ABSTRACT
Clinically, COVID-19 is often a mild or asymptomatic illness. However, in a subset of patients, a more severe illness with one or more organ dysfunction requiring intensive care (ICU) admission occurs (stated as critical COVID-19). Most studies assessing the immune responses in COVID-19 focus on patients with non-critical COVID-19, often assessing single biological domain (such as cytokines, leukocytes, proteomics, or transcriptomics) at single time point in patient’s illness. In this context, our cohort study of patients with critical COVID-19 with demographically similar pre-pandemic controls, characterised the longitudinal changes in multiple biological domains (28 plasma cytokines, 30 immune cell subsets identified using mass cytometry and pan-leukocyte transcriptome) at four clinically relevant timepoints between ICU admission and discharge. When compared with controls, on ICU admission day, patients with critical COVID-19, had altered cytokine/chemokine profile (high interleukin-6 (IL-6), IL-10, IL-13, CXCL10, with low CCL17, and CXCL5)), raised histones (H3.1, H3R8), robust plasmablast response despite lymphopenia, with enrichment of immunoglobulin production and interferon pathways in the transcriptome. Analyses of longitudinal transcriptome data highlights three immunologically distinct clusters that were discordant to clinical time points, indicating that the clinical time points do capture immune response trajectory. Complete integration of this multi-domain longitudinal data indicated that ~ 70% of immunological heterogeneity is explained by the transcriptome.
Subject(s)
COVID-19 , LymphopeniaABSTRACT
Positive end expiratory pressure (PEEP) is routinely used as part of lung protective ventilation strategies in the treatment of acute respiratory distress syndrome (ARDS). In the case of ARDS arising due to COVID-19 (CARDS), there is some debate as to whether the atypical pathophysiological characteristics of the disease which lead to hypoxaemia could warrant a modified approach to ventilator management, particularly with regards to PEEP settings. Here we review the available evidence for the existence of a unique underlying lung pathophysiology in CARDS, and for the suitability of standard approaches to setting PEEP, in both the invasive and non-invasive ventilation settings. We show how detailed computational models informed by this evidence can shed light on the available data, and help to interpret recent results in the literature.
Subject(s)
COVID-19 , Hypoxia , Respiratory Distress SyndromeABSTRACT
There is ongoing controversy regarding the potential for increased respiratory effort to generate patient self-inflicted lung injury (P-SILI) in spontaneously breathing patients with COVID-19 acute respiratory failure. However, direct clinical evidence linking increased inspiratory effort to lung injury is scarce. We adapted a recently developed computational simulator that replicates distinctive features of COVID-19 pathophysiology to quantify the mechanical forces that could lead to P-SILI at different levels of respiratory effort. In accordance with recent data, the simulator was calibrated to represent a spontaneously breathing COVID-19 patient with severe hypoxaemia (SaO2 80.6%) and relatively well-preserved lung mechanics (lung compliance of 47.5 ml/cmH2O), being treated with supplemental oxygen (FiO2 = 100%). Simulations were conducted at tidal volumes (VT) and respiratory rates (RR) of 7 ml/kg and 14 breaths/min (representing normal respiratory effort) and at VT/RR of 15/14, 7/20, 15/20, 10/30, 12/30, 10/35, 12/35, 10/40, 12/40 ml/kg / breaths/min. Lung compliance was unaffected by increased VT but decreased significantly at higher RR. While oxygenation improved, significant increases in multiple indicators of the potential for lung injury were observed at all higher VT/RR combinations tested. Pleural pressure swing increased from 10.1 cmH2O at baseline to 30 cmH2O at VT/RR of 15 ml/kg / 20 breaths/min and to 54.6 cmH2O at 12 ml/kg / 40 breaths/min. Dynamic strain increased from 0.3 to 0.49 at VT/RR of 12 ml/kg / 30 breaths/min, and to 0.6 at 15 ml/kg / 20 breaths/min. Mechanical power increased from 7.83 J/min to 17.7 J/min at VT/RR of 7 ml/kg / 20 breaths/min, and to 240.5 7 J/min at 12 ml/kg / 40 breaths/min. Our results suggest that the forces generated during increased inspiratory effort in severe COVID-19 are compatible with the development of P-SILI. If conventional oxygen therapy or non-invasive ventilation is ineffective in reducing respiratory effort, control of driving and transpulmonary pressures with invasive ventilation may reduce the risk of P-SILI and allow time for the resolution of the underlying condition.
