Coronavirus disease 2019 subphenotypes and differential treatment response to convalescent plasma in critically ill adults: secondary analyses of a randomized clinical trial

Fish, Matthew; Rynne, Jennifer; Jennings, A.R.; Lam, Carolyn K; Lamikanra, Abigail; Ratcliff, Jeremy; Cellone-Trevelin, S.; Timms, Emma; Jiriha, J.; Tosi, Isabella; Pramanik, Rashida; Simmonds, Peter; Seth, Sohan; Williams, J.D.; Gordon, Anthony; Knight, Julian C.; Smith, Debra; Whalley, Justin P.; Harrison, David A; Rowan, Kathryn M; Harvala, Heli; Klenerman, Paul; Estcourt, Lise J; Menon, David; Roberts, David; Shankar-Hari, Manu

doi:10.1007/s00134-022-06869-w

Cited by 15 publications

(10 citation statements)

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“…Comparing ICU discharge with ICU admission timepoint, CXCL10 was lower at discharge (Figure-1d). Correlations between cytokines were positive, and signi cant, at all-time points (Figure-1e), consistent with our previous report5 . On admission day there were two notable negative correlations.…”

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confidence: 92%

Assessment of longitudinal changes in immune responses in critically ill adults with COVID-19

Rynne,

Fish,

Jennings

et al. 2024

Preprint

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Clinically, COVID-19 is often a mild or asymptomatic illness. However, in a subset of patients, a more severe illness with one or more organ dysfunction requiring intensive care (ICU) admission occurs (stated as critical COVID-19). Most studies assessing the immune responses in COVID-19 focus on patients with non-critical COVID-19, often assessing single biological domain (such as cytokines, leukocytes, proteomics, or transcriptomics) at single time point in patient’s illness. In this context, our cohort study of patients with critical COVID-19 with demographically similar pre-pandemic controls, characterised the longitudinal changes in multiple biological domains (28 plasma cytokines, 30 immune cell subsets identified using mass cytometry and pan-leukocyte transcriptome) at four clinically relevant timepoints between ICU admission and discharge. When compared with controls, on ICU admission day, patients with critical COVID-19, had altered cytokine/chemokine profile (high interleukin-6 (IL-6), IL-10, IL-13, CXCL10, with low CCL17, and CXCL5)), raised histones (H3.1, H3R8), robust plasmablast response despite lymphopenia, with enrichment of immunoglobulin production and interferon pathways in the transcriptome. Analyses of longitudinal transcriptome data highlights three immunologically distinct clusters that were discordant to clinical time points, indicating that the clinical time points do capture immune response trajectory. Complete integration of this multi-domain longitudinal data indicated that ~ 70% of immunological heterogeneity is explained by the transcriptome.

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supporting

confidence: 92%

Assessment of longitudinal changes in immune responses in critically ill adults with COVID-19

Rynne,

Fish,

Jennings

et al. 2024

Preprint

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“…in a secondary analysis of convalescent plasma in the REMAP-CAP trial, 20 the same biomarkers measured in the LOVIT trial 7 were comparable between the vitamin C and placebo groups.…”

Section: Discussionmentioning

confidence: 92%

“…The results from the current study, which included both a critically ill population with mainly COVID-19 respiratory failure and a population that was not critically ill, are consistent with the LOVIT trial that included patients with sepsis who were treated with vasopressors. Existing analyses do not elucidate the mechanisms of harm, and while future biomarker analyses from the LOVIT-COVID trial may be informative, as shown in a secondary analysis of convalescent plasma in the REMAP-CAP trial, the same biomarkers measured in the LOVIT trial were comparable between the vitamin C and placebo groups. A meta-analysis of 9 trials (the largest included trial randomized 100 patients) found a reduced odds of mortality in patients with COVID-19 receiving vitamin C. These divergent results may be explained by the more extreme effects observed in the small trials …”

