Publications by authors named "Manu Shankar-Hari"

120 Publications

Antibody longevity and cross-neutralizing activity following SARS-CoV-2 wave 1 and B.1.1.7 infections.

medRxiv 2021 Jun 8. Epub 2021 Jun 8.

As SARS-CoV-2 variants continue to emerge globally, a major challenge for COVID-19 vaccination is the generation of a durable antibody response with cross-neutralizing activity against both current and newly emerging viral variants. Cross-neutralizing activity against major variants of concern (B.1.1.7, P.1 and B.1.351) has been observed following vaccination, albeit at a reduced potency, but whether vaccines based on the Spike glycoprotein of these viral variants will produce a superior cross-neutralizing antibody response has not been fully investigated. Here, we used sera from individuals infected in wave 1 in the UK to study the long-term cross-neutralization up to 10 months post onset of symptoms (POS), as well as sera from individuals infected with the B.1.1.7 variant to compare cross-neutralizing activity profiles. We show that neutralizing antibodies with cross-neutralizing activity can be detected from wave 1 up to 10 months POS. Although neutralization of B.1.1.7 and B.1.351 is lower, the difference in neutralization potency decreases at later timepoints suggesting continued antibody maturation and improved tolerance to Spike mutations. Interestingly, we found that B.1.1.7 infection also generates a cross-neutralizing antibody response, which, although still less potent against B.1.351, can neutralize parental wave 1 virus to a similar degree as B.1.1.7. These findings have implications for the optimization of vaccines that protect against newly emerging viral variants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/2021.06.07.21258351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202432PMC
June 2021

SARS-CoV-2 RNAemia and proteomic trajectories inform prognostication in COVID-19 patients admitted to intensive care.

Nat Commun 2021 06 7;12(1):3406. Epub 2021 Jun 7.

Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, London, UK.

Prognostic characteristics inform risk stratification in intensive care unit (ICU) patients with coronavirus disease 2019 (COVID-19). We obtained blood samples (n = 474) from hospitalized COVID-19 patients (n = 123), non-COVID-19 ICU sepsis patients (n = 25) and healthy controls (n = 30). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA was detected in plasma or serum (RNAemia) of COVID-19 ICU patients when neutralizing antibody response was low. RNAemia is associated with higher 28-day ICU mortality (hazard ratio [HR], 1.84 [95% CI, 1.22-2.77] adjusted for age and sex). RNAemia is comparable in performance to the best protein predictors. Mannose binding lectin 2 and pentraxin-3 (PTX3), two activators of the complement pathway of the innate immune system, are positively associated with mortality. Machine learning identified 'Age, RNAemia' and 'Age, PTX3' as the best binary signatures associated with 28-day ICU mortality. In longitudinal comparisons, COVID-19 ICU patients have a distinct proteomic trajectory associated with mortality, with recovery of many liver-derived proteins indicating survival. Finally, proteins of the complement system and galectin-3-binding protein (LGALS3BP) are identified as interaction partners of SARS-CoV-2 spike glycoprotein. LGALS3BP overexpression inhibits spike-pseudoparticle uptake and spike-induced cell-cell fusion in vitro.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-23494-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184784PMC
June 2021

Virological and serological characterization of critically ill patients with COVID-19 in the UK: Interactions of viral load, antibody status and B.1.1.7 variant infection.

J Infect Dis 2021 May 24. Epub 2021 May 24.

Microbiology Services, NHS Blood and Transplant, London, UK.

Background: Convalescent plasma containing neutralising antibody to SARS-CoV-2 is under investigation for COVID-19 treatment. We report diverse virological characteristics of UK intensive care patients enrolled in the Immunoglobulin Domain of the REMAP-CAP randomised controlled trial that potentially influence treatment outcomes.

Methods: SARS-CoV-2 RNA in nasopharyngeal swabs collected pre-treatment was quantified by PCR. Antibody status was determined by spike-protein ELISA. B.1.1.7 was differentiated from other SARS-CoV-2 strains using allele-specific probes or restriction site polymorphism (SfcI) targeting D1118H.

Results: Of 1274 subjects, 90% were PCR-positive with viral loads 118-1.7x10 11 IU/ml. Median viral loads were 40-fold higher in those seronegative for IgG antibodies (n=354; 28%) compared to seropositives (n=939; 72%). Frequencies of B.1.1.7 increased from <1% in early November, 2020 to 82% of subjects in January 2021. Seronegative individuals with wild-type SARS-CoV-2 had significantly higher viral loads than seropositives (medians 5.8x10 6 and 2.0 x10 5 IU/ml respectively; p=2x10 -15). However, viral load distributions were elevated in both seronegative and seropositive subjects infected with B.1.1.7 (4.0x10 6 and 1.6x10 6 IU/ml respectively).

Conclusions: High viral loads in seropositive B.1.1.7-infected subjects and resistance to seroconversion indicate less effective clearance by innate and adaptive immune responses. SARS-CoV-2 strain, viral loads and antibody status define subgroups for analysis of treatment efficacy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/infdis/jiab283DOI Listing
May 2021

The COVID-19 puzzle: deciphering pathophysiology and phenotypes of a new disease entity.

Lancet Respir Med 2021 06 6;9(6):622-642. Epub 2021 May 6.

Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Modena, Italy.

