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Response to: Is newly diagnosed diabetes a stronger risk factor than pre‐existing diabetes for COVID‐19 severity?

We appreciate the comments of Sathish et al on our pooled analysis for exploring the association between diabetes mellitus (DM) and coronavirus disease 2019 (COVID-19) since it provides us the opportunity to further discuss the intriguing relationship between hyperglycemia and the risk of unfavorable progression in patients with COVID-19. Although we basically agree with the concept that COVID-19 patients who are newly diagnosed with DM may have higher risk for adverse outcome than those with pre-existing DM, we would like to point out that the main driving factor here seems to be hyperglycemia rather than DM itself. In patients with critical illness, several lines of evidence demonstrate that uncontrolled hyperglycemia is a strong risk factor for all-cause mortality, length of stay in the intensive care unit (ICU), as well as for development of secondary infections and sepsis (ie, the so-called stress hyperglycemia). COVID-19 is not an exception to this rule, whereby it has now been clearly demonstrated that hyperglycemia in patients with severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) infection is associated with a higher risk of mechanical or nonmechanical ventilation, progression toward severe or critical illness, ICU admission, and death compared to normoglycemic COVID-19 patients. In particular, Lampasona et al recently showed that hyperglycemia is a significant predictor of death in COVID-19 patients with or even without a diagnosis of DM. In fact, COVID-19 patients with hyperglycemia at admission without a history of DM have a worse prognosis than those with DM, while in patients with DM, hyperglycemia at the admission is a more significant risk factor than glycosylated hemoglobin (HbA1c). Some underlying mechanisms have been proffered for explaining the link between hyperglycemia and illness severity in COVID-19 (Table 1), such as metabolic abnormalities (eg, electrolytes disturbances, mitochondrial dysfunction, etc.), impairment of host immune response, hyperinflammation, enhanced risk of developing oxidative stress-mediated thrombosis, and higher vulnerability to secondary infections, which are also hallmarks of patients with severe or critical forms of COVID-19. Additional evidence suggests that abnormal glycosylation of SARS-CoV-2 may contribute to impairing the immune response against the virus by camouflaging immunogenic protein epitopes. An abnormal pattern of glycosylation of both SARS-CoV-2 and angiotensin-converting enzyme 2 (ACE2), the natural viral receptor at the host cell surface, may also have a significant impact on the interaction between the viral spike protein and its host cell receptors. Hyperglycosylation may contribute to enhance tissue tropism and viral penetration within the cells, ultimately fostering SARS-CoV-2 virulence, pathogenicity, injury, and individual susceptibility to more clinically severe infections. In conclusion, although we agree that obtaining a timely diagnosis of DM is part of the management of SARS-CoV-2 infections, however, temporarily uncontrolled hyperglycemia, and not just newly onset DM, may be the real contributing factor influencing disease severity in these patients. Therefore, we recommend strict blood glucose monitoring in all patients diagnosed with SARS-CoV-2 infection rather than measuring HbA1c, which would only reflect glucose homeostasis over the previous 2 to 4 months.