Section: Discussionmentioning

confidence: 98%

Intravenous Vitamin C for Patients Hospitalized With COVID-19

Florescu,

Stanciu,

Zaharia

et al. 2023

JAMA

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ImportanceThe efficacy of vitamin C for hospitalized patients with COVID-19 is uncertain.ObjectiveTo determine whether vitamin C improves outcomes for patients with COVID-19.Design, Setting, and ParticipantsTwo prospectively harmonized randomized clinical trials enrolled critically ill patients receiving organ support in intensive care units (90 sites) and patients who were not critically ill (40 sites) between July 23, 2020, and July 15, 2022, on 4 continents.InterventionsPatients were randomized to receive vitamin C administered intravenously or control (placebo or no vitamin C) every 6 hours for 96 hours (maximum of 16 doses).Main Outcomes and MeasuresThe primary outcome was a composite of organ support–free days defined as days alive and free of respiratory and cardiovascular organ support in the intensive care unit up to day 21 and survival to hospital discharge. Values ranged from –1 organ support–free days for patients experiencing in-hospital death to 22 organ support–free days for those who survived without needing organ support. The primary analysis used a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented efficacy (improved survival, more organ support–free days, or both), an OR less than 1 represented harm, and an OR less than 1.2 represented futility.ResultsEnrollment was terminated after statistical triggers for harm and futility were met. The trials had primary outcome data for 1568 critically ill patients (1037 in the vitamin C group and 531 in the control group; median age, 60 years [IQR, 50-70 years]; 35.9% were female) and 1022 patients who were not critically ill (456 in the vitamin C group and 566 in the control group; median age, 62 years [IQR, 51-72 years]; 39.6% were female). Among critically ill patients, the median number of organ support–free days was 7 (IQR, −1 to 17 days) for the vitamin C group vs 10 (IQR, −1 to 17 days) for the control group (adjusted proportional OR, 0.88 [95% credible interval {CrI}, 0.73 to 1.06]) and the posterior probabilities were 8.6% (efficacy), 91.4% (harm), and 99.9% (futility). Among patients who were not critically ill, the median number of organ support–free days was 22 (IQR, 18 to 22 days) for the vitamin C group vs 22 (IQR, 21 to 22 days) for the control group (adjusted proportional OR, 0.80 [95% CrI, 0.60 to 1.01]) and the posterior probabilities were 2.9% (efficacy), 97.1% (harm), and greater than 99.9% (futility). Among critically ill patients, survival to hospital discharge was 61.9% (642/1037) for the vitamin C group vs 64.6% (343/531) for the control group (adjusted OR, 0.92 [95% CrI, 0.73 to 1.17]) and the posterior probability was 24.0% for efficacy. Among patients who were not critically ill, survival to hospital discharge was 85.1% (388/456) for the vitamin C group vs 86.6% (490/566) for the control group (adjusted OR, 0.86 [95% CrI, 0.61 to 1.17]) and the posterior probability was 17.8% for efficacy.Conclusions and RelevanceIn hospitalized patients with COVID-19, vitamin C had low probability of improving the primary composite outcome of organ support–free days and hospital survival.Trial RegistrationClinicalTrials.gov Identifiers: NCT04401150 (LOVIT-COVID) and NCT02735707 (REMAP-CAP)

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“…These findings are in line with previous results, indicating that the benefits of corticosteroids are greater for patients on IMV than patients on oxygen only 2 . Critically ill COVID-19 patients requiring IMV have greater systemic and pulmonary inflammation, alongside dysregulated immune responses 29 , with distinct COVID-19 immune response subpopulations (i.e., subphenotypes) 30 – 32 . Corticosteroids have genomic, and non-genomic effects that are dose dependent 33 .…”

Section: Discussionmentioning

confidence: 99%

Causal Bayesian machine learning to assess treatment effect heterogeneity by dexamethasone dose for patients with COVID-19 and severe hypoxemia

Blette

Granholm

et al. 2023

Sci Rep

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The currently recommended dose of dexamethasone for patients with severe or critical COVID-19 is 6 mg per day (mg/d) regardless of patient features and variation. However, patients with severe or critical COVID-19 are heterogenous in many ways (e.g., age, weight, comorbidities, disease severity, and immune features). Thus, it is conceivable that a standardized dosing protocol may not be optimal. We assessed treatment effect heterogeneity in the COVID STEROID 2 trial, which compared 6 mg/d to 12 mg/d, using a causal inference framework with Bayesian Additive Regression Trees, a flexible modeling method that detects interactive effects and nonlinear relationships among multiple patient characteristics simultaneously. We found that 12 mg/d of dexamethasone, relative to 6 mg/d, was probably associated with better long-term outcomes (days alive without life support and mortality after 90 days) among the entire trial population (i.e., no signals of harm), and probably more beneficial among those without diabetes mellitus, that were older, were not using IL-6 inhibitors at baseline, weighed less, or had higher level respiratory support at baseline. This adds more evidence supporting the use of 12 mg/d in practice for most patients not receiving other immunosuppressants and that additional study of dosing could potentially optimize clinical outcomes.

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Coronavirus disease 2019 subphenotypes and differential treatment response to convalescent plasma in critically ill adults: secondary analyses of a randomized clinical trial

Cited by 15 publications

References 50 publications

Assessment of longitudinal changes in immune responses in critically ill adults with COVID-19

Assessment of longitudinal changes in immune responses in critically ill adults with COVID-19

Intravenous Vitamin C for Patients Hospitalized With COVID-19

Causal Bayesian machine learning to assess treatment effect heterogeneity by dexamethasone dose for patients with COVID-19 and severe hypoxemia

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