Diabetes is a risk factor for the progression and prognosis of COVID‐19

Abstract Backgound To figure out whether diabetes is a risk factor influencing the progression and prognosis of 2019 novel coronavirus disease (COVID‐19). Methods A total of 174 consecutive patients confirmed with COVID‐19 were studied. Demographic data, medical history, symptoms and signs, laboratory findings, chest computed tomography (CT) as well the treatment measures were collected and analysed. Results We found that COVID‐19 patients without other comorbidities but with diabetes (n = 24) were at higher risk of severe pneumonia, release of tissue injury‐related enzymes, excessive uncontrolled inflammation responses and hypercoagulable state associated with dysregulation of glucose metabolism. Furthermore, serum levels of inflammation‐related biomarkers such as IL‐6, C‐reactive protein, serum ferritin and coagulation index, D‐dimer, were significantly higher (P < .01) in diabetic patients compared with those without, suggesting that patients with diabetes are more susceptible to an inflammatory storm eventually leading to rapid deterioration of COVID‐19. Conclusions Our data support the notion that diabetes should be considered as a risk factor for a rapid progression and bad prognosis of COVID‐19. More intensive attention should be paid to patients with diabetes, in case of rapid deterioration.

them worsened in a short period of time and died of multiple organ failure. 1 Angiotensin-converting enzyme 2 (ACE2) is the surface receptor for SARS coronavirus (SARS-CoV), directly interacting with the spike glycoprotein (S protein). 2 A recent study suggests that the affinity between ACE2 and the receptor-binding domain (RBD) of SARS-CoV-2 is 10 to 20 times higher than that with the RBD of SARS-CoV, indicating that ACE2 might also be the receptor for SARS-CoV-2. 3 ACE2 was reported to be widely expressed in various organ systems including the cardiovascular system, kidneys, lungs and brain, 4,5 which might provide an explanation for why some COVID-19 patients died of multiple organ failure.
Diabetes mellitus is one of the leading causes of morbidity worldwide and is anticipated to rise substantially over the next decades. 6 Several investigations have demonstrated a higher susceptibility to some infectious diseases in diabetic people, like Staphylococcus aureus and Mycobacterium tuberculosis, [7][8][9] probably owing to the dysregulated immune system. 10 It has reported that plasma glucose levels and diabetes are independent predictors for mortality and morbidity in patients with SARS. 11 A retrospective study in Wuhan, China revealed that of the 41 COVID-19 patients, 32% of them had underlying diseases, and among which 20% was diabetes. 12 Therefore, these diabetic patients might be at increased risk of COVID-19 and have a poorer prognosis.
To figure out whether diabetes is a risk factor to influence the progression and prognosis of COVID-19, 174 COVID-19 patients who were admitted to Wuhan Union Hospital from 10 February 2020 to 29 February 2020 were included in this study according to the inclusion criteria. Their basic information, laboratory examinations, chest computed tomography (CT) scans as well the treatment measures were collected and analysed. We found that, as a common underlying disease in COVID-19 patients, diabetes is associated with worse prognosis. We extracted demographic data, medical history, exposure history, symptoms and signs, laboratory findings, chest CT scans, and the treatment measures from electronic medical records. The date of disease onset was defined as the day when the first symptom showed up. Clinical outcomes were followed up to 3 March 2020. All data were analysed by the research team and double checked by two physicians (Y.S. and L.Z.).

| MATERIALS AND METHODS
Laboratory validation of SARS-CoV-2 was performed at Wuhan Union Hospital. Throat-swab specimens that obtained from the upper respiratory tract of patients at admission were stored in viraltransport medium. Total RNA was extracted within 2 hours using the respiratory sample RNA isolation kit (Zhongzhi, Wuhan, China). SARS-CoV-2 was examined by RT-PCR as described previously. 12 All COVID-19 patients met the following criteria: (a) Epidemiology history, (b) Fever or other respiratory symptoms, (c) Typical CT image abnormities of viral pneumonia, and (d) Positive result of RT-PCR for SARS-CoV-2 RNA. Patients were divided into the diabetes and non-diabetes group according to their medical history. Furthermore, CT imaging scores were used to quantify the pathological changes of COVID-19 patients. The values were obtained by two physicians, who were blinded to the patients' clinical data, using an introduced scoring system described as below.
On admission, abnormalities in chest CT images were detected among all patients. The prominent radiologic abnormalities were bilateral ground-glass opacity and subsegmental areas of consolidation, which is consistent with other recent reports. 1 The representative chest CT imaging of patients with or without diabetes were compared, and the latter showed more severe pathological changes than the former ( Figure 1A). Furthermore, the severity of pathological changes was evaluated by the quantifiable score system described before. We found that the diabetes group presented higher CT imaging score compared with non-diabetes group ( Figure 1B).  Table 4 and Figure 2) and neutrophils (  Further, we analysed the effect of SARS-CoV-2 on the pathology of diabetes. We found that patients with diabetes control blood glucose levels with insulin or oral medicine before admission. Among them, 29.2% of the patients took insulin before and increased the dose of insulin after admission, and 37.5% of the patients took oral medicine before admission and started insulin therapy after admission, which meant that patients had poor glycemic control during hospitalization. Of all the diabetic patients, only three had diabetic complications, and those patients with diabetic complications were more likely to die as shown in Table 5. Finally, we explored the impact of comorbidities on the prognosis of patients with diabetes. Through our analysis, although the indicators for diabetic patients with other comorbidities are slightly higher than those without other comorbidities, no matter evaluated from organ damage, inflammatory factors or hypercoagulability, other comorbidities have little effect on the prognosis of patients with diabetes (Table S2).

