifier models (interleukin 8, bicarbonate, protein C and vasopressor-use), previously developed in RCTs, were evaluated in EARLI and VALID with LCA-derived subphenotypes as the gold-standard.

Results: A 2-class model best fit the population in VALID (p=0.0010) and in EARLI (p<0.0001). Class 2 comprised 27% and 37% of the populations in VALID and EARLI, respectively. Consistent with the previously described 'hyperinflammatory' subphenotype, Class 2 was characterised by higher proinflammatory biomarkers, acidosis and increased shock and worse clinical outcomes. The similarities between these and prior RCT-derived subphenotypes were further substantiated by the performance of the parsimonious classifier models in both cohorts (area under the curves 0.92-0.94). The hyperinflammatory subphenotype was associated with increased prevalence of chronic liver disease and neutropenia and reduced incidence of chronic obstructive pulmonary disease. Measurement of novel biomarkers showed significantly higher levels of matrix metalloproteinase-8 and markers of endothelial injury in the hyperinflammatory subphenotype, whereas, matrix metalloproteinase-9 was significantly lower.

Conclusion: Previously described subphenotypes are generalisable to unselected populations of non-trauma ARDS.
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http://dx.doi.org/10.1136/thoraxjnl-2021-217158DOI Listing
July 2021

Acute respiratory distress syndrome.

Lancet 2021 08 1;398(10300):622-637. Epub 2021 Jul 1.

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

Acute respiratory distress syndrome (ARDS) is an acute respiratory illness characterised by bilateral chest radiographical opacities with severe hypoxaemia due to non-cardiogenic pulmonary oedema. The COVID-19 pandemic has caused an increase in ARDS and highlighted challenges associated with this syndrome, including its unacceptably high mortality and the lack of effective pharmacotherapy. In this Seminar, we summarise current knowledge regarding ARDS epidemiology and risk factors, differential diagnosis, and evidence-based clinical management of both mechanical ventilation and supportive care, and discuss areas of controversy and ongoing research. Although the Seminar focuses on ARDS due to any cause, we also consider commonalities and distinctions of COVID-19-associated ARDS compared with ARDS from other causes.
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http://dx.doi.org/10.1016/S0140-6736(21)00439-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248927PMC
August 2021

Accuracy of the Radiographic Assessment of Lung Edema Score for the Diagnosis of ARDS.

Front Physiol 2021 26;12:672823. Epub 2021 May 26.

Department of Intensive Care, Academic Medical Center, Amsterdam, Netherlands.

Bilateral opacities on chest radiographs are part of the Berlin Definition for Acute Respiratory Distress Syndrome (ARDS) but have poor interobserver reliability. The "Radiographic Assessment of Lung Edema" (RALE) score was recently proposed for evaluation of the extent and density of alveolar opacities on chest radiographs of ARDS patients. The current study determined the accuracy of the RALE score for the diagnosis and the prognosis of ARDS. analysis of a cohort of invasively ventilated intensive care unit (ICU) patients expected to need invasive ventilation for >24 h. The Berlin Definition was used as the gold standard. The RALE score was calculated for the first available chest radiograph after start of ventilation in the ICU. The primary endpoint was the diagnostic accuracy for ARDS of the RALE score. Secondary endpoints included the prognostic value of the RALE score for ICU and hospital mortality, and the association with ARDS severity, and the PaO/FiO. Receiver operating characteristic (ROC) curves were constructed, and the optimal cutoff was used to determine sensitivity, specificity and the negative and positive predictive value of the RALE score for ARDS. The study included 131 patients, of whom 30 had ARDS (11 mild, 15 moderate, and 4 severe ARDS). The first available chest radiograph was obtained median 0 [0 to 1] days after start of invasive ventilation in ICU. Compared to patients without ARDS, a higher RALE score was found in patients with ARDS (24 [interquartile range (IQR) 16-30] 6 [IQR 3-11]; < 0.001), with RALE scores of 20 [IQR 14-24], 26 [IQR 16-32], and 32 [IQR 19-36] for mild, moderate and severe ARDS, respectively, ( = 0.166). The area under the ROC for ARDS was excellent (0.91 [0.86-0.96]). The best cutoff for ARDS diagnosis was 10 with 100% sensitivity, 71% specificity, 51% positive predictive value and 100% negative predictive value. The RALE score was not associated with ICU or hospital mortality, and weakly correlated with the PaO/FiO. In this cohort of invasively ventilated ICU patients, the RALE score had excellent diagnostic accuracy for ARDS.
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http://dx.doi.org/10.3389/fphys.2021.672823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188799PMC
May 2021

Six-month and 12-month patient outcomes based on inflammatory subphenotypes in sepsis-associated ARDS: secondary analysis of SAILS-ALTOS trial.

Thorax 2021 Jun 10. Epub 2021 Jun 10.

Outcomes After Critical Illness and Surgery (OACIS) Group, Johns Hopkins University, Baltimore, Maryland, USA

Background: Prior acute respiratory distress syndrome (ARDS) trials have identified hypoinflammatory and hyperinflammatory subphenotypes, with distinct differences in short-term outcomes. It is unknown if such differences extend beyond 90 days or are associated with physical, mental health or cognitive outcomes.

