Acute Metabolic Emergencies in Diabetes and COVID-19: a systematic review and meta-analysis of case reports

Abstract

BackgroundCOVID-19 is associated with DKA (Diabetic Ketoacidosis), HHS (Hyperglycaemic Hyperosmolar State) and EDKA (Euglycaemic DKA). High mortality has been observed in COVID-19-related diabetic ketoacidosis; however, evidence is scarce.MethodsA systematic literature review was conducted using EMBASE, PubMed/Medline, and Google Scholar from January to December 2020 to identify all case reports describing DKA, HHS, and EDKA, in COVID-19 patients. The Joanna Briggs Institute critical appraisal checklist for case reports was used for quality assessment. Univariate and multivariate analysis assessed correlations of study origin, combined DKA/HHS, age, BMI, HbA1c, administered antidiabetics, comorbidities, symptoms onset, disease status (DS), CRP, ferritin, d-dimers, glucose, osmolarity, pH, bicarbonates, ketones, lactates, β-hydroxybutyric acid, anion gap, and acute kidney injury (AKI) with outcome. The relevant protocol was submitted to PROSPERO database (ID: 229356).ResultsFrom 312 identified publications, 41 including 71 cases analyzed qualitatively and quantitatively. The types of acute metabolic emergencies observed were DKA (45/71, 63.4%), EDKA (6/71, 8.5%), combined DKA/HHS (19/71, 26.8%), and HHS (1/71, 1.4%). Overall mortality was 32.4% (22/68 patients; 3 missing). Multivariate analysis by classical regression demonstrated that COVID-19 DS4 (P=3•10−8), presence of DKA/HHS (P=0.021), and development of AKI (P=0.037) were all independently correlated with death. Increased DS (P=0.003), elevated lactates (P<0.001), augmented anion gap (P<0.001), and presence of AKI (P=0.002) were associated with DKA/HHS. SGLT-2i administration was linked with EDKA (P=0.004); however, a negative association with AKI was noted (P=0.023).ConclusionCOVID-19 intertwines with acute metabolic emergencies in diabetes leading to increased mortality. Key determinants are critical COVID-19 illness, coexistence of DKA/HHS and AKI. Awareness of clinicians to timely assess them might enable early detection and immediate treatment commencing. As previous treatment with was negatively associated with AKI, thus implying a prophylactic effect on renal function, the issue of discontinuation of SGLT-2i in COVID-19 patients remains to be further evaluated.Key messagesWhat is already known on this subject▸Diabetes mellitus (DM) is a risk factor for poor outcomes in COVID-19 patients.▸Diabetic ketoacidosis (DKA) and hyperglycaemic hyperosmolar state (HHS) are not rare in COVID-19 diabetic and non-diabetic patients; key determinants of outcome remain unknown.What this study adds▸COVID-19 intertwines with acute metabolic emergencies in diabetes leading to increased mortality; key determinants are critical COVID-19 illness, coexistence of DKA and HHS as well as development of acute kidney injury.▸SGLT2-i administration is linked with euglycaemic DKA in patients with COVID-19, though preserving renal function.

Mortality of Diabetes-related Acute Metabolic Emergencies in COVID-19 patients: a systematic review and meta-analysis

“…Our findings are in keeping with a recent meta-analysis of 41 case reports carried out by our team, which yielded a mortality rate of 32.4% among 68 patients with known outcome [13]. We are totally aware that including a self-report in a meta-analysis can import a severe bias.…”

“…In contrast, two small case series exhibited significantly lower mortality rates that range from 7.7% [8] to 12.9% [12]. Additionally, a few dozen of case reports concerning acute emergencies related to glucose metabolism in COVID-19 patients have been reported, all reviewed in a very recent meta-analysis [13].…”

“…Interestingly, Chamorro-Pareja et al reported an unusually high mortality rate among 50 COVID-19 patients who presented DKA (50%)[11]. In fact, comparing relevant data from all included studies over a 2x4 contingency table (df=3), a statistically significant result is obtained (Chi-square P=0.014); this variability is partly explained by the meta-analysis of Papadopoulos et al who reported that, apart from the presence of mixed DKA/HHS, two other parameters, namely the presence of acute kidney injury as well as the necessity for mechanical ventilation of COVID-19 patients (critical illness or disease status 4 illness) are key determinants of outcome[13].…”

Predictors of intrahospital mortality in patients with coronavirus disease 2019 and cerebrovascular diseases: rapid systematic review and meta-analysis protocol

“…• Observational studies (cross-sectional studies, cohort studies, case-control studies, case reports, case series 25 ) describing adult patients (>18 years old, independently of sex/gender) with both COVID19 (confirmed by nasopharyngeal swab or bronchoalveolar lavage PCR test 37 ) and any cerebrovascular disease. • Clinical trials (randomized, quasi-randomized or nonrandomized) describing adult patients (>18 years old, independently of sex/gender) with both COVID19 (confirmed by nasopharyngeal swab or bronchoalveolar lavage PCR test 37 ) and any cerebrovascular disease. • No specific diagnostic criteria for cerebrovascular disorders will be considered if the studies describe their population as presenting the condition, as previously reported 38 .…”

The snapshot of metabolic health in evaluating micronutrient status, the risk of infection and clinical outcome of COVID-19

“…The hyperactivation of the cytokine cascade (cytokine storm), the viral breach in the lymphoid organs and the expression of spike protein's ligand, ACE2, by the lymphocytes comprise a suggested biological explanation towards the presence of lymphopenia [165]. Although the role of metabolism has been relatively unvisited in the subject, severe metabolic imbalances, such as metabolic acidosis, have been directly linked to COVID-19 clinical manifestations [166,167]. It has been demonstrated that elevations in serum lactic acid levels compromise T cell metabolism and function, leading to T cell reduction [168].…”