ABSTRACT
Background: We investigated whether abatacept, a selective costimulation modulator, provides additional benefit when added to standard-of-care for patients hospitalized with Covid-19. Methods: We conducted a master protocol to investigate immunomodulators for potential benefit treating patients hospitalized with Covid-19 and report results for abatacept. Intravenous abatacept (one-time dose 10 mg/kg, maximum dose 1000 mg) plus standard of care (SOC) was compared with shared placebo plus SOC. Primary outcome was time-to-recovery by day 28. Key secondary endpoints included 28-day mortality. Results: Between October 16, 2020 and December 31, 2021, a total of 1019 participants received study treatment (509 abatacept; 510 shared placebo), constituting the modified intention-to-treat cohort. Participants had a mean age 54.8 (SD 14.6) years, 60.5% were male, 44.2% Hispanic/Latino and 13.7% Black. No statistically significant difference for the primary endpoint of time-to-recovery was found with a recovery-rate-ratio of 1.14 (95% CI 1.00-1.29; p=0.057) compared with placebo. We observed a substantial improvement in 28-day all-cause mortality with abatacept versus placebo (11.0% vs. 15.1%; odds ratio [OR] 0.62 [95% CI 0.41-0.94]), leading to 38% lower odds of dying. Improvement in mortality occurred for participants requiring oxygen/noninvasive ventilation at randomization. Subgroup analysis identified the strongest effect in those with baseline C-reactive protein >75mg/L. We found no statistically significant differences in adverse events, with safety composite index slightly favoring abatacept. Rates of secondary infections were similar (16.1% for abatacept; 14.3% for placebo). Conclusions: Addition of single-dose intravenous abatacept to standard-of-care demonstrated no statistically significant change in time-to-recovery, but improved 28-day mortality. Trial registration: ClinicalTrials.gov (NCT04593940).
Subject(s)
COVID-19ABSTRACT
BackgroundImmune dysregulation contributes to poorer outcomes in severe Covid-19. Immunomodulators targeting various pathways have improved outcomes. We investigated whether infliximab provides benefit over standard of care. MethodsWe conducted a master protocol investigating immunomodulators for potential benefit in treatment of participants hospitalized with Covid-19 pneumonia. We report results for infliximab (single dose infusion) versus shared placebo both with standard of care. Primary outcome was time to recovery by day 29 (28 days after randomization). Key secondary endpoints included 14-day clinical status and 28-day mortality. ResultsA total of 1033 participants received study drug (517 infliximab, 516 placebo). Mean age was 54.8 years, 60.3% were male, 48.6% Hispanic or Latino, and 14% Black. No statistically significant difference in the primary endpoint was seen with infliximab compared with placebo (recovery rate ratio 1.13, 95% CI 0.99-1.29; p=0.063). Median (IQR) time to recovery was 8 days (7, 9) for infliximab and 9 days (8, 10) for placebo. Participants assigned to infliximab were more likely to have an improved clinical status at day 14 (OR 1.32, 95% CI 1.05-1.66). Twenty-eight-day mortality was 10.1% with infliximab versus 14.5% with placebo, with 41% lower odds of dying in those receiving infliximab (OR 0.59, 95% CI 0.39-0.90). No differences in risk of serious adverse events including secondary infections. ConclusionsInfliximab did not demonstrate statistically significant improvement in time to recovery. It was associated with improved 14-day clinical status and substantial reduction in 28- day mortality compared with standard of care. Trial registrationClinicalTrials.gov (NCT04593940).
