key: cord-0703843-twlt7hl9
authors: Gentile, Sandro; Strollo, Felice; Mambro, Andrea; Ceriello, Antonio
title: COVID‐19, ketoacidosis, and new‐onset Diabetes: might we envisage any cause‐effect relationships among them?
date: 2020-08-13
journal: Diabetes Obes Metab
DOI: 10.1111/dom.14170
sha: 9ddd9cc93c81e1b691ab9e3b7631805cbf1185d9
doc_id: 703843
cord_uid: twlt7hl9

nan

Word count: 1, 147 References : 19 Since the beginning of the SARS-CoV-2 pandemic at the turn of 2019 and 2020 in China, a large number of scientific reports published on the latest issues of Diabetes, Obesity and Metabolism and elsewhere almost unanimously showed that patients with diabetes mellitus (DM) had to face a more severe form of COVID-19, burdened with a high mortality rate (1) (2) (3) (4) . However, intriguingly, COVID-19 patients with newly diagnosed diabetes had the highest risk of all-cause mortality compared with COVID-19 patients with known diabetes or hyperglycaemia without diabetes (3) (4) .

As reported by one of the first Italian report on the disease, according to daily-recorded data from the Istituto Superiore di Sanità (ISS), the same applied to Italy, the first European country affected by the fury of the epidemic (5). Moreover, multi-organ failure signs, different from those typically characterizing more severe disease expression, were present in adults with DM, providing further explanation for the higher mortality rate observed (1) However, COVID-19-specific metabolic complications are not well characterized yet. Therefore, we were intrigued by the proposal of establishing an international registry of newly diagnosed DM put forward by an international group of experts (6). The above registry will aim (i) to establish the extent and phenotype of new-onset Covid-19-related DM, defined by SARS-CoV-2 infection and hyperglycaemia without any previous history of DM or elevated glycated haemoglobin levels, and (ii) to provide reliable answers to the many questions evoked by the association of DM with COVID-19 (6, 7) . A significant reason for that proposal is the high prevalence of diabetic This article is protected by copyright. All rights reserved.

ketoacidosis and hyperosmolarity warranting exceptionally high doses of insulin reported in patients with . This suggested the hypothesis that SARS-Co2 infection might either precipitate a new type of DM by a direct impact on pancreatic cells or might trigger new pathophysiological DM-related mechanisms (6) . Viral infection and its association with diabetes is a familiar concept. Indeed, the scientific community attributes the role of triggering events for Type 1 DM to infections from several viruses (including Epstein-Barr-and Entero-/Coxsackie-viruses among the others) (8) . Similarly, Hepatitis C infection is a well-known risk factor for Type 2 DM, which is also associated with β cell dysfunction (9) . Turning to coronaviruses, SARS-CoV-1 binds to the ACE2 receptor in the pancreatic islets, eventually causing cell damage and precipitating DM onset. Should that be the case for SARS-CoV-2, insulin deficiency and increased risk of DKA (Diabetic Keto-Acidosis) might follow for those already diagnosed as suffering from type 2 DM (10). However, being data on SARS-CoV-2 binding to the ACE2 receptor still scanty, such mechanism remains speculative, and there is insufficient evidence, at the moment, to establish whether (i) DKA is more prevalent than usual in the case of COVID-19 and (ii) SARS-CoV-2 poses an increased risk of DKA over other severe infectious diseases.

To date, only one study has described the prevalence of acidosis and ketoacidosis in a large number (n=658) of hospitalized patients with confirmed COVID-19 (11) . Out of that cohort, 42 (6.4%) presented with positive urine or serum ketones, with only three (7% of the latter) meeting the ADA criteria for DKA. Those with ketosis were about twice as likely to have diabetes at baseline, and the three individuals who developed DKA had underlying diabetes. Patients with ketosis with or without acidosis were younger (median age 47 vs. 58 years, P=0.003), and had suffered from higher This article is protected by copyright. All rights reserved.

rates of ARDS (28.6% vs. 13.5%, P=0.007), acute liver injury (14.3% vs. 5.4%, P=0.042), and digestive disorders (31.0% vs. 12.0%, P=0.0012).

