Predictors of COVID-19 outcome in type 2 diabetes mellitus: a hospital-based study

Background Diabetes has become a significant risk factor for COVID-19-related severe illness and death. Methods This was a retrospective cohort study of 104 patients, with or without type 2 (diabetes mellitus) DM, diagnosed with COVID-19 between June and September 2021 in Benha University Hospital, Egypt. Outcome measures including discharge after recovery, transfer to ICU and intubation, or death were recorded. Univariate and multivariate logistic regression analysis was done for the prediction of death in diabetic patients. Results Length of hospital stay was significantly higher in diabetic (median 15 days) compared to non-diabetic patients (median 10 days). ICU admission and intubation among diabetic patients were substantially higher than non-diabetics. Univariate regression analysis established that old age ( p = 0.02: OR = 1.03: CI 1.00–1.07), multiple comorbidities ( p = 0.005: OR = 8.66: CI 1.9–38.5), diabetic complications ( p = 0.000: OR = 6.401:CI 2.5–16.3), HbA1c ( p = 0.01: OR = 1.22: CI 1.04–1.43), length of hospital stay ( p = 0.005: OR = 1.07: CI 1.02–1.12), and ICU admission ( p = 0.00: OR = 44.1: CI 9.4–205.3) were predictors of death for diabetic patients as well as neutrophilic count, D-dimer, and CRP levels. Multivariate regression analysis concluded that ICU admission was the most significant predictor of death in diabetic patients. Conclusion Type 2 DM patients, infected with the COVID-19 virus exhibited more admission to ICU and intubation with longer hospital stays compared to those without diabetes with a similar death rate. Old age, HbA1C, comorbidities, diabetic complications, length of hospital stay and ICU admission, and inflammatory parameters were significant predictors of death in diabetic patients.


Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was, to begin with, depicted in Wuhan, China, in December 2019, and after that, it spread around the world.It was evaluated that the death rate for COVID-19 is roughly 0.5-1.0%[1][2][3].COVID-19 pandemic-hit zones have been confronting basic deficiencies with respect to supplies such as ventilators and intensive care units (ICU) [4].SARS-CoV-2 is a positive-stranded RNA infection that's encompassed by a protein-decorated lipid bilayer containing a single-stranded RNA genome; SARS-CoV-2 has 82% homology with human SARS-CoV, which causes severe acute respiratory disorder (SARS) [5].In human cells, SARS-CoV-2 enters the angiotensin-converting protein 2 (ACE2) receptor [6] which is profoundly found in lung alveolar cells, cardiac myocytes, vascular endothelium, and different other cell sorts [7].Like SARS-CoV and the related Middle Eastern respiratory syndrome (MERS)-CoV, SARS-CoV-2 infection causes mild symptoms in the first 2 weeks of infection however has the potential to develop severe illness, including a systemic inflammatory response, acute respiratory distress syndrome (ARDS), multi-organ affection and shock [8].Individuals of old age, male sex, cardiovascular disease (CVD), obesity, type 1 diabetes mellitus (DM), or type 2 diabetes mellitus (DM) are at a high risk of developing severe COVID-19 or passing away [9][10][11].In addition, Studies have shown that patients with COVID-19 admitted to ICUs frequently have underlying CVD and DM [12,13].The fundamental and clinical understanding of the potential interactions between COVID-19 and DM has been reviewed [14].Diabetes has become a significant risk factor for COVID-19-related severe illness and death [15].The first aspect to point out is that patients with COVID-19 also exhibit elevation of other inflammatory markers, such as D-dimer, ferritin, and IL-6 [16] which might raise the risk of microvascular and macrovascular complications originating from low-grade vascular inflammation in patients with DM [17].Furthermore, one should not forget that SARS-CoV-2 infection increases the risk of thromboembolism and is more likely to induce cardiorespiratory failure in diabetic individuals [18].And then, good glycemic control in the acute hospital setting in China was an important factor for better outcomes in patients with pre-existing type 2 DM [15].In the present study, the outcome of COVID-19 in diabetic compared to non-diabetic populations will be clarified for patients admitted to Benha University Hospital.

Outcome measures
Data starting from admission at the emergency department to either ICU, word, or word then ICU transfer with length of hospital stay were registered.The outcome of the disease includes discharge after recovery, transfer to ICU, or death.Medications for COVID-19 as well as intubation whenever needed were recorded.

Statistical analysis
The collected data were tabulated and analyzed using SPSS version 26 software (Spss Inc., Chicago, ILL Company).Categorical data were presented as numbers and percentages while quantitative data were expressed as mean ± standard deviation/median and interquartile range.Inter-group comparison of categorical data was performed by using the chi-square test (χ2 value) and Fisher exact test, Student's t test was used to compare the mean of two groups of numerical (parametric) data, for continuous non-parametric data, Mann-Whitney U test was used for inter-group analysis.Some investigated parameters were entered into a logistic regression model to determine which of these factors is considered a significant predictor.P value < 0.05 was considered statistically significant.