Subject(s)
Lung Diseases , Tachycardia, Ventricular , Hypoxia , COVID-19 , Respiratory InsufficiencyABSTRACT
Background. Clinical metagenomics (CMg) is being evaluated for translation from a research tool into routine diagnostic service, but its potential to significantly improve management of acutely unwell patients has not been demonstrated. The SARS-CoV-2 pandemic provides impetus to determine that benefit given increased risk of secondary infection and nosocomial transmission by multi-drug resistant (MDR) pathogens linked with expansion of critical care capacity. Methods. Prospective evaluation of CMg using nanopore sequencing was performed on 43 respiratory samples over 14 weeks from a cohort of 274 intubated patients across seven COVID-19 intensive care units. Results. Bacteria or fungi were cultured from 200 (73%) patients, with a predominance of Klebsiella spp. (31%) and C. striatum (7%) amongst other common respiratory pathogens. An 8 hour CMg workflow was 93% sensitive and 81% specific for bacterial identification compared to culture, and reported presence or absence of {beta}-lactam resistance genes carried by Enterobacterales that would modify initial guideline-recommended antibiotics in every case. CMg was also 100% concordant with quantitative PCR for detecting Aspergillus fumigatus (4 positive and 39 negative samples). Single nucleotide polymorphism (SNP)-typing using 24 hour sequence data identified an MDR-K. pneumoniae ST307 outbreak involving 4 patients and an MDR-C. striatum outbreak potentially involving 14 patients across three ICUs. Conclusion. CMg testing for ICU patients provides same-day pathogen detection and antibiotic resistance prediction that significantly improves initial treatment of nosocomial pneumonia and rapidly detects unsuspected outbreaks of MDR-pathogens.
Subject(s)
COVID-19 , Klebsiella Infections , Cross InfectionABSTRACT
BackgroundTo date the description of mechanically ventilated patients with Coronavirus Disease 2019 (COVID-19) has focussed on admission characteristics with no consideration of the dynamic course of the disease. Here, we present a data-driven analysis of granular, daily data from a representative proportion of patients undergoing invasive mechanical ventilation (IMV) within the United Kingdom (UK) to evaluate the complete natural history of COVID-19. MethodsWe included adult patients undergoing IMV within 48 hours of ICU admission with complete clinical data until intensive care unit (ICU) death or discharge. We examined factors and trajectories that determined disease progression and responsiveness to interventions used in acute respiratory distress syndrome (ARDS). Our data visualisation tool is available as a web-based widget (https://www.CovidUK.ICU). FindingsData for 633 adults with COVID-19 who were mechanically ventilated between 01 March 2020 and 31 August 2020 were analysed. Mortality, intensity of mechanical ventilation and severity of organ injury increased with severity of hypoxaemia. Median PaO2/FiO2 in non-survivors on the day of death was 12.3(8.9-18.4) kPa suggesting severe refractory hypoxaemia as a major contributor to mortality. Non-resolution of hypoxaemia over the first week of IMV was associated with higher ICU mortality (60.4% versus 17.6%; P<0.001). The reported ideal body weight overestimated our calculated ideal body weight derived from reported height, with three-quarters of all reported tidal volume values were above 6mL/kg of ideal body weight. Overall, 76% of patients with moderate hypoxaemia and 46% with severe did not undergo prone position at any stage of admission. Furthermore, only 45% showed a persistent oxygenation response on prone position. Non-responders to prone position show higher lactate, D-Dimers, troponin, cardiovascular component of the sequential organ failure assessment (SOFA) score, and higher ICU mortality (69.5% versus 31.1%; P<0.001). There was no difference in number of prone sessions between survivors and non-survivors, however, patients who died without receiving prone position had a greater number of missed opportunities for prone intervention (7(3-15.5) versus 2(0-6); P<0.001). InterpretationA sizeable proportion of patients with progressive worsening of hypoxaemia had no application of and were refractory to evidence based ARDS strategies and showed a higher mortality. Strategies for early recognition and management of COVID-19 patients refractory to conventional management strategies will be critical to improving future outcomes. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSBeyond the regular literature expertise of our consortium, we enhanced our literature review - due to the fast-evolving Covid-19 publication situation-by searching PubMed for articles published in English or with English language abstracts on October 26, 2020 (and before), with the terms "mechanical ventilation", "prone position", "AND ("coronavirus" OR "COVID-19"). Studies including patients not receiving ventilation were excluded, as were those reporting on paediatric and single-centre populations. Note, that neither of those studies analysed the data with respect to the temporal evolution of patients and at our level of granularity. Only four multicentre studies reported detailed ventilator settings and outcomes in ventilated patients with COVID-19. All studies showed only ventilator settings with restricted time points either on admission or the first 4 days of admission. None enabled granular visualisation and analysis of longitudinal ICU trajectory and management. Added value of this studyThis study provides a comprehensive analysis and visualisation of routine clinical measurements tracking the whole ICU time course of patients undergoing invasive mechanical ventilation for COVID-19. Mechanically ventilated patients with COVID-19 have a different natural history and trajectory from descriptions of non-COVID ARDS patients, not predictable from admission physiology. Refractory hypoxaemia is an attributable factor associated with poor outcomes in Covid-19 and hence, understanding of use and utility of evidence-based ARDS interventions is clinically crucial. Opportunities to apply prone positioning appropriately are frequently missed, application of high levels of PEEP, and higher tidal volume delivery than planned is common. Lack of responsiveness to advanced ARDS management is associated with hypercoagulation and cardiovascular instability. These data may help homogenise future clinical management protocols and suggest change-of-practice trials. Implications of all the available evidenceThis study shows that disease progression in Covid-19 during the first surge occurred more frequently and for longer than other forms of respiratory failure from pre-Covid19 studies. Furthermore, variations in clinical practise occur across sites which may benefit from standardisation of evidence-based practise. Patients that do not resolve hypoxaemia over the first week have a significantly higher mortality, and, crucially, that a significant proportion are refractory to prone interventions and show variability in responses to PEEP changes. Opportunities to implement prone position were missed in many patients and this was compounded with its reduced effect on oxygenation with delayed application. This lack of responsiveness is related to indices of inflammation, thrombosis, and cardiac dysfunction suggesting that pulmonary thrombosis could influence prone responsiveness and should be pro-actively investigated in the setting of refractory Covid-19 ARDS. Prediction of failure to resolve or respond to ARDS interventions could further focus research on this group with worse outcome.
