Tissue-Specific Immunopathology in Fatal COVID-19

Dorward, David A.; Russell, Clark D; Um, In Hwa; Elshani, Mustafa; Armstrong, Stuart D.; Penrice-Randal, Rebekah; Millar, Tracey; Lerpiniere, Chris E B; Tagliavini, Giulia; Hartley, Catherine; Randle, Nadine; Gachanja, Naomi N.; Potey, Philippe M D; Dong, Xiaofeng; Anderson, Alison; Campbell, Victoria; Duguid, Alasdair J; Al‐Qsous, Wael; BouHaidar, Ralph; Baillie, J Kenneth; Dhaliwal, Kevin; Wallace, William; Bellamy, Christopher; Prost, Sandrine; Smith, Colin; Hiscox, Julian A.; Harrison, David J.; Lucas, Christopher D.

doi:10.1164/rccm.202008-3265oc

Cited by 260 publications

(280 citation statements)

References 43 publications

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“…3,4 The host immune response is thought to play a key role in driving an acute inflammatory pneumonic process with diffuse alveolar damage, myeloid cell infiltrates, and microvascular thrombosis. 5 The beneficial effects of dexamethasone and other corticosteroids in COVID-19 patients with hypoxic lung damage suggest that other, more specific immunomodulatory agents may provide additional improvements in clinical outcomes. 6,7 Tocilizumab is a recombinant humanised anti-IL-6 receptor monoclonal antibody that inhibits the binding of IL-6 to both membrane and soluble IL-6 receptors, blocking IL-6 signalling and reducing inflammation.…”

Section: Introductionmentioning

confidence: 99%

Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): preliminary results of a randomised, controlled, open-label, platform trial

Horby

Pessoa-Amorim

Peto

et al. 2021

Preprint

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156

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Findings: Between 23 April 2020 and 25 January 2021, 4116 adults were included in the assessment of tocilizumab, including 562 (14%) patients receiving invasive mechanical ventilation, 1686 (41%) receiving non-invasive respiratory support, and. 1868 (45%) receiving no respiratory support other than oxygen. Median CRP was 143 [IQR 107-205] mg/L and 3385 (82%) patients were receiving systemic corticosteroids at randomisation. Overall, 596 (29%) of the 2022 patients allocated tocilizumab and 694 (33%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0.86; 95% confidence interval [CI] 0.77-0.96; p=0.007). Consistent results were seen in all pre-specified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital alive within 28 days (54% vs. 47%; rate ratio 1.23; 95% CI 1.12-1.34; p<0.0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (33% vs. 38%; risk ratio 0.85; 95% CI 0.78-0.93; p=0.0005). Interpretation: In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes regardless of the level of respiratory support received and in addition to the use of systemic corticosteroids.

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Section: Introductionmentioning

confidence: 99%

Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): preliminary results of a randomised, controlled, open-label, platform trial

Horby

Pessoa-Amorim

Peto

et al. 2021

Preprint

Self Cite

156

139

View full text Add to dashboard Cite

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“…SARS-CoV-2 has been in the human population for more than a year now, causing severe disease in some and resulting in a pandemic that continues to put severe strain on economies and healthcare infrastructures worldwide 1. In the UK, the first three vaccines have emergency use authorisation, and a national rollout is in progress.…”

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confidence: 99%

Covid-19: variants and vaccination

Darby

Hiscox

2021

BMJ

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“…Medical charts were reviewed by two physicians for data collection on demographics, comorbidities, risk factors, severity state, time of infection, etc (see Table 1). Median age and range for UC cohort was 37 (32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46), and 30 individuals were males (60%).…”

Section: Tablesmentioning

confidence: 99%

Integrated immunovirological profiling validates plasma SARS-CoV-2 RNA as an early predictor of COVID-19 mortality

Brunet-Ratnasingham

Anand

Gantner

et al. 2021

Preprint

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Despite advances in COVID-19 management, it is unclear how to recognize patients who evolve towards death. This would allow for better risk stratification and targeting for early interventions. However, the explosive increase in correlates of COVID-19 severity complicates biomarker prioritisation. To identify early biological predictors of mortality, we performed an immunovirological assessment (SARS-CoV-2 viral RNA, cytokines and tissue injury markers, antibody responses) on plasma samples collected from 144 hospitalised COVID-19 patients 11 days after symptom onset and used to test models predicting mortality within 60 days of symptom onset. In the discovery cohort (n=61, 13 fatalities), high SARS-CoV-2 vRNA, low RBD-specific IgG levels, low SARS-CoV-2-specific antibody-dependent cellular cytotoxicity, and elevated levels of several cytokines and lung injury markers were strongly associated with increased mortality in the entire cohort and the subgroup on mechanical ventilation. Model selection revealed that a three-variable model of vRNA, age and sex was very robust at identifying patients who will succumb to COVID-19 (AUC=0.86, adjusted HR for log-transformed vRNA=3.5; 95% CI: 2.0-6.0). This model remained robust in an independent validation cohort (n=83, AUC=0.85). Quantification of plasma SARS-CoV-2 RNA can help understand the heterogeneity of disease trajectories and identify patients who may benefit from new therapies.

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Tissue-Specific Immunopathology in Fatal COVID-19

Cited by 260 publications

References 43 publications

Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): preliminary results of a randomised, controlled, open-label, platform trial

Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): preliminary results of a randomised, controlled, open-label, platform trial

Covid-19: variants and vaccination

Integrated immunovirological profiling validates plasma SARS-CoV-2 RNA as an early predictor of COVID-19 mortality

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