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2.
JCI Insight ; 7(13)2022 Jul 08.
Article in English | MEDLINE | ID: covidwho-1861743

ABSTRACT

The role of immune responses to previously seen endemic coronavirus epitopes in severe acute respiratory coronavirus 2 (SARS-CoV-2) infection and disease progression has not yet been determined. Here, we show that a key characteristic of fatal outcomes with coronavirus disease 2019 (COVID-19) is that the immune response to the SARS-CoV-2 spike protein is enriched for antibodies directed against epitopes shared with endemic beta-coronaviruses and has a lower proportion of antibodies targeting the more protective variable regions of the spike. The magnitude of antibody responses to the SARS-CoV-2 full-length spike protein, its domains and subunits, and the SARS-CoV-2 nucleocapsid also correlated strongly with responses to the endemic beta-coronavirus spike proteins in individuals admitted to an intensive care unit (ICU) with fatal COVID-19 outcomes, but not in individuals with nonfatal outcomes. This correlation was found to be due to the antibody response directed at the S2 subunit of the SARS-CoV-2 spike protein, which has the highest degree of conservation between the beta-coronavirus spike proteins. Intriguingly, antibody responses to the less cross-reactive SARS-CoV-2 nucleocapsid were not significantly different in individuals who were admitted to an ICU with fatal and nonfatal outcomes, suggesting an antibody profile in individuals with fatal outcomes consistent with an "original antigenic sin" type response.


Subject(s)
COVID-19 , Spike Glycoprotein, Coronavirus , Antibodies, Viral , Antibody Formation , Epitopes , Humans , SARS-CoV-2
3.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-321804

ABSTRACT

Background: Reports indicate that COVID-19 patients have more bloodstream infections (BSI) on the intensive care unit (ICU) potentially due to lapses in infection control practice or other factors.Methods: Retrospective single-site study of ICU-BSIs in mechanically ventilated (MV) COVID-19 patients during the first pandemic year. Clinical, demographic and laboratory data including targeted pathogen genome sequencing was analysed during first (March 13th - May 31st 2020) and second (October 1st 2020 - March 15th 2021) pandemic waves.Findings: There were 305 MV-ICU patients in wave one and 440 in wave two with peak occupancy of 113 and 155 patients, respectively. The BSI rate was higher during both waves than pre-pandemic, but more in wave-two than wave-one, particularly during the first 28 days on ICU (14.1 vs. 9.4/1000 bed days;p=0.03) and with E. faecium (3.57 vs. 0.47/1000 bed days;p=0.0067). 22/28 (77%) of E. faecium BSIs had no microbiologically definable focus and the high wave-two rate could not be explained by transmission. Wave-two BSI-patients received more corticosteroids and tocilizumab and had higher crude hospital mortality compared with non-BSI patients (41% vs. 21% p<0.0001), a phenomenon not seen in wave one (32% vs. 27% p=0.551). Interpretation: MV-COVID-19 patients had a greater BSI-burden in wave two associated with the emergence of primary endogenous E. faecium. Identifying mechanisms and causal links between admission COVID-19 disease severity, immunomodulation, BSI and death could help identify new approaches to improving outcomes for COVID-19 patients.

