TYPE Original Research PUBLISHED 22 December 2022 DOI 10.3389/fendo.2022.1009028 Factors associated with critical OPEN ACCESS care requirements in diabetic EDITED BY Ricardo Gómez-Huelgas, Regional University Hospital of Malaga, patients treated with Spain REVIEWED BY dexamethasone for COVID-19 Chukwuma Okoye, University of Pisa, Italy Enrique Carretero-Anibarro, infection in the first wave of Andusian Health Service, Spain *CORRESPONDENCE the pandemia Núria Alonso nalonso.germanstrias@gencat.cat † Sol Batule 1,2†, Berta Soldevila 1,2†, Carme Figueredo 1, These authors have contributed equally to this work and share Marı́a Teresa Julián 1,2, Laia Egea-Cortés 3, first authorship Juliana Reyes-Ureña 3, Jordi Casabona 3, Lourdes Mateu 4, SPECIALTY SECTION This article was submitted to Roger Paredes 4,5, Bonaventura Clotet 4,5, Rosa López 6, Clinical Diabetes, Manel Puig-Domingo 1,2 and Núria Alonso 1,2* a section of the journal Frontiers in Endocrinology 1 Department of Endocrinology and Nutrition, Germans Trias i Pujol Research Institute and Hospital, Badalona, Spain, 2 Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain, RECEIVED 01 August 2022 3 Centre d'Estudis Epidemiològics sobre les Infeccions de Transmissió Sexual i Sida de Catalunya ACCEPTED 21 November 2022 (CEEISCAT), Badalona, Spain, 4 Infectious Disease Service, Germans Trias i Pujol Research Institute PUBLISHED 22 December 2022 and Hospital, Badalona, Spain, 5 IrsiCaixa AIDS Research Institute, Hospital Germans Trias i Pujol, CITATION Badalona, Spain, 6 Direcció d'Organització i Sistemes Gerència Territorial Metropolitana Nord, Batule S, Soldevila B, Figueredo C, Institut Català de la Salut, Badalona, Spain Julián MT, Egea-Cortés L, Reyes-Ureña J, Casabona J, Mateu L, Paredes R, Clotet B, López R, Puig-Domingo M and Alonso N (2022) Factors associated with critical care Introduction: Diabetes mellitus (DM) and hyperglycemia are important risk requirements in diabetic patients factors for poor outcomes in hospitalized patients with coronavirus disease treated with dexamethasone for COVID-19 infection in the 2019 (COVID-19). The aim of the present study was to analyze the factors first wave of the pandemia. associated with the composite outcome of the necessity of invasive Front. Endocrinol. 13:1009028. mechanical ventilation (IMV) or admission to the intensive care unit (ICU) in doi: 10.3389/fendo.2022.1009028 subjects with severe COVID-19 infection treated with dexamethasone COPYRIGHT © 2022 Batule, Soldevila, Figueredo, comparing patients with DM vs. patients without DM. Julián, Egea-Cortés, Reyes-Ureña, Casabona, Mateu, Paredes, Clotet, Research design and methods: An observational retrospective cohort study López, Puig-Domingo and Alonso. This is an open-access article distributed was performed, including hospitalized subjects with a diagnosis of SARS-CoV- under the terms of the Creative 2 pneumonia. Inclusion criteria were: age ≥18 years old with severe COVID-19 Commons Attribution License (CC BY). disease requiring daily intravenous 6 mg dexamethasone treatment for 10 days. The use, distribution or reproduction in other forums is permitted, provided Exclusion criteria were: <18 years old, non-severe illness and/or patients in the original author(s) and the charge of ICU. Variables related to clinical and analytical parameters, glycemic copyright owner(s) are credited and control, acquired-hospital superinfections, mortality, IMV requirement, ICU that the original publication in this journal is cited, in accordance with admission and length of stay were included. accepted academic practice. No use, distribution or reproduction is Results: Two hundred and nine individuals with COVID-19 disease treated with permitted which does not comply with these terms. dexamethasone were included. One hundred twenty-five out of these subjects (59.8%) were patients with DM. Overall, from the 209 subjects, 66 (31.6%) required IMV or were admitted to the ICU, with significant differences between patients with DM (n=50) vs. patients without DM (n=16) (76% vs. 24%, p=0.002). Frontiers in Endocrinology 01 frontiersin.org Batule et al. 10.3389/fendo.2022.1009028 Among the group of subjects with DM (n=125), those who required IMV or were admitted to the ICU showed higher serum concentrations of C-reactive protein, interleukin-6, D-dimer, ferritin and pro-calcitonin and significantly lower serum concentrations of albumin compared to those who did not require IMV or were not admitted to the ICU. Besides, between these two groups of patients with DM, we observed no differences in glycemic parameters, including median capillary blood glucose values, glycosylated hemoglobin, coefficient of variability and hypoglycemic episodes. In the multinomial analysis, factors independently associated with the composite outcome of IMV or admission to the ICU in the insulin-treated group were the National Early Warning Score (NEWS) 2 score (OR 1.55 [1.17-2.17], p=0.005) and the presence of hospital-acquired superinfections (OR 35.21 [5.11-386.99], p=0.001). Conclusions: In our study, parameters related to glycemic control were not associated with IMV requirement nor admission to the ICU in patients with DM and severe COVID-19 disease receiving daily 6 mg of dexamethasone for 10 days. However, hospital-acquired superinfections and disease severity at admission were independent factors associated with this composite outcome. KEYWORDS diabetes, hyperglycemia, COVID-19, dexamethasone, SARS-CoV-2 Introduction A frustrating challenge in the