The zoonotic SARS-CoV-2 virus that causes COVID-19 continues to spread worldwide, with devastating consequences. While the medical community has gained insight into the epidemiology of COVID-19, important questions remain about the clinical complexities and underlying mechanisms of disease phenotypes. Severe COVID-19 most commonly involves respiratory manifestations, although other systems are also affected, and acute disease is often followed by protracted complications. Such complex manifestations suggest that SARS-CoV-2 dysregulates the host response, triggering wide-ranging immuno-inflammatory, thrombotic, and parenchymal derangements. We review the intricacies of COVID-19 pathophysiology, its various phenotypes, and the anti-SARS-CoV-2 host response at the humoral and cellular levels. Some similarities exist between COVID-19 and respiratory failure of other origins, but evidence for many distinctive mechanistic features indicates that COVID-19 constitutes a new disease entity, with emerging data suggesting involvement of an endotheliopathy-centred pathophysiology. Further research, combining basic and clinical studies, is needed to advance understanding of pathophysiological mechanisms and to characterise immuno-inflammatory derangements across the range of phenotypes to enable optimum care for patients with COVID-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2213-2600(21)00218-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102044PMC
June 2021

Degradation of the Endothelial Glycocalyx Contributes to Metabolic Acidosis in Children Following Cardiopulmonary Bypass Surgery.

Pediatr Crit Care Med 2021 May 4. Epub 2021 May 4.

Paediatric Intensive Care, Evelina London Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom. Department of Women and Children's Health, School of Life Course Sciences, King's College London, St Thomas' Hospital, London, United Kingdom. Thrombosis and Vascular Biology Research Group, St Thomas' Hospital, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom. Department of Cardiology, Evelina London Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom. Institute of Women and Children's Health, King's College London, St Thomas' Hospital, London, United Kingdom. Department of Infectious Diseases, School of Immunology and Microbial Sciences, King's College London, Guy's Hospital, London, United Kingdom. Department of Intensive Care, St Thomas' Hospital, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom.

Objectives: Cardiopulmonary bypass surgery is complicated by metabolic acidosis, microvascular dysfunction, and capillary leak. The glycocalyx-a layer of proteins and sugars lining the vascular endothelium-is degraded during cardiopulmonary bypass. We aimed to describe the kinetics of glycocalyx degradation during and following cardiopulmonary bypass. We hypothesized that cleavage of negatively charged fragments of the glycocalyx would directly induce metabolic acidosis through changes in the strong ion gap (defined using Stewart's physicochemical approach to acid-base chemistry). We also investigated whether glycocalyx degradation was associated with failure of endothelial function and cardiovascular dysfunction.

Design: Single-center prospective cohort study.

Setting: Twenty-two bed surgical/medical PICU.

Patients: Twenty-seven term infants and children requiring cardiopulmonary bypass surgery for the correction/palliation of congenital heart disease.

Interventions: None.

Measurements And Main Results: We recruited 27 patients, 5 days to 57 months old. We prospectively sampled plasma prior to, during, and following cardiopulmonary bypass at predefined time points. We measured plasma concentrations of interleukin-6 (inflammatory marker), heparan sulfate (negatively charged glycocalyx glycosaminoglycan), and syndecan-1 (neutrally charged glycocalyx protein). We defined the following outcome measures: metabolic acidosis (strong ion gap), renal dysfunction (fold change in creatinine), capillary leak (fluid bolus volume), cardiovascular dysfunction (Vasoactive Inotropic Score), and length of ventilation. In linear regression models, maximum measured heparan sulfate concentration (negatively charged) was associated with metabolic acidosis (p = 0.016), renal dysfunction (p = 0.009), and length of ventilation (p = 0.047). In contrast, maximum measured syndecan-1 concentration (neutrally charged) was not associated with these clinical endpoints (p > 0.30 for all).

Conclusions: Our data show that metabolic acidosis (increased strong ion gap) is associated with plasma concentration of heparan sulfate, a negatively charged glycosaminoglycan cleaved from the endothelial glycocalyx during cardiopulmonary bypass. In addition, cleavage of heparan sulfate was associated with renal dysfunction, capillary leak, and global markers of cardiovascular dysfunction. These data highlight the importance of designing translational therapies to protect the glycocalyx in cardiopulmonary bypass.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PCC.0000000000002746DOI Listing
May 2021

Resilient SARS-CoV-2 diagnostics workflows including viral heat inactivation.

medRxiv 2021 Apr 10. Epub 2021 Apr 10.

There is a worldwide need for reagents to perform SARS-CoV-2 detection. Some laboratories have implemented kit-free protocols, but many others do not have the capacity to develop these and/or perform manual processing. We provide multiple workflows for SARS-CoV-2 nucleic acid detection in clinical samples by comparing several commercially available RNA extraction methods: QIAamp Viral RNA Mini Kit (QIAgen), RNAdvance Blood/Viral (Beckman) and Mag-Bind Viral DNA/RNA 96 Kit (Omega Bio-tek). We also compared One-step RT-qPCR reagents: TaqMan Fast Virus 1-Step Master Mix (FastVirus, ThermoFisher Scientific), qPCRBIO Probe 1-Step Go Lo-ROX (PCR Biosystems) and Luna Universal Probe One-Step RT-qPCR Kit (Luna, NEB). We used primer-probes that detect viral N (EUA CDC) and RdRP (PHE guidelines). All RNA extraction methods provided similar results. FastVirus and Luna proved most sensitive. N detection was more reliable than that of RdRP, particularly in samples with low viral titres. Importantly, we demonstrate that treatment of nasopharyngeal swabs with 70 degrees for 10 or 30 min, or 90 degrees for 10 or 30 min (both original variant and B 1.1.7) inactivates SARS-CoV-2 employing plaque assays, and that it has minimal impact on the sensitivity of the qPCR in clinical samples. These findings make SARS-CoV-2 testing portable to settings that do not have CL-3 facilities. In summary, we provide several testing pipelines that can be easily implemented in other laboratories and have made all our protocols and SOPs freely available at https://osf.io/uebvj/ .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/2020.04.22.20074351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043481PMC
April 2021

Neutralization potency of monoclonal antibodies recognizing dominant and subdominant epitopes on SARS-CoV-2 Spike is impacted by the B.1.1.7 variant.

