Impaired Ventilation Is Not Independently Associated With 28-day Mortality in COVID-19 ARDS (preprint)

Background: Surrogates for impaired ventilation such as estimated dead-space fractions and the ventilatory ratio have been shown to be independently associated with an increased risk of mortality in the acute respiratory distress syndrome and small case series of COVID-19 related ARDS. Methods: Secondary analysis from the PRoVENT-COVID study. The PRoVENT-COVID is a national, multicentre, retrospective observational study done at 22 intensive care units in the Netherlands. Consecutive patients aged at least 18 years were eligible for participation if they had received invasive ventilation for COVID-19 at a participating ICU during the first month of the national outbreak in the Netherlands. The aim was to quantify the dynamics and determine the prognostic value of surrogate markers of impaired ventilation patients with COVID-19 related ARDS. Results: 927 consecutive patients admitted with COVID-19 related ARDS were included in this study. Surrogates of impaired ventilation such as the estimated dead space fraction (by Harris-Benedict and direct method) and ventilatory ratio were significantly higher in non-survivors than survivors at baseline and during the following days of mechanical ventilation (p <0.001). The end-tidal-to-arterial PCO2 ratio was lower in non-survivors than in survivors (p<0.001). As ARDS severity increased, mortality increased with successive tertiles of dead space fraction by Harris-Benedict and by direct estimation, and for the VR. The same trend was observed with decreased levels in the tertiles for the end-tidal-to-arterial PCO2 ratio. After adjustment for a base risk model that included chronic comorbidities and ventilation- and oxygenation-parameters, none of the surrogates of impaired ventilation measured at the start of ventilation or the following days were significantly associated with 28-day mortality.Conclusions: There is significant impairment of ventilation in the early course of COVID-19 related ARDS but quantification of this impairment does not add prognostic information when added to a baseline risk-model.

Topoisomerase 1 inhibition therapy protects against SARS-CoV-2-induced inflammation and death in animal models. (preprint)

The ongoing pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is currently affecting millions of lives worldwide. Large retrospective studies indicate that an elevated level of inflammatory cytokines and pro-inflammatory factors are associated with both increased disease severity and mortality. Here, using multidimensional epigenetic, transcriptional, in vitro and in vivo analyses, we report that Topoisomerase 1 (Top1) inhibition suppresses lethal inflammation induced by SARS-CoV-2. Therapeutic treatment with two doses of Topotecan (TPT), a FDA-approved Top1 inhibitor, suppresses infection-induced inflammation in hamsters. TPT treatment as late as four days post-infection reduces morbidity and rescues mortality in a transgenic mouse model. These results support the potential of Top1 inhibition as an effective host-directed therapy against severe SARS-CoV-2 infection. TPT and its derivatives are inexpensive clinical-grade inhibitors available in most countries. Clinical trials are needed to evaluate the efficacy of repurposing Top1 inhibitors for COVID-19 in humans.

Designed proteins assemble antibodies into modular nanocages (preprint)

Antibodies are widely used in biology and medicine, and there has been considerable interest in multivalent antibody formats to increase binding avidity and enhance signaling pathway agonism. However, there are currently no general approaches for forming precisely oriented antibody assemblies with controlled valency. We describe the computational design of two-component nanocages that overcome this limitation by uniting form and function. One structural component is any antibody or Fc fusion and the second is a designed Fc-binding homo-oligomer that drives nanocage assembly. Structures of 8 antibody nanocages determined by electron microscopy spanning dihedral, tetrahedral, octahedral, and icosahedral architectures with 2, 6, 12, and 30 antibodies per nanocage match the corresponding computational models. Antibody nanocages targeting cell-surface receptors enhance signaling compared to free antibodies or Fc-fusions in DR5-mediated apoptosis, Tie2-mediated angiogenesis, CD40 activation, and T cell proliferation; nanocage assembly also increases SARS-CoV-2 pseudovirus neutralization by -SARS-CoV-2 monoclonal antibodies and Fc-ACE2 fusion proteins. We anticipate that the ability to assemble arbitrary antibodies without need for covalent modification into highly ordered assemblies with different geometries and valencies will have broad impact in biology and medicine.