COVID-19 pandemic has been the lack of effective treatments, particularly those of viricide effect Type 2 Diabetes Mellitus (T2D) is the second most frequent (11) during the first waves. At the time of writing this article, comorbidity after arterial hypertension in patients admitted for different new therapeutic approaches are available and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), vaccination has been performed in most of the developed the virus that causes coronavirus disease 2019 (COVID-19) (1). countries. Pre-exposure prophylaxis with monoclonal It is now well-established that T2D is a risk factor associated antibodies in severely immunocompromised individuals; early with COVID-19 disease severity, with meta-analyses indicating treatments in outpatients with mild-moderate COVID-19 at high that pre-existing diabetes mellitus (DM) is associated with a risk for progression to severe disease with Nirmatrelvir/Ritonavir, greater risk of severe disease and death with an odds ratio Remdesivir or monoclonal antibodies; and finally treatment of ranging from 1.9 to 2.68 (2), especially in those cases with a hospitalized patients with moderate-severe COVID-19 with poor blood glucose control during hospitalization (3). This risk Remdesivir, steroids, Tocilizumab or Barcitinib are currently has been reported to be increased both in subjects with type 1 available. Furthermore, the fourth dose of the vaccine will be diabetes mellitus (T1D) and T2D (4, 5). On the other hand, administered to patients at risk (12). However, when this study COVID-19 might also predispose infected individuals to the was carried out, we only had Remdesivir and steroids in development of hyperglycemia. This can be due to the enhanced hospitalized patients with moderate-severe COVID-19 and the viral-induced inflammation, in particular, interleukin 6 (IL-6) vaccination campaign just started in December 2020. During the mediated, which increases insulin resistance in a dose- first waves of the pandemic, no pharmacological intervention for dependent manner (6). Indeed, the so-called ‘cytokines storm’ COVID-19 disease has been as successful as steroids for treating scenario resulting from severe COVID-19 is associated not only acute illness aiming at minimizing the cytokine storm effects. The with an enhancement of insulin-resistance situation but also RECOVERY (Randomised Evaluation of COVID‐19 Therapy) with impaired insulin production from the pancreatic b cells (7). trial, found that dexamethasone at a dose of 6 mg once daily for Several studies have shown that uncontrolled inpatient up to 10 days reduces mortality by one‐third in ventilated hyperglycemia is associated with adverse outcomes, including patients and by one‐fifth in other patients, receiving oxygen increased rates of infection and mortality and longer hospital therapy (13). Following these results, the use of short courses length of stay (LOS) (8–10). of high doses of glucocorticoid therapy has been widely used. The Frontiers in Endocrinology 02 frontiersin.org Batule et al. 10.3389/fendo.2022.1009028 benefits of dexamethasone for patients with COVID-19 likely Inclusion and exclusion criteria arise from its immunosuppressive and anti-inflammatory properties. Indeed, some of the most potent anti-inflammatory Inclusion criteria were: age ≥18 years old with severe actions of glucocorticoids occur by inhibiting the production of COVID-19 disease requiring daily intravenous 6 mg pro-inflammatory cytokines (IL-1, TNF and IL-6) (14). However, dexamethasone treatment for 10 days. Dexamethasone was it is known that high doses of glucocorticoids also exacerbate implemented according to the Catalonia Department of Health hyperglycemia in people with DM, may unmask previously protocol based on Infectious Diseases Society of America undiagnosed DM and, in those at risk of DM development, guidelines (18) and the RECOVERY study (13). Severe may precipitate hyperglycemia and new-onset DM. It has to be COVID-19 disease was defined as when patients presented mentioned that no data are available in the RECOVERY trial with SpO2 ≤94% on room air, including those on regarding the occurrence of hyperglycemia at different times supplemental oxygen. In non-severe illness defined as during and after the use of dexamethasone, nor in the impact SpO2 >94% not requiring supplemental oxygen, that the use of corticosteroids may have on glycemic control. dexamethasone treatment was not indicated. Exclusion criteria Hyperglycemia, a common side effect of corticosteroids that were: <18 years old, non-severe illness and/or patients in charge usually requires insulin treatment, is associated with worse of ICU and/or IVM requirement. outcomes in COVID-19 (15, 16). To our knowledge, inpatient glycemic control in COVID-19 infected subjects treated with dexamethasone and its related Study variables outcomes has not been well documented in previous studies. Thus, the aim of the present study was to analyze the factors, The following baseline variables were collected: a) among them glycemic control, associated with the composite demographic and anthropometric data: ethnicity, sex, age and outcome of invasive mechanical ventilation (IMV) or admission body mass index (BMI); b) main pathological history: previously to intensive care unit (ICU) and LOS, in patients with COVID- known DM, hypertension, dyslipidemia, cardiovascular disease 19 treated with dexamethasone comparing patients with DM vs. (defined as myocardial infarction and/or heart failure), chronic patients without