Immunity 2021 06 1;54(6):1276-1289.e6. Epub 2021 Apr 1.

Department of Infectious Diseases, School of Immunology & Microbial Sciences, King's College London, London, UK; Genotype-to-Phenotype UK National Virology Consortium. Electronic address:

Interaction of the SARS-CoV-2 Spike receptor binding domain (RBD) with the receptor ACE2 on host cells is essential for viral entry. RBD is the dominant target for neutralizing antibodies, and several neutralizing epitopes on RBD have been molecularly characterized. Analysis of circulating SARS-CoV-2 variants has revealed mutations arising in the RBD, N-terminal domain (NTD) and S2 subunits of Spike. To understand how these mutations affect Spike antigenicity, we isolated and characterized >100 monoclonal antibodies targeting epitopes on RBD, NTD, and S2 from SARS-CoV-2-infected individuals. Approximately 45% showed neutralizing activity, of which ∼20% were NTD specific. NTD-specific antibodies formed two distinct groups: the first was highly potent against infectious virus, whereas the second was less potent and displayed glycan-dependant neutralization activity. Mutations present in B.1.1.7 Spike frequently conferred neutralization resistance to NTD-specific antibodies. This work demonstrates that neutralizing antibodies targeting subdominant epitopes should be considered when investigating antigenic drift in emerging variants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.immuni.2021.03.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015430PMC
June 2021

Impact of differences in acute respiratory distress syndrome randomised controlled trial inclusion and exclusion criteria: systematic review and meta-analysis.

Br J Anaesth 2021 Jul 1;127(1):85-101. Epub 2021 Apr 1.

Critical Care, Guy's and St Thomas' NHS Foundation Trust, London, UK; School of Immunology & Microbial Sciences, King's College London, London, UK. Electronic address:

Background: Control-arm mortality varies between acute respiratory distress syndrome (ARDS) RCTs.

Methods: We systematically reviewed ARDS RCTs that commenced recruitment after publication of the American-European Consensus (AECC) definition (MEDLINE, Embase, and Cochrane central register of controlled trials; January 1994 to October 2020). We assessed concordance of RCT inclusion criteria to ARDS consensus definitions and whether exclusion criteria are strongly or poorly justified. We estimated the proportion of between-trial difference in control-arm 28-day mortality explained by the inclusion criteria and RCT design characteristics using meta-regression.

Results: A literature search identified 43 709 records. One hundred and fifty ARDS RCTs were included; 146/150 (97.3%) RCTs defined ARDS inclusion criteria using AECC/Berlin definitions. Deviations from consensus definitions, primarily aimed at improving ARDS diagnostic certainty, frequently related to duration of hypoxaemia (117/146; 80.1%). Exclusion criteria could be grouped by rationale for selection into strongly or poorly justified criteria. Common poorly justified exclusions included pregnancy related, age, and comorbidities (infectious/immunosuppression, hepatic, renal, and human immunodeficiency virus/acquired immunodeficiency syndrome). Control-arm 28-day mortality varied between ARDS RCTs (mean: 29.8% [95% confidence interval: 27.0-32.7%; I=88.8%; τ=0.02; P<0.01]), and differed significantly between RCTs with different Pao:FiO ratio inclusion thresholds (26.6-39.9 kPa vs <26.6 kPa; P<0.01). In a meta-regression model, inclusion criteria and RCT design characteristics accounted for 30.6% of between-trial difference (P<0.01).

Conclusions: In most ARDS RCTs, consensus definitions are modified to use as inclusion criteria. Between-RCT mortality differences are mostly explained by the Pao:FiO ratio threshold within the consensus definitions. An exclusion criteria framework can be applied when designing and reporting exclusion criteria in future ARDS RCTs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bja.2021.02.027DOI Listing
July 2021

Expert consensus statements for the management of COVID-19-related acute respiratory failure using a Delphi method.

Crit Care 2021 03 16;25(1):106. Epub 2021 Mar 16.

Manchester University NHS Foundation Trust, Manchester, UK.

Background: Coronavirus disease 2019 (COVID-19) pandemic has caused unprecedented pressure on healthcare system globally. Lack of high-quality evidence on the respiratory management of COVID-19-related acute respiratory failure (C-ARF) has resulted in wide variation in clinical practice.

Methods: Using a Delphi process, an international panel of 39 experts developed clinical practice statements on the respiratory management of C-ARF in areas where evidence is absent or limited. Agreement was defined as achieved when > 70% experts voted for a given option on the Likert scale statement or > 80% voted for a particular option in multiple-choice questions. Stability was assessed between the two concluding rounds for each statement, using the non-parametric Chi-square (χ) test (p < 0·05 was considered as unstable).

Results: Agreement was achieved for 27 (73%) management strategies which were then used to develop expert clinical practice statements. Experts agreed that COVID-19-related acute respiratory distress syndrome (ARDS) is clinically similar to other forms of ARDS. The Delphi process yielded strong suggestions for use of systemic corticosteroids for critical COVID-19; awake self-proning to improve oxygenation and high flow nasal oxygen to potentially reduce tracheal intubation; non-invasive ventilation for patients with mixed hypoxemic-hypercapnic respiratory failure; tracheal intubation for poor mentation, hemodynamic instability or severe hypoxemia; closed suction systems; lung protective ventilation; prone ventilation (for 16-24 h per day) to improve oxygenation; neuromuscular blocking agents for patient-ventilator dyssynchrony; avoiding delay in extubation for the risk of reintubation; and similar timing of tracheostomy as in non-COVID-19 patients. There was no agreement on positive end expiratory pressure titration or the choice of personal protective equipment.

