TYPE Original Research PUBLISHED 16 May 2023 DOI 10.3389/fendo.2023.1167087 Post-COVID-19 syndrome OPEN ACCESS and diabetes mellitus: a EDITED BY Pranav Kumar Prabhakar, Lovely Professional University, India propensity-matched analysis of REVIEWED BY Sawai Singh Rathore, the International HOPE-II Dr. Sampurnanand Medical College, India Evgeny Shlyakhto, Almazov National Medical Research COVID-19 Registry Centre, Russia *CORRESPONDENCE Mohammad Abumayyaleh 1,2*, Iván J. Núñez Gil 3, Mohammad Abumayyaleh mohammad.abumayyaleh@medma.uni- Marı́a C. Viana-LLamas 4, Sergio Raposeiras Roubin 5, heidelberg.de Rodolfo Romero 6, Emilio Alfonso-Rodrı́guez 7, Aitor Uribarri 8,9, RECEIVED 15 February 2023 Gisela Feltes 10, Vı́ctor Manuel Becerra-Muñoz 11, ACCEPTED 27 April 2023 PUBLISHED 16 May 2023 Francesco Santoro 12, Martino Pepe 13, Alex Fernando Castro Mejı́a 14, CITATION Jaime Signes-Costa 15, Adelina Gonzalez 16, Francisco Marı́n 17, Abumayyaleh M, Núñez Gil IJ, Viana-LLamas MC, Raposeiras Roubin S, Javier López-Paı́s 18, Edoardo Manzone 19, Romero R, Alfonso-Rodrı´guez E, Uribarri A, Olalla Vazquez Cancela 20, Carolina Espejo Paeres 21, Feltes G, Becerra-Muñoz VM, Santoro F, Pepe M, Castro Mejı´a AF, Signes-Costa J, Alvaro López Masjuan 22, Lazar Velicki 23,24, Christel Weiß 25, Gonzalez A, Marı´n F, López-Paı´s J, Manzone E, Vazquez Cancela O, David Chipayo 3, Antonio Fernandez-Ortiz 3, Paeres CE, Masjuan AL, Velicki L, Weiß C, Ibrahim El-Battrawy 1,2,26, Ibrahim Akin 1,2 and HOPE Chipayo D, Fernandez-Ortiz A, El-Battrawy I, Akin I and HOPE COVID-19 COVID-19 investigators investigators (2023) Post-COVID-19 syndrome and diabetes mellitus: a 1 Department of Cardiology, Angiology, Haemostaseology and Medical Intensive Care, University propensity-matched analysis of the Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany, International HOPE-II COVID-19 Registry. 2 European Center for AngioScience (ECAS) and German Center for Cardiovascular Research (DZHK) Front. Endocrinol. 14:1167087. partner site Heidelberg/Mannheim, Mannheim, Germany, 3 Hospital Clı´nico San Carlos, Universidad doi: 10.3389/fendo.2023.1167087 Complutense de Madrid, Instituto de Investigación, Sanitaria del Hospital Clı´nico San Carlos (IdISSC), Madrid, Spain, 4 Hospital Universitario Guadalajara, Guadalajara, Spain, 5 University Hospital Álvaro COPYRIGHT Cunqueiro, Vigo, Spain, 6 Hospital Universitario Getafe, Getafe, Universidad Europea, Madrid, Spain, © 2023 Abumayyaleh, Núñez Gil, 7 Hospital University of Bellvitge, Barcelona, Spain, 8 Cardiology Department, Vall d’Hebron University Viana-LLamas, Raposeiras Roubin, Romero, Hospital and Research Institute, Universitat Autonoma de Barcelona, Barcelona, Spain, 9 Centro de Alfonso-Rodrı´guez, Uribarri, Feltes, Investigacion Biomedica en Red para Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain, Becerra-Muñoz, Santoro, Pepe, Castro Mejı´a, 10 Hospital Nuestra Señora de América, Madrid, Spain, 11 Hospital Clinico Universitario Virgen de la Signes-Costa, Gonzalez, Marı´n, López-Paı´s, Victoria, Malaga, Spain, 12 Department of Medical and Surgical Sciences, University of Foggia, Manzone, Vazquez Cancela, Paeres, Masjuan, Foggia, Italy, 13 Azienda Ospedaliero-Universitaria Consorziale Policlinico di Bari, Bari, Italy, 14 Hospital Velicki, Weiß, Chipayo, Fernandez-Ortiz, General del norte de Guayaquil IESS Los Ceibos, Guayaquil, Ecuador, 15 Hospital Clı´nico de Valencia, El-Battrawy, Akin, HOPE COVID-19 INCLIVA, Valencia, Spain, 16 Hospital Universitario Infanta Sofia, Madrid, Spain, 17 Hospital Clı´nico investigators. This is an open-access article Universitario Virgen de la Arrixaca, Murcia, Spain, 18 Complejo Hospitalario Universitario de Ourense, distributed under the terms of the Creative Ourense, Spain, 19 Hospital del Sureste, Madrid, Spain, 20 Complejo Hospitalario Universitario de Commons Attribution License (CC BY). The Santiago de Compostela, Santiago, Spain, 21 Hospital Universitario Prı´ncipe de Asturias, Madrid, Spain, use, distribution or reproduction in other forums is permitted, provided the original 22 Hospital Universitario Juan Ramón Jimenez, Huelva, Spain, 23 Faculty of Medicine, University of Novi author(s) and the copyright owner(s) are Sad, Novi Sad, Serbia, 24 Institute of Cardiovascular Diseases Vojvodina, Sremska Kamenica, Serbia, credited and that the original publication in 25 Department for Statistical Analysis, University Heidelberg, Mannheim, Germany, 