key: cord-0833553-00gtpho6
authors: Papadopoulos, V. P.; Koutroulos, M.-V.; Zikoudi, D.-G.; Bakola, S.-A.; Avramidou, P.; Touzlatzi, N.; Filippou, D. K.
title: Acute Metabolic Emergencies in Diabetes and COVID-19: a systematic review and meta-analysis of case reports
date: 2021-01-11
journal: nan
DOI: 10.1101/2021.01.10.21249550
sha: 5413e665ebd0a3ae4d2dce8b9ad5d5f58f15f966
doc_id: 833553
cord_uid: 00gtpho6

Introduction: COVID-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. Patients and Methods: A 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, CRP, ferritin, d-dimers, glucose, osmolarity, pH, bicarbonates, ketones, lactates, {beta}-hydroxybutyric acid, anion gap, and acute kidney injury (AKI) with outcome. Results: From 312 identified publications, 41 including 71 cases analyzed qualitatively and quantitatively. Multivariate analysis demonstrated that COVID-19 disease status 4 (P<0.001), AKI (P<0.001), pH [≤]7.12 (P=0.032), and osmolarity [≥]324 (P=0.034), are all independently correlated with death. COVID-19 Disease Status 4 (P=3x10-8), combined DKA/HHS (P=0.021), and AKI (P=0.037) are independently correlated with death. Conclusion: COVID-19 intertwines with acute metabolic emergencies in diabetes leading to increased mortality; key determinants are critical COVID-19 illness, co-presence of ketoacidosis and hyperosmosis and AKI.

4 single letter [19] . A systematic review of the literature concluded that DKA in COVID-19 patients portends a poor prognosis with a mortality rate approaching 50% and insisted on the need to differentiate isolated DKA from combined DKA/HHS as the latter, which represents nearly one-fifth of the DKA cases, tends to have higher mortality than DKA alone [20] . Therefore, diabetic COVID-19 patients should be assessed for disease severity and presence of complications of diabetes, while undiagnosed diabetes should be kept in mind of the clinician, especially in patients feeling unwell [21] .

The aim of the present systematic review and meta-analysis is to provide further evidence regarding the key features of COVID-19-related acute metabolic emergencies in diabetes (DKA, EDKA, HHS, and DKA/HHS) by identifying all relevant case reports that can provide detailed patient data and summarizing their results together. or binary variables); between absence or presence of prior administration of various antidiabetic agents including insulin, metformin, sulfonylureas, dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), sodium-glucose cotransporter-2 inhibitors (SGLT-2i), and pioglitazone; between absence and presence of comorbidities including T1D/T2D, arterial hypertension (AH), hyperlipidemia, coronary artery disease (CAD), asthma; within number of comorbidities, days from onset of symptoms, disease severity expressed as disease status, C-reactive protein (CRP), ferritin, d-dimers, glucose, osmolality, arterial pH, bicarbonates, ketones, lactates, β-hydroxybutyric acid (β-ΗΒ), and anion gap (treated either as continuous or binary variables); and between absence or presence of acute kidney injury (AKI), and Outcome (survival/discharge vs. death) was performed. AMSTAR 2 checklist was used to assess the quality of the present study [23, 24] .

The disease-status (DS) of COVID-19 patients was classified based on the adaptation of the Sixth Revised Trial Version of the Novel Coronavirus Pneumonia Diagnosis and Treatment Guidance, as described previously [25] . Mild cases (DS1) were defined as mild clinical symptoms (fever, myalgia, fatigue, diarrhea) and no sign of pneumonia on thoracic X-Ray or/and CT scan. Moderate cases (DS2) were defined as clinical symptoms associated with dyspnea and radiological findings of pneumonia on thoracic X-Ray or/and CT scan, and requiring a maximum of 3 L/min of oxygen. Severe cases (DS3) were defined as respiratory distress requiring more than 3 L/min of oxygen and no other organ failure. Critical cases (DS4) were defined as respiratory failure requiring mechanical ventilation, shock and/or other organ failure that require an intensive care unit (ICU).