Conclusion: Using a Delphi method, an agreement among experts was reached for 27 statements from which 20 expert clinical practice statements were derived on the respiratory management of C-ARF, addressing important decisions for patient management in areas where evidence is either absent or limited.

Trial Registration: The study was registered with Clinical trials.gov Identifier: NCT04534569.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13054-021-03491-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962430PMC
March 2021

Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19.

N Engl J Med 2021 04 25;384(16):1491-1502. Epub 2021 Feb 25.

From Imperial College London (A.C.G., F.A.-B.), Imperial College Healthcare NHS Trust, St. Mary's Hospital (A.C.G.), Intensive Care National Audit and Research Centre (P.R.M., K.M.R.), University College London Hospital (R.H.), King's College London (M.S.-H.), and Guy's and St. Thomas' NHS Foundation Trust (M.S.-H.), London, University of Oxford (A. Beane) and NHS Blood and Transplant (L.J.E.), Oxford, and University of Bristol, Bristol (C.A.B.) - all in the United Kingdom; Monash University (A.D.N., A. Buzgau, A.C.C., A.M.H., S.P.M., J.C.P., C.G., S.A.W.) and Alfred Health (A.D.N., A.C.C.), Melbourne, VIC, Fiona Stanley Hospital (E. Litton, K.O.) and University of Western Australia (E. Litton), Perth, WA, University of Sydney and Royal Prince Alfred Hospital, Sydney (A.E.P.), and St. John of God Hospital, Subiaco, WA (S.A.W.) - all in Australia; University College Dublin, Dublin (A.D.N.); King Saud bin Abdulaziz University for Health Sciences and King Abdullah International Medical Research Center, Riyadh, Saudi Arabia (Y.M.A.); Hospital Raymond Poincaré (Assistance Publique-Hôpitaux de Paris) and Université Paris Saclay-Université de Versailles Saint-Quentin-en-Yvelines-INSERM, Garches, and Université de Versailles Saint-Quentin-en-Yvelines-Université Paris Saclay, Montigny-le-Bretonneux - all in France (D.A.); University Medical Center Utrecht, Utrecht (W.B.-P., M.J.M.B., H.L.L., E.R., L.P.G.D.), and Radboudumc, Nijmegen (F.L.V.) - both in the Netherlands; Berry Consultants, Austin, TX (L.R.B., M.A.D., M.F., E. Lorenzi, A.M., C.T.S., R.J.L., S.B.); St. Michael's Hospital Unity Health (Z.B., J.C.M., M.S.S.) and University Health Network and University of Toronto (P.R.L.), Toronto, Université de Sherbrooke, Sherbrooke, QC (F.L.), University of British Columbia, Vancouver (S.M.), University of Alberta, Edmonton (W.I.S.), Université Laval, Québec City (A.F.T.), and University of Manitoba, Winnipeg, MB (R.Z.) - all in Canada; Jena University Hospital, Jena, Germany (F.M.B.); Auckland City Hospital (E.J.D., T.E.H., S.P.M., R.L.P., C.J.M.), Middlemore Hospital (S.C.M.), and University of Auckland (R.L.P.), Auckland, and Medical Research Institute of New Zealand, Wellington (T.E.H., S.P.M., A.M.T.) - all in New Zealand; University of Antwerp, Wilrijk, Belgium (H.G.); University of Oxford, Bangkok, Thailand (R.H.); National Intensive Care Surveillance, Colombo, Sri Lanka (R.H.); UPMC Children's Hospital of Pittsburgh (C.M.H.) and University of Pittsburgh (K.M.L., F.B.M., B.J.M., S.K.M., C.W.S., D.C.A.), Pittsburgh; Queen's University Belfast and Royal Victoria Hospital, Belfast, Northern Ireland (D.F.M.); University of Helsinki and Helsinki University Hospital, Helsinki (V.P.); and Harbor-UCLA Medical Center, Torrance, CA (R.J.L.).

Background: The efficacy of interleukin-6 receptor antagonists in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear.

Methods: We evaluated tocilizumab and sarilumab in an ongoing international, multifactorial, adaptive platform trial. Adult patients with Covid-19, within 24 hours after starting organ support in the intensive care unit (ICU), were randomly assigned to receive tocilizumab (8 mg per kilogram of body weight), sarilumab (400 mg), or standard care (control). The primary outcome was respiratory and cardiovascular organ support-free days, on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support to day 21. The trial uses a Bayesian statistical model with predefined criteria for superiority, efficacy, equivalence, or futility. An odds ratio greater than 1 represented improved survival, more organ support-free days, or both.

Results: Both tocilizumab and sarilumab met the predefined criteria for efficacy. At that time, 353 patients had been assigned to tocilizumab, 48 to sarilumab, and 402 to control. The median number of organ support-free days was 10 (interquartile range, -1 to 16) in the tocilizumab group, 11 (interquartile range, 0 to 16) in the sarilumab group, and 0 (interquartile range, -1 to 15) in the control group. The median adjusted cumulative odds ratios were 1.64 (95% credible interval, 1.25 to 2.14) for tocilizumab and 1.76 (95% credible interval, 1.17 to 2.91) for sarilumab as compared with control, yielding posterior probabilities of superiority to control of more than 99.9% and of 99.5%, respectively. An analysis of 90-day survival showed improved survival in the pooled interleukin-6 receptor antagonist groups, yielding a hazard ratio for the comparison with the control group of 1.61 (95% credible interval, 1.25 to 2.08) and a posterior probability of superiority of more than 99.9%. All secondary analyses supported efficacy of these interleukin-6 receptor antagonists.