DM. Also, the secondary endpoint was to obstructive pulmonary disease and chronic kidney disease analyze, in the group of patients treated with insulin, whether (defined as estimated glomerular filtration rate (eGFR) lower there are any differences between patients who have a long LOS, than 60 ml/min/1.73m2) and c) outpatient regular mortality, or hospital-acquired superinfections vs. those who antidiabetic treatment. do not. Severity on admission was graded according to the National Early Warning Score (NEWS) 2 scale (19) in which a score is allocated to six physiological parameters: respiratory rate, Materials and methods oxygen saturation, systolic blood pressure, pulse rate, temperature and level of consciousness. Each parameter scores Study design and setting from 0 to 3 and an additional two points are added if the patient is receiving oxygen therapy. The total possible score ranges from We performed an observational retrospective cohort study, 0 to 20 and, the higher the score the greater the clinical risk including individuals with a diagnosis of SARS-CoV-2 meaning the need for escalation, possible clinical intervention pneumonia according to the World Health Organization and more intensive monitoring. (WHO) guidelines (17) and admitted to the conventional ward The presence of acquired-hospital superinfections in charge of the Infectious Diseases Department from October (infections diagnosed >48 hours after admission), including 2020 to January 2021. sepsis, urinary tract infection, bacterial respiratory infection Data were obtained from an anonymized electronic health and mycosis, was recorded. We also analyzed the LOS and records database from the Germans Trias i Pujol University determined that a long LOS was more than 10 days from Hospital (HUGTiP) (Badalona, Spain). The database included admission until discharge or death. retrospective clinical information, information on admission, Blood laboratory variables were collected at admission: diagnostic and procedure codes, prescribed medications, and hemogram including leukocytes, lymphocytes and neutrophils laboratory parameters. All patients included in the study were recount; liver and renal function including aspartate followed up during the LOS from the start of dexamethasone aminotransferase (AST), alanine transaminase (ALT), gamma- treatment until discharge, ICU requirement or death, whichever glutamyl transferase (GGT), eGFR; lipid function including total occurred first. cholesterol, LDL-c, HDL-c, triglycerides; inflammatory The study was approved by the Ethics Committee of the parameters including fibrinogen, troponin, D-dimer, ferritin, HUGTiP (approval n° PI-20-175). IL-6, C-reactive protein (CRP), pro-calcitonin and albumin. Frontiers in Endocrinology 03 frontiersin.org Batule et al. 10.3389/fendo.2022.1009028 Assessment of metabolic status included blood glucose at number and percent (%). A bivariate analysis was carried out admission before starting dexamethasone treatment and HbA1c using the Mann-Whitney U test to compare medians and chi- measured within 48 hours of admission if the patient did not square tests to compare categorical differences. have a determination in the last three months. Multinomial logistic regression analyses were used to Regarding glycemic control, we defined patients with identify variables associated with the composite of IMV or diabetes as history of DM or use of any antidiabetic admission to the ICU and with the LOS in subjects treated medication before hospitalization, newly diagnosed DM with insulin. To reach the optimal model we use the Deletion/ (fasting glucose glucose ≥126 mg/dL or HbA1c ≥ 6.5% and no Substitution/Addition (DSA) algorithm, which is an iterative previous diagnosis of DM), prediabetes (HbA1c 5.7-6.4%) and process where the final model is selected by minimizing the glucocorticoid-induced hyperglycemia (HbA1c ≤ 5.6% but residual mean squared error (RMSE) using 5-fold cross- fasting glucose ≥126 mg/dL in more than one consecutive validation. As this method is based on cross-validation measure). Patients with normal glucose (fasting glucose (random method), we ran the DSA 50 times to make the concentrations below 126 mg/dL or capillary blood glucose results more consistent and to keep the exposures that appear measurement (CBGM) before main meals <180 mg/dL) were at least 5% of the time. We fixed age, gender, BMI and NEWS considered subjects without diabetes. score as potential confounding variables. For patients with previously known DM, insulin treatment was initiated at admission. In these patients, CBGM was performed according to the HUGTiP protocol, four times per Results day before main meals and bedtime. For patients without a previously known DM diagnosis, CBGM was performed three Two hundred and nine individuals with COVID-19 treated times per day, before main meals since the start of with dexamethasone were included. One hundred twenty-five dexamethasone treatment and, if glycemia was ≥180 mg/dL in out of these subjects were patients with DM and required insulin two consecutive measures, insulin was initiated. In patients with treatment during their hospital stay. Of these 125 subjects, 101 CBGM <180 and fasting blood glucose (FBG) <126 mg/dL presented DM previously known, 17 presented an unknown DM during the dexamethasone treatment period, insulin treatment with HbA1c value ≥ 6.5%, 6 had prediabetes (HbA1c 5.7-6.4%) was not indicated. Values of CBGM were recorded for further and only 1 subject had glucocorticoid-induced hyperglycemia