A myeloid program associated with COVID-19 severity is decreased by therapeutic blockade of IL-6 signaling

Altered myeloid inflammation and lymphopenia are hallmarks of severe infections, including with SARS-CoV-2. Here, we identified a gene program, defined by correlation with EN-RAGE (S100A12) gene expression, which was up-regulated in airway and blood myeloid cells from COVID-19 patients. The EN-RAGE program was expressed in 7 cohorts and observed in patients with both COVID-19 and acute respiratory distress syndrome (ARDS) from other causes. This program was associated with greater clinical severity and predicted future mechanical ventilation and death. EN-RAGE+ myeloid cells express features consistent with suppressor cell functionality, with low HLA-DR and high PD-L1 surface expression and higher expression of T cell-suppressive genes. Sustained EN-RAGE signature expression in airway and blood myeloid cells correlated with clinical severity and increasing expression of T cell exhaustion markers, such as PD-1. IL-6 treatment of monocytes in vitro upregulated many of the severity-associated genes in the EN-RAGE gene program, along with potential mediators of T cell suppression, such as IL-10. Blockade of IL-6 signaling by tocilizumab in a placebo-controlled clinical trial led to a rapid normalization of ENRAGE and T cell gene expression. This identifies IL-6 as a key driver of myeloid dysregulation associated with worse clinical outcomes in COVID-19 patients and provides insights into shared pathophysiological mechanisms in non-COVID-19 ARDS.

Tocilizumab treatment leads to early resolution of myeloid dysfunction and lymphopenia in patients hospitalized with COVID-19

Tocilizumab, an anti-interleukin-6 receptor inhibitor, is recommended in global treatment guidelines for patients hospitalized with severe COVID-19. Using proteomic and transcriptomic analysis, we characterized the immune profile and identified cellular and molecular pathways directly modified by tocilizumab in peripheral blood samples collected from patients enrolled in the COVACTA study, a phase 3, randomized, double-blind, placebo-controlled trial, to assess the efficacy and safety of tocilizumab in hospitalized patients with severe COVID-19 pneumonia. We identified factors predicting disease severity and clinical outcomes, including markers of inflammation, lymphopenia, myeloid dysfunction, and organ injury. Proteomic analysis confirmed a pharmacodynamic effect for tocilizumab. Transcriptomic analysis revealed that tocilizumab treatment leads to faster resolution of lymphopenia and myeloid dysfunction associated with severe COVID-19, thus defining an anti-inflammatory mechanism of action for the beneficial effects of tocilizumab in patients hospitalized with COVID-19. One sentence summaryInterleukin-6 receptor blockade with tocilizumab accelerated resolution of myeloid dysfunction and lymphopenia in patients hospitalized with COVID-19

Risk of Severe COVID-19 Outcomes Among Patients with Rheumatoid Arthritis in the United States

IntroductionCoronavirus disease 2019 (COVID-19) has infected over 22 million individuals worldwide. It remains unclear whether patients with COVID-19 and Rheumatoid Arthritis (RA) experience worse clinical outcomes compared to similar patients with COVID-19 without RA. AimThe aim of this study is to provide insights on how COVID-19 impacted patients with RA given the nature of the disease and medication used. MethodsRA cases were identified via International Classification of Diseases (ICD) codes and COVID-19 cases by laboratory results in the U.S. based TriNetX network. Patients with COVID-19 and RA were propensity-score matched based on demographics with patients with COVID-19 without RA at a 1:3 ratio. A hospitalized sub-population was defined by procedure codes. ResultsWe identified 1,014 COVID-19 patients with RA and 3,042 non-RA matches selected from 137,757 patients. The odds of hospitalization (non-RA:23%, RA:24.6%, OR:1.08, 95% CI: 0.88 to 1.33) or mortality (non-RA:5.4%, RA:6%, OR:0.93, 95% CI: 0.65 to 1.34) were not significantly different. The hospitalized sub-population included 249 patients with COVID-19 and RA and 745 non-RA matches selected from 21,435 patients. The risk of intensive care unit (ICU) admission (non-RA:18.8%, RA:18.1%, OR:0.94, 95% CI: 0.60 to 1.45), and inpatient mortality (non-RA:14.4%, RA:14.5%, OR:0.86, 95% CI: 0.53 to 1.40) were not significantly different. ConclusionWe didnt find evidence suggesting patients with COVID-19 and RA are more likely to have severe outcomes than patients with COVID-19 without RA. Key Messages- Patients with Rheumatoid Arthritis (RA) tend to be older, and often have co-morbidities which could put them at greater risk of severe COVID-19 outcomes. - This study is one of the largest studies of COVID-19 infected RA populations to date. We did not find increased risk of hospitalization, ICU admission, or mortality among RA patients vs. matched non-RA patients. - Patients previously exposed to anti-coagulants experienced higher risks of hospitalization and overall mortality. Extra attention is needed for treating such patients.