26 Department of this journal is cited, in accordance with Cardiology and Angiology, Bergmannsheil University Hospitals, Ruhr University of Bochum, accepted academic practice. No use, Bochum, Germany distribution or reproduction is permitted which does not comply with these terms. Background: Diabetes mellitus (DM) is one of the most frequent comorbidities in patients suffering from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with a higher rate of severe course of coronavirus disease (COVID-19). However, data about post-COVID-19 syndrome (PCS) in patients with DM are limited. Frontiers in Endocrinology 01 frontiersin.org Abumayyaleh et al. 10.3389/fendo.2023.1167087 Methods: This multicenter, propensity score-matched study compared long- term follow-up data about cardiovascular, neuropsychiatric, respiratory, gastrointestinal, and other symptoms in 8,719 patients with DM to those without DM. The 1:1 propensity score matching (PSM) according to age and sex resulted in 1,548 matched pairs. Results: Diabetics and nondiabetics had a mean age of 72.6 ± 12.7 years old. At follow-up, cardiovascular symptoms such as dyspnea and increased resting heart rate occurred less in patients with DM (13.2% vs. 16.4%; p = 0.01) than those without DM (2.8% vs. 5.6%; p = 0.05), respectively. The incidence of newly diagnosed arterial hypertension was slightly lower in DM patients as compared to non-DM patients (0.5% vs. 1.6%; p = 0.18). Abnormal spirometry was observed more in patients with DM than those without DM (18.8% vs. 13; p = 0.24). Paranoia was diagnosed more frequently in patients with DM than in non-DM patients at follow-up time (4% vs. 1.2%; p = 0.009). The incidence of newly diagnosed renal insufficiency was higher in patients suffering from DM as compared to patients without DM (4.8% vs. 2.6%; p = 0.09). The rate of readmission was comparable in patients with and without DM (19.7% vs. 18.3%; p = 0.61). The reinfection rate with COVID-19 was comparable in both groups (2.9% in diabetics vs. 2.3% in nondiabetics; p = 0.55). Long-term mortality was higher in DM patients than in non-DM patients (33.9% vs. 29.1%; p = 0.005). Conclusions: The mortality rate was higher in patients with DM type II as compared to those without DM. Readmission and reinfection rates with COVID-19 were comparable in both groups. The incidence of cardiovascular symptoms was higher in patients without DM. KEYWORDS diabetes mellitus, post-COVID-19 syndrome, SARS-CoV-2, respiratory complications, reinfection, vaccination rate, long-term mortality Introduction comorbidity and mortality of COVID-19 (10). In the Health Outcome Predictive Evaluation for COVID-19 II (HOPE-II Coronavirus disease 2019 (COVID-19) is caused by severe acute COVID-19) Registry, we investigated readmission, reinfection, respiratory syndrome coronavirus 2 (SARS-CoV-2) and is vaccination rate, cardiovascular, neuropsychiatric, respiratory, associated with significant morbidity and mortality (1). gastrointestinal, and other symptoms in hospitalized patients Among other related diseases such as arterial hypertension and suffering from COVID-19 and concomitant DM type II. obesity, diabetes mellitus (DM) is identified as a risk factor for the Complications related to COVID-19 and long-term mortality severe course of COVID-19, developing sepsis, and mortality (2–4). were also systematically analyzed. In patients suffering from COVID-19, SARS-CoV-2 binds the angiotensin-converting enzyme 2 (ACE2) receptor and uses it as a potential target for viral interventions (5). In diabetic mice, the Material and methods expression of ACE2 is increased as compared to mice without DM. In addition, patients who suffered from insufficient glycemic control Study design and participants showed worse outcomes, such as more complications and higher mortality rates (6). New-onset DM and metabolic complications in HOPE-II COVID-19 (NCT04334291) is an international project patients suffering from manifested DM with high doses of insulin at 55 international centers. It is designed as a retrospective and have been revealed in COVID-19 (7, 8). Furthermore, uncontrolled prospective cohort registry to investigate post-COVID-19 syndrome glycemic levels in DM patients cause organ injury and may be without any conflict of interest. We included hospitalized patients exacerbated in patients suffering from COVID-19 (9). with a confirmed diagnosis of COVID-19. There are no exclusion