analysis only in the group of patients who required insulin and (HbA1c ≤ 5.6%) (Figure 1). during the period of glucocorticoid treatment. According to Subjects with DM were older (median 72 [39.2-90] vs. 59.5 CBGM values, mean CBGM, standard deviation (SD) of CBGM [27.15-89.92] years, p<0.001), with a higher BMI (median 30.1 and glycemic coefficient of variability (CV) were assessed. [22.67-46.73] vs. 28.98 [20.89-37.75] kg/m², p=0.02) and Mean CBGM was calculated as the mean of all CBGM per presented more associated comorbidities such as day. The standard deviation of CBGM was calculated as the SD cardiovascular disease (38.4 vs. 19.05%, p=0.005), hypertension of the means of all CBGM measurements per day. Glycemic CV (69.6 vs. 30.95%, p<0.001) and dyslipidemia (62.4 vs. 44.05%, was calculated as SD of CBGM concentration/mean CBGM x100 p=0.013) compared with subjects without DM (Table 1). of all CBGM. We defined optimal glycemic control as a median Patients with DM also showed a higher NEWS2 score at CBGM ≤180 mg/dL and suboptimal glycemic control as a hospital admission (median 5 [0-10.9] vs. 3. [0-8] points, median CBGM >180 mg/dL. Hypoglycemic episodes were also p<0.001). Regarding biochemical parameters, subjects with assessed and were defined as grade 1 (54-70 mg/dL) and grade 2 DM showed significantly higher HbA1c values (median 7.45 (<54 mg/dL). [5.9-12.2] vs. 5.4 [5.2-5.5] %, p<0.001), higher admission blood We established a revised hospital protocol for the treatment glucose (median 156 [114-289] vs. 102 [96-106] mg/dL, of hyperglycemia in COVID-19 patients who were treated for 10 p<0.001) and lower serum levels of albumin compared with days with an intravenous dexamethasone dose of 6 mg per day. those who did not require insulin treatment (median 35.1 According to this protocol, the initial total dose of insulin ranged [27.52-42.97] vs. 39.65 [23.15-43.75] g/L, p=0.01). No from 0.5 up to 1.2 UI/Kg/d taking into account previous differences were observed in inflammatory parameters, diagnosis of DM, previous antidiabetic therapy and glycemic including CRP, pro-calcitonin, ferritin, IL-6 or fibrinogen, or control at admission (Appendix A). D-dimer levels between the two groups (Table 1). Statistical analysis Composite outcome of IMV requirement or admission to the ICU Quantitative variables were summarized according to their distribution [median, interquartile range or mean and standard From the 209 patients receiving dexamethasone treatment, deviation ( ± SD)] and categorical variables as frequency, 66 (31.5%) required IMV or were admitted to the ICU, with a Frontiers in Endocrinology 04 frontiersin.org Batule et al. 10.3389/fendo.2022.1009028 FIGURE 1 Flowchart of study population. significantly higher percentage in those with DM (n=50) higher in those who required IMV or admission to the ICU compared to those without DM (n=16) (76% vs. 24%, compared with those who did not (median 0.58 [0.31-0.93] vs. p=0.002) (Table 1). 0.48 [0.15-1.15] IU/Kg, p=0.039). No differences were observed Among the group of 125 patients with DM, those who in IMV requirement or ICU admission between subjects with required IMV or were admitted to the ICU (n=50) compared optimal glycemic control vs. those with suboptimal with those who did not (n=75), showed a significantly higher glycemic control. NEWS2 score (median 6 [2-13] vs. 4 [0-9] points, p<0.001), Factors independently associated with the composite of IMV serum concentrations of AST (median 35 [13.4-233.2] vs. 25.5 or admission to the ICU in the multinomial analysis were the [10.68-96.83] U/L, p=0.021), CRP (median 108.95 [7.92- NEWS2 score (OR 1.55 [1.17-2.17], p=0.005) and the presence 317.33] vs. 60.7 [4.64-211.95] mg/L, p=0.003), IL-6 (median of hospital-acquired superinfections (OR 35.21 [5.11-386.99], 49,78 [3.93-778.67] vs. 29.98 [1.58-92.08] pg/mL, p=0.005), D- p=0.001). No variables associated with glycemic control were dimer (median 1071 [210.6-7232] vs. 648 [193.8-5469.6] ng/ found as independent factors associated with this outcome. mL, p=0.018), ferritin (median 547 [90.8-1914.8] vs. 344 [22- 1502.4] ng/mL, p=0.009) and pro-calcitonin (median 0.16 [0.02-3.28] vs. 0.1 [0.02-0.5] ng/mL, p=0.008) and Overall in-hospital mortality significantly lower serum concentrations of albumin (median 33.75 [26.92-42.39] vs. 36 [29.47-43.12] g/L, p=0.002) (Table 2). The overall in-hospital mortality was 9.09% (19 patients out Furthermore, in the group of subjects with DM, no differences of 209). This mortality rate was higher (12% vs. 4.8%) among were observed in glycemic parameters, such as plasmatic patients with DM (n=15) compared with those without DM glycemic levels at admission, median CBGM values, SD of (n=4) but not statistically significant (Table 1). CBGM, HbA1c, CV and hypoglycemic episodes in both grade Among the subjects with DM, those who died were older 1 and grade 2, between those who required IVM or admission (median 84 [67-94] vs. 71 [37-90] years, p<0.001), showed to the ICU compared with those who did not (Table 2). significantly higher AST (median 52.5 [17.65-101.9] vs. 26 [11- However, the mean daily dose of insulin per kilogram (IU/ 151.35] U/L, p=0.009) and D-Dimer serum concentrations Kg) of body weight during the follow-up was significantly (median 1764.5 [516.38-3550.7] vs. 734 [194.3-8262.9] ng/mL, Frontiers in Endocrinology 05 frontiersin.org Batule et al. 10.3389/fendo.2022.1009028 TABLE 1 Baseline clinical characteristics of patients with COVID-19 treated with dexamethasone. Patients without DM