Prognostic and predictive biomarkers in patients with COVID-19 treated with tocilizumab in a randomised controlled trial

BackgroundRetrospective observational studies suggest that interleukin-6 (IL-6), C-reactive protein (CRP), lactate dehydrogenase (LDH), ferritin, lymphocytes, monocytes, neutrophils, D-dimer, and platelets are associated with disease progression, treatment outcomes, or both, in patients with COVID-19 pneumonia. We explored these candidate prognostic and predictive biomarkers with efficacy outcomes after treatment with tocilizumab, an anti-IL-6 receptor antibody using data from the COVACTA trial for patients hospitalised with severe COVID-19 pneumonia. MethodsCandidate biomarkers were measured in 295 patients in the tocilizumab arm and 142 patients in the placebo arm. Efficacy outcomes assessed were clinical status on a seven-category ordinal scale (1, discharge; 7, death), mortality, time to hospital discharge, and mechanical ventilation (if not receiving it at randomisation) through day 28. Prognostic and predictive biomarkers were evaluated continuously with proportional odds, binomial or Fine-Gray models, and additional sensitivity analyses. FindingsModelling in the placebo arm showed all candidate biomarkers except LDH and D-dimer were strongly prognostic for day 28 clinical outcomes of mortality, mechanical ventilation, clinical status, and time to hospital discharge. Modelling in the tocilizumab arm showed a predictive value of ferritin for day 28 clinical outcomes of mortality (predictive interaction p=0.03), mechanical ventilation (predictive interaction p=0.01), and clinical status (predictive interaction p=0.02) compared with placebo. InterpretationMultiple biomarkers prognostic for clinical outcomes were confirmed in COVACTA. Ferritin was identified as a predictive biomarker for the effects of tocilizumab in the COVACTA patient population; high ferritin levels were associated with better clinical outcomes for tocilizumab compared with placebo at day 28. RESEARCH IN CONTEXT Evidence before this studyThe efficacy and safety of the anti-interleukin-6 receptor antibody tocilizumab in the treatment of patients hospitalised with COVID-19 pneumonia was investigated in COVACTA, a double-blind, randomised, placebo-controlled trial. The primary endpoint of improved clinical status on a seven-category ordinal scale (1, discharged/ready for discharge; 7, death) at day 28 was not met in this trial. Among the secondary endpoints, no difference in mortality at day 28 was observed, but time to hospital discharge was shorter in the tocilizumab group. Subgroup analysis suggested there might be a treatment benefit in patients grouped according to their ordinal scale category at baseline. We searched PubMed on September 14, 2020, using the terms "tocilizumab AND (COVID-19 OR coronavirus) AND biomarker" with no language or date restrictions. The search retrieved 18 articles, four of which identified laboratory measures as potential biomarkers in patients who received tocilizumab for the treatment of COVID-19 pneumonia. The biomarkers reported in these studies include interleukin-6, C-reactive protein, ferritin, fibrinogen, liver transaminases, lymphocytes, platelets, and D-dimer. However, these previous studies were single-centre, retrospective, observational studies. Larger, prospective, controlled trials are needed to investigate potential prognostic and predictive biomarkers to assess the outcomes and response to treatments for COVID-19. Added value of this studyThis exploratory analysis of data from COVACTA demonstrated interleukin-6, C-reactive protein, ferritin, neutrophils (percentage and absolute count), neutrophil-to-lymphocyte ratio, lymphocytes (percentage and absolute count), monocytes (percentage), and platelets as strong prognostic biomarkers in patients hospitalised with severe COVID-19 pneumonia. More important, ferritin showed predictive value for tocilizumab treatment effects on day 28 clinical outcomes of mortality, mechanical ventilation (among the subgroup of patients not receiving mechanical ventilation at randomisation), and clinical status compared with placebo. Implications of all the available evidenceIn patients with elevated levels of ferritin at baseline, tocilizumab decreased the probability of death, mechanical ventilation, and worsening clinical status at day 28 compared with placebo, suggesting that ferritin might be useful as a predictive biomarker of efficacy outcomes for tocilizumab in patients with severe COVID-19 pneumonia.