4.
Genome Med ; 13(1): 182, 2021 11 17.
Article in English | MEDLINE | ID: covidwho-1523323

ABSTRACT

BACKGROUND: Clinical metagenomics (CMg) has the potential to be translated from a research tool into routine service to improve antimicrobial treatment and infection control decisions. The SARS-CoV-2 pandemic provides added impetus to realise these benefits, given the increased risk of secondary infection and nosocomial transmission of multi-drug-resistant (MDR) pathogens linked with the expansion of critical care capacity. METHODS: CMg using nanopore sequencing was evaluated in a proof-of-concept study on 43 respiratory samples from 34 intubated patients across seven intensive care units (ICUs) over a 9-week period during the first COVID-19 pandemic wave. RESULTS: An 8-h CMg workflow was 92% sensitive (95% CI, 75-99%) and 82% specific (95% CI, 57-96%) for bacterial identification based on culture-positive and culture-negative samples, respectively. CMg sequencing reported the presence or absence of ß-lactam-resistant genes carried by Enterobacterales that would modify the initial guideline-recommended antibiotics in every case. CMg was also 100% concordant with quantitative PCR for detecting Aspergillus fumigatus from 4 positive and 39 negative samples. Molecular typing using 24-h sequencing data identified an MDR-K. pneumoniae ST307 outbreak involving 4 patients and an MDR-C. striatum outbreak involving 14 patients across three ICUs. CONCLUSION: CMg testing provides accurate pathogen detection and antibiotic resistance prediction in a same-day laboratory workflow, with assembled genomes available the next day for genomic surveillance. The provision of this technology in a service setting could fundamentally change the multi-disciplinary team approach to managing ICU infections. The potential to improve the initial targeted treatment and rapidly detect unsuspected outbreaks of MDR-pathogens justifies further expedited clinical assessment of CMg.


Subject(s)
COVID-19/pathology , Cross Infection/transmission , Metagenomics , Anti-Bacterial Agents/therapeutic use , COVID-19/virology , Coinfection/drug therapy , Coinfection/microbiology , Corynebacterium/genetics , Corynebacterium/isolation & purification , Cross Infection/microbiology , DNA, Bacterial/chemistry , DNA, Bacterial/metabolism , Drug Resistance, Multiple, Bacterial/genetics , Female , Humans , Intensive Care Units , Klebsiella pneumoniae/genetics , Klebsiella pneumoniae/isolation & purification , Male , Middle Aged , Polymorphism, Single Nucleotide , SARS-CoV-2/isolation & purification , Sequence Analysis, DNA , beta-Lactamases/genetics
5.
PLoS Pathog ; 17(9): e1009804, 2021 09.
Article in English | MEDLINE | ID: covidwho-1416909

ABSTRACT

Prior studies have demonstrated that immunologic dysfunction underpins severe illness in COVID-19 patients, but have lacked an in-depth analysis of the immunologic drivers of death in the most critically ill patients. We performed immunophenotyping of viral antigen-specific and unconventional T cell responses, neutralizing antibodies, and serum proteins in critically ill patients with SARS-CoV-2 infection, using influenza infection, SARS-CoV-2-convalescent health care workers, and healthy adults as controls. We identify mucosal-associated invariant T (MAIT) cell activation as an independent and significant predictor of death in COVID-19 (HR = 5.92, 95% CI = 2.49-14.1). MAIT cell activation correlates with several other mortality-associated immunologic measures including broad activation of CD8+ T cells and non-Vδ2 γδT cells, and elevated levels of cytokines and chemokines, including GM-CSF, CXCL10, CCL2, and IL-6. MAIT cell activation is also a predictor of disease severity in influenza (ECMO/death HR = 4.43, 95% CI = 1.08-18.2). Single-cell RNA-sequencing reveals a shift from focused IFNα-driven signals in COVID-19 ICU patients who survive to broad pro-inflammatory responses in fatal COVID-19 -a feature not observed in severe influenza. We conclude that fatal COVID-19 infection is driven by uncoordinated inflammatory responses that drive a hierarchy of T cell activation, elements of which can serve as prognostic indicators and potential targets for immune intervention.


Subject(s)
COVID-19/immunology , COVID-19/mortality , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Antigens, CD/immunology , Antigens, Differentiation, T-Lymphocyte/immunology , B-Lymphocytes/immunology , Biomarkers/blood , Blood Proteins/metabolism , Cohort Studies , Critical Illness/mortality , Female , Humans , Immunophenotyping , Influenza, Human/immunology , Lectins, C-Type/immunology , Lymphocyte Activation , Male , Middle Aged , Mucosal-Associated Invariant T Cells/immunology , Patient Acuity
6.
J Infect ; 83(2): 167-174, 2021 08.
Article in English | MEDLINE | ID: covidwho-1271692