| DISCUSSION
Common perceptions associate diabetes with a generally increased mortality and morbidity to infectious diseases, although epidemiologic data that would prove this are surprisingly scarce. However, it seems to be confirmed that diabetes predisposes to certain types of infection and death, [6][7][8][9]11 but it is still unknown whether diabetes is a risk factor for the prognosis of COVID-19. Type 2 diabetes is widely viewed as a chronic, low-grade inflammatory disease caused by longterm immune system imbalance, metabolic syndrome or nutrient excess associated with obesity. 14,15 Obesity-associated inflammation is characterized by an increased abundance and activation of innate and adaptive immunity cells in adipose tissue along with an increased release of inflammatory factors and chemokines locally and systemically. 16 On   20 According to the quantifiable score, we found that the diabetes group presented higher CT imaging score compared with non-diabetes group, which means pneumonia in diabetic patients is more severe than non-diabetic patients.
In addition to imaging results, laboratory results also give us some hints. Biochemical results showed that some indicative enzymes were abnormally elevated in the blood of patients with SARS-CoV-2 pneumonia, including LDH, HBDH, ALT and GGT, which indicated the injury of myocardium, kidney and liver. This result is consistent with the extensive distribution of SARS-CoV-2 receptors ACE2, 5 and can also partially explain why some patients died from multiple organ failure. 1 It is important to note that the levels of these enzymes were even higher in patients with diabetes when compared to patients without diabetes, which give us a clue that the injure of organs was much more serious in diabetes patients group than those without diabetes. In addition, our study found that the levels of total protein, albumin, prealbumin and haemoglobin are significantly lower in patients with diabetes compared to individuals without diabetes, which means diabetes patients are more likely to be undernourished.
According to a recent report, after analysing 138 hospitalized patients with COVID-19, they found that neutrophilia related to cytokine storm induced by virus invasion, coagulation activation related to sustained inflammatory response and acute kidney injury related to direct effects of the virus might be associated with the death of patients with COVID-19. 12 And other study also found that patients with SARS-CoV-2 pneumonia, especially those with severe pneumonia, have significantly reduced lymphocyte counts and significantly increased inflammatory factors, such as IL-6. 20 In fact, in the advanced stage of SARS and Ebola virus infections, cytokine storms are also the main cause of eventual death for many patients. In our study, we found that, compared to patients without diabetes, absolute count of lymphocytes in peripheral blood of patients with diabetes is significantly lower, while the absolute count of neutrophils is remarkably higher. Furthermore, the serum levels of some inflammation-related biomarker are much higher compared to those without diabetes, such as IL-6, serum ferritin, ESR and CRP. It's noteworthy that for diseases that can induce a cytokine storm. IL-6 is a very good predictor of disease severity and prognosis, and its expression time is longer than other cytokines (TNF and IL-1). 21 In addition, a significant rise in serum F I G U R E 2 Biochemical examination results of the patients with diabetes and patients without diabetes. P < .05 was considered statistically significant ferritin indicates the activation of the monocyte-macrophage system, which is a crucial part of inflammatory storm. These results indicate that patients with diabetes are susceptible to form an inflammatory storm, which eventually lead to rapid deterioration of COVID-19.
During the inflammatory storm, the D-dimer increases significantly.
In the early stage, this is the result of inflammation activating plasmin.
However, as inflammation progresses and the presence of hypoxia, hypoxia-induced molecules can activate thrombin directly, and the activation of monocyte-macrophages would also secrete a mass of tissue factors and activate the exogenous coagulation pathway, which lead to an overall hypercoagulable state or even disseminated intravascular coagulation. In our study, we found that level of D-dimer and FIB was significantly higher in patients with diabetes, which indicate that they are more prone to a hypercoagulable state than patients without diabetes.
Clinical medication showed that the insulin dose increased after the patient was infected with SARS-CoV-2, which shows that the virus has an impact on the patient's glucose metabolism. Dysregulation of glucose metabolism will aggravate diabetes and then affect the severity of pneumonia, which works as an amplification loop. Meanwhile, the diabetic complications signify the severity of diabetes, and these patients with diabetic complications showed a higher mortality rate, which further proves that diabetes is a risk factor for the prognosis of COVID-19, and the severity of diabetes is positively correlated with the poor prognosis.
All in all, whether interference from other comorbidities is present or not, we found that SARS-CoV-2 pneumonia patients with diabetes are more severe than those without diabetes evaluating from organ damage, inflammatory factors or hypercoagulability, and are more likely to progress into a worse prognosis. Therefore, diabetes might could be considered as a risk factor for the outcome of SARS-CoV-2 pneumonia, and more intensive attention should be paid to patients with diabetes, in case of rapid deterioration.
F I G U R E 3 Other laboratory tests of the patients with diabetes and patients without diabetes. A, Blood test results of the patients with diabetes and patients without diabetes. B, Inflammation-related laboratory results of the patients with diabetes and patients without diabetes. C, Coagulation-related laboratory results of the patients with diabetes and patient without diabetes. P < .05 was considered statistically significant