Risk factors for mortality among hospitalized patients with COVID-19

ObjectivesTo develop a prognostic model to identify and quantify risk factors for mortality among patients admitted to the hospital with COVID-19. DesignRetrospective cohort study. Patients were randomly assigned to either training (80%) or test (20%) sets. The training set was used to fit a multivariable logistic regression. Predictors were ranked using variable importance metrics. Models were assessed by C-indices, Brier scores, and calibration plots in the test set. SettingOptum(R) de-identified COVID-19 Electronic Health Record dataset. Participants17,086 patients hospitalized with COVID-19 between February 20, 2020 and June 5, 2020. Main outcome measureAll-cause mortality during hospital stay. ResultsThe full model that included information on demographics, comorbidities, laboratory results and vital signs had good discrimination (C-index = 0.87) and was well calibrated, with some overpredictions for the most at-risk patients. Results were generally similar on the training and test sets, suggesting that there was little overfitting. Age was the most important risk factor. The performance of models that included all demographics and comorbidities (C-index = 0.79) was only slightly better than a model that only included age (C-index = 0.76). Across the study period, predicted mortality was 1.2% for 18-year olds, 8.4% for 55-year olds, and 28.6% for 85-year olds. Predicted mortality across all ages declined over the study period from 21.7% by March to 13.3% by May. ConclusionAge was the most important predictor of all-cause mortality although vital signs and laboratory results added considerable prognostic information with oxygen saturation, temperature, respiratory rate, lactate dehydrogenase, and white blood cell count being among the most important predictors. Demographic and comorbidity factors did not improve model performance appreciably. The model had good discrimination and was reasonably well calibrated, suggesting that it may be useful for assessment of prognosis.

Tocilizumab in Hospitalized Patients With COVID-19 Pneumonia

BACKGROUNDCOVID-19 is associated with immune dysregulation and hyperinflammation. Tocilizumab is an anti-interleukin-6 receptor antibody. METHODSPatients hospitalized with severe COVID-19 pneumonia receiving standard care were randomized (2:1) to double-blinded intravenous tocilizumab 8 mg/kg or placebo. The primary outcome measure was clinical status on a 7-category ordinal scale at day 28 (1, discharged/ready for discharge; 7, death). RESULTSOverall, 452 patients were randomized; the modified-intention-to-treat population included 294 tocilizumab-treated and 144 placebo-treated patients. Clinical status at day 28 was not statistically significantly improved for tocilizumab versus placebo (P=0.36). Median (95% CI) ordinal scale values at day 28: 1.0 (1.0 to 1.0) for tocilizumab and 2.0 (1.0 to 4.0) for placebo (odds ratio, 1.19 [0.81 to 1.76]). There was no difference in mortality at day 28 between tocilizumab (19.7%) and placebo (19.4%) (difference, 0.3% [95% CI, -7.6 to 8.2]; nominal P=0.94). Median time to hospital discharge was 8 days shorter with tocilizumab than placebo (20.0 and 28.0, respectively; nominal P=0.037; hazard ratio 1.35 [95% CI 1.02 to 1.79]). Median duration of ICU stay was 5.8 days shorter with tocilizumab than placebo (9.8 and 15.5, respectively; nominal P=0.045). In the safety population, serious adverse events occurred in 34.9% of 295 patients in the tocilizumab arm and 38.5% of 143 in the placebo arm. CONCLUSIONSIn this randomized placebo-controlled trial in hospitalized COVID-19 pneumonia patients, tocilizumab did not improve clinical status or mortality. Potential benefits in time to hospital discharge and duration of ICU stay are being investigated in ongoing clinical trials. Trial registrationClinicalTrials.gov NCT04320615

Descriptive epidemiology of 16,780 hospitalized COVID-19 patients in the United States

1.BackgroundDespite the significant morbidity and mortality caused by the 2019 novel coronavirus disease (COVID-19), our understanding of basic disease epidemiology remains limited. This study aimed to describe key patient characteristics, comorbidities, treatments, and outcomes of a large U.S.-based cohort of patients hospitalized with COVD-19 using electronic health records (EHR). MethodsWe identified patients in the Optum De-identified COVID-19 EHR database who had laboratory-confirmed COVID-19 or a presumptive diagnosis between 20 February 2020 and 6 June 2020. We included hospitalizations that occurred 7 days prior to, or within 21 days after, COVID-19 diagnosis. Among hospitalized patients we describe the following: vital statistics and laboratory results on admission, relevant comorbidities (using diagnostic, procedural, and revenue codes), medications (NDC, HCPC codes), ventilation, intensive care unit (ICU) stay, length of stay (LOS), and mortality. FindingsWe identified 76,819 patients diagnosed with COVID-19, 16,780 of whom met inclusion criteria for COVID-related hospitalization. Over half the cohort was over age 50 (74.5%), overweight or obese (77.2%), or had hypertension (56.6%). At admission, 30.3% of patients presented with fever (>38{degrees} C) and 32.3% had low oxygen saturation (<90%). Among the 16,099 patients with complete hospital records, we observed that 58.9% had hypoxia, 23.4% had an ICU stay during hospitalization, 18.1% were ventilated, and 16.2% died. The median LOS was 6 days (IQR: 4, 11). InterpretationTo our knowledge, this is the largest descriptive study of patients hospitalized with COVID-19 in the United States. We report summary statistics of key clinical outcomes that provide insights to better understand COVID-19 disease epidemiology.