ABSTRACT

OBJECTIVES: Assess the feasibility and impact of nanopore-based 16S rRNA gene sequencing (Np16S) service on antibiotic treatment for acute severe pneumonia on the intensive care unit (ICU). METHODS: Speciation and sequencing accuracy of Np16S on isolates with bioinformatics pipeline optimisation, followed by technical evaluation including quality checks and clinical-reporting criteria analysing stored respiratory samples using single-sample flow cells. Pilot service comparing Np16S results with all routine respiratory tests and impact on same-day antimicrobial prescribing. RESULTS: Np16S correctly identified 140/167 (84%) isolates after 1h sequencing and passed quality control criteria including reproducibility and limit-of-detection. Sequencing of 108 stored respiratory samples showed concordance with routine culture in 80.5% of cases and established technical and clinical reporting criteria. A 10-week same-day pilot Np16S service analysed 45 samples from 37 patients with suspected community (n=15) or hospital acquired (n=30) pneumonia. Np16S showed concordance compared with all routine culture or molecular tests for 27 (82%) of 33 positive samples. It identified the causative pathogen in 32/33 (97%) samples and contributed to antimicrobial treatment changes for 30 patients (67%). CONCLUSIONS: This study demonstrates feasibility of providing a routine same-day nanopore sequencing service that makes a significant contribution to early antibiotic prescribing for bacterial pneumonia in the ICU.


Subject(s)
Nanopores , Genes, rRNA , Humans , Intensive Care Units , RNA, Ribosomal, 16S/genetics , Reproducibility of Results
7.
Crit Care Explor ; 2(11): e0279, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-939582

ABSTRACT

OBJECTIVES: To propose the optimal timing to consider tracheostomy insertion for weaning of mechanically ventilated patients recovering from coronavirus disease 2019 pneumonia. We investigated the relationship between duration of mechanical ventilation prior to tracheostomy insertion and in-hospital mortality. In addition, we present a machine learning approach to facilitate decision-making. DESIGN: Prospective cohort study. SETTING: Guy's & St Thomas' Hospital, London, United Kingdom. PATIENTS: Consecutive patients admitted with acute respiratory failure secondary to coronavirus disease 2019 requiring mechanical ventilation between March 3, 2020, and May 5, 2020. INTERVENTIONS: Baseline characteristics and temporal trends in markers of disease severity were prospectively recorded. Tracheostomy was performed for anticipated prolonged ventilatory wean when levels of respiratory support were favorable. Decision tree was constructed using C4.5 algorithm, and its classification performance has been evaluated by a leave-one-out cross-validation technique. MEASUREMENTS AND MAIN RESULTS: One-hundred seventy-six patients required mechanical ventilation for acute respiratory failure, of which 87 patients (49.4%) underwent tracheostomy. We identified that optimal timing for tracheostomy insertion is between day 13 and day 17. Presence of fibrosis on CT scan (odds ratio, 13.26; 95% CI [3.61-48.91]; p ≤ 0.0001) and Pao2:Fio2 ratio (odds ratio, 0.98; 95% CI [0.95-0.99]; p = 0.008) were independently associated with tracheostomy insertion. Cox multiple regression analysis showed that chronic obstructive pulmonary disease (hazard ratio, 6.56; 95% CI [1.04-41.59]; p = 0.046), ischemic heart disease (hazard ratio, 4.62; 95% CI [1.19-17.87]; p = 0.027), positive end-expiratory pressure (hazard ratio, 1.26; 95% CI [1.02-1.57]; p = 0.034), Pao2:Fio2 ratio (hazard ratio, 0.98; 95% CI [0.97-0.99]; p = 0.003), and C-reactive protein (hazard ratio, 1.01; 95% CI [1-1.01]; p = 0.005) were independent late predictors of in-hospital mortality. CONCLUSIONS: We propose that the optimal window for consideration of tracheostomy for ventilatory weaning is between day 13 and 17. Late predictors of mortality may serve as adverse factors when considering tracheostomy, and our decision tree provides a degree of decision support for clinicians.

