Risk factors for severe COVID-19 differ by age: a retrospective study of hospitalized adults

BackgroundRisk stratification for hospitalized adults with COVID-19 is essential to inform decisions for individual patients and allocation of potentially scarce resources. So far, risk models for severe COVID outcomes have included age but have not been optimized to best serve the needs of either older or younger adults. Additionally, existing risk models have been limited to either small sample sizes, or modeling mortality over an entire hospital admission. Further, previous models were developed on data from early in the pandemic, before improvements in COVID-19 treatment, the SARS-CoV-2 delta variant, and vaccination. There remains a need for early, accurate identification of patients who may need invasive mechanical ventilation (IMV) or die, considering multiple time horizons. MethodsThis retrospective study analyzed data from 6,906 hospitalized adults with COVID-19 from a community health system with 51 hospitals and 1085 clinics across five states in the western United States. Risk models were developed to predict mechanical ventilation illness or death across one to 56 days of hospitalization, using clinical data collected available within the first hour after either admission with COVID-19 or a first positive SARS-CoV-2 test. The relative importance of predictive risk factors features for all models was determined using Shapley additive explanations. FindingsThe percentage of patients who required mechanical ventilation or died within seven days of admission to the hospital due to COVID-19 was 10.82%. For the seven-day interval, models for age [≥] 18 and < 50 years reached AUROC 0.80 (95% CI: 0.70-0.89) and models for age [≥] 50 years reached AUROC 0.83 (95% CI: 0.79-0.88). Models revealed differences in the statistical significance and relative predictive value of risk factors between older and younger patients, including age, BMI, vital signs, and laboratory results. In addition, sex and chronic comorbidities had lower predictive value than vital signs and laboratory results. InterpretationFor hospitalized adults, baseline data that is readily available within one hour after hospital admission or a first positive inpatient SARS-CoV-2 test can predict critical illness within one day, and up to 56 days later. Further, the relative importance of risk factors differs between older and younger patients.

Baricitinib plus Standard of Care for Hospitalised Adults with COVID-19 on Invasive Mechanical Ventilation or Extracorporeal Membrane Oxygenation: Results of a Randomized, Placebo-Controlled Trial.