Based on the above, then, when looking at ketoacidosis in people with DM, we should try to accurately dissect "true" from "spurious" newly diagnosed DM. To do so, we should carefully take into account several clinical and logistic considerations. Indeed, some completely different conditions might have underlain the inclusion of DM into the list of hospital discharge DRGs (Diagnosis-Relates Groups), on which the many retrospective analyses conducted so far are based (12) (13) (14) . In detail, when focusing on new-onset DM, those conditions might correspond to (i) the socalled pre-diabetic state (impaired fasting glucose [IFG] and impaired glucose tolerance [IGT], first), which have persistently normal HbA1c levels, or (ii) the temporary hyperglycaemic effect typically shown by any acute or severe inflammatory diseases, or (iii) the symptoms and signs of ketoacidosis affecting subjects with DM (8, 11) . Now, concerning the latter argument, when overwhelmed by the emergency of overcrowded intensive care units, doctors might have classified as DKA any event occurring in people with high blood sugar levels, independently of reflecting real DKA or no more than respiratory acidosis with superimposed malnutrition-driven ketosis. A confounder may also be the high blood concentrations attained by inflammatory markers in COVID-19 cases, which is also typical of DKA independent of accompanying illness (15) (16) . It is still unclear whether the inflammatory cascades engaged in DKA and severe COVID-19 act synergistically to worsen clinical outcomes. However, despite being quite elevated in DKA, IL-6 seems to be a driver rather than a consequence of ketosis, and is likely to play a significant role in maladaptive immune responses to the SARS-CoV-2 virus (15). This article is protected by copyright. All rights reserved.

During the most dramatic phases of the epidemic, several patients entered the hospital wards quite massively in Italy (as well as in other countries), thus exceeding available ICU beds and breathing devices. Therefore, as reported in some interviews appearing on the media throughout the first part of the lockdown period, most resuscitators overtly admitted to have given top priority to vital function preservation. As a consequence of that, similarly to what happens during any severe acute illnesses, like myocardial infarction or surgical stress (17) , being the patients either already known to have DM or unexpectedly hyperglycaemic posed a minimal problem. In other words, physicians strived hard mainly to save lives by using insulin as planned, without getting lost in unnecessary and risky time-consuming classification dilemmas. Within such context, they did what expected to do by sticking to well-established protocols for severe acid-base unbalance per se and adding insulin as needed in case of hyperglycaemia, leaving aside subtle underlying mechanisms. Due to that, when closing medical records, they might have included DKA among primary or secondary DRGs sometimes, thus eventually contributing to an increase in the percentage of DM-related death rates associated with COVID-19 (unpublished, anecdotal and personal data). Should this have happened on a broad scale, such an increase might have easily turned out to be an artifact.

Nevertheless, health care personnel from the ICU should get trained to identify and treat DKA promptly in critically ill and medically complex patients. In patients suffering from the severe metabolic unbalance and nutritional defects caused by DM per se and further aggravated by SARS-CoV-2 infection, such an attitude could ensure success (18) . In any case, recognition and prompt treatment of real DKA in the ICU setting is essential to enable health care personnel to implement the best individually tailored treatment strategy for critically ill and medically complex patients (19) .

This article is protected by copyright. All rights reserved.

COVID-19 in people living with diabetes: An international consensus

Influence of diabetes mellitus on the severity and fatality of SARS-CoV-2 (COVID-19) infection

Online ahead of print

Prevalence of co-morbidities and their association with mortality in patients with COVID-19: A systematic review and meta-analysis

Newly diagnosed diabetes is associated with a higher risk of mortality than known diabetes in hospitalized patients with COVID-19

COVID-19 infection in Italian people with diabetes: Lessons learned for our future (an experience to be used)

New-Onset Diabetes in Covid-19

Diabetes, obesity and COVID-19: A complex interplay

Diabetic Ketoacidosis in COVID-19: Unique Concerns and Considerations

Hepatitis C virus infection and development of type 2 diabetes mellitus: Systematic review and meta-analysis of the literature

Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes

COVID-19 infection may cause ketosis and ketoacidosis

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Association of blood glucose control and outcomes in patients with COVID-19 and preexisting Type 2 Diabetes

Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan

Why is hyperglycaemia worsening COVID-19 and its prognosis?

Proinflammatory cytokines, markers of cardiovascular risks, oxidative stress, and lipid peroxidation in patients with hyperglycemic crises

This article is protected by copyright. All rights reserved

Hyperglycemia and the worse prognosis of COVID-19. Why a fast blood glucose control should be mandatory

Study Group of the European Association for the Study of Diabetes (EASD). Issues for the management of people with diabetes and COVID-19 in ICU

The Need for Diabetes Care Customization in the ICU at the Time of SARS-CoV-2 Outbreak Diabetes Ther