Conclusions: In critically ill patients with Covid-19 receiving organ support in ICUs, treatment with the interleukin-6 receptor antagonists tocilizumab and sarilumab improved outcomes, including survival. (REMAP-CAP ClinicalTrials.gov number, NCT02735707.).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa2100433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953461PMC
April 2021

Initial setting of high-flow nasal oxygen post extubation based on mean inspiratory flow during a spontaneous breathing trial.

J Crit Care 2021 Jun 27;63:40-44. Epub 2020 Dec 27.

Department of Adult Critical Care, Guy's and St Thomas' NHS Foundation Trust, King's Health Partners, Division of Centre of Human Applied Physiological Sciences, King's College London, London, UK. Electronic address:

Purpose: High flow nasal cannula (HFNC) is commonly used post-extubation in intensive care (ICU). Patients' comfort during HFNC is affected by flow rate. The study aims to describe the relationship between pre-extubation inspiratory flow requirements and the post-extubation flow rates on HFNC that maximises patient's comfort.

Methods: This was an observational, retrospective study conducted in a university-affiliated ICU. We included patients extubated following successful spontaneous breathing trial (SBT). During the SBT we recorded variables including inspiratory flow. Patients who passed the SBT were extubated onto HFNC. HFNC was titrated from 20 L/min and increased in steps of 10 L/min, up to 60 L/min. At each step, patient's level of comfort was assessed. Fraction of inspired oxygen was titrated to maintain oxygen saturation 92-97%.

Results: Nineteen participants were enrolled in the study. There was a significant positive correlation between mean inspiratory flow pre-extubation and the flow setting on HFNC which achieved the best comfort post-extubation (r 0.88; p < 0.001). Overall, greatest comfort was observed for HFNC flows between 30 and 40 L/min but with individual variability.

Conclusion: Measuring mean inspiratory flow during an SBT allows for individualised setting of HFNC flow rate immediately post-extubation and achieves the greatest comfort and interface tolerance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jcrc.2020.12.022DOI Listing
June 2021

Immunological Subpopulations Within Critically Ill COVID-19 Patients.

Chest 2021 05 18;159(5):1706-1708. Epub 2021 Feb 18.

School of Immunology & Microbial Sciences (J. Wilson and M. Shankar-Hari), Kings College London, London, England; Guy's and St Thomas' NHS Foundation Trust (M. Shankar-Hari), ICU Support Offices, St Thomas' Hospital, London, England. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.chest.2021.01.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889441PMC
May 2021

Sepsis Subclasses: A Framework for Development and Interpretation.

Crit Care Med 2021 May;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.
View Article and Find Full Text PDF

Download full-text PDF

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

Impact of the B.1.1.7 variant on neutralizing monoclonal antibodies recognizing diverse epitopes on SARS-CoV-2 Spike.

bioRxiv 2021 Feb 3. Epub 2021 Feb 3.

The interaction of the SARS-CoV-2 Spike receptor binding domain (RBD) with the ACE2 receptor on host cells is essential for viral entry. RBD is the dominant target for neutralizing antibodies and several neutralizing epitopes on RBD have been molecularly characterized. Analysis of circulating SARS-CoV-2 variants has revealed mutations arising in the RBD, the N-terminal domain (NTD) and S2 subunits of Spike. To fully understand how these mutations affect the antigenicity of Spike, we have isolated and characterized neutralizing antibodies targeting epitopes beyond the already identified RBD epitopes. Using recombinant Spike as a sorting bait, we isolated >100 Spike-reactive monoclonal antibodies from SARS-CoV-2 infected individuals. ≈45% showed neutralizing activity of which ≈20% were NTD-specific. None of the S2-specific antibodies showed neutralizing activity. Competition ELISA revealed that NTD-specific mAbs formed two distinct groups: the first group was highly potent against infectious virus, whereas the second was less potent and displayed glycan-dependant neutralization activity. Importantly, mutations present in B.1.1.7 Spike frequently conferred resistance to neutralization by the NTD-specific neutralizing antibodies. This work demonstrates that neutralizing antibodies targeting subdominant epitopes need to be considered when investigating antigenic drift in emerging variants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/2021.02.03.429355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872354PMC
February 2021

Utilising mass cytometry with CD45 barcoding and standardised leucocyte phenotyping for immune trajectory assessment in critically ill patients.

Br J Anaesth 2021 04 3;126(4):e149-e152. Epub 2021 Feb 3.

Department of Infectious Diseases, School of Immunology and Microbial Sciences, King's College London, London, UK; Department of Intensive Care Medicine, Guy's and St Thomas' NHS Foundation Trust, London, UK. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bja.2021.01.006DOI Listing
April 2021

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

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

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

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

Download full-text PDF

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

Current Understanding of Leukocyte Phenotypic and Functional Modulation During Extracorporeal Membrane Oxygenation: A Narrative Review.

Front Immunol 2020 8;11:600684. Epub 2021 Jan 8.

Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia.

A plethora of leukocyte modulations have been reported in critically ill patients. Critical illnesses such as acute respiratory distress syndrome and cardiogenic shock, which potentially require extracorporeal membrane oxygenation (ECMO) support, are associated with changes in leukocyte numbers, phenotype, and functions. The changes observed in these illnesses could be compounded by exposure of blood to the non-endothelialized surfaces and non-physiological conditions of ECMO. This can result in further leukocyte activation, increased platelet-leukocyte interplay, pro-inflammatory and pro-coagulant state, alongside features of immunosuppression. However, the effects of ECMO on leukocytes, in particular their phenotypic and functional signatures, remain largely overlooked, including whether these changes have attributable mortality and morbidity. The aim of our narrative review is to highlight the importance of studying leukocyte signatures to better understand the development of complications associated with ECMO. Increased knowledge and appreciation of their probable role in ECMO-related adverse events may assist in guiding the design and establishment of targeted preventative actions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2020.600684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821656PMC
June 2021

Genetic mechanisms of critical illness in COVID-19.

