Dysglycemias in patients admitted to ICUs with severe acute respiratory syndrome due to COVID-19 versus other causes - a cohort study.

BACKGROUND: Dysglycemias have been associated with worse prognosis in critically ill patients with COVID-19, but data on the association of dysglycemia with COVID-19 in comparison with other forms of severe acute respiratory syndrome are lacking. This study aimed to compare the occurrence of different glycemic abnormalities in patients with severe acute respiratory syndrome and COVID-19 admitted to intensive care units versus glycemic abnormalities in patients with severe acute respiratory syndrome from other causes, to evaluate the adjusted attributable risk associated with COVID-19 and dysglycemia and to assess the influence of these dysglycemias on mortality. METHODS: We conducted a retrospective cohort of consecutive patients with severe acute respiratory syndrome and suspected COVID-19 hospitalized in intensive care units between March 11 and September 13, 2020, across eight hospitals in Curitiba-Brazil. The primary outcome was the influence of COVID-19 on the variation of the following parameters of dysglycemia: highest glucose level at admission, mean and highest glucose levels during ICU stay, mean glucose variability, percentage of days with hyperglycemia, and hypoglycemia during ICU stay. The secondary outcome was the influence of COVID-19 and each of the six parameters of dysglycemia on hospital mortality within 30 days from ICU admission. RESULTS: The sample consisted of 841 patients, of whom 703 with and 138 without COVID-19. Comparing patients with and without COVID-19, those with COVID-19 had significantly higher glucose peaks at admission (165 mg/dL vs. 146 mg/dL; p = 0.002) and during ICU stay (242 mg/dL vs. 187md/dL; p < 0.001); higher mean daily glucose (149.7 mg/dL vs. 132.6 mg/dL; p < 0.001); higher percentage of days with hyperglycemia during ICU stay (42.9% vs. 11.1%; p < 0.001); and greater mean glucose variability (28.1 mg/dL vs. 25.0 mg/dL; p = 0.013). However, these associations were no longer statistically significant after adjustment for Acute Physiology and Chronic Health Evaluation II scores, Sequential Organ Failure Assessment scores, and C-reactive protein level, corticosteroid use and nosocomial infection. Dysglycemia and COVID-19 were each independent risk factors for mortality. The occurrence of hypoglycemia (< 70 mg/dL) during ICU stay was not associated with COVID-19. CONCLUSION: Patients with severe acute respiratory syndrome due to COVID-19 had higher mortality and more frequent dysglycemia than patients with severe acute respiratory syndrome due to other causes. However, this association did not seem to be directly related to the SARS-CoV-2 infection.

COVID-19-related hyperglycemia is associated with infection of hepatocytes and stimulation of gluconeogenesis.

Occurrence of hyperglycemia upon infection is associated with worse clinical outcome in COVID-19 patients. However, it is still unknown whether SARS-CoV-2 directly triggers hyperglycemia. Herein, we interrogated whether and how SARS-CoV-2 causes hyperglycemia by infecting hepatocytes and increasing glucose production. We performed a retrospective cohort study including patients that were admitted at a hospital with suspicion of COVID-19. Clinical and laboratory data were collected from the chart records and daily blood glucose values were analyzed to test the hypothesis on whether COVID-19 was independently associated with hyperglycemia. Blood glucose was collected from a subgroup of nondiabetic patients to assess pancreatic hormones. Postmortem liver biopsies were collected to assess the presence of SARS-CoV-2 and its transporters in hepatocytes. In human hepatocytes, we studied the mechanistic bases of SARS-CoV-2 entrance and its gluconeogenic effect. SARS-CoV-2 infection was independently associated with hyperglycemia, regardless of diabetic history and beta cell function. We detected replicating viruses in human hepatocytes from postmortem liver biopsies and in primary hepatocytes. We found that SARS-CoV-2 variants infected human hepatocytes in vitro with different susceptibility. SARS-CoV-2 infection in hepatocytes yields the release of new infectious viral particles, though not causing cell damage. We showed that infected hepatocytes increase glucose production and this is associated with induction of PEPCK activity. Furthermore, our results demonstrate that SARS-CoV-2 entry in hepatocytes occurs partially through ACE2- and GRP78-dependent mechanisms. SARS-CoV-2 infects and replicates in hepatocytes and exerts a PEPCK-dependent gluconeogenic effect in these cells that potentially is a key cause of hyperglycemia in infected patients.