The Association between Poor Glycemic Control in Diabetes Mellitus and Progression of COVID-19

Background: Coronavirus disease 2019 (COVID-19) is a newly recognized disease whose rapid spread has resulted in a global pandemic. In this resepct, there are several comorbidities presumed to be associated with presentation of complications in COVID-19 such as diabetes mellitus (DM), hypertension (HTN), and cardiovascular diseases (CVDs). Therefore, this study aimed to explore whether DM was a risk factor inuencing presentation, progression, and prognosis of COVID-19 or not. Methods: A total number of 447 patients with conrmed COVID-19 were selected from two centers for COVID-19 in the city of Shiraz, south-central Iran, from February 20 to April 29, 2020. Then, demographic data, medical history, signs and symptoms, laboratory test results, as well as chest computed tomography (CT) scan reports were collected and analyzed. Results: This study revealed that older age, HTN, and CVDs could be mostly seen in diabetic patients with COVID-19. In addition, such patients had prolonged hospital stay, lower oxygen (O 2 ) saturation, and abnormal laboratory test results such as higher white blood cell (WBC) count, lower lymphocyte count, elevated serum tumor markers such as aspartate aminotransferase (AST), and abnormal kidney function. Conclusion: DM is an important risk factor for adverse endpoints in patients with COVID-19. In diabetic patients, proper consideration of clinical characteristics is thus of utmost importance. In addition, special clinical insight for disease prevention, good glycemic control during hospitalization, and efforts to develop a vaccine can help improve disease outcomes in this population.


Introduction
A novel coronavirus (nCoV) was identi ed, at the end of 2019, as the cause of a cluster of pneumonia cases in Wuhan, a city in Hubei Province of China. It then rapidly spread, resulting in an epidemic throughout China, followed by an increasing number of cases in other countries across the world. In February 2020, the World Health Organization (WHO) also designated coronavirus disease 2019 (COVID- 19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
On February 19, the rst o cial report of the cases with COVID-19 in the city of Qom, Iran, was correspondingly released. As of September 25, 2020, the COVID-19 outbreak has infected at least 32 million people worldwide. Concurrently, according to the WHO statistics, over 435,000 cases and the death toll exceeding 25,000 people has been so far reported in Iran. Based on the report by Shiraz University of Medical Sciences, Shiraz, Iran, COVID-19 cases in Fars Province, Iran, had surpassed 50,000 people as of September 20, 2020, while the mortality rate from this fast-spreading disease had crossed 940 patients.
To this point, the disease manifestations have varied from asymptomatic infection to severe fulminant pneumonia, respiratory failure, and death; however, the proportion of severe or fatal infections may also show a discrepancy by location. Such estimates are rapidly changing as more data are becoming available. With reference to the most recent WHO COVID-19 Situation Report, the global mortality rate is 5.3% [1].
The incubation period for COVID-19 is generally within 14 days following exposure, with most cases occurring approximately four to ve days after being infected [2][3][4]. The proportions of asymptomatic infections have not been thus far investigated in a systematic and prospective manner. As estimated in the literature review, it is as high as 30-40% [5,6].
The spectrum of symptomatic infections range from mild to critical and most infections are not severe [2,7,8]. Pneumonia seems to be the most frequent serious manifestation of this infection, primarily characterized by fever, cough, dyspnea, and bilateral in ltrates on chest imaging tests [8][9][10]. However, other features including upper respiratory tract infection (URTI) symptoms, myalgia, diarrhea, and loss of smell or taste are common. There are no speci c clinical characteristics that can reliably distinguish COVID-19 from other viral respiratory infections, although development of dyspnea several days after the onset of initial symptoms is suggestive [4,11]. Reviewing the complications, acute respiratory distress syndrome (ARDS) is assumed as the major complication in patients with the severe type of the disease and can manifest shortly after the onset of dyspnea. Furthermore, other side effects can be arrhythmias, acute cardiac injury, thromboembolic complications, and shock [3,10,[12][13][14].
Comorbidities and other conditions, introduced to be associated with the severe cases of the disease and mortality are various. The severe condition can accordingly occur in healthy individuals of any age, but it is predominantly observed in older adults or those with underlying medical comorbidities such as cardiovascular diseases (CVDs), diabetes mellitus (DM), hypertension (HTN), chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), types of cancer, obesity, and smoking [11,[15][16][17][18][19].
As well, DM and poor glycemic control are regarded as major risk factors of infections especially in uenza and pneumonia. In addition, studies on patients with DM have found that viral respiratory infections possibly cause a more severe type of the disease compared with non-diabetic cases [20].
Indeed, DM has been widely investigated in previous epidemics and pandemics such as in uenza A virus subtype H1N1 (A/H1N1), SARS, and Middle East respiratory syndrome-related coronavirus (MER-SCoV), and it has been further identi ed as an important risk factor for mortality and morbidity [21][22][23].
There are some data regarding the association between DM and COVID-19, supporting that DM should be taken into account as a major risk factor for rapid progression and poor prognosis of COVID-19 [20,24].
They also demonstrate a signi cant association between DM status and higher mortality rate in diabetic patients with COVID-19 [17] and indicate that glycemia is associated with markedly improved outcomes in patients with COVID-19 and pre-existing DM if it is well-controlled [25], but there is still considerable ambiguity with regard to diabetic patients with COVID-19 (29,30) This study aimed to explore whether DM was a risk factor in uencing presentation, progression, and prognosis of COVID-19 or not. Accordingly, a total number of 447 COVID-19 patients admitted to Aliasghar Hospital and Chamran Hospital, and dedicated to COVID management and a liated to Shiraz University of Medical Sciences, in the city of Shiraz, south-central Iran, from February 20 to April 29, 2020, was included to evaluate risk factors, comorbidities, and probable associated factors with this disease.