The international Health Outcome Predictive Evaluation for criteria, except for the patient’s explicit refusal to participate. Initially, COVID-19 (HOPE COVID-19) Registry was initiated to investigate data on 8,828 hospitalized patients suffering from COVID-19 were Frontiers in Endocrinology 02 frontiersin.org Abumayyaleh et al. 10.3389/fendo.2023.1167087 collected until 30th September 2021. In this study, we excluded 56 mortality were identified by univariate analysis. Predictors with p < patients due to age <18 and 53 patients with DM type I. Data from 0.05 were analyzed by logistic multivariable regression. The 8,719 consecutive patients with COVID-19 regarding their multivariable regression test was used to investigate predictors of concomitant DM type II status were analyzed. mortality, adjusting for all significant variables: age; male as sex; obesity; comorbidities such as arterial hypertension, dyslipidemia, DM type II, renal insufficiency, heart disease, cerebrovascular disease, Ethics approval liver disease, and cancer disease; immunosuppression; home oxygen therapy; premedication; symptomatic; clinical parameters such as This study was executed in compliance with the Declaration of peripheral oxygen saturation (SpO2) <92% and reduced blood Helsinki regarding human subjects, and the study was approved by pressure (systolic blood pressure <90 mmHg or diastolic blood the center ethics committee of Hospital Clinico San Carlos (Internal pressure <60 mmHg); and laboratory parameters. p-value of <0.05 Code: 21/128-E) and, when needed, in all involved centers. was recognized as statistically significant. Statistical analysis was performed with IBM SPSS Statistics version 27. DM type II Results DM type II was known and diagnosed by medical physicians. Data were collected from the patient’s medical records. Baseline characteristics and in-hospital complications Post-COVID-19 syndrome Data from 8,719 consecutive hospitalized patients (n = 1,578 with DM; n = 7,141 with non-DM) with confirmed COVID-19 were Patients suffering from post-COVID-19 syndrome describe new- collected. The 1:1 propensity score matching (PSM) according to age onset symptoms following initial recovery from an acutely confirmed and sex resulted in 1,548 matched pairs. The mean age of matched COVID-19 or ongoing from the initial illness. This condition occurs 3 pairs was 72.6 ± 12.7 years old. Even more, the male sex was 63.5% in months from the onset of COVID-19 with symptoms that last for at both groups. Diabetics suffered from more chronic conditions such as least 2 months and cannot be explained by an alternative diagnosis. arterial hypertension (77.5% vs. 58.5%; p < 0.0001), renal insufficiency Symptoms may also fluctuate or relapse over time (11). (13.6% vs. 8.1%; p < 0.0001), and liver disease (5.7% vs. 3.4%; p = 0.002). In-hospital complications were observed more in diabetics as compared to nondiabetics, for example, respiratory insufficiency Outcomes and follow-up (62.1% vs. 56.3%; p = 0.001), acute kidney injury (26.6% vs. 19.8%; p < 0.0001), and sepsis (15.4% vs. 12.8%, p = 0.04). Other baseline We described long-term mortality as a primary endpoint. characteristics, immunosuppression, home oxygen therapy, Readmission, reinfection rate, respiratory complications, premedication, symptomatic, clinical, and laboratory parameters, cardiovascular, neuropsychiatric, respiratory, gastrointestinal, and in-hospital complications, and intervention procedures during other symptoms as secondary endpoints were also evaluated. hospitalization are presented in Table 1. Follow-up for the overall population for mortality was 20 months (mean post-COVID-19; 2.6 ± 4.6). Clinical outcomes at long-term follow-up Statistical analysis Mean follow-up (2.6 ± 4.6 months) data were available for 412 diabetics and 443 nondiabetics. The readmission rate due to any Descriptive and comparative analyses were presented. cause was similar in diabetics and nondiabetics, respectively (19.7% Continuous variables were shown as mean ± standard deviation if vs. 18.3%; p = 0.61). The reinfection rate with COVID-19 was also the distribution was normal or median (min–max) if not. Categorical comparable in patients with DM than those without DM (2.9% vs. variables were presented as frequency rates and percentages. The Chi- 2.3%; p = 0.55). Additionally, diabetics were vaccinated more than square test was used for categorical variables for group