Analysis of clinical and laboratory characteristics
This after COVID-19 infection, while the percentage of diabetic patients on insulin had increased from 26.7 to 88.9%.In terms of biochemical measures, neutrophils, FPG, HbA1c, s. creatinine was significantly higher in diabetic compared to non-diabetic patients (Table 2).Total leucocytic count, neutrophilic counts, and ESR were significantly higher in uncontrolled diabetic patients (HbA1c > 7%) (Table 3).

Analysis of outcome of COVID-19
Length of hospital stay was significantly higher in diabetic (median 15 days) compared to non-diabetic patients (median 10 days) (p = 0.025).ICU admission (either from the start or afterward admission) among diabetic patients (No. 25) was substantially higher than among non-diabetics (No. 19) (p = 0.01).Intubation was done for 48.9 % of diabetic patients but for 27.1 % of non-diabetic patients (p = 0.02).Mortality was nonsignificant between diabetic and non-diabetic groups (p = 0.134) (Table 1).The bad outcome of COVID-19 infections was noted in the form of higher ICU admissions in the uncontrolled diabetic patients (22 patients) compared to the controlled group (7 patients) (p = 0.001) while non-significant difference concerning the length of hospital stay, death, and intubation between the same groups ( for treatment of DM while 23.7% of non-diabetic patients used insulin for hyperglycemia after COVID-19 infection.At admission, it was noted the finding of elevation of the fasting plasma glucose (median FPG was 120 mg/ dl) in patients with HbA1c < 6.5% (non-diabetic group).Stress hyperglycemia, which is typically defined as a brief increase in blood sugar in the presence of an acute illness or following surgery in a patient with an A1C below 6.5%, is linked to an extended hospital stay, an extended amount of time spent managing the patient's ventilator, and an increased mortality rate in critically ill patients [22].Due to a lack of follow-up after hospital release, it is impossible to determine if these patients should be classified as newly diagnosed type 2 DM, having glucocorticoid effect during treatment of COVID-19, or suffering stress-induced acute hyperglycemia in the study.
In our results, it was illustrated that no significant difference in comorbidities between diabetic and nondiabetic patients.In contrast, it was found that Diabetic patients have more comorbid diseases than non-diabetics, including hypertension, coronary artery disease, chronic renal disease, asthma, and cerebrovascular disease [23].Univariate logistic regression in the present study identified that multiple comorbidities were a predictor for death in diabetic patients.In another study, it was found that congestive heart failure was the only comorbidity that is strongly related to increased mortality [24].According to multicenter research from Turkey, among patients with CKD, 21.9% were admitted to the ICU, and 14.2% died [25].All our patients in the present study received hydroxychloroquine according to the protocol of treatment of the Egyptian Ministry of Health.However, according to certain studies, using hydroxychloroquine as a therapy for COVID-19 is not effective [26].In the current study, steroid treatment was given to 24.5% of diabetic compared to 30.5% of non-diabetic patients in the form of dexamethasone or Methylprednisolone.Contrarily, the administration of corticosteroids as low-dose or pulse therapy has been a recognized method of treating patients with acute respiratory distress syndrome (ARDS) and other acute lung disorders to have an immediate immunosuppressive effect [27].Our results revealed that serum ferritin, CRP, D-dimer, ESR, and lymphocytes were non significantly different between diabetic and non-diabetic patients, while only neutrophilic count was significantly higher in the diabetic group compared to the non-diabetic group.Total leucocytic count, neutrophilic counts, and ESR were significantly higher in uncontrolled diabetic patients.Neutrophil, D-dimer, and CRP were significant predictors of death in diabetic patients.Neutrophils, CRP, and lymphocytes were not significant predictors of death among diabetics, according to one study that examined 42 regressors (variables) in unbiased multivariate logistic regression analysis against the primary outcome of death [28].Absolute neutrophil count (ANC) and CRP were greater in type 2 DM patients than in non-diabetic controls, and lymphocytic and eosinophilic counts were lower [29].In addition, one study disclosed higher levels of C-reactive protein in diabetic COVID019 patients [30].
In our study, the death rate was non significantly higher in diabetic patients than in non-diabetics.The death rate in our study represented 25.9% overall of admitted COVID-19 infection with 33.3% in diabetic patients vs. 20.3% in non-diabetic patients.However, one study found a 10% death rate [24] and another study revealed high mortality in diabetic people and older age groups [31].A study of 174 Chinese COVID-19-positive patients  reported that patients with diabetes who had no other comorbidities had higher mortality rates (16.7% vs. 0%, P = 0.03) [32].Another study demonstrated death of hospitalized positive COVID-19 was higher in diabetic patients [16].Initial records in the UK indicated that diabetic patients constituted one-third of COVID-19 patients dying in hospitals [33].However, the presence of DM was not independently related to in-hospital fatalities, according to data from a large-scale, multi-center, retrospective investigation in Wuhan that included 1561 COVID-19 patients [34].Data from 463 COVID-19 patients in the USA further demonstrates that there is no connection between diabetes mellitus (DM) and death, ICU admission risk, or need for mechanical ventilation [35].In contrast, death was significantly higher in diabetic compared to non-diabetic patients in another study [33].Our data constituted a small-sized sample in comparison to other studies so we could not assess the real mortality in the Egyptian population.we evaluated the death among the admitted cases, not the whole population.Univariate logistic regression in the present study identified that HbA 1c was a predictor for death in diabetic patients.Poorer glycemic control may increase the risk of worse health outcomes, according to preclinical research on the mechanistic relationships between glucose control and Middle East respiratory syndrome coronavirus (MERS-CoV) infection and the impact of long-term glycemic control on the clinical outcomes of COVID-19-infected subjects with type 2 diabetes [36].In mice that have a longer time to respond to MERS-CoV infection, type 2 diabetes mellitus is linked to a slower inflammatory response.By decreasing immune system components including leukocyte chemotaxis and phagocytosis, hyperglycemia itself has harmful effects.According to estimates, major infections like COVID-19 would cause substantial levels of morbidity and death due to these host response deficits in people with diabetes [31].Angiotensin-converting enzyme 2 (ACE2) immunostaining was also found in pancreatic islet cells, which are identical to the myocardium and lung alveolar epithelium.This was discovered using immunohistochemistry labeling of cadaveric pancreatic tissue.Direct islet cell toxicity during infection appears plausible as a cause of acute hyperglycemia, and ACE2 is a recognized receptor protein for coronavirus attachment [29,37].In the current study, ICU admission and endotracheal intubations in diabetics were significantly higher than in nondiabetic patients.Also, the admissions to the ICU were significantly higher in uncontrolled diabetic patients than in controlled diabetic patients.Patients with type 2 diabetes had a threefold higher risk of hospitalization and a fourfold higher risk of ICU admission during the 2009 influenza A (H1N1) pandemic.However, a nationwide analysis in China that included roughly one-third as many patients as those included in our studies revealed that patients with diabetes had higher rates of death (10.0% vs. 2.5%) and ICU admission (14.6% vs. 5.5%) compared to those without diabetes [31].In our results, older age is a predictor for death in diabetics (confidence interval, CI 1.00-1.07;p = 0.02) Similar to a previous study [24].The reason for such differences in severity and outcomes in diabetic patients with COVID-19 is likely due to the multifactorial syndromic nature of diabetes.In our cohort, for instance, we found that diabetic patients had a higher percentage of death rate (25.9 % overall with 33.3% in diabetics vs. 20.3% in non-diabetic patients) but our data was among admitted patients with COVID-19 infection only.