Design and Settings
This study was a retrospective evaluation of 447 patients with COVID-19, admitted from February 20 to April 29, 2020, to two hospitals for COVID-19, a liated to Shiraz University of Medical Sciences, Shiraz, as the provincial center of Fars Province, in south-central Iran, with an area of 122842 km2 and a population of about 4,851,274 people, of whom 50.7% of the population are male and 49.3% are female [26].

Data Collection
COVID-19 diagnosis in these patients was validated either with positive reverse-transcription polymerase chain reaction (RT-PCR) from the upper respiratory tract or con rmation made by an expert team based on clinical symptoms and high-resolution computed tomography (HRCT) scan reports. Moreover, throatswab specimens obtained from the upper respiratory tract of the patients upon their admission were stored in a viral-transport medium (VTM). Total ribonucleic acid (RNA) was further extracted using QIAamp™ viral RNA mini kit from Qiagen™ according to the manufacturer's instructions. With E-gene and Rdrp-gene probe/primer and superscript™ III platinum, one-step qRT-PCR kit of Invitrogen company mixtures was prepared. The mixtures transferred to Roche Light cycler™ 96 and Applied Biosystem ABI step one plus™ real time thermal cyclers with positive control and no template control (NTC) as well as an internal control. After 45 cycles the produced graphs were observed, any rise after the noise and before cycle 32 was considered as positive for SARS-COV 2 [27,28]. SARS-CoV-2 was also examined by RT-PCR. These individuals were selected by the convenience sampling method. For each patient, one questionnaire including demographic data, medical history, DM history and its medications, exposure history, and signs and symptoms of COVID-19 at presentation time was completed.
Laboratory test results, chest CT scan reports, and theraputic measures were additionally extracted from electronic medical records. Hospital course and clinical outcomes followed for each patient, ward or intensive care unit (ICU) admission, any comorbidity such as CKD, CVDs, or respiratory failure, and death were additionally recorded.

Ethical Considerations
This study was approved by the Ethics Committee of Shiraz University of Medical Sciences (No. IR.SUMS.REC.1399.076), Shiraz, Iran. Written informed consent was also completed for each patient.

Statistical Analysis
The qualitative and quantitative data were respectively described by frequency (percentage) and mean ± standard deviation (SD). Independent-samples t-test was also practiced for compression of mean of quantitative laboratory data (such as white blood cell [WBC] count, platelets, hemoglobin (Hb), polymorphonuclear leukocytes [PMNs], etc.) in non-diabetic, no-comorbidity, and diabetic groups. Chisquare test was further employed for compression of DM prevalence and no-comorbidity with categorical data (such as age group, gender, comorbidities, etc.). All statistical analyses were performed using the SPSS Statistics software (version 19) for windows. A p-value less than 0.05 was also considered statistically signi cant.

Results
Of the 406 patients, 241 (59.4%) cases were male, 107 (26.4%) individuals had preexisting DM, and 79 (19.5%) cases had a history of HTN. The most common symptoms were dyspnea (63.8%), dry cough (57.4%), and fever (28.8%). Besides, the prevalence of DM was highest among older patients (49.5% in those aged over 65 years old, p < 0.001). Moreover, the study results revealed that comorbidities like HTN (35.5% vs. 13.7%, p < 0.001) and CVDs (26.2% vs. 13.4%, p = 0.002) were signi cantly more prevalent among the diabetic patients in comparison with the non-diabetic individuals. Gender, respiratory failure, hypothyroidism, CKD, history of malignancy, and signs and symptoms, and chest CT scan reports did not show differences between the diabetic and non-diabetic patients (Table 1). Although lymphocyte count was lower, and PMN, C-reactive protein (CRP), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and creatinine were higher in the diabetic group, these differences were not statistically signi cant (Table 2).