comparisons. nondiabetics at follow-up with the same time to vaccination (11.9 ± Quantitative variables were performed using the Mann–Whitney U 3.1 months in diabetics vs. 12.2 ± 2.9 months in nondiabetics) test for nonparametric variables and the Student’s t-test for (57.3% vs. 51.7%; p = 0.10). At follow-up, cardiovascular symptoms parametric variables, as verified by the Kolmogorov–Smirnov test. such as dyspnea and an increase in resting heart rate after discharge We applied a propensity score (PS)-based matching method to occurred less frequently in patients suffering from DM (13.2% vs. control for confounding baseline variables due to the 16.4%; p = 0.01) than those without DM (2.8% vs. 5.6%; p = 0.05), nonrandomized nature of the study and the different participating respectively. In addition, the mortality rate at the 20-month follow- centers. In a multivariable logistic regression test, hazard ratio (HR) up was significantly higher in DM than in non-DM patients (33.9% with 95% confidence intervals (95% CI) was calculated for the vs. 29.1%; p = 0.005). Cardiovascular, neuropsychiatric, respiratory, determination of risk factors for the endpoint. Predictors of gastrointestinal, and other symptoms are presented in Table 2. Frontiers in Endocrinology 03 frontiersin.org Abumayyaleh et al. 10.3389/fendo.2023.1167087 TABLE 1 Patients with diabetes mellitus type II as compared to patients without DM II, baseline characteristics, laboratory and radiographic findings, complications, and clinical outcomes. Characteristic Diabetics (N = 1,548) Nondiabetics (N = 1,548) p-value* Age (mean ± SD (years)) 72.6 ± 12.7 72.6 ± 12.7 1.00 Male as sex (no. (%)) 983 (63.5) 983 (63.5) 1.00 Chronic conditions (no. (%)) Arterial hypertension 1,200 (77.5) 906 (58.5) <0.0001 Dyslipidemia 927 (59.9) 551 (35.6) <0.0001 Obesity 486 (31.4) 221 (14.3) <0.0001 Current smoking 86 (6.2) 83 (5.9) 0.73 a Renal insufficiency 211 (13.6) 126 (8.1) <0.0001 Lung disease 362 (30.1) 329 (28) 0.26 Cardiac disease 538 (34.8) 414 (26.7) <0.0001 Cerebrovascular disease 192 (12.4) 164 (10.6) 0.12 Connective tissue disease 48 (3.1) 43 (2.8) 0.60 Liver disease 88 (5.7) 52 (3.4) 0.002 Cancer disease 291 (18.8) 237 (15.3) 0.009 b Immunosuppression 134 (8.7) 112 (7.2) 0.14 Home oxygen therapy 74 (4.8) 71 (4.6) 0.80 Premedication (no. (%)) ASA 453 (29.3) 263 (17) <0.0001 Antiplatelet drug 119 (7.7) 75 (4.8) 0.001 Oral anticoagulation 251 (16.2) 220 (14.2) 0.12 Beta-blockers 420 (27.1) 287 (18.5) <0.0001 ACEI/ARB 863 (55.8) 638 (41.2) <0.0001 Symptomatic (no. (%)) Asymptomatic 81 (5.2) 105 (6.8) 0.07 Dyspnea 961 (62.9) 911 (59.5) 0.05 Tachypnea > 22 breaths/min 485 (31.4) 455 (29.4) 0.24 Hemoptysis 26 (1.7) 32 (2.1) 0.42 Fatigue 727 (47) 718 (46.4) 0.75 Anosmia/hyposmia 55 (3.6) 67 (4.3) 0.27 Dysgeusia 66 (4.3) 73 (4.7) 0.54 Sore throat 117 (7.6) 159 (10.3) 0.01 Fever 1,102 (71.3) 1,150 (74.4) 0.06 Cough 950 (61.5) 944 (61.1) 0.83 Vomiting 107 (6.9) 95 (6.1) 0.38 Diarrhea 268 (17.3) 234 (15.1) 0.10 Erythromelalgia 369 (23.9) 443 (28.7) 0.003 Clinical parameters (no. (%)) Peripheral oxygen saturation < 92% 690 (44.6) 604 (39.1) 0.002 (Continued) Frontiers in Endocrinology 04 frontiersin.org Abumayyaleh et al. 10.3389/fendo.2023.1167087 TABLE 1 Continued Characteristic Diabetics (N = 1,548) Nondiabetics (N = 1,548) p-value* Abnormal blood pressurec 139 (9.9) 116 (8.3) 0.13 GCS < 15 149 (11.8) 144 (11) 0.62 Laboratory parameters (no. (%) or median (min–max)) Elevated D-dimer 953 (61.6) 903 (58.4) 0.07 Elevated procalcitonin 302 (19.5) 231 (14.9) 0.0007 Elevated CRP 1,382 (89.4) 1,343 (86.9) 0.03 Elevated TnI 206 (13.3) 165 (10.7) 0.02 Elevated transaminasesd 505 (32.7) 579 (37.5) 0.006 Elevated ferritin 494 (32) 515 (33.3) 0.42 Elevated triglyceride 172 (11.1) 129 (8.3) 0.009 Elevated LDH 1,018 (65.9) 1,033 (66.8) 0.59 Creatinine (mg/dl) 1.02 (0.38–11.3) 0.96 (0.12–33.9) 0.0005 Leukocytes (10E9/L) 7,000 (550–90,004) 6,440 (440–88,400) <0.0001 Lymphocytes (10E9/L) 960 (12–41,100) 930 (244–77,100) 0.25 Hemoglobin (g/dl) 13 (1–19.3) 14 (4–18) <0.0001 Thrombocytes (10E9/L) 201,000 (13,000–716,000) 190,000 (10,000–980,000) <0.0001 Natrium level (mmol/L) 137 (115–179) 138 (117–180) <0.0001 In-hospital complication Respiratory insufficiency 958 (62.1) 867 (56.3) 0.001 Heart failure 191 (12.4) 128 (8.3) 0.0002 Acute kidney injury 411 (26.6) 305 (19.8) <0.0001 Upper respiratory tract infection 257 (16.7) 240 (15.6) 0.41 Pneumonia 1,344 (89.4) 1,336 (88.4) 0.41 