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1.
Lancet Respir Med ; 2021 Jul 23.
Article in English | MEDLINE | ID: covidwho-1591647

ABSTRACT

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.

2.
Am J Respir Crit Care Med ; 204(11): 1274-1285, 2021 12 01.
Article in English | MEDLINE | ID: covidwho-1546620

ABSTRACT

Rationale: Two distinct subphenotypes have been identified in acute respiratory distress syndrome (ARDS), but the presence of subgroups in ARDS associated with coronavirus disease (COVID-19) is unknown. Objectives: To identify clinically relevant, novel subgroups in COVID-19-related ARDS and compare them with previously described ARDS subphenotypes. Methods: Eligible participants were adults with COVID-19 and ARDS at Columbia University Irving Medical Center. Latent class analysis 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 for corticosteroid use in subgroups was tested. Measurements and Main Results: From March 2, 2020, to April 30, 2020, 483 patients with COVID-19-related ARDS met study criteria. A two-class latent class analysis model best fit the population (P = 0.0075). Class 2 (23%) had higher proinflammatory markers, troponin, creatinine, and lactate, lower bicarbonate, and lower blood pressure than class 1 (77%). Ninety-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. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RT-PCR cycle threshold was associated with mortality in the hypoinflammatory but not the hyperinflammatory phenotype. Heterogeneity of treatment effect 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.

3.
Crit Care ; 25(1): 404, 2021 11 23.
Article in English | MEDLINE | ID: covidwho-1533274

ABSTRACT

Identifying new effective treatments for the acute respiratory distress syndrome (ARDS), including COVID-19 ARDS, remains a challenge. The field of ARDS investigation is moving increasingly toward innovative approaches such as the personalization of therapy to biological and clinical sub-phenotypes. Additionally, there is growing recognition of the importance of the global context to identify effective ARDS treatments. This review highlights emerging opportunities and continued challenges for personalizing therapy for ARDS, from identifying treatable traits to innovative clinical trial design and recognition of patient-level factors as the field of critical care investigation moves forward into the twenty-first century.

4.
Am J Respir Crit Care Med ; 2021 Nov 24.
Article in English | MEDLINE | ID: covidwho-1533154
5.
Curr Opin Crit Care ; 2021 Oct 19.
Article in English | MEDLINE | ID: covidwho-1475903

ABSTRACT

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.

6.
EClinicalMedicine ; 40: 101099, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1385454

ABSTRACT

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 (n = 135), Spain (n = 133), Switzerland (n = 20) and the United States (n = 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 p-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.

7.
Nat Commun ; 12(1): 5152, 2021 08 26.
Article in English | MEDLINE | ID: covidwho-1376195

ABSTRACT

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.


Subject(s)
COVID-19/genetics , RNA/genetics , Respiratory Distress Syndrome/genetics , Trachea/immunology , Adult , Aged , Aged, 80 and over , COVID-19/immunology , COVID-19/virology , Case-Control Studies , Cohort Studies , Critical Illness , Cytokines/genetics , Cytokines/immunology , Female , Gene Expression Profiling , Humans , Male , Middle Aged , RNA/metabolism , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/virology , SARS-CoV-2/physiology , Sequence Analysis, RNA
9.
Lancet ; 398(10300): 622-637, 2021 08 14.
Article in English | MEDLINE | ID: covidwho-1294339

ABSTRACT

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.


Subject(s)
Respiration, Artificial/methods , Respiratory Distress Syndrome/physiopathology , Respiratory Distress Syndrome/therapy , COVID-19/epidemiology , COVID-19/therapy , Humans , Pandemics , Respiratory Distress Syndrome/diagnostic imaging , Respiratory Distress Syndrome/etiology , Risk Factors , SARS-CoV-2 , Tomography, X-Ray Computed , Ultrasonography
10.
Lancet Respir Med ; 9(6): 549-551, 2021 06.
Article in English | MEDLINE | ID: covidwho-1233649
12.
Nat Commun ; 11(1): 5854, 2020 11 17.
Article in English | MEDLINE | ID: covidwho-933683

ABSTRACT

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.


Subject(s)
Betacoronavirus/physiology , Coronavirus Infections/immunology , Coronavirus Infections/virology , Immunity, Innate/genetics , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , COVID-19 , COVID-19 Testing , Clinical Laboratory Techniques , Coronavirus Infections/diagnosis , Diagnosis, Differential , Gene Expression , Host-Pathogen Interactions/immunology , Humans , Immunity, Innate/immunology , Nasopharynx/immunology , Nasopharynx/virology , Pandemics , Pneumonia, Viral/diagnosis , Respiratory Tract Infections/diagnosis , Respiratory Tract Infections/immunology , Respiratory Tract Infections/virology , SARS-CoV-2 , Sensitivity and Specificity , Viral Load
13.
Intensive Care Med ; 46(12): 2136-2152, 2020 12.
Article in English | MEDLINE | ID: covidwho-932503

ABSTRACT

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.


Subject(s)
Phenotype , Respiratory Distress Syndrome/genetics , Biomarkers , Humans , Precision Medicine/trends , Radiography/methods , Radiography/trends , Respiratory Distress Syndrome/complications , Respiratory Distress Syndrome/physiopathology
14.
Lancet Respir Med ; 8(12): 1233-1244, 2020 12.
Article in English | MEDLINE | ID: covidwho-867256

ABSTRACT

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; I2=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.