A structured data collection form was used to extract the following data from each study: title of the study, name of the first author, country where the study was conducted, type of diabetes-related acute metabolic emergency, age, BMI, HbA1c, previously administered antidiabetic agents (including insulin, metformin, sulfonylureas, DPP-4i, GLP-1 RAs, SGLT-2i, and pioglitazone), comorbidities (including T1D/T2D, AH, hyperlipidemia, CAD, asthma), days from onset of symptoms, DS, CRP, ferritin, d-dimers, glucose, osmolality, arterial pH, bicarbonates, ketones, lactates, β-HB, anion gap, AKI, and outcome (survival/discharge or death). who performed data extraction working simultaneously as three independent couples of investigators (consisting of one for extracting data and another for checking the extracted data); the process was performed manually and the three couples were blinded to each other's decisions. D.F. closely observed the process and was responsible for any discordance. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted January 11, 2021. ; https://doi.org/10.1101/2021.01. 10.21249550 doi: medRxiv preprint Quality assessment of the studies The Joanna Briggs Institute (JBI) critical appraisal checklist for case reports, which includes 8 questions addressing the internal validity and risk of bias of case reports designs, particularly confounding and information bias, in addition to the importance of clear reporting, was used for quality assessment [26] [27] [28] [29] .

All studies that failed to fulfill requirements of first six questions were considered as of "suboptimal quality"; controversially, an "optimal quality" remark was given. The process was carried out by six reviewers (V.P., M.-V.K., D.-G.Z., S.-A.B., P.A., and N.T.) who performed quality assessment as three independent couples of investigators; in case of disagreement within a couple, D.F, who closely observed the process, was responsible to dissolve any discordance.

As variability values associated to each study were lacking, neither data synthesis nor classical metaregression was applicable for case reports. Therefore, our option was to use classical regression without weighing each data point; this procedure still offered the advantage of a useful insight in cases that values were not too spread, despite that precise estimations could not be achieved. Thus, univariate analysis was performed to assess potent correlations of independent variables (study origin, presence of combined DKA/HHS, age, BMI, HbA1c, previously administered antidiabetics, comorbidities, days from onset of symptoms, DS, CRP, ferritin, d-dimers, glucose, osmolarity, arterial pH, bicarbonates, ketones, lactates, β-HB, anion gap, AKI) with outcome (survival/discharge or death), which was considered as dependent variable, with the aid of binary regression. At a next step, multivariate analysis was performed with binary logistic regression over discretized, imputed, and regularized data; outcome was considered as a dependent variable, while all variables that reached a level of statistical significance <0.10 in the univariate analysis were treated as potent independent ones (the probability for stepwise entry and removal were set to 0.05 and 0.10 accordingly, the classification cutoff was set to 0.5 and the maximum number of iterations was set to 20). During this process, ridge regression was used to avoid model overfitting, tolerate large variances and overcome collinearity obstacles, all at the least possible additive bias; all variables of interest, if not already binary, were transformed to binary ones through nominal optimal scaling along with discretization to two groups, imputing of missing data was added, and 10-fold cross-validation was selected through Optimal Scaling procedure (SPSS CATREG option). Models including parameters with tolerance <0.67 (variance inflation factor >1.5), as deduced from corresponding linear regression analysis assessing numerical values to outcome, were rejected to avoid collinearity. Imputed data tolerated missing values at a maximum of 25% for the entire model. Univariate comparisons were performed with the use of Pearson's χ 2 for discrete variables; Fisher's exact test was alternatively preferred in case that expected frequencies were <5 in more than one cell. Kappa statistics were used for the evaluation of inter-rater agreement between authors. The is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint were used to construct a forest plot for visualization purposes using Revman 5.3 software from the Cochrane Collaboration [30] . is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted January 11, 2021. ; https://doi.org/10.1101/2021.01.10.21249550 doi: medRxiv preprint All characteristics regarding title of the study, name of the first author, country where the study was conducted, type of diabetes-related acute metabolic emergency, age, BMI, HbA1c, previously administered antidiabetic agents, comorbidities, days from onset of symptoms, DS, CRP, ferritin, d-dimers, glucose, osmolality, arterial pH, bicarbonates, ketones, lactates, β-HB, anion gap, acute kidney injury, and outcome are analytically presented in Table 1 .