BackgroundThe oral, selective Janus kinase (JAK)1/JAK2 inhibitor baricitinib demonstrated efficacy in hospitalised adults with COVID-19. This study evaluates the efficacy and safety of baricitinib in critically ill adults with COVID-19 requiring invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO). MethodsCOV-BARRIER was a global, phase 3, randomised, double-blind, placebo-controlled trial in patients with confirmed SARS-CoV-2 infection (ClinicalTrials.gov NCT04421027). This addendum trial added a critically ill cohort not included in the main COV-BARRIER trial. Participants on baseline IMV/ECMO were randomly assigned 1:1 to baricitinib 4-mg (n=51) or placebo (n=50) for up to 14 days in combination with standard of care (SOC). Prespecified endpoints included all-cause mortality through days 28 and 60, and number of ventilator-free days, duration of hospitalisation, and time to recovery through day 28. Efficacy and safety analyses included the intent-to-treat and safety populations, respectively. FindingsSOC included baseline systemic corticosteroid use in 86% of participants. Treatment with baricitinib significantly reduced 28-day all-cause mortality compared to placebo (39{middle dot}2% vs 58{middle dot}0%; hazard ratio [HR]=0{middle dot}54 [95%CI 0{middle dot}31-0{middle dot}96]; p=0{middle dot}030). One additional death was prevented for every six baricitinib-treated participants. Significant reduction in 60-day mortality was also observed (45{middle dot}1% vs 62{middle dot}0%; HR=0{middle dot}56 [95%CI 0{middle dot}33-0{middle dot}97]; p=0{middle dot}027). Baricitinib-treated participants showed numerically more ventilator-free days (8.1 vs 5.5 days, p=0.21) and spent over 2 days less in the hospital than placebo-treated participants (23{middle dot}7 vs 26{middle dot}1 days, p=0{middle dot}050). The rates of infections, blood clots, and adverse cardiovascular events were similar between treatment arms. InterpretationIn critically ill patients with COVID-19 already receiving IMV/ECMO, treatment with baricitinib as compared to placebo (in combination with SOC, including corticosteroids) showed mortality HR of 0{middle dot}56, corresponding to a 44% relative reduction at 60 days. This is consistent with the mortality reduction observed in less severely ill hospitalised primary COV-BARRIER study population. FundingEli Lilly and Company. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe evaluated current and prior studies assessing the efficacy and safety of interventions in patients requiring invasive mechanical ventilation (IMV) and searched current PubMed using the terms "COVID-19", "SARS-CoV-2", "treatment", "critical illness", "invasive mechanical ventilation", "baricitinib", and "JAK inhibitor" for articles in English, published until December 1, 2020, regardless of article type. We also reviewed the NIH and IDSA COVID-19 guidelines and reviewed similar terms on clinicaltrials.gov. When the critical illness addendum study to COV-BARRIER study was designed, there was only one open-label study of dexamethasone showing mortality benefit in hospitalised patients with COVID-19 requiring IMV. Small studies of interleukin-6 inhibitors had shown no effect and larger trials were underway. Guidelines recommended use of dexamethasone with or without remdesivir and recommended against the use of interleukin-6 inhibitors, except in a clinical trial. Overall, there were no reported double-blind, placebo-controlled phase 3 trials which included corticosteroids as part of SOC investigating the efficacy and safety of novel treatments in the NIAID-OS 7 population. Baricitinibs mechanism of action as a JAK1 and JAK2 inhibitor was identified as a potential intervention for the treatment of COVID-19 given its known anti-cytokine properties and potential antiviral mechanism for targeting host proteins mediating viral endocytosis Data from the NIAID sponsored ACTT-2 trial showed that baricitinib when added to remdesivir improved time to recovery and other outcomes including mortality compared to placebo plus remdesivir. A numerically larger proportion of participants who received baricitinib plus remdesivir showed an improvement in ordinal scale compared to those who received placebo plus remdesivir at day 15 in participants requiring IMV (NIAID-OS score of 7) at baseline. We designed COV-BARRIER, a phase 3, global, double-blind, randomised, placebo-controlled trial, to evaluate the efficacy and safety of baricitinib in combination with SOC (including corticosteroids) for the treatment of hospitalised adults with COVID-19 who did not require mechanical ventilation (i.e., NIAID-OS 4-6). A significant reduction in mortality was found after 28 days between baricitinib and placebo (HR 0{middle dot}57, corresponding to a 43% relative reduction, p=0{middle dot}0018); one additional death was prevented per 20 baricitinib-treated participants. In the more severely ill NIAID-OS 6 subgroup, one additional death was prevented per nine baricitinib-treated participants (HR 0{middle dot}52, corresponding to a 48% relative reduction, p=0{middle dot}0065). We therefore implemented an addendum to the COV-BARRIER trial to evaluate the benefit/risk of baricitinib in the critically ill NIAID-OS 7 population and considered the sample size of 100 participants sufficient for this trial. Added value of this studyThis was the first phase 3 study to evaluate baricitinib in addition to the current standard of care (SOC), including antivirals, anticoagulants, and corticosteroids, in patients who were receiving IMV or extracorporeal membrane oxygenation at enrolment. This was a multinational, randomised, double-blind, placebo-controlled trial in regions with high COVID-19 hospitalisation rates. Treatment with baricitinib reduced 28-day all-cause mortality compared to placebo (HR 0{middle dot}54, 95% CI 0{middle dot}31-0{middle dot}96; nominal p=0{middle dot}030), corresponding to a 46% relative reduction, and significantly reduced 60-day all-cause mortality (HR 0{middle dot}56, 95% CI 0{middle dot}33-0{middle dot}97; p=0{middle dot}027); overall, one additional death was prevented per six baricitinib-treated participants. Numerical improvements in endpoints such as number of ventilator-free days, duration of hospitalisation, and time to recovery were demonstrated. The frequency of serious adverse events, serious infections, and venous thromboembolic events was similar between baricitinib and placebo, respectively. The COV-BARRIER study overall trial results plus these COV-BARRIER addendum study data in mechanically ventilated and ECMO patients provide important information in context of other large, phase 3 randomised trials in participants with invasive mechanical ventilation at baseline. The RECOVERY study reported mortality of 29{middle dot}3% following treatment with dexamethasone compared to 41{middle dot}4% for usual care (rate ratio of 0{middle dot}64, corresponding to a 36% relative reduction) and 49% mortality in participants who received tocilizumab compared to 51% for usual care (rate ratio of 0.93, corresponding to a 7% relative reduction). The ACTT-2 study reported 28-day mortality of 23{middle dot}1% and 22{middle dot}6% in the baricitinib plus remdesivir and placebo plus remdesivir groups, respectively, in this critically ill patient population; however, the primary outcome of this trial was time to recovery, so was not powered to detect a change in mortality. Implications of all the available evidenceIn this phase 3 addendum trial, baricitinib given in addition to SOC (which predominantly included corticosteroids) had a significant effect on mortality reduction by 28 days in critically ill patients, an effect which was maintained by 60 days. These data were comparable with those seen in the COV-BARRIER primary study population of hospitalised patients, but which excluded patients who required IMV or extracorporeal membrane oxygenation at enrolment. These findings suggest that baricitinib has synergistic effects to other SOC treatment modalities including remdesivir and dexamethasone. Based on the available evidence, baricitinib is a novel treatment option to decrease mortality in hospitalised, critically ill patients with COVID-19 even when started late in the disease process after steroids, mechanical ventilation, and ECMO have already been implemented.