Conclusion
Our findings demonstrated that type 2DM patients, infected with the COVID-19 virus, were exhibited more admission to ICU and intubation with longer hospital stays compared to those without diabetes.However, mortality rates were similar in both groups.Glycemic control additionally, could worsen the inflammatory response and the need for ICU admission.Old age, HbA1C, comorbidities, diabetic complications, length of hospital stay and ICU admission, neutrophil count, D-dimer, and CRP levels were significant predictors of death in diabetic patients.As recommended by national recommendations, doctors should manage stress hyperglycemia and uncontrolled diabetes in critically ill patients with basalbolus insulin therapy in the majority of non-ICU patients and continuous insulin infusion in the critically sick.

Strength of the study
Our results evaluated the effect of glycemic control on the inflammatory response and outcome of the COVID-19 infection.

Limitations of the study
Firstly, retrospective observational research was done on patients who had recorded incidents.Data on pertinent risk variables may therefore not be taken into consideration given their potential to have a significant impact on COVID-19 progression.For that reason, the impact of diabetes on the clinical outcomes would not have been as accurate as in a prospective study.Secondly, the sample size is small.Thirdly, this study did not consider detailed diabetes history such as duration, treatments, and complications of diabetes as well as type 1 DM.Lastly, age is an important risk factor in COVID-19 outcomes and the diabetic patient's group was significantly older than the control (not diabetic) group, which caused bias in the results so it was better to choose an age-matched control group.

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Elsayed et al.The Egyptian Journal of Internal Medicine (2024) 36:2 Treatment given to the patients was recorded including medications given for COVID-19 treatments.Clinical examination was performed in detail including vital signs, SpO 2 on arrival to the emergency department, and body mass index (BMI).
Data collectionAll patients were subjected to full history taking with stress on age, sex, comorbidities, medication history, presence of DM, and diabetes-related complications.

Table 1
Clinical characteristics and outcome data of COVID-19-infected patients *Significant as P value ≤ 0.05 **High significant as P value ≤ 0.001

Table 2
Laboratory data of COVID-19 infection patients in diabetic and non-diabetic *Significant as P value ≤ 0.05 **High significant as P value ≤ 0.001

Table 3
Laboratory features of controlled and uncontrolled diabetic patients

Table 4
Outcome of controlled and uncontrolled diabetic patients **High significant as P value ≤ 0.001

Table 5
Univariate and multivariate logistic regression analysis of various variables for prediction of death among diabetic patients *Significant as P value ≤ 0.05