Can euglycemic Diabetic Ketoacidosis Caused by SGLT2 Inhibitors be avoided in Covid-19 and other acute Infections?

Introduction: We present a case of anion gap euglycemic diabetic ketoacidosis (EuDKA) in a patient with COVID-19 infection. Patients with diabetes mellitus are at increased risk of severe illness, and hyperglycaemia is associated with higher morbidity and mortality in patients infected with COVID-19. Case Description: A 76-year-old male with diabetes mellitus treated with SGLT2 inhibitor tested positive for COVID-19 infection on day 3 after his admission. In the emergency room he had a high anion gap metabolic acidosis and a blood glucose of 248 mg/dl. His urine tested strongly positive for ketones. A diagnosis of euglycemic diabetic ketoacidosis was made and he was treated with intravenous insulin and normal saline; his antidiabetic medications were stopped. His metabolic acidosis gradually resolved, and he was discharged. Discussion: Euglycemic diabetic ketoacidosis is a rare complication of COVID-19 infection. It is defined by the American Diabetes Association as the triad of anion gap metabolic acidosis with arterial pH <7.3, serum bicarbonate <18 mmol/l and ketonuria or ketonemia. It is a life-threatening complication which usually occurs in type 1 diabetes mellitus patients but may also occur in type 2 diabetes mellitus patients. As described earlier, it is associated with hyperglycaemia but if blood glucose is low or near normal but <250 mg/dl it is then named euglycemic diabetic ketoacidosis. Patients treated with SGLT2 inhibitors are at increased risk of euglycemic diabetic ketoacidosis. Conclusions: COVID-19 infection precipitated euglycemic diabetic ketoacidosis in our patient. SGLT2 inhibitors must be stopped when this adverse reaction occurs. As their use increases, the risk of this adverse reaction is higher as well. Their prescription should be restricted to trained physicians who are able to educate their patients and treat them appropriately in situations that may arise. LEARNING POINTS: COVID-19 infected patients are at increased risk of developing diabetic ketoacidosis or euglycemic ketoacidosis when treated with SGLT-2 inhibitors.It is practical to discontinue the drug at the onset of any symptoms consistent with acute infection to prevent the development of euglycemic diabetic ketoacidosis.

ACTIVATE-2: A Double-Blind Randomized Trial of BCG Vaccination Against COVID-19 in Individuals at Risk.

In a recent study of our group with the acronym ACTIVATE, Bacillus Calmete-Guérin (BCG) vaccination reduced the occurrence of new infections compared to placebo vaccination in the elderly. Most benefit was found for respiratory infections. The ACTIVATE-2 study was launched to assess the efficacy of BCG vaccination against coronavirus disease 2019 (COVID-19). In this multicenter, double-blind trial, 301 volunteers aged 50 years or older were randomized (1:1) to be vaccinated with BCG or placebo. The trial end points were the incidence of COVID-19 and the presence of anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) antibodies, which were both evaluated through 6 months after study intervention. Results revealed 68% relative reduction of the risk to develop COVID-19, using clinical criteria or/and laboratory diagnosis, in the group of BCG vaccine recipients compared with placebo-vaccinated controls, during a 6-month follow-up (OR 0.32, 95% CI 0.13-0.79). In total, eight patients were in need of hospitalization for COVID-19: six in the placebo group and two in the BCG group. Three months after study intervention, positive anti-SARS-CoV-2 antibodies were noted in 1.3% of volunteers in the placebo group and in 4.7% of participants in BCG-vaccinated group. These data indicate that BCG vaccination confers some protection against possible COVID-19 among patients older than 50 years with comorbidities. BCG vaccination may be a promising approach against the COVID-19 pandemic.

Corrigendum: ACTIVATE-2: A double-blind randomized trial of BCG vaccination against COVID-19 in individuals at risk.

[This corrects the article DOI: 10.3389/fimmu.2022.873067.].

Effect of Colchicine vs Standard Care on Cardiac and Inflammatory Biomarkers and Clinical Outcomes in Patients Hospitalized With Coronavirus Disease 2019: The GRECCO-19 Randomized Clinical Trial.

Importance: Severe acute respiratory syndrome coronavirus 2 infection has evolved into a global pandemic. Low-dose colchicine combines anti-inflammatory action with a favorable safety profile. Objective: To evaluate the effect of treatment with colchicine on cardiac and inflammatory biomarkers and clinical outcomes in patients hospitalized with coronavirus disease 2019 (COVID-19). Design, Setting, and Participants: In this prospective, open-label, randomized clinical trial (the Greek Study in the Effects of Colchicine in COVID-19 Complications Prevention), 105 patients hospitalized with COVID-19 were randomized in a 1:1 allocation from April 3 to April 27, 2020, to either standard medical treatment or colchicine with standard medical treatment. The study took place in 16 tertiary hospitals in Greece. Intervention: Colchicine administration (1.5-mg loading dose followed by 0.5 mg after 60 min and maintenance doses of 0.5 mg twice daily) with standard medical treatment for as long as 3 weeks. Main Outcomes and Measures: Primary end points were (1) maximum high-sensitivity cardiac troponin level; (2) time for C-reactive protein to reach more than 3 times the upper reference limit; and (3) time to deterioration by 2 points on a 7-grade clinical status scale, ranging from able to resume normal activities to death. Secondary end points were (1) the percentage of participants requiring mechanical ventilation, (2) all-cause mortality, and (3) number, type, severity, and seriousness of adverse events. The primary efficacy analysis was performed on an intention-to-treat basis. Results: A total of 105 patients were evaluated (61 [58.1%] men; median [interquartile range] age, 64 [54-76] years) with 50 (47.6%) randomized to the control group and 55 (52.4%) to the colchicine group. Median (interquartile range) peak high-sensitivity cardiac troponin values were 0.0112 (0.0043-0.0093) ng/mL in the control group and 0.008 (0.004-0.0135) ng/mL in the colchicine group (P = .34). Median (interquartile range) maximum C-reactive protein levels were 4.5 (1.4-8.9) mg/dL vs 3.1 (0.8-9.8) mg/dL (P = .73), respectively. The clinical primary end point rate was 14.0% in the control group (7 of 50 patients) and 1.8% in the colchicine group (1 of 55 patients) (odds ratio, 0.11; 95% CI, 0.01-0.96; P = .02). Mean (SD) event-free survival time was 18.6 (0.83) days the in the control group vs 20.7 (0.31) in the colchicine group (log rank P = .03). Adverse events were similar in the 2 groups, except for diarrhea, which was more frequent with colchicine group than the control group (25 patients [45.5%] vs 9 patients [18.0%]; P = .003). Conclusions and Relevance: In this randomized clinical trial, participants who received colchicine had statistically significantly improved time to clinical deterioration. There were no significant differences in high-sensitivity cardiac troponin or C-reactive protein levels. These findings should be interpreted with caution. Trial Registration: ClinicalTrials.gov Identifier: NCT04326790.

