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Crit Care ; 25(1): 171, 2021 05 17.
Article in English | MEDLINE | ID: covidwho-1232432


BACKGROUND: Estimates for dead space ventilation 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, multicenter, 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 wasted ventilation in patients with COVID-19-related ARDS. RESULTS: A total of 927 consecutive patients admitted with COVID-19-related ARDS were included in this study. Estimations of wasted 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 with an increase in 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 dead space estimates 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. TRIAL REGISTRATION: ISRCTN04346342. Registered 15 April 2020. Retrospectively registered.

COVID-19/mortality , Patient Acuity , Respiration, Artificial , Respiratory Dead Space , Respiratory Distress Syndrome/therapy , Adult , Biomarkers , COVID-19/complications , COVID-19/physiopathology , Female , Humans , Intensive Care Units , Male , Prognosis , ROC Curve , Respiratory Distress Syndrome/etiology , Respiratory Function Tests , Respiratory Mechanics , Retrospective Studies
Cell ; 184(10): 2618-2632.e17, 2021 05 13.
Article in English | MEDLINE | ID: covidwho-1157174


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), an FDA-approved TOP1 inhibitor, suppresses infection-induced inflammation in hamsters. TPT treatment as late as 4 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 severe coronavirus disease 2019 (COVID-19) in humans.

COVID-19 Drug Treatment , DNA Topoisomerases, Type I/metabolism , SARS-CoV-2/metabolism , Topoisomerase I Inhibitors/pharmacology , Topotecan/pharmacology , Animals , COVID-19/enzymology , COVID-19/pathology , Chlorocebus aethiops , Humans , Inflammation/drug therapy , Inflammation/enzymology , Inflammation/pathology , Inflammation/virology , Mesocricetus , Mice , Mice, Transgenic , THP-1 Cells , Vero Cells
Arterioscler Thromb Vasc Biol ; 40(11): 2586-2597, 2020 11.
Article in English | MEDLINE | ID: covidwho-1015731


The severe acute respiratory syndrome coronavirus-2 emerged as a serious human pathogen in late 2019, causing the disease coronavirus disease 2019 (COVID-19). The most common clinical presentation of severe COVID-19 is acute respiratory failure consistent with the acute respiratory distress syndrome. Airway, lung parenchymal, pulmonary vascular, and respiratory neuromuscular disorders all feature in COVID-19. This article reviews what is known about the effects of severe acute respiratory syndrome coronavirus-2 infection on different parts of the respiratory system, clues to understanding the underlying biology of respiratory disease, and highlights current and future translation and clinical research questions.

Betacoronavirus/pathogenicity , Coronavirus Infections/virology , Lung/virology , Pneumonia, Viral/virology , Respiration , Respiratory Distress Syndrome/virology , Respiratory Insufficiency/virology , Translational Research, Biomedical , Animals , COVID-19 , Coronavirus Infections/diagnosis , Coronavirus Infections/physiopathology , Coronavirus Infections/therapy , Host-Pathogen Interactions , Humans , Lung/physiopathology , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/physiopathology , Pneumonia, Viral/therapy , Prognosis , Pulmonary Embolism/physiopathology , Pulmonary Embolism/therapy , Pulmonary Embolism/virology , Respiration, Artificial , Respiratory Distress Syndrome/diagnosis , Respiratory Distress Syndrome/physiopathology , Respiratory Distress Syndrome/therapy , Respiratory Insufficiency/diagnosis , Respiratory Insufficiency/physiopathology , Respiratory Insufficiency/therapy , Risk Factors , SARS-CoV-2 , Venous Thromboembolism/physiopathology , Venous Thromboembolism/therapy , Venous Thromboembolism/virology
JAMA Pediatr ; 175(3): 240-242, 2021 03 01.
Article in English | MEDLINE | ID: covidwho-962135