Subject(s)
COVID-19ABSTRACT
BACKGROUND: COVID-19 has been reported to be a prothrombotic condition. We aimed to compare the prevalence of vascular thrombosis in patients with either severe COVID-19 or non-COVID-19 viral pneumonia. METHODS: We analysed whole-body CT scanners obtained in consecutive patients admitted in three centers of the English national ECMO service. We included consecutive patients with either COVID-19 or non-COVID-19 viral pneumonia admitted from January 2019. The presence of vascular thrombosis (defined as pulmonary artery thrombus, venous thrombus, systemic arterial thrombus, or end organ infarct) and hemorrhage was recorded. Clinical outcomes were examined using a 7-point ordinal scale. RESULTS: 136 patients (45.2±10.6 years of age, 39/146 (27%) female) requiring ECMO support underwent whole-body CT scanner on admission. Of these 86 had COVID-19 pneumonia, and 50 had non-COVID-19 viral pneumonia. Vascular thrombosis was seen more often in patients with COVID-19 (OR 12.9 (95% CI 4.5;36.8)). There was no difference between the groups in the prevalence of hemorrhage (OR 2.1 (95%CI 0.6;7.2)). The risk of mortality was 1.8 (95%CI 0.97;3.44, p=0.06) in those with COVID-19 compared with non-COVID-19 pneumonia. Mortality was no different in COVID-19 patients with or without vascular thrombosis (HR 1.03 (95% CI 0.38;2.76, p=0.96) but was higher in those patients with hemorrhage on admission (HR 3.0 (95% CI 1.06;8.5, p=0.038)). CONCLUSION: COVID-19 is associated with a significantly higher prevalence of vascular thrombosis compared with non-COVID-19 viral pneumonias. Despite this, vascular thrombosis was not linked to poorer short-term prognosis in those with COVID-19.FUNDING STATEMENT: No funding to declare.DECLARATION OF INTERESTS: The authors have no conflict of interest to declare.ETHICS APPROVAL STATEMENT: The study was approved by the institutional review boards of the 3 centers with a waiver for consent due to the observational nature of the study.
Subject(s)
Thrombosis , Pneumonia, Viral , COVID-19ABSTRACT
The rapidly evolving understanding of Coronavirus Disease 2019 (COVID-19) respiratory failure pathogenesis, limited disease-specific evidence and demand-resource imbalances have posed significant challenges for intensive care clinicians. In this single-centre retrospective cohort study we describe the outcomes of COVID-19 patients admitted to Guy’s and St. Thomas’ NHS Foundation Trust (GSTT) critical care service. Patients were managed according to a local respiratory failure management pathway that was predicated on timely invasive ventilation when indicated and tailored ventilatory strategies according to pulmonary mechanics. Between 2nd March and 25th May 2020 GSTT critical care service admitted 316 patients with confirmed COVID-19. Of the 201 patients admitted directly through the Emergency Department with a completed critical care outcome, 71.1% survived to critical care discharge. These favourable outcomes may serve to inform the wider debate on the optimal ventilatory management in COVID-19.
Subject(s)
COVID-19 , Respiratory InsufficiencyABSTRACT
The Coronavirus Disease 2019 (COVID-19) pandemic has resulted in a significant surge of critically ill patients and an unprecedented demand on intensive care services. The rapidly evolving understanding of pathogenesis, limited disease specific evidence and demand-resource imbalances have posed significant challenges for intensive care clinicians. COVID-19 is a complex multisystem inflammatory vasculopathy with a significant mortality implication for those admitted to intensive care. Institutional strategic preparation and meticulous intensive care support are essential to maximising outcomes during the pandemic. The significant mortality variation observed between institutions and internationally, despite a single aetiology and uniform presentation, highlights the potential influence of management strategies on outcome. Given that optimal organ support and adjunctive therapies for COVID-19 have not yet been well defined by trial-based outcomes, strategies are predicated on existing literature and experiential learning. This review outlines the relevant pathophysiology and management strategies for critically ill patients with COVID-19, and shares some of the collective learning accumulated in a high volume Severe Respiratory Failure centre in London.