Methods: 568 patients in the multicentre Statins for Acutely Injured Lungs from Sepsis trial of rosuvastatin versus placebo were included and assigned a subphenotype. Among 6-month and 12-month survivors (N=232 and 219, respectively, representing 243 unique survivors), subphenotype status was evaluated for association with a range of patient-reported outcomes (eg, mental health symptoms, quality of life). Patient subsets also were evaluated with performance-based tests of physical function (eg, 6 min walk test) and cognition.

Findings: The hyperinflammatory versus hypoinflammatory subphenotype had lower overall 12-month cumulative survival (58% vs 72%, p<0.01); however, there was no significant difference in survival beyond 90 days (86% vs 89%, p=0.70). Most survivors had impairment across the range of outcomes, with little difference between subphenotypes at 6-month and 12-month assessments. For instance, at 6 months, in comparing the hypoinflammatory versus hyperinflammatory subphenotypes, respectively, the median (IQR) patient-reported SF-36 mental health domain score was 47 (33-56) vs 44 (35-56) (p=0.99), and the per cent predicted 6 min walk distance was 66% (48%, 80%) vs 66% (49%, 79%) (p=0.76).

Interpretation: Comparing the hyperinflammatory versus hypoinflammatory ARDS subphenotype, there was no significant difference in survival beyond 90 days and no consistent findings of important differences in 6-month or 12-month physical, cognitive and mental health outcomes. These findings, when considered with prior results, suggest that inflammatory subphenotypes largely reflect the acute phase of illness and its short-term impact.
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http://dx.doi.org/10.1136/thoraxjnl-2020-216613DOI Listing
June 2021

Immunotherapy in COVID-19: why, who, and when?

Lancet Respir Med 2021 06 18;9(6):549-551. Epub 2021 May 18.

Department of Medicine, Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, and Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA.

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http://dx.doi.org/10.1016/S2213-2600(21)00232-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128672PMC
June 2021

Transepithelial nasal potential difference in patients with, and at risk of acute respiratory distress syndrome.

Thorax 2021 Nov 22;76(11):1099-1107. Epub 2021 Apr 22.

Intensive Care Unit, Royal Victoria Hospital, Belfast, UK

Background: Impaired alveolar fluid clearance, determined in part by alveolar sodium transport, is associated with acute respiratory distress syndrome (ARDS). Nasal sodium transport may reflect alveolar transport. The primary objective of this prospective, observational study was to determine if reduced nasal sodium transport, as measured by nasal potential difference (NPD), was predictive of the development of and outcome from ARDS.

Methods: NPD was measured in 15 healthy controls and in 88 patients: 40 mechanically ventilated patients defined as 'at-risk' for ARDS, 61 mechanically ventilated patients with ARDS (13 who were previously included in the 'at-risk' group) and 8 ARDS survivors on the ward.

Results: In at-risk subjects, maximum NPD (mNPD) was greater in those who developed ARDS (difference -8.4 mV; 95% CI -13.8 to -3.7; p=0.005) and increased mNPD predicted the development of ARDS before its onset (area under the curve (AUC) 0.75; 95% CI 0.59 to 0.89). In the ARDS group, mNPD was not significantly different for survivors and non-survivors (p=0.076), and mNPD was a modest predictor of death (AUC 0.60; 95% CI 0.45 to 0.75). mNPD was greater in subjects with ARDS (-30.8 mV) than in at-risk subjects (-24.2 mV) and controls (-19.9 mV) (p<0.001). NPD values were not significantly different for survivors and controls (p=0.18).

Conclusions: Increased NPD predicts the development of ARDS in at-risk subjects but does not predict mortality. NPD increases before ARDS develops, is greater during ARDS, but is not significantly different for controls and survivors. These results may reflect the upregulated sodium transport necessary for alveolar fluid clearance in ARDS. NPD may be useful as a biomarker of endogenous mechanisms to stimulate sodium transport. Larger studies are now needed to confirm these associations and predictive performance.
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http://dx.doi.org/10.1136/thoraxjnl-2020-215587DOI Listing
November 2021

Impaired antibacterial immune signaling and changes in the lung microbiome precede secondary bacterial pneumonia in COVID-19.

medRxiv 2021 Mar 26. Epub 2021 Mar 26.

