ABSTRACT
Background. COVID-19 vaccines reduce the incidence of severe clinical outcomes, however, some patients remain at risk of severe disease. The primary aim of this large, nationwide retrospective cohort was to identify risk factors for severe disease despite vaccination. Methods. Nationwide cohort study of US Veteran patients with laboratoryconfirmed SARS-CoV-2 infection after vaccination. The primary outcome was development of severe COVID-19 disease, defined as a hospitalization within 14 days of a positive SARS-CoV-2 diagnostic test and either SpO2 <= 94%, receipt of supplemental oxygen, mechanical ventilation, or death within 28 days. Exposure variables included demographic and clinical risk factors, receipt of an additional vaccine dose, and calendar months since initial vaccination series. Data were analyzed using logistic regression, and adjusted odds ratios (aORs) are presented. Results. Among 111,151 breakthrough infections, 110,760 had disease severity assessments and were included. 14,690/110,790 (13.3%) were hospitalized with severe COVID-19 or died. Risk factors for severe disease are presented in Figure 1. The strongest risk factor for severe disease despite vaccination was age. Immunocompromising conditions, including immunosuppressive medications (Cytokine-blocking, aOR, 1.73, CI, 1.37-2.18;receipt of glucocorticoids, aOR, 2.41, CI, 2.25, 2.58;leukocyte inhibitory, aOR 2.44, CI, 1.98-2.99;lymphocyte-depleting, aOR, 2.12, 1.61-2.79), cytotoxic chemotherapy within 6 months (aOR, 2.69;CI, 2.25, 3.21), and leukemias/lymphomas were also associated with increased risk (aOR, 1.84, CI, 1.59-2.14), as were chronic conditions associated with end-organ disease. Receipt of an additional (booster) dose of vaccine was associated with reduced odds of severe disease, with risk reduction from vaccination and boosting strongest during the months immediately following vaccine doses. Variables with aOR <1 are associated with reduced odds of severe breakthrough infections and variables with aOR >1 are associated with increased odds of severe breakthrough infections. Referent groups for multicategory variables are listed in bold. Presented with a logarithmic scale. Conclusion. In this nationwide cohort, we identified risk factors for severe disease despite vaccination. Findings can be used to inform outreach efforts for booster vaccinations and to inform clinical decision making about risk and to identify patients who would benefit from interventions in addition to vaccination, such as preexposure prophylaxis and antiviral therapy. (Table Presented).
ABSTRACT
Background. The aim of this pragmatic, embedded adaptive trial was to measure the effectiveness of subcutaneous sarilumab in addition to an evolving standard of care for clinical management of inpatients with moderate to severe COVID-19 disease (NCT04359901). The study is also a real-world demonstration of the realization of a prospective learning healthcare system. Methods. Two-arm, randomized, open-label controlled 5-center trial comparing standard care alone to standard care (SOC), which evolved over time, with addition of subcutaneous sarilumab (200 mg or 400 mg anti-IL6R) among hospitalized patients with moderate to severe COVID-19 not requiring mechanical ventilation. The primary outcome was 14-day incidence of intubation or death. The trial used a randomized play-the-winner design and was fully embedded within the EHR system, including the adaptive randomization process. Results. Among 417 patients screened, 162 were eligible based on chart review, 53 consented, and 50 were evaluated for the primary endpoint of intubation or death ( >30% of eligible patients enrolled) (Figure 1). After the second interim review, the unblinded Data Monitoring Committee recommended that the study be stopped due to concern for safety: a high probability that rates of intubation or death were higher with addition of sarilumab to SOC (92.6%), and a very low probability (3.4%) that sarilumab would be found to be superior. Conclusion. This randomized trial of patients hospitalized with COVID-19 and requiring supplemental oxygen but not mechanical ventilation found no evidence of benefit from subcutaneous sarilumab in addition to an evolving standard-of-care. The numbers of patients and events were too low to allow independent conclusions to be drawn, but this study contributes valuable information about the role of subcutaneous IL-6 inhibition in the treatment of patients hospitalized with COVID-19. The major innovation of this trial was the advancement of embedded, point-of-care clinical trials for FDA-approved drugs;this represents a realization of the learning healthcare system. Methods developed and piloted during the conduct of this trial can be used in future investigations to speed the advancement of clinical science.