8.
Eur Arch Otorhinolaryngol ; 278(5): 1595-1604, 2021 May.
Article in English | MEDLINE | ID: covidwho-692740

ABSTRACT

PURPOSE: COVID-19 patients requiring mechanical ventilation can overwhelm existing bed capacity. We aimed to better understand the factors that influence the trajectory of tracheostomy care in this population to facilitate capacity planning and improve outcomes. METHODS: We conducted an observational cohort study of patients in a high-volume centre in the worst-affected region of the UK including all patients that underwent tracheostomy for COVID-19 pneumonitis ventilatory wean from 1st March 2020 to 10th May 2020. The primary outcome was time from insertion to decannulation. The analysis utilised Cox regression to account for patients that are still progressing through their tracheostomy pathway. RESULTS: At the point of analysis, a median 21 days (IQR 15-28) post-tracheostomy and 39 days (IQR 32-45) post-intubation, 35/69 (57.4%) patients had been decannulated a median of 17 days (IQR 12-20.5) post-insertion. The overall median age was 55 (IQR 48-61) with a male-to-female ratio of 2:1. In Cox regression analysis, FiO2 at tracheostomy ≥ 0.4 (HR 1.80; 95% CI 0.89-3.60; p = 0.048) and last pre-tracheostomy peak cough flow (HR 2.27; 95% CI 1.78-4.45; p = 0.001) were independent variables associated with prolonged time to decannulation. CONCLUSION: Higher FiO2 at tracheostomy and higher pre-tracheostomy peak cough flow are associated with increased delay in COVID-19 tracheostomy patient decannulation. These finding comprise the most comprehensive report of COVID-19 tracheostomy decannulation to date and will assist service planning for future peaks of this pandemic.


Subject(s)
COVID-19 , Tracheostomy , Device Removal , Female , Humans , Male , Middle Aged , Respiration, Artificial , SARS-CoV-2
10.
Eur Arch Otorhinolaryngol ; 277(8): 2173-2184, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-88519

ABSTRACT

PURPOSE: The COVID-19 pandemic is placing unprecedented demand upon critical care services for invasive mechanical ventilation. There is current uncertainty regarding the role of tracheostomy for weaning ventilated patients with COVID-19 pneumonia. This is due to a number of factors including prognosis, optimal healthcare resource utilisation, and safety of healthcare workers when performing such a high-risk aerosol-generating procedure. METHODS: Literature review and proposed practical guideline based on the experience of a tertiary healthcare institution with 195 critical care admissions for COVID-19 up until 4th April 2020. RESULTS: A synthesis of the current international literature and reported experience is presented with respect to prognosis, viral load and staff safety, thus leading to a pragmatic recommendation that tracheostomy is not performed until at least 14 days after endotracheal intubation in COVID-19 patients. Practical steps to minimise aerosol generation in percutaneous tracheostomy are outlined and we describe the process and framework for setting up a dedicated tracheostomy team. CONCLUSION: In selected COVID-19 patients, there is a role for tracheostomy to aid in weaning and optimise healthcare resource utilisation. Both percutaneous and open techniques can be performed safely with careful modifications to technique and appropriate enhanced personal protective equipment. ORL-HNS surgeons can play a valuable role in forming tracheostomy teams to support critical care teams during this global pandemic.


Subject(s)
Infectious Disease Transmission, Patient-to-Professional/prevention & control , Intubation, Intratracheal , Practice Guidelines as Topic , Respiration, Artificial , Tracheostomy/methods , Aerosols , Betacoronavirus , COVID-19 , Coronavirus Infections/epidemiology , Coronavirus Infections/prevention & control , Coronavirus Infections/transmission , Humans , Intubation, Intratracheal/standards , Pandemics/prevention & control , Personal Protective Equipment , Pneumonia, Viral/epidemiology , Pneumonia, Viral/prevention & control , Pneumonia, Viral/transmission , Respiration, Artificial/standards , SARS-CoV-2 , Tracheostomy/standards
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