Patients with DM P-value Patients n(%) 84 (40.19) 125 (69.81) Age (years)* 59.5 (27.2-90) 72 (39.2-90) <0.001 Sex (F) n(%) 34 (40.5) 59 (47.2) 0.414 BMI (Kg/m²)* 28.98 (20.9-37.8) 30.1 (22.7-46.7) 0.02 Medical History Diabetes mellitus, n(%) – 101 (80.8-9) Cardiovascular disease, n(%) 16 (19.1) 48 (38.4) 0.005 Chronic kidney disease, n(%) 12 (14.3) 32 (25.6) 0.411 Hypertension, n(%) 26 (31) 87 (69.6) <0.001 Dyslipidemia, n(%) 37 (44.1) 78 (62.4) 0.013 NEWS2 score* 3 (0-8) 5 (0-11) <0.001 Remdesivir treatment, n(%) 35 (41.7) 48 (38.4) 0.777 Glycemic parameters* Admission plasmatic glucose (mg/dL) 102 (96-106) 156 (114-289) <0.001 HbA1c (%) 5.4 (5.2-5.5) 7.45 (5.9-12.2) <0.001 Biochemical markers* Leukocytes count (x109/L) 6.2(3.2-20.6) 7 (2.9-13.3) 0.336 Neutrophil count (x109/L) 4.4 (1.9-17.5) 4.7 (1.7-12) 0.372 Lymphocyte count (x109/L) 1 (0.3-2.19) 0.9 (0.3-2.5) 0.793 CRP (mg/L) 58.8 (6.42-283.9) 75.9 (5.2-287.7) 0.485 Pro-calcitonin (ng/mL) 0.1 (0-1.3) 0.1 (0-2) 0.131 D-Dimer (ng/mL) 830 (238.3-20572.6) 808.5 (195.1-7597.8) 0.844 Troponin (pg/mL) 6.4 (0-108.9) 8.3 (0.4-123.9) 0.045 Ferritin (ng/mL) 460 (34.8-3965.5) 415.5 (26.4-1864.3) 0.287 IL-6 (pg/mL) 37.8 (4.8-202) 39.8 (1.68-244.4) 0.56 Fibrinogen 727 (426.8-1008.7) 708 (376-1049.1) 0.366 Albumin (g/L) 37.7 (23.2-43.8) 35.1 (27.5-43) 0.01 AST (U/L) 29.5 (15-104.6) 27 (11-129.3) 0.821 ALT (U/L) 30.5 (9.7-131.2) 25 (8.1-146.6) 0.1 GGT (U/L) 44 (10.2-368.3) 49 (15.8-600.8) 0.926 Cholesterol (mg/dL) 168 (68-232.4) 146.5 (54.5-237.4) 0.323 HDL-c (mg/dL) 46.3 (24.5-71.5) 38.1 (20.2-75) 0.049 LDL-c (mg/dL) 122.5 (34.1-187.5) 85.5 (20.5-165.3) 0.011 Triglycerides (mg/dL) 161.5 (47-437.1) 137 (46.8-387.1) 0.552 2) eGFR (ml/min/1.73m 90 (20.3-90) 87 (21.2-90) 0.156 Outcomes IMV requirement/ICU admission, n(%) 16 (19.1) 50 (40) 0.002 Length of stay, days* 9 (3-28) 13 (4-46) <0.001 Mortality, n(%) 4 (4.8) 15 (12) 0.124 Superinfections n (%) 10 (11.9) 16 (12.8) 1 Data are median (IQR95%). DM, diabetes mellitus; BMI, body mass index; CRP, C-reactive protein; IL-6, interleukin 6; AST, aspartate aminotransferase; ALT, alanine transaminase; GGT, gamma-glutamyl transferase; eGFR, estimated glomerular filtration rate. p=0.002) compared with those who lived. No differences were In order to enhance the statistical power of the comparison, observed between dead vs. alive patients in CBGM, SD of we have pooled mortality together with the composite outcome CBGM, CV, HbA1c, plasmatic glycemic concentrations at of IMV requirement or admission to the ICU. We found that admission and mean daily dose of insulin during the follow- patients who required ICU/IMV or died (n=58) presented a up. Finally, no differences in mortality were observed between significantly longer LOS (median 19 [6-31] vs. 11 [6-16] days, patients with DM with optimal glycemic control vs. those with p<0.001), higher NEWS2 (median 6 [3-9] vs. 4 [2-6] points, suboptimal glycemic control. p<0.001), higher leukocytes (median 8.5 [2.3-14.7] vs. 6.5 [3.8- Frontiers in Endocrinology 06 frontiersin.org Batule et al. 10.3389/fendo.2022.1009028 TABLE 2 Baseline clinical characteristics and glycemic parameters in patients with diabetes mellitus related to IMV requirement or admission to ICU. Patients who did not require IMV nor were Patients who required IMV or were P-value admitted to ICU admitted to ICU Patients n(%) 75 (60) 50 (40) Age (years)* 75 (32.9-92.3) 70 (45-83.8) 0.046 Sex (F/M), n 39/36 20/30 0.257 BMI (Kg/m²)* 30.1 (22.5-45.5) 30 (23.8-45.3) 0.784 Medical History Diabetes mellitus, n(%) 60 (80) 41 (82) 0.963 Cardiovascular disease, n 35 (46.7) 13 (26) 0.032 (%) Chronic kidney disease, n 20 (26.7) 12 (24) 0.917 (%) Hypertension, n(%) 52 (69.3) 35 (70) 1 Dyslipidemia, n(%) 47 (62.7) 31 (62) 1 Glycemic parameters CBG (mg/dL)* 204 (123-317) 207 (129-283) 0.672 SD of CBG (mg/dL)* 68 (32-104) 60 (27-88) 0.22 HbA1c (%)* 7.05 (6-12.2) 7.8 (5.7-10.3) 0.146 CV (%)* 32.3 (19.2-46.2) 28.4 (12.1-44.7) 0.344 Total dose of insulin 0.48 (0.15-1.15) 0.58 (0.31-0.93) 0.039 (units/Kg)* Grade 1 hypoglycemia 12 1 0.727 (episodes) Grade 2 hypoglycemia 13 1 0.871 (episodes) Biochemical markers* Leukocytes count (x109/L) 6.9(2.9-12.7) 7.2 (2.9-13.8) 0.12 Neutrophil count (x109/L) 4.5 (1.6-10.2) 5.4 (2-13.9) 0.162 Lymphocyte count (x109/L) 1 (0.3-2.4) 0.8 (0.3-2.9) 0.167 CRP (mg/L) 60.7 (4.6-212) 109 (7.9-317.3) 0.003 Pro-calcitonin (ng/mL) 0.1 (0-0.5) 0.2 (0-3.3) 0.008 D-Dimer (ng/mL) 648 (194-5469.6) 1071 (210.6-7232) 0.018 Troponin (pg/mL) 8.6 (0.7-115.7) 7.9 (0.1-372.3) 0.947 Ferritin (ng/mL) 344 (22-1502.4) 547 (90.8-1914.8) 0.009 IL-6 (pg/mL) 30 (1.6-92.1) 49.8 (3.9-778.7) 0.005 Fibrinogen 682 (382.4-1055.2) 731.5 (380.9-1024.7) 0.14 Albumin (g/L) 36 (29.5-43.1) 33.8 (26.9-42.4) 0.002 AST (U/L) 25.5 (10.7-96.8) 35 (13.4-233.2) 0.021 ALT (U/L) 22 (8.9-149.8) 32.5 (8.7-86.7) 0.075 GGT (U/L) 50 (15-411.5) 46.5 (17.2-615.3) 0.539 Cholesterol (mg/dL) 148.5 (8.3-235.6) 144.5 (64.1-239.4) 0.749 HDL-c (mg/dL) 38.1 (23.9-106.8) 37.8 (19.1-71.2) 0.714 LDL-c (mg/dL) 80 (23.1-171) 91 (23-156) 0.39 Triglycerides (mg/dL) 144 (55.3-450.3) 132.5 (43.8-234.2) 0.239 eGFR (ml/min/1.73m2) 85.5 (20-90) 90 (27.4-90) 0.245 *Data are median (IQR95%). BMI, body mass index; CBG, capillary blood glucose; CV, coefficient of variability; TDI, total daily insulin dose; CRP, C-reactive protein; IL-6, interleukin 6; AST, aspartate aminotransferase; ALT, alanine transaminase; GGT, gamma-glutamyl transferase; eGFR, estimated glomerular filtration rate. 9.1] x109/L, p=0.013), AST (median 49 [39-101] vs. 30 [10-49] p=0.001) serum concentrations compared with patients who did U/L, p=0.007) and RCP (median 117.19 [32.28-202.1] vs. 69.93 not require ICU/IMV and stayed alive (n=67). We found no [11.67-128.19] mg/L, p=0.001) serum concentrations and lower significant differences regarding glycemic parameters between albumin (median 34.03 [29.68-38.38] vs. 36.72 [32.54-40.9] g/L, both groups. Frontiers in Endocrinology 07 frontiersin.org Batule et al. 10.3389/fendo.2022.1009028 Length of stay treatment (6 mg daily for 10 days) reduced mortality in hospitalized patients with COVID-19 and respiratory failure Length of hospital stay was significantly longer in patients who required therapy with supplemental oxygen or mechanical with DM compared with patients without DM (median 13 [IQR ventilation. Despite 25% of subjects in the RECOVERY trial 4-45.5) vs. 9 [IQR 3.08-27.7] days, p<0.001) (Table 1). having DM, this subset of patients was not analyzed separately. Among those with DM, no differences were observed in LOS Hyperglycemia, a common side effect of corticosteroids that between optimal vs. suboptimal controlled patients. Also, we usually requires insulin treatment, is associated with worse found no statistical differences between long vs. short LOS in outcomes in COVID-19 (2, 3). Therefore, data regarding median CBGM, SD of CBGM, CV, plasmatic glycemic levels at glycemic control and its relationship with clinical prognosis in admission and total daily insulin dose per kg. Statistically subjects with DM treated with the same regimen of significant associations were found regarding higher AST dexamethasone as that used in the RECOVERY trial, are needed. (median 28.5 [13-193.38] vs. 24 [10-53] IU/L, p=0.035) and The present study shows that in hospitalized patients with D-Dimer serum concentrations (median 980 [204.75-5664.5] vs COVID-19 treated with dexamethasone at the same regimen as 568 [189.3-9281.85] ng/mL, p=0.037) and higher prevalence of in the RECOVERY trial, those with DM required more IMV or superinfections (12.8% vs 0%, p=0.001) between subjects with admission to the ICU and presented a longer LOS than subjects long vs. short LOS. In the multinomial analysis, superinfections without DM. Also, mortality was higher in people with DM, were associated with a longer LOS (p<0.001). although differences were not statistically significant, probably due to the lower number of cases. These results are in line with previous studies that showed that mortality risk in subjects with DM and COVID-19 is increased between two and three-fold Acquired-hospital superinfections times compared with subjects without DM (1, 2, 4, 20). As far as we know, this is the first study reporting on the impact of several Superinfections were not different between patients with vs. factors, among them glycemic metabolic control, on the patients without DM (12.8% vs 11.9%) (Table 1). composite outcome of IMV or admission to the ICU in However, among subjects with DM, those who presented subjects with COVID-19 treated with dexamethasone. superinfections had a lower BMI (27.4 [22.4-41] vs 30.3 [22.8- We also found that, in subjects with DM, superinfections are 8.47], p=0.007), lower HbA1c (6.7 [5.6-8.6] vs. 7.6 [6-12.2] %, associated with both an increased risk of the composite outcome p=0.012), and required a higher total daily insulin dose (0.48 of IMV or admission to the ICU as well as with a longer LOS. [0.15-1.15] vs. 0.58 [0.31-0.93] vs.0.48 [0.15-1.15], p=0.039) than Previous studies suggest that viral respiratory diseases and those without superinfections. Regarding to biochemical COVID-19 in particular, may predispose to other fungal, parameters, patients with superinfections had higher bacterial, and viral co-infections and superinfections (21). On inflammatory parameters than those without superinfections, the other hand, corticosteroid therapy has been reported to be namely higher CRP (109 [210.6-7232] vs. 60.7 [4.6-212] mg/L, associated with an increased risk of infections (22), partly due to p=0.003), pro-calcitonin (0.2 [0-3.3] vs.0.1 [0-0.5] ng/mL, its immunosuppressive effects. However, few data exist in the p=0.008), ferritin (547 [90.8-1914.8] vs. 344 [22-1502.4] ng/ literature regarding superinfections in subjects with COVID-19 mL, p=0.009), IL-6 (547 [90.8-1914.8] vs. 30 [1.6-92.1] pg/mL, during hospital stay. In a recently published study by Garcia- p=0.005) and lower albumin (33.8 [26.9-42.4] vs. 36 [29.5-43.1] Vidal et al, the prevalence reported of superinfections in subjects g/L, p=0.002) serum concentrations. In addition, subjects with admitted with COVID-19 was 4,7% (23) although no data superinfections presented higher D-dimer (1071 [210.6-7232] regarding steroid treatment was reported. However, they vs. 648 [194-5469.6] ng/mL, p=0.018) and AST levels (35 [13.4- observed that patients with superinfections had prolonged LOS 233.2] vs. 25.5 [10.7-96.8] U/L, p=0.021) than those without and higher mortality, similar to the results obtained in the superinfections. Finally, no differences were found in plasmatic present study. glycemic levels at admission, median CBMG, CV nor grade 1 In addition, our results show that disease severity at and grade 2 hypoglycemic e pisodes between both admission, reflected by the NEWS2 score within 24 hours of groups (Table 3). hospital admission, is independently associated with the risk of the composite outcome of IVM or admission to the ICU whereas the inflammatory cytokine IL-6 concentrations are associated Discussion with a longer hospital stay. To