The quality of the present study was evaluated as "high" using the AMSTAR 2 checklist.

Quality assessment of the studies Quality remarks are provided in Table 1 ; all details concerning quality assessment items are depicted analytically in Table 2 . The inter-rater agreement between the two authors carried out the quality assessment process was high, as kappa was 0.87 (95% CI: 0.79-0.95). There was no difference between studies of "optimal" and "suboptimal" quality regarding outcome (P=0.756).

Overall mortality was 32. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted January 11, 2021. ; https://doi.org/10.1101/2021.01.10.21249550 doi: medRxiv preprint (P=0.083), osmolarity (P=0.076), pH value (P=0.063), and β-ΗΒ (P=0.052) were considered needing further evaluation and thus were included in multivariate regression analysis.

The most parsimonious multivariate model is highly significant (P=10 -4 ), suggesting that COVID-19 Disease is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted January 11, 2021. ; https://doi.org/10.1101/2021.01.10.21249550 doi: medRxiv preprint

We describe three major determinants of outcome during acute metabolic emergencies in diabetes in COVID-19 patients: i) COVID-19 critical illness necessitating mechanical ventilation or else COVID-19 disease status 4, ii) simultaneous presence of ketoacidosis and hyperosmosis in the form of combined DKA/HHS (P=0.021), and iii) acute kidney injury. To the best of our belief, this is the first time that COVID-19 is demonstrated to intertwine with acute metabolic emergencies in diabetes leading to increased mortality.

Our study revealed an overall mortality of 32.4% (22/68 patients; 3 missing) in COVID-19 patients who had developed DKA, DKA/HHS, and HHS. Interestingly, two recently published case series, whose data are not included in the present study as they are not presented analytically, report mortality rates that range from as low as 7.7% (2/26 patients) [12] and 1/7 patients (12.9%) [71] , to 50% (25/50 patients) [19] ; however, these case series derive from a single centers and thus might not be representative.

Our findings regarding the independent correlation of critical illness and mortality during COVID-19-related acute metabolic emergencies in diabetes are in keeping with what is already reported [19] . Moreover, we exhibited an independent correlation of acute kidney injury with mortality during COVID-19related DKA, DKA/HHS, and HHS. AKI is quite common among patients without critical illness and usually has a mixed etiology intertwining sepsis, ischemia and nephrotoxicity and perplexing recognition and treatment [72] . Chamorro et al. report that AKI was observed in 92% (23/25) and 60% (15/25) of COVID-19-related DKA non-survivors and survivors, respectively; these data indicate that AKI is significantly correlated with death in patients with COVID-19-related DKA (P=0.008). Similarly, renal replacement therapy was required in 40% (10/25) and 4% (1/25) COVID-19-related DKA non-survivors and survivors, respectively, implying that renal replacement therapy is significantly correlated with death in these patients (P=0.002) [19] .

Additionally, we demonstrated an independent correlation of mixed DKA/HHS related to COVID-19 infection with non-surviving. Our results are in keeping with the ones reported in the systematic review of Pal et al., who describe a statistically significant difference in arterial blood pH between COVID-19-related DKA survivors (7.23, 95% CI: 7.09-7.26) when compared with non-survivors (7.00, 95% CI: 6.91-7.11); P=0.017 [20] . Despite that data linking increased osmolarity with increased fatality rate in COVID-19 patients are lacking, it is well known that death occurs in 5-16% of patients with HHS in general, a rate that is about 10-fold higher than that reported for DKA [73] [74] [75] . Moreover, a hypertonic environment, as it prevails in hyperosmolar states such as hyperglycemia of diabetes mellitus, has been shown to impair the immune is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted January 11, 2021. ; https://doi.org/10.1101/2021.01.10.21249550 doi: medRxiv preprint response, thus facilitating the development of infection. In detail, osmotic cell shrinkage blunts the stimulatory action of antigen exposure on IFN-gamma production, an effect explained at least partially by suppression of transcription factor activation [76] .