Subject(s)
Pneumonia , COVID-19ABSTRACT
BACKGROUNDEquity in vaccination coverage is a cornerstone to a successful public health response to COVID-19. To deepen understand of the extent to which vaccination coverage compared to initial strategies for equitable vaccination, we explore primary vaccine series and booster rollout over time and by race/ethnicity, social vulnerability, and geography. METHODS AND FINDINGSWe analyzed data from the Missouri State Department of Health and Senior Services on all COVID-19 vaccinations administered across 7 counties in the St. Louis region and 4 counties in the Kansas City Region. We compared rates of receiving the primary COVID-19 vaccine series and boosters relative to time, race/ethnicity, zip code-level social vulnerability index (SVI), vaccine location type, and COVID-19 disease burden. We adapted a well-established tool for measuring inequity--the Lorenz curve--to quantify inequities in COVID-19 vaccination relative to these key metrics. Between 12/15/2020 and 2/15/2022, 1,762,508 individuals completed the primary series and 871,896 had received a booster. During early phases of the primary series rollout, Black and Hispanic individuals from high SVI zip codes were vaccinated at less than half the rate of White individuals, but rates increased over time until they were higher than rates in White individuals after June 2021; Asian individuals maintained high levels of vaccination throughout. Increasing vaccination rates in Black and Hispanic communities corresponded with periods when more vaccinations were offered at small community-based sites such as pharmacies rather than larger health systems and mass vaccination sites. Using Lorenz curves, zip codes in the quartile with the lowest rates of primary series completion accounted for 19.3%, 18.1%, 10.8%, and 8.8% of vaccinations but represented 25% of either the total population, cases, deaths, or population-level SVI, respectively. When tracking Gini coefficients, these disparities were greatest earlier during rollout, but improvements were slow and modest and vaccine disparities remained across all metrics even after one year. Patterns of disparities for boosters were similar but often of much greater magnitude during rollout in Fall 2021. Study limitations include inherent limitations in vaccine registry dataset such as missing and misclassified race/ethnicity and zip code variables and potential changes in zip code population sizes since census enumeration. CONCLUSIONSRacial inequity in the initial COVID-19 vaccination and booster rollout in two large U.S. metropolitan areas were apparent across racial/ethnic communities, across levels of social vulnerability, over time, and across types of vaccination administration sites. Disparities in receipt of the primary vaccine series attenuated over time during a period in which sites of vaccination administration diversified, but were recapitulated during booster rollout. These findings highlight how public health strategies from the outset must directly target these deeply embedded structural and systemic determinants of disparities and track equity metrics over time to avoid perpetuating inequities in health care access. AUTHOR SUMMARYO_ST_ABSWhy Was This Study Done?C_ST_ABSO_LIEquitable vaccine strategies are critical for the public health response to COVID-19, but there is limited understanding of how vaccination campaigns compared to different metrics for equity. C_LIO_LIMany initial approaches to vaccine allocation sought to acknowledge the known disparities in exposure risk, disease burden, needs, and access by formally considering social vulnerability or race/ethnicity in plans to prioritize vaccinations, but there is limited empirical evaluation of how actual primary vaccine series and subsequent booster efforts aligned with the initial goals set out for equity. C_LIO_LIWe quantify COVID-19 vaccine-related inequities in receipt of the primary vaccine series and booster across key equity metrics including race/ethnicity, social vulnerability, location, and time using a novel application of Lorenz curves and Gini coefficients--tools from economics to measure inequalities--in the St. Louis and Kansas City regions of Missouri. C_LI What Did the Researchers Do and Find?O_LIWe analyzed data from the Missouri State Department of Health and Senior Services on all COVID-19 vaccinations administered in the St. Louis region and Kansas City Regions. We compared rates of receiving the primary COVID-19 vaccine series and boosters relative to time, race/ethnicity, zip code-level social vulnerability index (SVI), vaccine location type, and COVID-19 disease burden. We adapted Lorenz curves and Gini coefficients to quantify the inequities in COVID-19 vaccination relative to these key metrics and examined how they changed over time. C_LIO_LIBlack and Hispanic individuals from high SVI zip codes completed the primary series at less than half the rate of