Baricitinib plus Standard of Care for Hospitalized Adults with COVID-19

BackgroundBaricitinib, an oral selective Janus kinase 1 and 2 inhibitor, improved outcomes in a previous randomized controlled trial of hospitalized adults with COVID-19, in combination with remdesivir. MethodsIn this phase 3, global, double-blind, randomized, placebo-controlled trial, 1525 hospitalized adults with COVID-19 receiving standard of care (SOC) were randomly assigned (1:1) to once-daily baricitinib 4-mg (N=764) or placebo (N=761) for up to 14 days. SOC included systemic corticosteroids in [~]79% of participants (dexamethasone [~]90%). The primary endpoint was the proportion who progressed to high-flow oxygen, non-invasive ventilation, invasive mechanical ventilation, or death by day 28. A key secondary endpoint was all-cause mortality by day 28. ResultsOverall, 27.8% of participants receiving baricitinib vs 30.5% receiving placebo progressed (primary endpoint, odds ratio 0.85, 95% CI 0.67-1.08; p=0.18). The 28-day all-cause mortality was 8.1% for baricitinib and 13.1% for placebo, corresponding to a 38.2% reduction in mortality (hazard ratio [HR] 0.57, 95% CI 0.41-0.78; nominal p=0.002); 1 additional death was prevented per 20 baricitinib-treated participants. Reduction in mortality was seen for all pre-specified subgroups of baseline severity (most pronounced for participants on high-flow oxygen/non-invasive ventilation at baseline [17.5%, baricitinib vs 29.4%, placebo; HR 0.52, 95% CI 0.33-0.80; nominal p=0.007]). The frequency of adverse events, serious adverse events, serious infections, and venous thromboembolic events was similar between groups. ConclusionsWhile reduction of disease progression did not achieve statistical significance, treatment with baricitinib in addition to SOC (predominantly dexamethasone) significantly reduced mortality with a similar safety profile between groups of hospitalized COVID-19 participants.

Heterogeneous immunological recovery trajectories revealed in post-acute COVID-19

The immunological picture of how different patients recover from COVID-19, and how those recovery trajectories are influenced by infection severity, remain unclear. We investigated 140 COVID-19 patients from diagnosis to convalescence using clinical data, viral load assessments, and multi-omic analyses of blood plasma and circulating immune cells. Immune-phenotype dynamics resolved four recovery trajectories. One trajectory signals a return to pre-infection healthy baseline, while the other three are characterized by differing fractions of persistent cytotoxic and proliferative T cells, distinct B cell maturation processes, and memory-like innate immunity. We resolve a small panel of plasma proteins that, when measured at diagnosis, can predict patient survival and recovery-trajectory commitment. Our study offers novel insights into post-acute immunological outcomes of COVID-19 that likely influence long-term adverse sequelae.

Application of a 27-protein candidate cardiovascular surrogate endpoint to track risk ascendancy and resolution in COVID-19.

BackgroundThere is an urgent need for tools allowing the early prognosis and subsequent monitoring of individuals with heterogeneous COVID-19 disease trajectories. Pre-existing cardiovascular (CV) disease is a leading risk factor for COVID-19 susceptibility and poor outcomes, and cardiac involvement is prevalent in COVID-19 patients both during the acute phase as well as in convalescence. The utility of traditional CV risk biomarkers in mild COVID-19 disease or across disease course is poorly understood. We sought to determine if a previously validated 27-protein predictor of CV outcomes served a purpose in COVID-19. MethodsThe 27-protein test of residual CV (RCV) risk was applied without modification to n=860 plasma samples from hospitalized and non-hospitalized SARS-CoV-2 infected individuals at disease presentation from three independent cohorts to predict COVID-19 severity and mortality. The same test was applied to an additional n=991 longitudinal samples to assess sensitivity to change in CV risk throughout the course of infection into convalescence. ResultsIn each independent cohort, RCV predictions were significantly related to maximal subsequent COVID-19 severity and to mortality. At the baseline blood draw, the mean protein-predicted likelihood of an event in subjects who died during the study period ranged from 88-99% while it ranged from 8-36% in subjects who were not admitted to hospital. Additionally, the test outperformed existing risk predictors based on commonly used laboratory chemistry values or presence of comorbidities. Application of the RCV test to sequential samples showed dramatic increases in risk during the first few days of infection followed by risk reduction in the survivors; a period of catastrophically high cardiovascular risk (above 50%) typically lasted 8-12 days and had not resolved to normal levels in most people within that timescale. ConclusionsThe finding that a 27-protein candidate CV surrogate endpoint developed in multi-morbid patients prior to the pandemic is both prognostic and acutely sensitive to the adverse effects of COVID-19 suggests that this disease activates the same biologic risk-related mechanisms. The test may be useful for monitoring recovery and drug response.

Characteristics and Factors Associated with COVID-19 Infection, Hospitalization, and Mortality Across Race and Ethnicity

BackgroundData on the characteristics of COVID-19 patients disaggregated by race/ethnicity remain limited. We evaluated the sociodemographic and clinical characteristics of patients across racial/ethnic groups and assessed their associations with COVID-19 outcomes. MethodsThis retrospective cohort study examined 629,953 patients tested for SARS-CoV-2 in a large health system spanning California, Oregon, and Washington between March 1 and December 31, 2020. Sociodemographic and clinical characteristics were obtained from electronic health records. Odds of SARS-CoV-2 infection, COVID-19 hospitalization, and in-hospital death were assessed with multivariate logistic regression. Results570,298 patients with known race/ethnicity were tested for SARS-CoV-2, of whom 27.8% were non-White minorities. 54,645 individuals tested positive, with minorities representing 50.1%. Hispanics represented 34.3% of infections but only 13.4% of tests. While generally younger than White patients, Hispanics had higher rates of diabetes but fewer other comorbidities. 8,536 patients were hospitalized and 1,246 died, of whom 56.1% and 54.4% were non-White, respectively. Racial/ethnic distributions of outcomes across the health system tracked with state-level statistics. Increased odds of testing positive and hospitalization were associated with all minority races/ethnicities. Hispanic patients also exhibited increased morbidity, and Hispanic race/ethnicity was associated with in-hospital mortality (OR: 1.39 [95% CI: 1.14-1.70]). ConclusionMajor healthcare disparities were evident, especially among Hispanics who tested positive at a higher rate, required excess hospitalization and mechanical ventilation, and had higher odds of in-hospital mortality despite younger age. Targeted, culturally-responsive interventions and equitable vaccine development and distribution are needed to address the increased risk of poorer COVID-19 outcomes among minority populations. Key pointsRacial/ethnic disparities are evident in the disaggregated characteristics of COVID-19 patients. Minority patients experience increased odds of SARS-CoV-2 infection and COVID-19 hospitalization. Hospitalized Hispanic patients presented with more severe illness, experienced increased morbidity, and faced increased mortality.

Reinfection with SARS-CoV-2 and Failure of Humoral Immunity: a case report.