Discussion
It has been acknowledged that diabetic patients, compared with non-diabetic population, are more vulnerable to infection as well as development of poor prognosis once affected. In this resepct, DM with its high prevalence is an important comorbidity in patients with COVID-19 as some data have con rmed increased incidence and severity of COVID-19 in diabetic cases [29].
The United States Centers for Disease Control and Prevention (CDC) has further created a list of certain comorbidities associated with severe COVID-19 (de ned as infection resulting in hospitalization, admission in ICUs, intubation or mechanical ventilation, or death). Among these comorbidities, DM has been introduced as an established risk factor for progression of COVID-19 [25,30,31]. The CDC has also declared increased mortality in individuals with DM (2.3% overall and 7.3% patients with DM) [32].
The main ndings of this study were in line with this statement. In this report, diabetic patients had prolonged hospital stay with more organ dysfunctions, presented by drastic alterations in laboratory test results such as elevated serum markers (namely, LDH and AST), uremia (viz. rise of BUN and creatinine), and lower O 2 saturation, which were consistent with the results of previous reports [24][25][26][33][34][35][36].
It should be noted that patients with DM have impairments in their immune system. They also suffer from poor innate immunity, dysregulated immune response, and dysfunctional exaggerated proin ammatory cytokine activation [37].
In addition, type 2 DM is associated with activation of the renin-angiotensin system in different tissues that may contribute to higher adverse risks in these patients with COVID-19 [38].
By binding to angiotensin-converting enzyme 2 (ACE2), SARS-CoV-2 enters into the cells and reduces the expression of ACE2 [39]. The wide distribution of ACE2 level in the lungs, vascular endothelium, heart, kidney, and intestines can thus partially explain the underlying mechanism of multi-organ failure (MOF), especially myocardial, kidney, and liver injury in COVID-19 patients [24,31].
Moreover, in diabetic patients treated with ACE inhibitors and angiotensin II receptor blockers (ARBs), the ACE2 expression is considerably augmented, which is presumed to contribute to COVID severity [40].
There is also a bidirectional relationship between COVID-19 and DM [41]. Not only COVID-19 can have an effect on the pathophysiology of DM but also blood glucose control is very important for COVID-19 patients. Besides, DM is associated with an increased risk of severe COVID-19 and transient insulin resistance along with worsening of blood glucose control, which have been reported in previous CoV infection outbreaks as well as COVID-19 [21,37]. This could be due to cytokine storm, direct virus-mediated beta-cell damage, and special medications prescribed in the treatment course of viral infections such as anti-viral drugs or corticosteroids [31,42].
Poor glycemic control has been generally speci ed as a factor affecting poor recovery of hospitalized patients in various studies [25,43,44]. This process is explained by a wide variety of immune response alterations associated with hyperglycemia. It has been further explained that even transient stress hyperglycemia can cause innate immune response dysfunction such as impairments in polymorphonuclear and monocytic cell chemotaxis and phagocytosis, complement function, and cytokine dysregulation [25,44].
It has been well established that other comorbidities mainly CVDs, HTN, and age in uence the association between DM and poor outcomes in patients with COVID-19 [45,46]. Reviewing the related literature, the most combined comorbidities with DM are HTN and CVDs [33]. Based on the most recent meta-analysis conducted by Weiliang Tang et al. [26], older age and conditions such as HTN, DM, and CVDs could greatly affect the prognosis of COVID-19.
Aging and chronic diseases such as DM and HTN can thus predispose patients to long-term stress and subsequent immune dysfunction. These basic impairments in addition to the long-term deterioration of vascular structures and in ammation can consequently make the organs vulnerable to severe infection with worse prognosis [36].
There is still some controversies surrounding the effect of DM on mortality rate in COVID-19 patients, however, the bulk of studies have reported this association [24][25][26]35]. In the present study, in-hospital death rate was higher in patients with pre-existing DM relative to the non-diabetic individuals. In spite of this, the difference was not statistically signi cant. It seems that respiratory failure involving lung volumes, pulmonary diffusing capacity, control of ventilation, bronchomotor tone, and bronchial neuroadrenergic innervation in diabetic patients with COVID-19 contribute to mortality [47].

Conclusion
In conclusion, DM can be assumed an important risk factor for adverse endpoints in COVID-19 patients.
In diabetic cases, proper consideration of clinical characteristics can be of utmost importance. In addition, special clinical insight for disease prevention, good glycemic control during hospitalization, and efforts to develop a vaccine can help improve disease outcomes in this population.

Limitations
This study had several limitations. First, the data came from admitted diabetic patients with COVID-19, and the ones in outpatient settings were not included. Second, the glycemic data of pre-hospital status of these individuals was not accessible, which could be signi cantly associated with numerous clinical parameters. As well, evaluation of changes in blood glucose level was not possible because of COVID-19 progression. Third, given the retrospective nature of this study, determination of the effect of good blood sugar management on prognosis of the infection was not feasible. Therefore, large-scale prospective cohort studies are required to understand the association and the importance of glycemic control in progression of COVID-19. Availability of data and materials The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests