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Predictors of COVID-19 related death in diabetes patients: A case-control study in Iran

Background Identifying the predictors of COVID-19 related death in diabetes patients can assist physicians for detecting risk factors related to the worse outcome in these patients. In this study we investigated the predictors of the death in patients with diabetes compared with non-diabetic COVID-19 patients. Methods In the present case-control study, the case group were diabetic patients with COVID-19 and the control group included Non-diabetic COVID-19 patients. The data source regarding the demographic characteristics, clinical symptoms, laboratory, and radiological findings on admission as well as the complications, treatment, and outcomes during hospitalization were gathered from their medical record through two trained nurses. Adjusted and unadjusted odds ratios (OR) estimate were calculated using the simple and multiple logistic regression through backward model. Results The mean (SD) age of the case group was higher than that of the control group; [65.24 (12.40) years vs. 59.35 (17.34) years, respectively (P < 0.001)]. Results of the adjusted logistic regression model showed that, advanced age (+60 year) (OR = 5.13, P = 0.006), addiction (OR = 5.26, P = 0.033), high level of Blood urea nitrogen (OR = 5.85, P < 0.001), and high level of Alkaline Phosphatase (OR = 3.38, P = 0.012) in diabetic patients were significantly associated with increase the odds of death in COVID-19 patients. Conclusion We found that in COVID-19 patients with diabetes; advanced age, addiction, high level of BUN and Alp and in non-diabetic COVID-19 patients advanced age, dyspnea, high level of BUN and SGOT were associated with increase risk of death in these patients.


Introduction
Diabetes is one of the most common non-communicable diseases worldwide and there is evidence of its substantial increasing trend in recent years [1]. Several studies have revealed a higher vulnerability to some infectious diseases in diabetic people [2,3].
Decreased T cellemediated immune response and impaired neutrophil functionin diabetics can explain this higher susceptibility [2].
Alongside severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS), coronavirus disease 2019)COVID-19(is another common type of coronavirus that infect humans [4]. The role of diabetes in increasing of mortality and morbidity in patients with SARS have been shown previously [5]. Also, noticeable proportion of identified COVID-19 patients are diabetic. In such a way that, the rate of diabetes and COVID-19 comorbidity is range from 20 to 50% in different global regions [6]. Published studies showed that some underlying diseases such as hypertension and diabetes mellitus are important risk factors for the fatality of COVID-19 patients [7e9].
Although, studies have been designed to identify death-related factors in COVID-19 patients. However, most of them are conducted on the total COVID-19 cases, regardless of having an underlying disease or not, or the investigated variables were rare. Identifying the predictors of death in diabetic COVID-19 patients helps in better management of them, and assist physicians for detecting risk factors which contributes to the severity and mortality of COVID-19 in these patients. This study was conducted in order to identify the predictors of the worse outcome in patients with diabetes in whom COVID-19 was confirmed compared with non-diabetic COVID-19 patients.

Materials and method
In the present case-control study, we identified all patients admitted to Sina Hospital and Beheshti Hospital in Hamadan province, the west of Iran, which was assigned to admit COVID-19 adult patients. Patients recruited from January 2020 to January 2021.
The Ethics Committee of the Hamadan University of Medical Sciences approved this study (IR.UMSHA.REC.1399.841). In this study, patients with positive real time reverse transcriptase polymerase chain reaction (RT-PCR) on samples from upper respiratory nasopharyngeal swabs were enrolled to the study.
The case group included diabetic patients with COVID-19 and the control group included Non-diabetic COVID-19 patients. Accordingly, all 420 diagnosed diabetic patients with confirmed COVID-19 in the above mentioned time period were included and considered as case group and for increase the statistical power of the study, compared them with 1260 non-diabetic patients with COVID-19, as controls group. Controls were selected at the same time and from the same hospital in order to overcome some potential confounders such as quality of care and type of prescription drugs.
The data source regarding the demographic characteristics, clinical symptoms, laboratory, and radiological findings on admission as well as the complications, treatment, and outcomes during hospitalization were gathered from their medical record through two trained nurses and was modified according the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) [10].
The variables registered included demographic data, epidemiological information, comorbidities (chronic cardiac disease, chronic pulmonary disease, cancer, hypertension and chronic liver disease), baseline laboratory tests result (hemoglobin lymphocyte count, platelet count), signs and symptoms at admission (fever, cough, dyspnea, myalgia and headache) and outcome including mortality in hospital.

Logistic regression (LR)
LR is an exceedingly popular classical statistical technique used for classifications type prediction problems, has traditionally been the choice of many studies to determine the relationship between target variable of with a set of independent variables [11]. The model can be present as follows: In this model's are factors, a and b i 's are regression coefficients that state the measure of effect size. (x) indicate the probability of success and given a specific value of covariates and p/1Àp indicate the odds ratio of classifying the response [12]. The result induces the Odds ratio (OR) of death in diabetic patients with COVID-19 in one group compared to non-diabetic patients with COVID-19. We used the chi-square test to compare categorical variables and the t-test to compare the continuous variables. Adjusted and unadjusted odds ratios (OR) estimate were calculated using the simple and multiple logistic regression through backward model. All statistical analyses were performed at a significance level of 0.05, using Stata software, version 16 (StataCorp, College Station, TX, USA).

Results
The mean (SD) age of the case group was higher than that of the control group; [65.24 (12.40) years vs. 59.35 (17.34) years, respectively (P < 0.001)]. In addition, the proportion of females was significantly higher in case than in control (57.1% versus 43.6%; P < 0.001). The details of cases and controls, including demographic characteristics, epidemiological information, comorbidities, signs and symptoms at admission and laboratory tests results are shown in Table 1. As shown, two groups were heterogenic in regards of gender, headache and fever sign, cardiovascular and hypertension co-morbidity, and ESR, BUN, BS, NA, K, HCT and Hb markers (P < 0.05).
The effect of various potential risk factors for mortality of COVID-19 in diabetic AND non-diabetic patients is given in Tables 2 and 3 using crude ( Table 2) and adjusted (Table 3) OR.

Discussion
In this study we analyzed the demographic characteristics, epidemiological information, comorbidities, signs and symptoms at admission and laboratory tests results of COVID-19 patients with diabetes compared COVID-19 patients without diabetes and identified the risk factors associated with in-hospital death of these patients. In this study we found that in COVID-19 patients with diabetes advanced age, addiction, high level of BUN and Alp and in non-diabetic COVID-19 patients advanced age, dyspnea, high level of BUN and SGOT were associated with increase risk of death in these patients.
Similar to our study, in previous studies advaned age has been considered as a risk factor of death in non-diabetic COVID-19 patients and also in COVID-19 patients with diabete type 1 and 2 diabetes [13]. In Cheng et al. study age older than 60 years was identified as a independent risk factors for serious disease in SARS-CoV-2 infection [14]. Tehrani and collagenous revealed that advanced age contribute to a fatal outcome in hospitalized COVID-19 patients [15]. It has been shown that high mortality rate of elderly patients with COVID-19 is mainly due to the frequent occurrence of multiple comorbidities including but not limited to hyperglycemia [16].
We observed that non-diabetic COVID-19 patients with dyspnea were significantly more likely to die than patients without dyspnea. Dyspnea is a sign of respiratory disease, so can be an important risk factor for progression COVID-19 to advanced stages [17]. Shi et al.  reported that presence of dyspnea was a risk factors for death in SARS-CoV-2 infection [18].It has been reported in several studies that COVID-19 patients with dyspnea had a higher risk for hospitalization, ICU addmission, mechanical ventilation, severe disease, disease progression and mortality than those without dyspnea [19e22].
Other finding of present study showed that addiction is a risk factor of death in COVID-19 patients with diabetes. It may be because patients with diabetes are at higher risk of receiving polypharmacy than patiens without diabetes. So, addicted patiens with diabetes have increased risks of adverse drug events [23]. In this regard, Baillargeon et al. indicated that COVID-19 patients with substance use are at greater risk for adverse outcomes [24]. Wang et al. found COVID-19 patients with substance use especially opioids use are at increased risk for adverse outcomes [25].
In present study, high BUN levels was another rsik factor of COVID-19 related death in diabetic and non-diabetic patients. Recently, there is a lot of evidence of increase in COVID-19 mortality rate in patients with higher serum BUN levels [26]. According to Pazoki et al. study, kidney damage indicators, including serum creatinine and blood urea nitrogen (BUN) is linked with higher mortality in COVID-19 patients [27]. A meta-analysis conducted by Shao and collagenous on 40 studies and 25,278 patients revealed a positive relationship between BUN levels and mortality rate in patients with COVID-19 [28].
In our study, high ALP and SGOT (AST) levels respectively in diabetic and non-diabetic patients were associated with increased risk of COVID-19 related death. Both of these enzymes are indicators of liver damage and dysfunction, which can be seen in more than half of patients with COVID-19 [29]. It has been shown that the SARS-CoV-2 virus may also bind to ACE2 on cholangiocytes and induce a systemic inflammatory response leading to liver injury [30]. Also, it has been suspected that some detrimental effects on liver injury is mainly due to certain medications used during COVID-19 hospitalization [31]. In agreement with our findings, Pazoki et al. showed that high serum levels of ALP and AST was a risk factor of in-hospital mortality and disease severity in diabetic patients with confirmed or clinically suspected COVID-19  [32]. However, liver damage and increased levels of liver enzymes in serum including AST and ALP is also reported in the diabetic patients in Islam et al. study [33].
Limitations of this study include the following: first, due to the retrospective nature of the study, we could not assess all clinical and laboratory information such as d-dimer for all patients. Secondly, in this study we included only hospitalized patients with relatively severe symptoms and patients with mild or moderate symptoms were not assessed in the present study.

Conclusion
We found that in COVID-19 patients with diabetes; advanced age, addiction, high level of BUN and Alp and in non-diabetic COVID-19 patients advanced age, dyspnea, high level of BUN and SGOT were associated with increase risk of death in these patients.

Funding
Hamadan University of Medical Sciences financially supported this study.

Declaration of competing interest
The authors claimed no conflict of interest. Table 3 Association between covid-19 mortality and potential risk factors in diabetic and non-diabetic patients using adjusted odds ratio.