SIRS 389 (25.2) 355 (23) 0.16 Sepsis 238 (15.4) 197 (12.8) 0.04 Any relevant bleedinge 65 (4.2) 46 (3) 0.07 Embolic event 49 (3.2) 47 (3.1) 0.84 Oxygen therapy O2 at the admission 1,238 (80.2) 1,157 (75.1) 0.0007 High-flow nasal cannula 347 (22.5) 336 (21.8) 0.65 Noninvasive mechanical ventilation 250 (16.2) 237 (15.4) 0.54 Invasive mechanical ventilation 163 (10.6) 123 (8) 0.01 Another medication or intervention procedures during the admission Prone position 196 (12.7) 169 (11) 0.14 ECMO 119 (7.7) 82 (5.3) 0.007 Use of glucocorticoids 546 (35.4) 526 (34.1) 0.47 Use of hydroxychloroquine 1,173 (76) 1,180 (76.6) 0.69 Use of antiviral drugsf 714 (46.2) 812 (53) 0.0003 Use of interferon 180 (11.7) 233 (15.1) 0.005 (Continued) Frontiers in Endocrinology 05 frontiersin.org Abumayyaleh et al. 10.3389/fendo.2023.1167087 TABLE 1 Continued Characteristic Diabetics (N = 1,548) Nondiabetics (N = 1,548) p-value* Use of tocilizumab 131 (8.5) 128 (8.3) 0.85 Use of antibiotics 1,181 (76.5) 1,113 (72.2) 0.007 g ACEI/ARB 476 (30.9) 354 (23) <0.0001 Anticoagulation 856 (81.7) 791 (75.8) 0.001 Discharge ACEI/ARB 82 (30.8) 71 (24.7) 0.11 Antiplatelet drug 226 (14.7) 147 (9.6) <0.0001 Anticoagulation 413 (26.8) 365 (23.7) 0.05 ASA, acetylsalicylic acid; ACEI/ARB, angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker; CRP, C-reactive protein; GCS, Glasgow coma scale; ECMO, extracorporeal membrane oxygenation; SIRS, systemic inflammatory response syndrome; TnI, high-sensitivity troponin I (cardiac injury; troponin > 99th percentile upper reference limit). a CrCL < 30. b Immunosuppressive therapy for psoriatic arthritis, lung transplantation, kidney transplantation, or systemic lupus erythematosus; oncological diseases such as mamma-ca, prostate-ca, myelodysplastic syndrome, or gammopathy; glucocorticoid therapy caused by COPD; dialysis; HIV; or hepatitis. c Systolic blood pressure < 90 mmHg or diastolic blood pressure < 60 mmHg. d ALAT and ASAT. e Rectorrhagia, hematuria, epistaxis, and popliteal aneurysm bleeding with relevant decreased hemoglobin > 2 mg/l. f Lopinavir or/and ritonavir. g Premedication with ACEI/ARB is not stopped. *Statistical significance level is set at 0.05 and value of statistical significance is emphasized in bold. TABLE 2 Follow-up in patients suffering from DM type II as compared to those without DM. Diabetics (N = 1,548) Nondiabetics (N = 1,548) p-value* Follow-up (mean ± SD) Follow-up time (months (PCS)) 2.6 ± 4.6 2.8 ± 4.9 0.77 Duration to recovery (months) 2.2 ± 4.6 2.4 ± 4.9 0.51 Duration to readmission (months) 2.5 ± 4.5 2.6 ± 4.6 0.95 Number of patients (n) 412 443 – Readmission 81 (19.7) 81 (18.3) 0.61 Vaccination 236 (57.3) 229 (51.7) 0.10 Time to vaccination (months) 11.9 ± 3.1 12.2 ± 2.9 0.74 Reinfection with COVID-19 12 (2.9) 10 (2.3) 0.55 Clinical event after discharge 171 (43.1) 181 (42) 0.75 Cardiovascular symptoms Fatigue 114 (28.7) 125 (29) 0.93 Dyspnea 204 (13.2) 254 (16.4) 0.01 Dizziness 34 (8.6) 35 (8.1) 0.82 Chest pain 28 (7.1) 28 (6.5) 0.75 Acute coronary syndrome 3 (0.8) 4 (0.9) 1.00 Palpitation 24 (6.1) 37 (8.6) 0.16 Increase in resting heart rate 11 (2.8) 24 (5.6) 0.05 Syncope 2 (0.5) 8 (1.9) 0.11 Arrhythmias 27 (6.8) 22 (5.1) 0.30 Atrial fibrillation 21 (5.3) 26 (6) 0.65 (Continued) Frontiers in Endocrinology 06 frontiersin.org Abumayyaleh et al. 10.3389/fendo.2023.1167087 TABLE 2 Continued Diabetics (N = 1,548) Nondiabetics (N = 1,548) p-value* Perimyocarditis 1 (0.3) 2 (0.5) 1.00 Limb edema 13 (3.3) 18 (4.2) 0.50 New hypertension 2 (0.5) 7 (1.6) 0.18 New left ventricular dysfunction 5 (1.3) 7 (1.6) 0.66 Relevant bleeding 5 (1.3) 5 (1.2) 0.90 Neuropsychiatric symptoms Headache 11 (2.8) 21 (4.9) 0.12 Migraine 5 (1.3) 11 (2.6) 0.18 Ageusia 17 (4.3) 19 (4.4) 0.93 Anosmia 12 (3) 18 (4.2) 0.38 Attention disorder 16 (4) 25 (5.8) 0.24 Memory loss 31 (7.8) 34 (7.9) 0.97 Cognitive disorder 18 (4.5) 20 (4.6) 0.94 Anxiety 34 (8.6) 54 (12.5) 0.06 Depression 26 (6.6) 35 (8.1) 0.39 Tinnitus or hearing loss 9 (2.3) 14 (3.3) 0.39 Sleeping disorder 27 (6.8) 36 (8.4) 0.40 Mood disorder 22 (5.5) 31 (7.2) 0.33 Paranoia 16 (4) 5 (1.2) 0.009 Respiratory symptoms Cough 33 (8.3) 42 (9.7) 0.47 Reduce pulmonary diffusing capacity 28 (7.1) 44 (10.2) 0.11 Polypnea 15 (3.8) 19 (4.4) 0.65 Sleep apnea 13 (3.3) 9 (2.1) 0.29 Gastrointestinal symptoms Tongue involvement 1 (0.3) 7 (1.6) 0.07 Digestive disorder 20 (5) 17 (3.9) 0.45 Nausea/vomiting 10 (2.5) 8 (1.9) 0.51 Other symptoms Intermittent