Nature 2021 03 11;591(7848):92-98. Epub 2020 Dec 11.

Intensive Care Unit, Royal Infirmary of Edinburgh, Edinburgh, UK.

Host-mediated lung inflammation is present, and drives mortality, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-020-03065-yDOI Listing
March 2021

Trends in Intensive Care for Patients with COVID-19 in England, Wales, and Northern Ireland.

Am J Respir Crit Care Med 2021 03;203(5):565-574

Clinical Trials Unit, Intensive Care National Audit & Research Centre, London, United Kingdom.

By describing trends in intensive care for patients with coronavirus disease (COVID-19) we aim to support clinical learning, service planning, and hypothesis generation. To describe variation in ICU admission rates over time and by geography during the first wave of the epidemic in England, Wales, and Northern Ireland; to describe trends in patient characteristics on admission to ICU, first-24-hours physiology in ICU, processes of care in ICU and patient outcomes; and to explore deviations in trends during the peak period. A cohort of 10,741 patients with COVID-19 in the Case Mix Program national clinical audit from February 1 to July 31, 2020, was used. Analyses were stratified by time period (prepeak, peak, and postpeak periods) and geographical region. Logistic regression was used to estimate adjusted differences in 28-day in-hospital mortality between periods. Admissions to ICUs peaked almost simultaneously across regions but varied 4.6-fold in magnitude. Compared with patients admitted in the prepeak period, patients admitted in the postpeak period were slightly younger but with higher degrees of dependency and comorbidity on admission to ICUs and more deranged first-24-hours physiology. Despite this, receipt of invasive ventilation and renal replacement therapy decreased, and adjusted 28-day in-hospital mortality was reduced by 11.8% (95% confidence interval, 8.7%-15.0%). Many variables exhibited u-shaped or n-shaped curves during the peak. The population of patients with COVID-19 admitted to ICUs, and the processes of care in ICUs, changed over the first wave of the epidemic. After adjustment for important risk factors, there was a substantial improvement in patient outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1164/rccm.202008-3212OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924583PMC
March 2021

A Proteomics-Based Assessment of Inflammation Signatures in Endotoxemia.

Mol Cell Proteomics 2021 Feb 24;20:100021. Epub 2021 Feb 24.

King's College London British Heart Foundation Centre, School of Cardiovascular Medicine and Sciences, London, United Kingdom. Electronic address:

We have previously shown that multimers of plasma pentraxin-3 (PTX3) were predictive of survival in patients with sepsis. To characterize the release kinetics and cellular source of plasma protein changes in sepsis, serial samples were obtained from healthy volunteers (n = 10; three time points) injected with low-dose endotoxin (lipopolysaccharide [LPS]) and analyzed using data-independent acquisition MS. The human plasma proteome response was compared with an LPS-induced endotoxemia model in mice. Proteomic analysis of human plasma revealed a rapid neutrophil degranulation signature, followed by a rise in acute phase proteins. Changes in circulating PTX3 correlated with increases in neutrophil-derived proteins following LPS injection. Time course analysis of the plasma proteome in mice showed a time-dependent increase in multimeric PTX3, alongside increases in neutrophil-derived myeloperoxidase (MPO) upon LPS treatment. The mechanisms of oxidation-induced multimerization of PTX3 were explored in two genetic mouse models: MPO global knock-out (KO) mice and LysM Cre Nox2 KO mice, in which NADPH oxidase 2 (Nox2) is only deficient in myeloid cells. Nox2 is the enzyme responsible for the oxidative burst in neutrophils. Increases in plasma multimeric PTX3 were not significantly different between wildtype and MPO or LysM Cre Nox2 KO mice. Thus, PTX3 may already be stored and released in a multimeric form. Through in vivo neutrophil depletion and multiplexed vascular proteomics, PTX3 multimer deposition within the aorta was confirmed to be neutrophil dependent. Proteomic analysis of aortas from LPS-injected mice returned PTX3 as the most upregulated protein, where multimeric PTX3 was deposited as early as 2 h post-LPS along with other neutrophil-derived proteins. In conclusion, the rise in multimeric PTX3 upon LPS injection correlates with neutrophil-related protein changes in plasma and aortas. MPO and myeloid Nox2 are not required for the multimerization of PTX3; instead, neutrophil extravasation is responsible for the LPS-induced deposition of multimeric PTX3 in the aorta.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1074/mcp.RA120.002305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7950208PMC
February 2021

Using Bayesian Methods to Augment the Interpretation of Critical Care Trials. An Overview of Theory and Example Reanalysis of the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial.

Am J Respir Crit Care Med 2021 03;203(5):543-552

PAIR (Palliative and Advanced Illness Research) Center Clinical Trials Methods and Outcomes Lab.