White individuals during early phases of the primary series rollout, but surpassed rates in White individuals after June 2021. These relative increases in primary series completion rates in Black and Hispanic communities corresponded to periods when vaccinations became more available at small community-based sites. C_LIO_LILorenz curves demonstrated that zip codes in the quartile with the lowest rates of primary series completion accounted for 19.3%, 18.1%, 10.8%, and 8.8% of vaccinations but represented 25% of either the total population, cases, deaths, or population-level SVI, respectively. Tracking Gini coefficients over time demonstrated that these disparities were greatest earlier during rollout, but only improved slowly and modestly over time. C_LIO_LIPatterns of disparities for boosters were similar but often of much greater magnitude that those seen with completion of the primary vaccine series. patterns of disparities were similar but often of greater magnitude during booster rollout in Fall 2021. C_LI What Do These Findings Mean?O_LIVaccination coverage for both the primary series and boosters demonstrated substantial disparities across race/ethnicity, levels of social vulnerability, types of vaccine administration sites, and over time. C_LIO_LIDespite well-documented inequities for COVID-19 and need for equitable vaccine approaches, the strategies employed did not overcome deeply entrenched systemic inequities in health care and society. C_LIO_LIPublic health strategies must proactively target these deeply embedded structural determinants of disparities from the outset and should systematically track equity metrics over time to avoid perpetuating inequities in health care access. C_LI
Subject(s)
Death , COVID-19ABSTRACT
Coronavirus disease 2019 (COVID-19) is characterized by a high incidence of acute respiratory failure. The underlying immunopathology of that failure and how it compares to other causes of severe respiratory distress, such as influenza virus infection, are not fully understood. Here we addressed this by developing a prospective observational cohort of COVID-19 and influenza subjects with varying degrees of disease severity and assessing the quality and magnitude of their immune responses at the cellular and protein level. Additionally, we performed single-cell RNA transcriptional profiling of peripheral blood mononuclear cells from select subjects. The cohort consists of 79 COVID-19 subjects, 26 influenza subjects, and 15 control subjects, including 35 COVID-19 and 7 influenza subjects with acute respiratory failure. While COVID-19 subjects exhibited largely equivalent or greater activated lymphocyte counts compared to influenza subjects, they had fewer monocytes and lower surface HLA-class II expression on monocytes compared to influenza subjects and controls. At least two distinct immune profiles were observed by cytokine levels in severe COVID-19 patients: 3 of 71 patients were characterized by extreme inflammation, with greater than or equal to ~50% of the 35 cytokines measured greater than 2 standard deviations from the mean level of other severe patients (both influenza and COVID-19); the other immune profile, which characterized 68 of 71 subjects, had a mixed inflammatory signature, where 28 of 35 cytokines in COVID-19 patients had lower mean cytokine levels, though not all were statistically significant. Only 2 cytokines were higher in COVID-19 subjects compared to influenza subjects (IL-6 and IL-8). Influenza and COVID-19 patients could be distinguished statistically based on cytokine module expression, particularly after controlling for the significant effects of age on cytokine expression, but again with lower levels of most cytokines in COVID-19 subjects. Further, high circulating levels of IL-1RA and IL-6 were associated with increased odds of intubation in the combined influenza and COVID-19 cohort [OR = 3.93 and 4.30, respectively] as well as among only COVID-19 patients. Single cell transcriptional profiling of COVID-19 and influenza subjects with respiratory failure identified profound suppression in type I and type II interferon signaling in COVID-19 patients across multiple clusters. In contrast, COVID-19 cell clusters were enriched for alterations in metabolic, stress, and apoptotic pathways. These alterations were consistent with an increased glucocorticoid response in COVID-19 patients compared to influenza. When considered across the spectrum of innate and adaptive immune profiles, the immune pathologies underlying severe influenza and COVID-19 are substantially distinct. The majority of COVID-19 patients with acute respiratory failure do not have a cytokine storm phenotype but instead exhibit profound type I and type II IFN immunosuppression when compared to patients with acute influenza. Upregulation of a small number of inflammatory mediators, including IL-6, predicts acute respiratory failure in both COVID-19 and influenza patients.