fever 8 (2) 10 (2.3) 0.76 Chills 6 (1.5) 8 (1.9) 0.70 Hair loss 20 (5) 18 (4.2) 0.55 Joint pain 19 (4.8) 25 (5.8) 0.52 Myalgia 26 (6.6) 32 (7.4) 0.62 Sweat 5 (1.3) 4 (0.9) 0.74 Weight loss 24 (6.1) 23 (5.3) 0.66 Cutaneous involvement 6 (1.5) 13 (3) 0.15 New diabetes – 4 (0.9) – New renal insufficiency 19 (4.8) 11 (2.6) 0.09 (Continued) Frontiers in Endocrinology 07 frontiersin.org Abumayyaleh et al. 10.3389/fendo.2023.1167087 TABLE 2 Continued Diabetics (N = 1,548) Nondiabetics (N = 1,548) p-value* Pain 12 (3) 8 (1.9) 0.28 Red eyes 4 (1) 6 (1.4) 0.76 Flushing 4 (1) 2 (0.5) 0.43 Incident neoplasia 2 (0.5) 6 (1.4) 0.29 Management after discharge Home oxygen therapy 43 (10.8) 37 (8.6) 0.27 ASA 99 (24.9) 58 (13.5) <0.0001 Antiplatelet drug 34 (8.6) 23 (5.3) 0.07 Anticoagulation 69 (17.4) 54 (12.5) 0.05 ACEI/ARB 140 (35.3) 113 (26.2) 0.005 Beta-blockers 75 (18.9) 69 (16) 0.27 Beta agonist inhalation therapy 34 (8.6) 46 (10.7) 0.31 Vitamin supplementation 72 (18.1) 80 (18.6) 0.88 Antidepressant 47 (11.8) 64 (14.9) 0.20 Statin 151 (38) 103 (23.9) <0.0001 Diagnostic test after discharge Elevated di-dimer 137 (34.6) 151 (35.2) 0.86 Elevated CRP 167 (42.2) 183 (42.7) 0.89 Elevated procalcitonin 45 (11.4) 34 (7.9) 0.09 Elevated TnI 18 (4.6) 16 (3.7) 0.56 Elevated NT-proBNP 23 (5.8) 29 (6.8) 0.57 a Elevated transaminases 92 (23.2) 100 (23.3) 0.98 Abnormal spirometry 21 (18.8) 17 (13) 0.24 Any chest X-ray abnormality 99 (39.4) 103 (38.9) 0.99 Any CT abnormality 37 (35.6) 48 (35.3) 0.60 In-hospital mortality 492 (31.8) 426 (27.5) 0.009 Long-term mortality 524 (33.9) 451 (29.1) 0.005 PCS, post-COVID-19 syndrome; ASA, acetylsalicylic acid; ACEI/ARB, angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker; CRP, C-reactive protein; TnI, high-sensitivity troponin I cardiac injury; troponin > 99th percentile upper reference limit. aALAT and ASAT. *Statistical significance level is set at 0.05 and value of statistical significance is emphasized in bold. Summarized, - means not available. PSM and predictors of mortality Discussion The mortality rate at long-term follow-up was significantly This study presents characteristics of PCS in patients suffering higher in patients with DM than those without, in the overall from DM as compared to those without DM. The main findings of cohort and in the matched cohort, respectively (p < 0.0001 and p = this study are as follows: (1) readmission rate for any cause was 0.005). The Kaplan–Meier curve with landmark analysis is similar in diabetics than nondiabetics at follow-up; (2) reinfection displayed in Figure 1. In the multivariable analysis for mortality, rate with COVID-19 was similar in both groups; (3) symptoms such age, and male sex were determined as predictors for mortality, as dyspnea and an increase of resting heart rate occurred less in respectively (HR: 2.34; p < 0.0001) (HRK 1.23; p = 0.008). Other diabetics as compared to nondiabetics; (4) The incidence of newly predictors are performed in Table 3. Clinical outcomes before PSM diagnosed arterial hypertension was less in diabetics than are presented in the Supplementary Appendix. nondiabetics without statistical significance; (5) respiratory Frontiers in Endocrinology 08 frontiersin.org Abumayyaleh et al. 10.3389/fendo.2023.1167087 improve metabolic function which may be beneficial for the long- term management of patients with PCS (23). In this study, PCS was slightly comparable despite the different comorbidities and in- hospital complications in both groups. Cardiovascular symptoms In our study, dyspnea and an increase in resting heart rate occurred more significantly in nondiabetics as compared to FIGURE 1 diabetics. Additionally, newly diagnosed arterial hypertension was Kaplan–Meier curve for long-term mortality divided by diabetics vs. also revealed slightly more in nondiabetics than diabetics. nondiabetics in the overall population and matched cohort. In both comparisons, a worse outcome in diabetics was detected. Regarding that, the persistence of cardiovascular symptoms was recently reported (24). In one of the studies from Wuhan, Huang et al. showed that patients infected with SARS-CoV-2 suffered from complications were revealed in diabetics and nondiabetics; and (5) acute cardiac injury (25). Subclinical myocarditis with an increased long-term mortality was higher in patients suffering from DM as risk of arrhythmias may play a role in PCS (26). Data about the compared to those without