the best of our knowledge, publications regarding the performance of the NEWS and its Treatment with dexamethasone has been shown to improve modification, NEWS2, in COVID-19 patients are scarce. These prognostic outcomes in subjects infected with COVID-19, scores are validated for the identification of patient deterioration especially in severe cases. The impressive results of the in a range of clinical conditions and settings (24) and the WHO RECOVERY trial (13) established that dexamethasone recommends its use in COVID-19 patients (17). Recently, it has Frontiers in Endocrinology 08 frontiersin.org Batule et al. 10.3389/fendo.2022.1009028 TABLE 3 Baseline clinical characteristics and glycemic parameters between patients with diabetes mellitus related to superinfections. Patients who did not have any superinfection Patients who had any superinfection P-value Patients n(%) 109 (87.2) 16 (12.8) Age (years)* 71 (37-91) 77 (61-89) 0.077 Sex (F/M), n 48/61 11/5 0.114 BMI (Kg/m²)* 30.3 (22.8-47) 27.4 (22.4-41) 0.007 Medical History Diabetes mellitus, n(%) 88 (80.7) 13 (81.3) 1 Cardiovascular disease, n(%) 41 (37.6) 7 (43.8) 0.845 Chronic kidney disease, n(%) 26 (23.9) 6 (38) 0.414 Hypertension, n(%) 73 (67) 14 (88) 0.169 Dyslipidemia, n(%) 65 (59.6) 13 (81.3) 0.164 Glycemic parameters CBG (mg/dL)* 204 (124-316) 206 (139-226) 0.602 SD of CBG (mg/dL)* 63 (31-104) 70 (39-90) 0.566 HbA1c (%)* 7.6 (6-12.2) 6.7 (5.6-8.6) 0.012 CV (%)* 31 (17.1-46.1) 34.4 (19.2-44) 0.122 Total dose of insulin (units/Kg)* 0.54 (0.2-1) 0.45 (0.1-0.7) 0.126 Grade 1 hypoglycemia (episodes) 12 1 0.856 Grade 2 hypoglycemia (episodes) 12 2 0.286 Biochemical markers* Leukocytes count (x109/L) 7 (2.9-13.5) 6.6 (3.1-13) 0.979 Neutrophil count (x109/L) 4.7 (1.8-12) 4.3 (1.7-11.2) 0.932 Lymphocyte count (x109/L) 0.9 (0.3-2.6) 0.9 (0.4-1.9) 0.697 CRP (mg/L) 75.9 (6.3-287.4) 76 (4.4-264.2) 0.765 Pro-calcitonin (ng/mL) 0.1 (0-2.5) 0.2 (0.1-1.2) 0.01 D-Dimer (ng/mL) 771 (194.3-8357.3) 1666.5 (398.6-3795.3) 0.025 Troponin (pg/mL) 8.3 (0.32-119) 10.9 (2.5-186.5) 0.548 Ferritin (ng/mL) 413.5 (24.5-1584.1) 479 (73.3-2014.3) 0.808 IL-6 (pg/mL) 32.5 (1.5-240.7) 44.3 (6.2-1014.8) 0.129 Fibrinogen 712.5 (406.2-1034.1) 644 (345.6-1052.8) 0.607 Albumin (g/L) 35.2 (28.2-43.2) 34 (27.7-40.7) 0.379 AST (U/L) 28 (11-154.5) 24.5 (14.5-80.3) 0.576 ALT (U/L) 26 (8-150.5) 20 (10.1-77.1) 0.167 GGT (U/L) 46 (14.2-544.6) 55.5 (21.9-652) 0.279 Cholesterol (mg/dL) 146.5 (35.7-239.4) 139.5 (70.5-218.3) 0.548 HDL-c (mg/dL) 37.6 (20.4-62.4) 39.1 (19.7-1693.5) 0.72 LDL-c (mg/dL) 88 (30.8-165.6) 68.5 (9.3-141.4) 0.296 Triglycerides (mg/dL) 137 (44.8-378.6) 141 (66-391.9) 0.91 eGFR (ml/min/1.73m2) 88 (20.7-90) 69.5 (27.8-126.9) 0.077 *Data are median (IQR95%). BMI, body mass index; CBG, capillary blood glucose; CV, coefficient of variability; TDI, total daily insulin dose; CRP, C-reactive protein; IL-6, interleukin 6; AST, aspartate aminotransferase; ALT, alanine transaminase; GGT, gamma-glutamyl transferase; eGFR, estimated glomerular filtration rate. been reported that NEWS and NEWS2 are good predictors of obtained in the present study confirm that NEWS2 is an death and ICU admission in subjects with COVID-19 (25). A important predictor for the composite outcome of IMV or retrospective study involving 334 patients, reported that NEWS admission to the ICU in subjects with DM and receiving was the most accurate predictor of ICU admission treatment with dexamethasone. (AUROC=0.80 (0.76-0.84)) along with NEWS2 (AUROC=0.78 In subjects with COVID-19, several biomarkers among them (0.73-0.82)) within 48h of emergency department arrival (26). IL-6, CRP, ferritin, and low albumin levels have been reported to Furthermore, in a smaller study, Gidari et al. showed similar be predictive of mortality in hospitalized patients with COVID- AUROC values (AUROC=0.90 (0.82-0.97) for ICU requirement 19 (28). On the other hand, a great amount of data worldwide using NEWS2 score at admission (27). Consistently, results reveals that COVID-19 patients with hyperglycemia or T2D Frontiers in Endocrinology 09 frontiersin.org Batule et al. 10.3389/fendo.2022.1009028 have a greatly enhanced release of inflammatory cytokines or the Most analyses reported so far have not accounted for disease cytokine storm syndrome, which leads to immunosuppression severity at the time of hospital admission. In the present study, in and multi-organ failure (29), providing further evidence of a our severe cases requiring dexamethasone treatment, parameters potential link between DM and COVID-19 due to inflammation related to glycemic control were not associated with IMV or and immune deficiency. In our study, neither inflammatory admission to the ICU possibly due to the fact that the markers nor parameters related to glycemic control were inflammatory response was modulated by the corticosteroid found as independent factors associated with the composite therapy which attenuated the deleterious effect of hyperglycemia. outcome of IMV requirement or ICU admission, which may This was a retrospective study and therefore, the studied be due to the protective effects of dexamethasone. Regarding groups were not strictly matched. Also, the prevalence of DM in LOS, in our study higher IL-6 levels were associated with more our study was higher (59%) compared to the prevalence of days of admission. This finding correlates with the study results inpatients with DM and COVID-19 during the first wave in of Laguna-Goya R et al. (28) (R²= 0.12; p<0.001). Indeed, other Spanish studies (19.4-27%) (20, 