Recovery from COVID-19 is associated with production of anti-SARS-CoV-2 antibodies, but it is uncertain whether these confer immunity. We describe viral RNA shedding duration in hospitalized patients and identify patients with recurrent shedding. We sequenced viruses from two distinct episodes of symptomatic COVID-19 separated by 144 days in a single patient, to conclusively describe reinfection with a new strain harboring the spike variant D614G. With antibody and B cell analytics, we show correlates of adaptive immunity, including a differential response to D614G. Finally, we discuss implications for vaccine programs and begin to define benchmarks for protection against reinfection from SARS-CoV-2.

Magnitude and Dynamics of the T-Cell Response to SARS-CoV-2 Infection at Both Individual and Population Levels

T cells are involved in the early identification and clearance of viral infections and also support the development of antibodies by B cells. This central role for T cells makes them a desirable target for assessing the immune response to SARS-CoV-2 infection. Here, we combined two high-throughput immune profiling methods to create a quantitative picture of the T-cell response to SARS-CoV-2. First, at the individual level, we deeply characterized 3 acutely infected and 58 recovered COVID-19 subjects by experimentally mapping their CD8 T-cell response through antigen stimulation to 545 Human Leukocyte Antigen (HLA) class I presented viral peptides (class II data in a forthcoming study). Then, at the population level, we performed T-cell repertoire sequencing on 1,815 samples (from 1,521 COVID-19 subjects) as well as 3,500 controls to identify shared "public" T-cell receptors (TCRs) associated with SARS-CoV-2 infection from both CD8 and CD4 T cells. Collectively, our data reveal that CD8 T-cell responses are often driven by a few immunodominant, HLA-restricted epitopes. As expected, the T-cell response to SARS-CoV-2 peaks about one to two weeks after infection and is detectable for at least several months after recovery. As an application of these data, we trained a classifier to diagnose SARSCoV-2 infection based solely on TCR sequencing from blood samples, and observed, at 99.8% specificity, high early sensitivity soon after diagnosis (Day 3-7 = 85.1% [95% CI = 79.9-89.7]; Day 8-14 = 94.8% [90.7-98.4]) as well as lasting sensitivity after recovery (Day 29+/convalescent = 95.4% [92.1-98.3]). These results demonstrate an approach to reliably assess the adaptive immune response both soon after viral antigenic exposure (before antibodies are typically detectable) as well as at later time points. This blood-based molecular approach to characterizing the cellular immune response has applications in clinical diagnostics as well as in vaccine development and monitoring.

Multiomic Immunophenotyping of COVID-19 Patients Reveals Early Infection Trajectories

Host immune responses play central roles in controlling SARS-CoV2 infection, yet remain incompletely characterized and understood. Here, we present a comprehensive immune response map spanning 454 proteins and 847 metabolites in plasma integrated with single-cell multi-omic assays of PBMCs in which whole transcriptome, 192 surface proteins, and T and B cell receptor sequence were co-analyzed within the context of clinical measures from 50 COVID19 patient samples. Our study reveals novel cellular subpopulations, such as proliferative exhausted CD8+ and CD4+ T cells, and cytotoxic CD4+ T cells, that may be features of severe COVID-19 infection. We condensed over 1 million immune features into a single immune response axis that independently aligns with many clinical features and is also strongly associated with disease severity. Our study represents an important resource towards understanding the heterogeneous immune responses of COVID-19 patients and may provide key information for informing therapeutic development.

Shared Antigen-specific CD8+ T cell Responses Against the SARS-COV-2 Spike Protein in HLA A*02:01 COVID-19 Participants

We report here on antigens from the SARS-CoV-2 virus spike protein, that when presented by Class I MHC, can lead to cytotoxic CD8+ T cell anti-viral responses in COVID-19 patients. We present a method in which the SARS-CoV-2 spike protein is converted into a library of peptide antigen-Major Histocompatibility Complexes (pMHCs) as single chain trimers that contain the peptide antigen, the MHC HLA allele subunit, and the {beta}-2 microglobulin subunit. This library is used to detect the evolution of virus-specific T cell populations in four COVID-19 study participants two of which share one HLA allele, and the other two a second HLA allele, at two time points over the initial course of infection. HLA-matched participants exhibit similar virus-specific T cell populations, but very different time-trajectories of those populations. This strategy can be used to track those virus-specific T cell populations over the course of an infection, thus providing deep insight into the SARS-CoV-2 immune system trajectories observed in different COVID-19 patients.