DM. comparison between diabetics and nondiabetics are limited. Recently, it has been reported that the progression of type II DM is associated with increased insulin resistance accompanied by chronic inflammation and endothelial and ß-cell dysfunction (12). On the Neuropsychiatric symptoms other hand, the inflammatory response in infected patients with SARS-CoV-2 may worsen insulin resistance and endothelial This study presented neuropsychiatric symptoms generally dysfunction (13). The existence of both diseases may further more common in nondiabetics as compared to diabetics without enhance the inflammation and decrease interferon levels, neutrophil statistical significance, for example, headache, sleeping disorder, chemotaxis, and T lymphocyte-mediated immune response with and anxiety. However, paranoia was observed significantly more in impairment of cytokine production (14–16). That is associated with diabetics than nondiabetics at a 3-month follow-up. Studies a severe course of COVID-19 in DM patients. Furthermore, ACE2 reported that headache and other neuropsychiatric symptoms expression increases insulin resistance. This receptor and dipeptidyl occurred after 3 months in patients infected with SARS-CoV-2 peptidase 4 (DPP4), which may be a factor in the severity of COVID- (27, 28). Guedj et al. reported that more areas in the brain showed 19 infection, are present in several physiological processes and are hypometabolism in patients with PCS as compared to healthy modulated by hyperglycemia and pharmacological therapies that are subjects (29). Controlled, randomized studies are needed to common in DM patients (17). In addition, chronic hyperglycemia investigate the neuropsychiatric symptoms in patients with DM leads to chronic vascular and kidney disease. Other comorbidities, as compared to those without DM. such as obesity and hypertension, are present in concurrent DM. These diabetes-related comorbidities may negatively impact outcomes in DM patients with COVID-19 (18, 19). Respiratory symptoms Renal insufficiency and cardiac disease were observed more in DM as a risk factor for post-COVID-19 patients with DM than non-DM, while the rate of lung diseases was syndrome similar in matched pairs. At follow-up, our data presented a similar rate of sleep apnea in diabetics and nondiabetics. Furthermore, Our DM cohort had more comorbidities such as arterial computer tomography (CT) and chest X-ray abnormalities were hypertension, renal insufficiency, liver disease, and cardiac disease revealed in both groups, but dyspnea occurred significantly more in than patients without DM. Furthermore, respiratory insufficiency nondiabetics as compared to diabetics at follow-up. In one requiring oxygen therapy and invasive mechanical ventilation (MV) retrospective study with 77 days of follow-up, spirometry (9.3%) was observed more in diabetics as compared to nondiabetics. and chest radiology (19%) abnormalities were detected in 277 During hospitalizations, sepsis and acute kidney injury occurred patients, of whom 51% had PCS (30). In 22 patients after more often in diabetics than nondiabetics. A prospective study COVID-19-associated acute respiratory distress syndrome showed that the persistence of symptoms was associated with the (ARDS), signs of lung fibrosis were detected in 55% of patients at severity of the disease at the beginning and that the intensive care 3-month follow-up (31). In patients with critical COVID-19, 9.5% unit (ICU) admission was an independent risk factor for PCS (20). of patients needed home oxygen therapy after discharge at a 1-year In addition, the need for MV was determined as a predictor for the follow-up (32). Furthermore, DM was identified as a risk factor for development of PCS (21). However, it has been reported that 60% of the requirement of oxygen therapy in patients suffering from low-risk patients for mortality with COVID-19 suffered from severe COVID-19 (33). In our multivariable analysis, DM was not PCS (22). In patients with DM, optimizing hyperglycemia therapy identified as a predictor for mortality. Frontiers in Endocrinology 09 frontiersin.org Abumayyaleh et al. 10.3389/fendo.2023.1167087 TABLE 3 Predictors of mortality, multivariable analysis. Variable Univariable analysis Multivariable analysis HR p-value HR p-value Patient demographics Age ≥70 2.90 <0.0001 2.34 <0.0001 Male 1.19 0.01 1.23 0.008 Chronic conditions Dyslipidemia 1.12 0.07 Diabetes mellitus 1.18 