Subject(s)
COVID-19/blood , Cytokine Release Syndrome/blood , Interleukin-6/blood , Biomarkers/blood , COVID-19/immunology , Cytokine Release Syndrome/immunology , Humans , Interleukin-6/immunology , Respiratory Distress Syndrome/blood , Respiratory Distress Syndrome/immunology , Sepsis/blood , Sepsis/immunology , Severity of Illness Index
16.
BMJ ; 370: m3379, 2020 09 04.
Article in English | MEDLINE | ID: covidwho-744846

ABSTRACT

UPDATES: This is a living guideline. It replaces earlier versions (4 September 2020, 20 November 2020, 17 December 2020, 31 March 2021, 6 July 2021, and 23 September 2021). The previous versions can be found as data supplements. New recommendations will be published as updates to this guideline. CLINICAL QUESTION: What is the role of drugs in the treatment of patients with covid-19? CONTEXT: The evidence base for therapeutics for covid-19 is increasing with numerous randomized controlled trials (RCTs) underway. This update includes recommendations on convalescent plasma, informed by pooled data from 16 RCTs with 16,236 patients. NEW RECOMMENDATION: The Guideline Development Group (GDG) made a strong recommendation against the use of convalescent plasma in patients with non-severe illness, and a recommendation against its use in patients with severe and critical illness, except in the context of an RCT. UNDERSTANDING THE NEW RECOMMENDATIONS: When moving from evidence to recommendations against the use of convalescent plasma, the GDG considered a combination of evidence assessing relative benefits and harms, values and preferences, and feasibility issues. The GDG recognised there was no clear benefit for critical outcomes such as mortality and mechanical ventilation for patients with non-severe, severe, or critical illness, and significant resource requirements in terms of cost and time for administration. Thus, the strong recommendation against use reflects the GDG's view that plasma administration, especially for patients with non-severe illness where there is a low baseline risk of mortality and other important clinical outcomes, is not justified. The GDG believed that, although convalescent plasma should not be used in any severity subgroups as part of routine care, there was sufficient uncertainty in patients with severe and critical illness to warrant continuation of RCTs. PRIOR RECOMMENDATIONS: • Recommended for patients with severe and critical covid-19­A strong recommendation for systemic corticosteroids; a strong recommendation for interleukin-6 receptor blockers (tocilizumab or sarilumab); a conditional recommendation for casirivimab and imdevimab, for those having seronegative status. • Recommended for patients with non-severe covid-19­A conditional recommendation for casirivimab and imdevimab, for those at highest risk of severe disease. • Not recommended for patients with non-severe covid-19­A conditional recommendation against systemic corticosteroids. • Not recommended, regardless of covid-19 disease severity­A conditional recommendation against remdesivir; a strong recommendation against hydroxychloroquine; a strong recommendation against lopinavir/ritonavir; a recommendation against ivermectin, except in the context of a clinical trial. ABOUT THIS GUIDELINE: This living guideline, from the World Health Organization (WHO), incorporates new recommendations on therapies for covid-19 and provides updates on existing recommendations. The GDG typically evaluates a therapy when WHO judges sufficient evidence is available to make a recommendation. While the GDG takes an individual-patient perspective in making recommendations, it also considers resource implications, acceptability, feasibility, equity, and human rights. This guideline was developed according to standards and methods for trustworthy guidelines. MAGIC Evidence Ecosystem Foundation provides methodological support, including the coordination of living systematic reviews with network meta-analysis to inform the recommendations. READERS' NOTE: This is the seventh version (update 6) of the living guideline (BMJ 2020;370:m3379). It was published on 7 December 2021. When citing this article, please consider adding the update number and date of access for clarity. Guidelines for the use of drugs to prevent (rather than treat) covid-19 are published separately on the WHO website and in The BMJ.


Subject(s)
Adrenal Cortex Hormones/therapeutic use , Betacoronavirus , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , COVID-19 , Humans , Pandemics , SARS-CoV-2 , World Health Organization
17.
Lancet Respir Med ; 8(12): 1209-1218, 2020 12.
Article in English | MEDLINE | ID: covidwho-731948

ABSTRACT

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 (PaO2/FiO2) 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 PaO2/FiO2. 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.


Subject(s)
COVID-19/classification , Respiratory Distress Syndrome/classification , APACHE , COVID-19/blood , COVID-19/mortality , Case-Control Studies , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/mortality , Female , Humans , Male , Middle Aged , Phenotype , Prospective Studies , Receptors, Tumor Necrosis Factor, Type I , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/mortality
18.
Lancet Respir Med ; 8(8): 816-821, 2020 08.
Article in English | MEDLINE | ID: covidwho-634549

ABSTRACT

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.


Subject(s)
Betacoronavirus , Coronavirus Infections/therapy , Pneumonia, Viral/therapy , Respiration, Artificial/methods , Respiratory Distress Syndrome/therapy , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/physiopathology , Humans , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/physiopathology , Respiratory Distress Syndrome/physiopathology , Respiratory Distress Syndrome/virology , Respiratory Mechanics , SARS-CoV-2
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