Most randomized trials are designed and analyzed using frequentist statistical approaches such as null hypothesis testing and values. Conceptually, values are cumbersome to understand, as they provide evidence of data incompatibility with a null hypothesis (e.g., no clinical benefit) and not direct evidence of the alternative hypothesis (e.g., clinical benefit). This counterintuitive framework may contribute to the misinterpretation that the absence of evidence is equal to evidence of absence and may cause the discounting of potentially informative data. Bayesian methods provide an alternative, probabilistic interpretation of data. The reanalysis of completed trials using Bayesian methods is becoming increasingly common, particularly for trials with effect estimates that appear clinically significant despite values above the traditional threshold of 0.05. Statistical inference using Bayesian methods produces a distribution of effect sizes that would be compatible with observed trial data, interpreted in the context of prior assumptions about an intervention (called "priors"). These priors are chosen by investigators to reflect existing beliefs and past empirical evidence regarding the effect of an intervention. By calculating the likelihood of clinical benefit, a Bayesian reanalysis can augment the interpretation of a trial. However, if priors are not defined , there is a legitimate concern that priors could be constructed in a manner that produces biased results. Therefore, some standardization of priors for Bayesian reanalysis of clinical trials may be desirable for the critical care community. In this Critical Care Perspective, we discuss both frequentist and Bayesian approaches to clinical trial analysis, introduce a framework that researchers can use to select priors for a Bayesian reanalysis, and demonstrate how to apply our proposal by conducting a novel Bayesian trial reanalysis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1164/rccm.202006-2381CPDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924582PMC
March 2021

Prognostic Factors for 30-Day Mortality in Critically Ill Patients With Coronavirus Disease 2019: An Observational Cohort Study.

Crit Care Med 2021 01;49(1):102-111

Intensive Care National Audit & Research Centre (ICNARC), London, United Kingdom.

Objectives: To identify characteristics that predict 30-day mortality among patients critically ill with coronavirus disease 2019 in England, Wales, and Northern Ireland.

Design: Observational cohort study.

Setting: A total of 258 adult critical care units.

Patients: A total of 10,362 patients with confirmed coronavirus disease 2019 with a start of critical care between March 1, 2020, and June 22, 2020, of whom 9,990 were eligible (excluding patients with a duration of critical care less than 24 hr or missing core variables).

Measurements And Main Results: The main outcome measure was time to death within 30 days of the start of critical care. Of 9,990 eligible patients (median age 60 yr, 70% male), 3,933 died within 30 days of the start of critical care. As of July 22, 2020, 189 patients were still receiving critical care and a further 446 were still in acute hospital. Data were missing for between 0.1% and 7.2% of patients across prognostic factors. We imputed missing data ten-fold, using fully conditional specification and continuous variables were modeled using restricted cubic splines. Associations between the candidate prognostic factors and time to death within 30 days of the start of critical care were determined after adjustment for multiple variables with Cox proportional hazards modeling. Significant associations were identified for age, ethnicity, deprivation, body mass index, prior dependency, immunocompromise, lowest systolic blood pressure, highest heart rate, highest respiratory rate, Pao2/Fio2 ratio (and interaction with mechanical ventilation), highest blood lactate concentration, highest serum urea, and lowest platelet count over the first 24 hours of critical care. Nonsignificant associations were found for sex, sedation, highest temperature, and lowest hemoglobin concentration.

Conclusions: We identified patient characteristics that predict an increased likelihood of death within 30 days of the start of critical care for patients with coronavirus disease 2019. These findings may support development of a prediction model for benchmarking critical care providers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/CCM.0000000000004740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737692PMC
January 2021

Longitudinal observation and decline of neutralizing antibody responses in the three months following SARS-CoV-2 infection in humans.

Nat Microbiol 2020 12 26;5(12):1598-1607. Epub 2020 Oct 26.

Centre for Clinical Infection and Diagnostics Research, Department of Infectious Diseases, Guy's and St Thomas' NHS Foundation Trust, London, UK.

Antibody responses to SARS-CoV-2 can be detected in most infected individuals 10-15 d after the onset of COVID-19 symptoms. However, due to the recent emergence of SARS-CoV-2 in the human population, it is not known how long antibody responses will be maintained or whether they will provide protection from reinfection. Using sequential serum samples collected up to 94 d post onset of symptoms (POS) from 65 individuals with real-time quantitative PCR-confirmed SARS-CoV-2 infection, we show seroconversion (immunoglobulin (Ig)M, IgA, IgG) in >95% of cases and neutralizing antibody responses when sampled beyond 8 d POS. We show that the kinetics of the neutralizing antibody response is typical of an acute viral infection, with declining neutralizing antibody titres observed after an initial peak, and that the magnitude of this peak is dependent on disease severity. Although some individuals with high peak infective dose (ID > 10,000) maintained neutralizing antibody titres >1,000 at >60 d POS, some with lower peak ID had neutralizing antibody titres approaching baseline within the follow-up period. A similar decline in neutralizing antibody titres was observed in a cohort of 31 seropositive healthcare workers. The present study has important implications when considering widespread serological testing and antibody protection against reinfection with SARS-CoV-2, and may suggest that vaccine boosters are required to provide long-lasting protection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41564-020-00813-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610833PMC
December 2020

Paediatric Inflammatory Multisystem Syndrome Temporally-Associated with SARS-CoV-2 Infection: An Overview.

Intensive Care Med 2021 01 14;47(1):90-93. Epub 2020 Oct 14.

Department of Women and Children's Health, School of Life Course Sciences, King's College London, London, UK.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00134-020-06273-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556601PMC
January 2021

COVID-19 in critical care: epidemiology of the first epidemic wave across England, Wales and Northern Ireland.

Intensive Care Med 2020 11 9;46(11):2035-2047. Epub 2020 Oct 9.

Intensive Care National Audit and Research Centre (ICNARC), Napier House, 24 High Holborn, London, WC1V 6AZ, UK.

Purpose: To describe critical care patients with COVID-19 across England, Wales and Northern Ireland and compare them with a historic cohort of patients with other viral pneumonias (non-COVID-19) and with international cohorts of COVID-19.