0.01 Obesity 1.01 0.88 Renal insufficiency 1.86 <0.0001 1.33 0.003 Cancer disease 1.46 <0.0001 Immunosuppression 1.41 0.0009 1.40 0.003 Premedication ASA 1.38 <0.0001 Oral anticoagulation 1.66 <0.0001 Clinical parameters SpO2 < 92%a 3.14 <0.0001 2.13 <0.0001 b Abnormal blood pressure 2.09 <0.0001 1.36 0.002 GCS < 15 2.67 <0.0001 1.50 <0.0001 Clinical presentation Dyspnea 1.48 <0.0001 Tachypnea > 22 breaths/min 2.17 <0.0001 1.41 <0.0001 Dysgeusia 0.32 <0.0001 0.40 0.001 Sore throat 0.79 0.07 Cough 0.77 <0.0001 0.84 0.02 Erythromelalgia 0.73 <0.0001 Laboratory parameters Elevated procalcitonin 1.89 <0.0001 1.53 <0.0001 Elevated CRP 1.60 <0.0001 Elevated LDH 1.50 <0.0001 1.20 0.04 HR, hazard ratio; ASA, acetylsalicylic acid; SpO2, peripheral oxygen saturation; GCS, Glasgow coma scale. a SpO2 < 92% at admission. b Systolic blood pressure < 90 mmHg or diastolic blood pressure < 60 mmHg. Statistical significance level is set at 0.05 and value of statistical significance is emphasized in bold. This study has some limitations. It has a retrospective character; nondiabetics. DM was not determined as a risk factor for mortality not all laboratory tests were done on all patients. Furthermore, data at follow-up. on hemoglobin A1c (HbA1c), antihyperglycemic treatment including metformin and DPP-4 inhibitors, and statin therapy at baseline are missing. A strength of our study is the sample size of patients with COVID-19 and concomitant DM type II at 55 Data availability statement international centers. The results are therefore real-world evidence. To summarize, PCS was observed in diabetics and nondiabetics. The raw data supporting the conclusions of this article will be However, the mortality rate was higher in diabetics as compared to made available by the authors, without undue reservation. Frontiers in Endocrinology 10 frontiersin.org Abumayyaleh et al. 10.3389/fendo.2023.1167087 Ethics statement Acknowledgments This study was executed in compliance with the Declaration of The authors thank all HOPE-II researchers. Helsinki regarding in human subjects and the study was approved by the center Ethics Committee of Hospital Clinico San Carlos (Internal Code: 21/128-E) and, when needed, in all involved centers. Conflict of interest Written informed consent for participation was not required for this study in accordance with the national legislation and the The authors declare that the research was conducted in the institutional requirements. absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Author contributions MA, IG, IE-B, and IA made substantial contributions to the Publisher’s note study’s concept and design. All authors obtained ethical approval. Data were collected by MA, IG, MV-L, SR, RR, EA-R, AU, GF, VB- All claims expressed in this article are solely those of the authors M, FS, MP, AM, JS-C, AG, FM, JL-P, EM, OC, CP, AM, LV, DC, and do not necessarily represent those of their affiliated AF-O, MA, and CW analyzed all the data. CW supported the organizations, or those of the publisher, the editors and the descriptive statistics. IJNG and IA approved the statistical analysis. reviewers. Any product that may be evaluated in this article, or MA, IG, IE-B, and IA prepared the manuscript. All authors claim that may be made by its manufacturer, is not guaranteed or contributed to the article and approved the submission version. endorsed by the publisher. Funding Nonconditioned grant (Fundació n Interhospitalaria para la Supplementary material Investigació n cardiovascular, FIC, Madrid, Spain). This nonprofit institution had no role in the study design; collection, analysis, or The Supplementary Material for this article can be found online interpretation of data; in the writing of the report; or in the decision at: https://www.frontiersin.org/articles/10.3389/fendo.2023.1167087/ to submit the paper for publication. full#supplementary-material References 1. Nunez-Gil IJ, Fernandez-Perez C, Estrada V, Becerra-Munoz VM, El-Battrawy I, 10. Nunez-Gil IJ, Estrada V, Fernandez-Perez C, Feltes G, Vedia O, Vergara- Uribarri A, et al. Mortality risk assessment in spain and italy, insights of the hope covid- Uzcategui CE, et al. Health outcome predictive evaluation for covid 19 international 19 registry. Intern Emerg Med (2021) 16(4):957–66. doi: 10.1007/s11739-020-02543-5 registry (hope covid-19), rationale and design. Contemp Clin Trials Commun (2020) 2. 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