ORCID Profile
0009-0003-7054-9939
Current Organisation
University of Manchester
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Publisher: American Medical Association (AMA)
Date: 05-04-2022
Publisher: Elsevier BV
Date: 08-2023
Publisher: Springer Science and Business Media LLC
Date: 07-03-2022
DOI: 10.1038/S41586-022-04576-6
Abstract: Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care 1 or hospitalization 2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from in iduals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill in iduals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling ( IL10RB and PLSCR1 ), leucocyte differentiation ( BCL11A ) and blood-type antigen secretor status ( FUT2 ). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase ( ATP11A ), and increased expression of a mucin ( MUC1 )—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules ( SELE , ICAM5 and CD209 ) and the coagulation factor F8 , all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease.
Publisher: Elsevier BV
Date: 05-2023
Publisher: American Medical Association (AMA)
Date: 11-04-2023
Abstract: Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor n = 10), or no RAS inhibitor (control n = 264) for up to 10 days. The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. ClinicalTrials.gov Identifier: NCT02735707
Publisher: Elsevier BV
Date: 05-2021
Publisher: Cold Spring Harbor Laboratory
Date: 16-10-2020
DOI: 10.1101/2020.10.10.20207449
Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection resulting in the clinical syndrome COVID-19 is associated with an exaggerated immune response and monocyte infiltrates in the lungs and other peripheral tissues. It is now increasingly recognised that chronic morbidity persists in some patients. We recently demonstrated profound alterations of monocytes in hospitalised COVID-19 patients. It is currently unclear whether these abnormalities resolve or progress following patient discharge. We show here that blood monocytes in convalescent patients at their 12 week follow up, have a greater propensity to produce pro-inflammatory cytokines TNFα and IL-6, which was consistently higher in patients with resolution of lung injury as indicated by a normal chest X-ray and no shortness of breath (a key symptom of lung injury). Furthermore, monocytes from convalescent patients also displayed enhanced levels of molecules involved in leucocyte migration, including chemokine receptor CXCR6, adhesion molecule CD31/PECAM and integrins VLA-4 and LFA-1. Expression of migration molecules on monocytes was also consistently higher in convalescent patients with a normal chest X-ray. These data suggest persistent changes in innate immune function following recovery from COVID-19 and indicate that immune modulating therapies targeting monocytes and leucocyte migration may be useful in recovering COVID-19 patients with persistent symptoms.
Publisher: Springer Science and Business Media LLC
Date: 06-09-2023
Publisher: Elsevier BV
Date: 05-2021
Publisher: Springer Science and Business Media LLC
Date: 11-07-2023
Publisher: Elsevier BV
Date: 10-2023
Publisher: Springer Science and Business Media LLC
Date: 08-07-2021
DOI: 10.1038/S41586-021-03767-X
Abstract: The genetic make-up of an in idual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.
Publisher: American Medical Association (AMA)
Date: 02-11-2021
Publisher: Elsevier BV
Date: 07-2022
Publisher: American Medical Association (AMA)
Date: 25-10-2023
Publisher: American Medical Association (AMA)
Date: 03-01-2023
Abstract: The longer-term effects of therapies for the treatment of critically ill patients with COVID-19 are unknown. To determine the effect of multiple interventions for critically ill adults with COVID-19 on longer-term outcomes. Prespecified secondary analysis of an ongoing adaptive platform trial (REMAP-CAP) testing interventions within multiple therapeutic domains in which 4869 critically ill adult patients with COVID-19 were enrolled between March 9, 2020, and June 22, 2021, from 197 sites in 14 countries. The final 180-day follow-up was completed on March 2, 2022. Patients were randomized to receive 1 or more interventions within 6 treatment domains: immune modulators (n = 2274), convalescent plasma (n = 2011), antiplatelet therapy (n = 1557), anticoagulation (n = 1033), antivirals (n = 726), and corticosteroids (n = 401). The main outcome was survival through day 180, analyzed using a bayesian piecewise exponential model. A hazard ratio (HR) less than 1 represented improved survival (superiority), while an HR greater than 1 represented worsened survival (harm) futility was represented by a relative improvement less than 20% in outcome, shown by an HR greater than 0.83. Among 4869 randomized patients (mean age, 59.3 years 1537 [32.1%] women), 4107 (84.3%) had known vital status and 2590 (63.1%) were alive at day 180. IL-6 receptor antagonists had a greater than 99.9% probability of improving 6-month survival (adjusted HR, 0.74 [95% credible interval {CrI}, 0.61-0.90]) and antiplatelet agents had a 95% probability of improving 6-month survival (adjusted HR, 0.85 [95% CrI, 0.71-1.03]) compared with the control, while the probability of trial-defined statistical futility (HR & .83) was high for therapeutic anticoagulation (99.9% HR, 1.13 [95% CrI, 0.93-1.42]), convalescent plasma (99.2% HR, 0.99 [95% CrI, 0.86-1.14]), and lopinavir-ritonavir (96.6% HR, 1.06 [95% CrI, 0.82-1.38]) and the probabilities of harm from hydroxychloroquine (96.9% HR, 1.51 [95% CrI, 0.98-2.29]) and the combination of lopinavir-ritonavir and hydroxychloroquine (96.8% HR, 1.61 [95% CrI, 0.97-2.67]) were high. The corticosteroid domain was stopped early prior to reaching a predefined statistical trigger there was a 57.1% to 61.6% probability of improving 6-month survival across varying hydrocortisone dosing strategies. Among critically ill patients with COVID-19 randomized to receive 1 or more therapeutic interventions, treatment with an IL-6 receptor antagonist had a greater than 99.9% probability of improved 180-day mortality compared with patients randomized to the control, and treatment with an antiplatelet had a 95.0% probability of improved 180-day mortality compared with patients randomized to the control. Overall, when considered with previously reported short-term results, the findings indicate that initial in-hospital treatment effects were consistent for most therapies through 6 months.