We have noticed that all patients but one (a patient with gestational diabetes) who had developed EDKA received SGLT-2i treatment (Fisher's exact P=0.004). Treatment with SGLT-2i has been reported to trigger EDKA in T2D patients with [39] or without COVID-19 infection, usually during other infections, sepsis or surgery [77] [78] [79] . These regimens might be prescribed even for T1D, even without reimbursement;

interestingly, a single case report of a patient with T1D who received empagliflozin 25mg q24h and developed EDKA during COVID-19 pneumonia has been recently published [40] . Glycaemic stability can mislead the clinician, since hyperglycosuria induced by SGLT-2i may blunt hyperglycaemia during infection and contribute to a lack of insulin, finally promoting ketogenesis [77] . Therefore, it is strongly advised that the use of SGLT-2i should be discontinued at once in both T2D and T1D patients as soon as COVID-19 is diagnosed; in these cases, exclusive administration of insulin is considered to be the safest choice [79] [80] [81] .

As far as antidiabetic regimens other than SGLT-2i are concerned, we have not detected any correlation of any antidiabetic drug category with any special type of metabolic emergency or outcome; this observation conveys the limitations of the small sample size of the present study. It has been reported that liraglutide counteracts the downregulating effect of diabetes on the pulmonary expression of ACE2 in rats without influencing glucose and insulin levels. GLP-1 RAs were also shown to have anti-inflammatory effects and to reduce lung inflammation in murine models of experimental lung injury. In humans, GLP-1 RAs reduce circulating inflammatory biomarkers in diabetic and/or obese patients while insulin reduces these biomarkers in critically ill patients. Pioglitazone was also shown to upregulate ACE2 in hepatocytes of rats fed with a high fat diet. Finally, the DPP-4 is the entry receptor of MERSCoV, raising concerns about the impact of DPP-4i during the course of coronavirus infection [82] .

Another interesting point that was addressed in the present study was the fact that patients who were treated with insulin presented an increased OR to succumb in contrast with those treated with metformin.

Interestingly, insulin usage was associated with poor prognosis (OR 3.58, 95% CI: 1.37, 9.35, P=0.009) [83] .

However, insulin administration has been shown to restore ACE and ACE2 levels in the serum, which may indicate a protective effect at least in patients that are non-insulin-depleted [84] . Therefore, this finding could reflect a confounder effect due to either the type of diabetes, or increased age. T1D patients, who are by definition insulin-dependent, when compared with T2D patients, are more prone to adverse outcome during COVID-19 infection (OR 2.40, 95% CI: 1.82-3.16; P<0.0001 and 1.37, 95% CI: 1.28-1.47; P<0.0001, respectively) [5] . Moreover, unfavorable outcome was observed more often in older patients presenting COVID-19-related DKA (p<0.001) [19] . is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted January 11, 2021. ; https://doi.org/10.1101/2021.01.10.21249550 doi: medRxiv preprint

There are several explanations for the intertwining of COVID-19, and especially its severe form, with DKA.