Methods: Extracted data on patient characteristics, acute illness severity, organ support and outcomes from the Case Mix Programme, the national clinical audit for adult critical care, for a prospective cohort of patients with COVID-19 (February to August 2020) are compared with a recent retrospective cohort of patients with other viral pneumonias (non-COVID-19) (2017-2019) and with other international cohorts of critical care patients with COVID-19, the latter identified from published reports.

Results: 10,834 patients with COVID-19 (70.1% male, median age 60 years, 32.6% non-white ethnicity, 39.4% obese, 8.2% at least one serious comorbidity) were admitted across 289 critical care units. Of these, 36.9% had a PaO/FiO ratio of ≤ 13.3 kPa (≤ 100 mmHg) consistent with severe ARDS and 72% received invasive ventilation. Acute hospital mortality was 42%, higher than for 5782 critical care patients with other viral pneumonias (non-COVID-19) (24.7%), and most COVID-19 deaths (88.7%) occurred before 30 days. Meaningful international comparisons were limited due to lack of standardised reporting.

Conclusion: Critical care patients with COVID-19 were disproportionately non-white, from more deprived areas and more likely to be male and obese. Conventional severity scoring appeared not to adequately reflect their acute severity, with the distribution across PaO/FiO ratio categories indicating acutely severe respiratory disease. Critical care patients with COVID-19 experience high mortality and place a great burden on critical care services.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00134-020-06267-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545019PMC
November 2020

Translational Research in the Time of COVID-19-Dissolving Boundaries.

PLoS Pathog 2020 09 30;16(9):e1008898. Epub 2020 Sep 30.

Centre for Clinical Infection and Diagnostics Research, Department of Infectious Diseases, School of Immunology and Microbial Sciences, King's College London, London, United Kingdom.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.ppat.1008898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526890PMC
September 2020

Outcomes in mechanically ventilated patients with hypoxaemic respiratory failure caused by COVID-19.

Br J Anaesth 2020 12 3;125(6):e480-e483. Epub 2020 Sep 3.

Guy's and St Thomas' NHS Foundation Trust, St Thomas' Hospital, London, UK; School of Immunology & Microbial Sciences, King's College London, London, UK.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bja.2020.08.047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470709PMC
December 2020

Development, Validation, and Clinical Utility Assessment of a Prognostic Score for 1-Year Unplanned Rehospitalization or Death of Adult Sepsis Survivors.

JAMA Netw Open 2020 09 1;3(9):e2013580. Epub 2020 Sep 1.

Intensive Care National Audit & Research Centre, Napier House, London, United Kingdom.

Importance: The longer-term risk of rehospitalizations and death of adult sepsis survivors is associated with index sepsis illness characteristics.

Objective: To derive and validate a parsimonious prognostic score for unplanned rehospitalizations or death in the first year after hospital discharge of adult sepsis survivors.

Design, Setting, And Participants: This cohort study used data from the Intensive Care National Audit & Research Centre Case Mix Programme database on adult sepsis survivors identified from consecutive critical care admissions to 192 adult general critical care units in England, United Kingdom, between April 1, 2009, and March 31, 2014 (94 748 patients in the derivation cohort), and between April 1, 2014, and March 31, 2015 (24 669 patients in the validation cohort). Statistical analysis was performed from July 5 to October 31, 2019. Generic characteristics (age, sex, race/ethnicity, 2015 Index of Multiple Deprivation [IMD2015] in England quintiles, preadmission dependence, previous hospitalizations in the year preceding index sepsis admission, comorbidity, admission type, Acute Physiology and Chronic Health Evaluation II physiology score, hospital length of stay, worst blood lactate and blood hemoglobin concentrations, and type of hospital) and sepsis-specific characteristics (site of infection, numbers of organ dysfunctions, and organ support) at the index sepsis admission were used as predictors.

Main Outcomes And Measures: Prognostic score derived and validated using multivariable logistic regression for the outcome of unplanned rehospitalization or death in the first year after hospital discharge of adult sepsis survivors, as well as clinical usefulness assessed using decision curve analysis. Prognostic score validation was performed for internal validation with bootstrapping and temporal cohort external validation.

Results: This cohort study included 94 748 patients (51 164 men [54.0%]; mean [SD] age, 61.3 [17.0] years) in the derivation cohort and 24 669 patients (13 255 men [53.7%]; mean [SD] age, 62.1 [16.8%]) in the validation cohort. Unplanned rehospitalization or death in the first year after hospital discharge occurred for 48 594 patients (51.3%) in the derivation cohort and 13 129 patients (53.2%) in the validation cohort. Eight independent predictors were identified and weighted to generate a prognostic score for every patient: previous hospitalizations, age in 10-year increments, IMD2015 in England quintiles, preadmission dependence, comorbidities, admission type, blood hemoglobin level, and site of infection. The total prognostic score ranged from 0 to 22 points, with lower scores indicating a lower risk of the outcome. The derivation and validation cohorts had similar rates of prognostic scores of 0 to 4 points (5088 of 16 684 patients [30.5%] and 471 of 1725 patients [27.3%]) and prognostic scores of 11 points or more (15 732 of 21 641 patients [72.7%] and 5753 of 7952 patients [72.3%]). The area under the receiver operating characteristic curve for the prognostic score was 0.675 (95% CI, 0.672-0.679). The decision curve analysis highlighted an optimal score cutoff of 7 points or more.

Conclusions And Relevance: The prognostic score reported in this study uses 8 internationally feasible predictors measured during the index sepsis admission and provides clinically useful information on sepsis survivors' risk of unplanned rehospitalization or death in the first year after hospital discharge.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamanetworkopen.2020.13580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490647PMC
September 2020