Publisher: Massachusetts Medical Society
Date: 19-07-2100
Publisher: Springer Science and Business Media LLC
Date: 17-05-2023
DOI: 10.1038/S41586-023-06034-3
Abstract: Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown 1 to be highly efficient for discovery of genetic associations 2 . Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group 3 . Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling ( JAK1 ), monocyte–macrophage activation and endothelial permeability ( PDE4A ), immunometabolism ( SLC2A5 and AK5 ), and host factors required for viral entry and replication ( TMPRSS2 and RAB2A ).
Publisher: Elsevier BV
Date: 02-2022
Publisher: Elsevier BV
Date: 02-2021
Publisher: Springer Science and Business Media LLC
Date: 15-10-2022
Publisher: European Respiratory Society (ERS)
Date: 15-03-2023
DOI: 10.1183/13993003.02226-2022
Abstract: COVID-19 is associated with a dysregulated immune response but it is unclear how immune dysfunction contributes to the chronic morbidity persisting in many COVID-19 patients during convalescence (long COVID). We assessed phenotypical and functional changes of monocytes in COVID-19 patients during hospitalisation and up to 9 months of convalescence following COVID-19, respiratory syncytial virus or influenza A. Patients with progressive fibrosing interstitial lung disease were included as a positive control for severe, ongoing lung injury. Monocyte alterations in acute COVID-19 patients included aberrant expression of leukocyte migration molecules, continuing into convalescence (n=142) and corresponding with specific symptoms of long COVID. Long COVID patients with unresolved lung injury, indicated by sustained shortness of breath and abnormal chest radiology, were defined by high monocyte expression of C-X-C motif chemokine receptor 6 (CXCR6) (p .0001) and adhesion molecule P-selectin glycoprotein ligand 1 (p .01), alongside preferential migration of monocytes towards the CXCR6 ligand C-X-C motif chemokine ligand 16 (CXCL16) (p .05), which is abundantly expressed in the lung. Monocyte CXCR6 and lung CXCL16 were heightened in patients with progressive fibrosing interstitial lung disease (p .001), confirming a role for the CXCR6–CXCL16 axis in ongoing lung injury. Conversely, monocytes from long COVID patients with ongoing fatigue exhibited a sustained reduction of the prostaglandin-generating enzyme cyclooxygenase 2 (p .01) and CXCR2 expression (p .05). These monocyte changes were not present in respiratory syncytial virus or influenza A convalescence. Our data define unique monocyte signatures that define subgroups of long COVID patients, indicating a key role for monocyte migration in COVID-19 pathophysiology. Targeting these pathways may provide novel therapeutic opportunities in COVID-19 patients with persistent morbidity.
Publisher: Massachusetts Medical Society
Date: 25-02-2021
Publisher: Elsevier BV
Date: 2022
Publisher: Elsevier BV
Date: 10-2022
DOI: 10.1016/J.CMI.2022.05.010
Abstract: We aim to identify the preoperative and perioperative risk factors associated with post-surgical Staphylococcus aureus prosthetic joint infections (PJI) and to develop and validate risk-scoring systems, to allow a better identification of high-risk patients for more efficient targeted interventions. We performed a multicenter matched case-control study of patients who underwent a primary hip and knee arthroplasty from 2014 to 2016. Two multivariable models by logistic regression were performed, one for the preoperative and one for perioperative variables predictive scores also were developed and validated in an external cohort. In total, 130 cases and 386 controls were included. The variables independently associated with S. aureus-PJI in the preoperative period were (adjusted OR 95% CI): body mass index >30 kg/m Predictive scores for S. aureus-PJI were developed and validated this information would be useful for implementation of specific preventive measures.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Gabriella Lindergard.