Efficacy and safety of metabolic interventions for the treatment of severe COVID-19: in vitro, observational, and non-randomized open-label interventional study

Background: Viral infection is associated with a significant rewire of the host metabolic pathways, presenting attractive metabolic targets for intervention. Methods: We chart the metabolic response of lung epithelial cells to SARS-CoV-2 infection in primary cultures and COVID-19 patient samples and perform in vitro metabolism-focused drug screen on primary lung epithelial cells infected with different strains of the virus. We perform observational analysis of Israeli patients hospitalized due to COVID-19 and comparative epidemiological analysis from cohorts in Italy and the Veteran's Health Administration in the United States. In addition, we perform a prospective non-randomized interventional open-label study in which 15 patients hospitalized with severe COVID-19 were given 145 mg/day of nanocrystallized fenofibrate added to the standard of care. Results: SARS-CoV-2 infection produced transcriptional changes associated with increased glycolysis and lipid accumulation. Metabolism-focused drug screen showed that fenofibrate reversed lipid accumulation and blocked SARS-CoV-2 replication through a PPARα-dependent mechanism in both alpha and delta variants. Analysis of 3233 Israeli patients hospitalized due to COVID-19 supported in vitro findings. Patients taking fibrates showed significantly lower markers of immunoinflammation and faster recovery. Additional corroboration was received by comparative epidemiological analysis from cohorts in Europe and the United States. A subsequent prospective non-randomized interventional open-label study was carried out on 15 patients hospitalized with severe COVID-19. The patients were treated with 145 mg/day of nanocrystallized fenofibrate in addition to standard-of-care. Patients receiving fenofibrate demonstrated a rapid reduction in inflammation and a significantly faster recovery compared to patients admitted during the same period. Conclusions: Taken together, our data suggest that pharmacological modulation of PPARα should be strongly considered as a potential therapeutic approach for SARS-CoV-2 infection and emphasizes the need to complete the study of fenofibrate in large randomized controlled clinical trials. Funding: Funding was provided by European Research Council Consolidator Grants OCLD (project no. 681870) and generous gifts from the Nikoh Foundation and the Sam and Rina Frankel Foundation (YN). The interventional study was supported by Abbott (project FENOC0003). Clinical trial number: NCT04661930

Mortality in Central Java: results from the indonesian mortality registration system strengthening project

Background. Mortality statistics from death registration systems are essential for health policy and development. Indonesia has recently mandated compulsory death registration across the entire country in December 2006. This article describes the methods and results from activities to ascertain causes of registered deaths in two pilot registration areas in Central Java during 2006-2007. The methods involved several steps, starting with adaptation of international standards for reporting causes of registered deaths for implementation in two sites, Surakarta (urban) and Pekalongan (rural). Causes for hospital deaths were certified by attending physicians. Verbal autopsies were used for home deaths. Underlying causes were coded using ICD-10. Completeness of registration was assessed in a sample of villages and urban wards by triangulating data from the health sector, the civil registration system, and an independent household survey. Finally, summary mortality indicators and cause of death rankings were developed for each site. Findings. A total of 10,038 deaths were registered in the two sites during 2006-2007; yielding annual crude death rates of 5.9 to 6.8 per 1000. Data completeness was higher in rural areas (72.5%) as compared to urban areas (52%). Adjusted life expectancies at birth were higher for both males and females in the urban population as compared to the rural population. Stroke, ischaemic heart disease and chronic respiratory disease are prominent causes in both populations. Other important causes are diabetes and cancer in urban areas; and tuberculosis and diarrhoeal diseases in rural areas. Conclusions. Non-communicable diseases cause a significant proportion of premature mortality in Central Java. Implementing cause of death reporting in conjunction with death registration appears feasible in Indonesia. Better collaboration between health and registration sectors is required to improve data quality. These are the first local mortality measures for health policy and monitoring in Indonesia. Strong demand for data from different stakeholders can stimulate further strengthening of mortality registration systems

Index Files

Index File

Appendix A. The bivariate Gaussian log-linear model.

The bivariate Gaussian log-linear model