Secondary bacterial infections, including ventilator-associated pneumonia (VAP), lead to worse clinical outcomes and increased mortality following viral respiratory infections. Critically ill patients with coronavirus disease 2019 (COVID-19) face an elevated risk of VAP, although susceptibility varies widely. Because mechanisms underlying VAP predisposition remained unknown, we assessed lower respiratory tract host immune responses and microbiome dynamics in 36 patients, including 28 COVID-19 patients, 15 of whom developed VAP, and eight critically ill controls. We employed a combination of tracheal aspirate bulk and single cell RNA sequencing (scRNA-seq). Two days before VAP onset, a lower respiratory transcriptional signature of bacterial infection was observed, characterized by increased expression of neutrophil degranulation, toll-like receptor and cytokine signaling pathways. When assessed at an earlier time point following endotracheal intubation, more than two weeks prior to VAP onset, we observed a striking early impairment in antibacterial innate and adaptive immune signaling that markedly differed from COVID-19 patients who did not develop VAP. scRNA-seq further demonstrated suppressed immune signaling across monocytes/macrophages, neutrophils and T cells. While viral load did not differ at an early post-intubation timepoint, impaired SARS-CoV-2 clearance and persistent interferon signaling characterized the patients who later developed VAP. Longitudinal metatranscriptomic analysis revealed disruption of lung microbiome community composition in patients who developed VAP, providing a connection between dysregulated immune signaling and outgrowth of opportunistic pathogens. Together, these findings demonstrate that COVID-19 patients who develop VAP have impaired antibacterial immune defense weeks before secondary infection onset.

One Sentence Summary: COVID-19 patients with secondary bacterial pneumonia have impaired immune signaling and lung microbiome changes weeks before onset.
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http://dx.doi.org/10.1101/2021.03.23.21253487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010763PMC
March 2021

Longitudinal single-cell epitope and RNA-sequencing reveals the immunological impact of type 1 interferon autoantibodies in critical COVID-19.

bioRxiv 2021 Mar 10. Epub 2021 Mar 10.

Type I interferon (IFN-I) neutralizing autoantibodies have been found in some critical COVID-19 patients; however, their prevalence and longitudinal dynamics across the disease severity scale, and functional effects on circulating leukocytes remain unknown. Here, in 284 COVID-19 patients, we found IFN-I autoantibodies in 19% of critical, 6% of severe and none of the moderate cases. Longitudinal profiling of over 600,000 peripheral blood mononuclear cells using multiplexed single-cell epitope and transcriptome sequencing from 54 COVID-19 patients, 15 non-COVID-19 patients and 11 non-hospitalized healthy controls, revealed a lack of IFN-I stimulated gene (ISG-I) response in myeloid cells from critical cases, including those producing anti-IFN-I autoantibodies. Moreover, surface protein analysis showed an inverse correlation of the inhibitory receptor LAIR-1 with ISG-I expression response early in the disease course. This aberrant ISG-I response in critical patients with and without IFN-I autoantibodies, supports a unifying model for disease pathogenesis involving ISG-I suppression via convergent mechanisms.
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http://dx.doi.org/10.1101/2021.03.09.434529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987018PMC
March 2021

Sepsis Subclasses: A Framework for Development and Interpretation.

Crit Care Med 2021 05;49(5):748-759

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.

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

Acute Respiratory Distress Syndrome Subphenotypes beyond the Syndrome: A Step toward Treatable Traits?

Am J Respir Crit Care Med 2021 06;203(12):1449-1451

Department of Medicine, Dentistry and Biomedical Sciences Queen's University Belfast Belfast, United Kingdom, and.

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http://dx.doi.org/10.1164/rccm.202101-0218EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8483225PMC
June 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.
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http://dx.doi.org/10.1183/16000617.0317-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8522998PMC
March 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.

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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 2021 05 23;320(5):L892-L902. Epub 2020 Dec 23.

Department of Medicine, 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. Olfactomedin 4 (), a matrix glycoprotein of neutrophil-specific granules, defines a distinct neutrophil subset that may be an independent risk factor for poor outcomes in sepsis. We hypothesized that increased percentage of OLFM4 neutrophils on sepsis presentation would be associated with mortality. 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 200 µL of whole blood within 24 h of admission and stained for the neutrophil surface marker CD66b followed by intracellular staining for OLFM4 quantitated by flow cytometry. The predictors for 60-day mortality were ) percentage of OLFM4 neutrophils and ) OLFM4 neutrophils at a cut point of ≥37.6% determined by the Youden Index. Of 120 enrolled patients with suspected sepsis, 97 had sepsis and 23 had nonsepsis SIRS. The mean percentage of OLFM4 neutrophils was significantly increased in both sepsis and nonsepsis SIRS patients who died ( ≤ 0.01). Among sepsis patients with elevated OLFM4 (≥37.6%), 56% died, compared with 18% with OLFM4 <37.6% ( = 0.001). The association between OLFM4 and mortality withstood adjustment for age, sex, absolute neutrophil count, comorbidities, and standard measures of severity of illness (SOFA score, APACHE III) ( < 0.03). In summary, OLFM4 neutrophil percentage is independently associated with 60-day mortality in sepsis and may represent a novel measure of the heterogeneity of host response to sepsis.
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http://dx.doi.org/10.1152/ajplung.00090.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174834PMC
May 2021

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

Eur Respir J 2021 07 1;58(1). Epub 2021 Jul 1.

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

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. Lipopolysaccharide (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. Extracellular vesicles derived from normal MSCs restored barrier integrity and normal levels of oxidative phosphorylation while an extracellular vesicles preparation which did not contain mitochondria was not effective. , presence of mitochondria was critical for extracellular vesicles 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.
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http://dx.doi.org/10.1183/13993003.02978-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8318599PMC
July 2021

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.

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