COVID-19 might either induce new onset diabetes or unmask previously undiagnosed diabetes (type 1 or type 2). This is reflected at HbA1c values at the time of admission; normal and elevated HbA1c values at the time of admission suggest new onset and previously undiagnosed diabetes, respectively [3] . SARS-CoV-2 can trigger severe diabetic ketoacidosis at presentation in individuals with new-onset diabetes; however, there is no hard evidence that SARS-CoV-2 is etiologically linked with T1DM for the time being [85] . As DKA occurs as a result of insulin deficiency and increased counterregulatory responses, which favor the production of ketones, the unique interactions between SARS-CoV-2 and the RAAS might provide yet another mechanism in the pathophysiology of DKA firstly by direct entry of SARSCoV-2 into pancreatic islet cells that might worsen b-cell injury and secondly by downregulation of ACE2 after viral entry that can lead to unopposed angiotensin II and subsequent insulin secretion impedance [86] . Lastly, little is known on the potent etiological role of dexamethasone, which is administered in COVID-19, and its potent effect on DKA evolution; in fact, an anecdotal case of corticosteroids-stimulated DKA in a non-diabetic COVID-19 patient with ARDS has been observed after the fifth day of dexamethasone administration [Skendros, personal communication]. Nevertheless, rigorous and proper restoration of volume and insulin adequacy, along with potassium preservation should be commenced immediately in any case of COVID-19-related DKA. As the relationship between SARS-CoV-2 and the RAAS can complicate DKA management due to increased pulmonary vascular permeability and worsened damage to lung parenchyma, fluid replacement needs to be administered judiciously to avoid aggravating pulmonary injury. This also raises the importance of careful assessment of fluid status through objective hemodynamic parameters to determine the amount of fluid replacement. Another important aspect in DKA management is that of monitoring and correcting electrolyte abnormalities. As angiotensin II stimulates aldosterone secretion and increases renal potassium loss, this can potentiate the risk of hypokalemia, which might necessitate additional potassium supplementation in order to continue intravenous insulin to suppress ketogenesis [86] [87] [88] [89] .

It has been proposed that direct cytopathic effects of SARS-CoV-2 on pancreatic b-cell populations may contribute to this high prevalence of severe COVID-19-associated DKA in T2DM; ACE2 expression at both the mRNA and protein is increased substantially in human beta cells in response to inflammatory cytokines, presumably rendering these cells more susceptible to infection [90] . Both SARS and COVID-19 have been reported to trigger transient insulin resistance and hyperglycaemia. SARS results in elevated glucose during admission however glucose intolerance is resolved at hospital discharge. This COVID-19 induced insulin resistance may explain in part poor responses to standard DKA management [39] . Indeed, emerging data indicate a bidirectional relationship between T2D and Covid-19 [91] . Firstly, preexisting diabetes is a risk factor for poor outcomes and death after Covid-19. Impairment of the innate and adaptive immune response tames the ability to fight infection in patients with diabetes and particularly in those who are is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted January 11, 2021. ; https://doi.org/10.1101/2021.01.10.21249550 doi: medRxiv preprint obese. Furthermore, severe Covid-19 infection significantly reduces the numbers of natural killer cells, notably CD4+ and CD8+ cells, as well as CD4+ as CD8+ lymphocytes yet in an unclear mechanism. The association between Covid-19 and hyperglycemia in elderly patients with T2D might reflect metabolic inflammation and exaggerated cytokine release. SARS-CoV2 infection can deteriorate glycemic control, involving both profound insulin resistance and impaired insulin secretion, together leading to DKA and increasing hospital admissions and mortality [10, 92] .

A major limitation of the present study is that it relies only in case reports, which lack the ability to generalize or to establish cause-effect relationship, while conveying all danger of over-interpretation, publication bias, retrospective design, and distraction of reader when focusing on the unusual. However, the major merits of case reporting focus, among other, on detecting novelties, and generating hypotheses, is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted January 11, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted January 11, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted January 11, 2021. ; https://doi.org/10.1101/2021.01.10.21249550 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted January 11, 2021. ; https://doi.org/10.1101/2021.01.10.21249550 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted January 11, 2021. ; https://doi.org/10.1101/2021.01.10.21249550 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted January 11, 2021. ; https://doi.org/10.1101/2021.01.10.21249550 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted January 11, 2021. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted January 11, 2021. Supplementary References S1. Naguib MN, Raymond JK, Vidmar AP. New onset diabetes with diabetic ketoacidosis in a child with multisystem inflammatory syndrome due to COVID-19. J Pediatr Endocrinol Metab. 2020 Nov 12:/j/jpem.ahead-of-print/jpem-2020-0426/jpem-2020-0426.xml. doi: is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

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SARS-CoV-2 Receptor Angiotensin I-Converting Enzyme Type 2 (ACE2) Is Expressed in Human Pancreatic β-Cells and in the Human Pancreas Microvasculature. Front Endocrinol (Lausanne)

COVID-19 in people with diabetes: understanding the reasons for worse outcomes