36). However, the DM inflammatory indices, including LDH, CRP and IL-6 may help definition used in these studies was more strict. In a Turkish to identify cases with dismal prognoses in COVID-19 subjects cohort using a similar definition of DM, the prevalence of DM and perform a prompt intervention in order to improve (59.3%) was comparable to the one obtained in our study (37). outcomes (30). Besides inflammatory markers, in our study we An additional limitation was that the follow-up time was found that AST was significantly higher in patients with a longer restricted to hospital stay or death. Although the small size of LOS, IMV requirement or admission to the ICU and mortality. the study (209 subjects), the main strength of this study These results are similar to those found in a retrospective treatment was very homogeneous in a single hospital and with multicenter study involving 5,771 patients where AST at the same protocol applied to all of the patients, including the admission was strongly associated with mortality risk same dose and start time of dexamethasone and the same basal- suggesting liver damage (31). bolus insulin regimen. In this study, no parameters related to glycemic control were In conclusion, people with DM had about 3 times worse associated with the composite outcomes, regardless that prior to outcomes and IMV/ICU requirements than those without DM the COVID-19 pandemic, DM was associated with increased risk while severely infected with COVID-19. Parameters related to for multiple infections, and infection-related morbidity and glycemic control in these patients in treatment with daily 6 mg of mortality often proportional to the degree of glycemic control dexamethasone for 10 days were not associated with IMV (32). These results may thus be interpreted as a protective effect requirement, admission to ICU, LOS nor mortality. These of dexamethasone in DM subjects, irrespective of their glycemic findings support a positive action on dexamethasone treatment control, therefore reinforcing the appropriateness of including able to attenuate the deleterious effect of hyperglycemia, while this drug in the treatment of patients severely affected by nosocomial infections and disease severity at admission were the COVID-19 infection and, particularly, in those having DM, a main factors independently associated with the composite condition that has been recognized as an important risk factor outcome studied (IMV requirement and/or ICU admission). for worse outcomes in such patients, including mortality. Hyperglycemia is a well-known marker of disease severity, and its association with poor outcomes in patients with COVID-19 Data availability statement has been previously reported. Insulin administration is the preferred way to control hyperglycemia in hospitalized patients The original contributions presented in the study are with a starting threshold below 180 mg/dl (33). This has been included in the article/Supplementary Material. Further described for hyperglycemia at hospital admission (20), for inquiries can be directed to the corresponding author. severe hyperglycemia after hospital admission as well as for poorly controlled blood glucose during hospital stay (34). Recent retrospective studies have suggested that insulin levels might be Ethics statement related to death rate in COVID-19 subjects with DM (35). In the present study, insulin doses during LOS were higher in subjects The studies involving human participants were reviewed and who required IMV or were admitted to the ICU compared with approved by Ethics Committee of the HUGTiP (approval no: PI- those who did not, reflecting an enhanced insulin-resistance state 20-175). Written informed consent for participation was not in these patients, insulin dose was not independently associated required for this study in accordance with the national with the composite endpoint of IMV or admission to the ICU. legislation and the institutional requirements. Frontiers in Endocrinology 10 frontiersin.org Batule et al. 10.3389/fendo.2022.1009028 Author contributions Publisher’s note All authors had full access to all of the data in this study and All claims expressed in this article are solely those of the took complete responsibility for the integrity of the data and the authors and do not necessarily represent those of their affiliated accuracy of the data analysis. All named authors meet the organizations, or those of the publisher, the editors and the International Committee of Medical Journal Editors (ICMJE) reviewers. Any product that may be evaluated in this article, or criteria for authorship for this manuscript, take responsibility for claim that may be made by its manufacturer, is not guaranteed the integrity of the work as a whole, and have given final or endorsed by the publisher. approval for the version to be published. Conflict of interest Supplementary material The authors declare that the research was conducted in the The Supplementary Material for this article can be found absence of any commercial or financial relationships that could online at: https://www.frontiersin.org/articles/10.3389/ be construed as a potential conflict of interest. fendo.2022.1009028/full#supplementary-material References 1. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors 14. Quatrini L, Ugolini S. New insights into the cell- and tissue-specificity of for mortality of adult inpatients with COVID-19 in wuhan, China: A retrospective glucocorticoid actions. 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