Impact of the time rate of blood pressure variation on left ventricular mass.

OBJECTIVES: Blood pressure (BP) changes are steeper in hypertensive than in normotensive individuals, whereas an increased rate of BP fluctuations is associated with medial hypertrophy of the carotid arteries. We evaluated the association between the rate of BP variation derived from ambulatory blood pressure monitoring (ABPM) data analysis and left ventricular mass (LVM). METHODS: ABPM and echocardiographic measurements of LVM were performed in 365 normotensive, 185 white-coat hypertensive (WCH) and 448 uncomplicated hypertensive individuals. RESULTS: The daytime and night-time rate of systolic blood pressure (SBP) and diastolic BP variation were significantly higher in hypertensive than in normotensive (P < 0.001) and WCH (P < 0.05) individuals. In the entire study population multiple linear regression models revealed independent determinants of LVM in the following rank order: body mass index (beta + 0.266, P < 0.001), daytime SBP (beta + 0.264, P < 0.001), male sex (beta +0.220, P < 0.001), age (beta + 0.203, P < 0.001), daytime heart rate (HR; beta - 0.191, P < 0.001), daytime rate of SBP variation (beta + 0.167, P < 0.001), and SBP dipping (beta - 0.132, P < 0.001). A 0.1 mmHg/min increase in the daytime rate of SBP variation correlated with an increment of 7.087 g (95% confidence interval 4.775-9.399) in the LVM. The addition of the daytime rate of SBP variation in the multiple regression model for the prediction of LVM significantly increased the adjusted model R [R change 0.024 (2.4%); P for change < 0.001]. CONCLUSION: Steeper BP variations may produce a greater stress on the left ventricular wall and may have an additive role to body habitus, BP and HR levels in the detection of cardiac hypertrophy. Target-organ damage in hypertensive patients, in addition to BP levels, dipping status and BP variability, may also be related to a steeper rate of BP oscillations.

Combination of infliximab and high-dose intravenous immunoglobulin for toxic epidermal necrolysis: successful treatment of an elderly patient.

Toxic epidermal necrolysis (TEN) is a rare, severe cutaneous adverse drug reaction with average mortality 25-35%, especially among elderly multimorbid patients. Established therapeutic guidelines do not exist and controversies underlie many of the presently suggested treatment regimens. Herein we present the use of the recently described combination scheme of methylprednisolone (500 mg methylprednisolone bolus i.v.) followed by infliximab (5 mg/kg i.v.) and high-dose intravenous immunoglobulin (2 g/kg over 5 days) to treat an elderly, 74-year-old female patient with TEN (SCORTEN 3) within the premises of a district hospital. Already from the second day of hospitalization the skin condition markedly stabilized and the patient's status improved rapidly thereafter. She was discharged after 19 days in stationary care in excellent general condition and remained without any sequels 9 months afterwards. The present paper further supports the feasibility, efficacy, and safety of the proposed combination modality for the treatment of elderly patients with TEN, a population susceptible to more severe TEN.

Diurnal correlation of ambulatory blood pressure and interstitial glucose in patients with normal glucose tolerance.

OBJECTIVE: Among the physiological variables whose diurnal profile is governed by circadian rhythmicity, plasma glucose concentrations, and arterial blood pressure constitute key elements of the physiological regulation of energy homeostasis. Evidence on their diurnal association derived from frequent measurements of both variables is, however, lacking in humans. METHODS: We investigated the relationship between blood pressure levels recorded by an ambulatory device and interstitial glucose concentrations on an outpatient basis, in patients with normal glucose tolerance (N=20), either normotensive (group A; N=10), or newly diagnosed with essential hypertension (group B; N=10). RESULTS: In the population throughout the 24-h monitoring period, there was a significant positive correlation between interstitial glucose concentrations and systolic, diastolic, and mean 24-h blood pressure levels, which was retained in patients with hypertension compared with normotensive patients. In patients with newly diagnosed hypertension, interstitial glucose concentrations exhibit significant correlation to systolic blood pressure levels during the 24-h period, but no association with diastolic and mean blood pressure during the night, whereas the reverse is the case in patients with normal glucose tolerance and normal blood pressure. CONCLUSION: Diurnal variations of continuously monitored interstitial glucose concentrations significantly associate with blood pressure levels in both normotensive and hypertensive humans, indicating a common pathway of circadian autoregulation, probably stemming from both central mechanisms and peripheral inputs. Such a pathway might underlie similar pathophysiological aberration in disease states such as the metabolic syndrome.