RESUMO
We sought to identify the primary causes of death of adult patients admitted to the medical ICU with symptomatic COVID-19 who ultimately suffered in-hospital mortality over the span of three major waves of COVID-19: Wild-type, alpha/epsilon, and delta. DESIGN: Retrospective single-center cohort study from March 2020 to December 2021. SETTING: One medical ICU in a 600-bed Tertiary Care Hospital in Los Angeles, CA. PATIENTS: Adult (n = 306) ICU patients admitted with symptomatic COVID-19 who suffered in-hospital mortality. INTERVENTIONS: None. MAIN RESULTS: Of the 306 patients with COVID-19 who died in the hospital, 86.3% were Hispanic/Latino. The leading cause of death was respiratory failure, occurring in 57.8% of patients. There was no significant change in the rate of pulmonary deaths across the three waves of COVID-19 in our study period. The mean time from symptom onset to admission was 6.5 days, with an average hospital length of stay of 18 days. This did not differ between pulmonary and other causes of death. Sepsis was the second most common cause of death at 23.9% with a significant decrease from the wild-type wave to the delta wave. Among patients with sepsis as the cause of death, 22% (n = 16) were associated with fungemia. There was no significant association between steroid administration and cause of death. Lastly, the alpha/epsilon wave from December 2020 to May 2021 had the highest mortality rate when compared with wild-type or delta waves. CONCLUSIONS: We found the primary cause of death in ICU patients with COVID-19 was acute respiratory failure, without significant changes over the span of three waves of COVID-19. This finding contrasts with reported causes of death for patients with non-COVID-19 acute respiratory distress syndrome, in which respiratory failure is an uncommon cause of death. In addition, we identified a subset of patients (5%) who died primarily due to fungemia, providing an area for further investigation.
RESUMO
Recombinant, Escherichia coli-derived outer membrane vesicles (rOMVs), which display heterologous protein subunits, have potential as a vaccine adjuvant platform. One drawback to rOMVs is their lipopolysaccharide (LPS) content, limiting their translatability to the clinic due to potential adverse effects. Here, we explore a unique rOMV construct with structurally remodeled lipids containing only the lipid IVa portion of LPS, which does not stimulate human TLR4. The rOMVs are derived from a genetically engineered B strain of E. coli, ClearColi, which produces lipid IVa, and which was further engineered in our laboratory to hypervesiculate and make rOMVs. We report that rOMVs derived from this lipid IVa strain have substantially attenuated pyrogenicity yet retain high levels of immunogenicity, promote dendritic cell maturation, and generate a balanced Th1/Th2 humoral response. Additionally, an influenza A virus matrix 2 protein-based antigen displayed on these rOMVs resulted in 100% survival against a lethal challenge with two influenza A virus strains (H1N1 and H3N2) in mice with different genetic backgrounds (BALB/c, C57BL/6, and DBA/2J). Additionally, a two-log reduction of lung viral titer was achieved in a ferret model of influenza infection with human pandemic H1N1. The rOMVs reported herein represent a potentially safe and simple subunit vaccine delivery platform.