key: cord-0726728-0pa2ipuu
authors: Huang, Yun; Guo, Heming; Zhou, Yan; Guo, Jingjing; Wang, Tiantian; Zhao, Xuming; Li, Hui; Sun, Yihui; Bian, Xuna; Fang, Chen
title: The association between plasma glucose and mortality of COVID-19 in patients without diabetes
date: 2020-09-16
journal: Diabetes Res Clin Pract
DOI: 10.1016/j.diabres.2020.108448
sha: 898c495619c2345119ac6c29e03e2e16bfb86e4f
doc_id: 726728
cord_uid: 0pa2ipuu

Aims Coronavirus disease 2019 (COVID-19) which is a novel pneumonia can rapidly progress to acute respiratory distress syndrome, septic shock, and multiple organ dysfunction syndrome. It has appeared in 196 countries around the world. We aimed to clarify the association between plasma glucose and mortality of COVID-19 in patients without diabetes. Methods We performed a retrospective, single-center study of 151 patients without diabetes at Tongji Hospital from January 1, 2020 to February 28, 2020. Patients were analyzed for clinical features, laboratory parameters and divided the patients into three groups according to the fasting plasma glucose, to evaluate the association between current medications and fasting plasma glucose. Results Compared with survivors, non-survivors were more likely to have underlying medical conditions including hypertension, cardiovascular disease, cerebrovascular diseases, and chronic pulmonary diseases. Non-survivors had higher C-reactive protein (CRP), procalcitonin (PCT), white blood cell counts, interleukin (IL)-2R, IL-6, IL-8 and , tumor necrosis factor-α (TNF-α). Besides, patients with higher fasting plasma glucose (FPG) had higher IL-6, IL-8, CRP, and mortality. Lymphocyte counts lower in patients with better FPG. After adjusting for age and gender, the risk of death increased 3.54 folds for each tertile increment. Conclusions Because the increase of fasting plasma glucose is strongly associated with the risk of mortality in patients without diabetes, the novel parameter may need to be monitored during hospitalization.

A novel pneumonia of unknown cause was detected in Wuhan, China, which was later named as Corona Virus Disease 2019 (COVID-19) by the World Health Organization (WHO), and the virus that caused this epidemic was named as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) [1] .The outbreak of COVID-19 swept across China has aroused global concerns. As of May 5, 2020, more than 3.6 million COVID-19 cases have 5 been confirmed around the world. According to different retrospective studies, among the patients with COVID-19, the case-fatality rate has huge variation [2, 3] . However, severe cases were prone to suffer various complications, especially death cases. Aged patients with underlying comorbidities including diabetes, hypertension, coronary heart disease etc. are at greater risk to have poor prognosis. Thus, the clinical features of patients who have poor prognosis remain to be comprehensively analysis which is helpful to manage the patients.

Recently, more and more studies highlighted the positive correlation between blood glucose and COVID-19 [4, 5] .COVID-19 patients with hyperglycemia have a crude mortality rate of about 7.3%, much higher than that of COVID-19 patients with normal blood glucose (0.9%) [6] . Intensive care patients with diabetes are account for 22.2%, the proportion of nonintensive care patients is only 5.9% [7] . Besides, among the severe cases of death, 34% had hyperglycemia [8] . Thus, it is important to clarify the association between blood glucose and COVID-19 in patients with or without diabetes. However, previous studies focus on the management of blood glucose in patients with diabetes.

In this study, we firstly aim to describe demographic and clinical characteristics, laboratory and radiological parameters as well as treatment and outcomes of patients who were discharged or died with COVID-19 infection in two hospitals in Wuhan, China. We also 6 divided the patients into three groups according to the fasting plasma glucose, to evaluate the association between current medications and fasting plasma glucose, and provide a reference for clinical treatment of patients with COVID-19.

This retrospective study was carried out at Tongji Hospital. Diagnosis of COVID-19 was according to "Diagnosis and Treatment Scheme of New Coronavirus Infected Pneumonia" (trial version 6)" [9] . All cases had a history of exposure and most had clinical manifestations including fever or respiratory symptoms. The patients included in this study met the following criteria: (1) They were diagnosed new coronavirus infected pneumonia after examination of SARS-CoV-2 RNA by real-time polymerase chain reaction (RT-PCR). (2) They were admitted and treated in the Tongji Hospital from January 1, 2020 to February 28, 2020. (3) All the patients have no history of diabetes and their HbA1c are lower than 6.1%.

We screened 1024 hospitalized patients from the two hospitals. The medical records of 151 patients were collected and examined by the research team from the two hospitals.

Epidemiological, clinical, laboratory characteristics and treatment and outcomes data were acquired by the hospitalization management system. 7 Plasma were collected from patients after an overnight fast. We test the blood urea nitrogen (BUN), creatinine (Cr) and estimated glomerular filtration rate (eGFR) to evaluate the kidney function. We investigated the aspartate aminotransferase (AST) and alanine aminotransferase (ALT) to evaluate the liver function. We test the cardiac troponin I (CTnl), myoglobin, brain natriuretic peptide (BNP) to evaluate the cardiovascular disease. We also investigated Creactive protein (CRP), procalcitonin (PCT), interleukin (IL)-1β, IL-2R, IL-6, IL-8, IL-10, tumor necrosis factor-α (TNF-α), white blood cells (WBC) and lymphocytes to evaluate the infection and immunity in COVID-19 patients. COVID-19 was tested by RT-PCR according to WHO interim guidance.

Analyses were performed using SAS version 9.3 (https://support.sas.com/documentation/ -installcenter/ 93/index.html). Data were presented as median (interquartile range). Man -n-Whitney U test or χ2 test were performed to compare differences among different groups. Logistic regression was used to assess the associations between mortality and fasting plasma glucose levels after adjustments for age and sex. Two-sided p < 0.05 was considered as representing statistical significance. 8 We observed substantial differences in laboratory findings between patients who died of covid-19 and those who recovered from it. A total of 151 cases with COVID-19 were admitted to the two centers, including 70 females and 81 males. By April 1, 15 of 151 cases died and their median duration from hospital admission to death was 11 days. 136 of 158 cases were discharged and their median duration from hospital admission to discharge was 22 days. We compared clinical and laboratory characteristics between survivors and deceased patients.

The results revealed that non-survivors were older than those survivors. Among deceased patients, the number of male patient is more than female patient ( (97%vs92%) during hospitalization. Non-survivors have significantly higher AST levels (23IU/L vs 40IU/L). Although chronic kidney disease had no effect on the risk of death according to the data. But non-survivors reported higher BUN (4.3mmol/L vs 7.6mmol/L), Cr (69umol/L vs 84umol/L) and eGFR (93ml/h·1.73m2 vs 64ml/h·1.73m2). Creatine kinase isoenzyme (CKMB), myoglobin and BNP are higher in deceased patients. 26.7% of nonsurvivors' D-dimer were higher than 21μg/ml. Non-survivors had higher CRP (113.3mg/L vs 5.6mg/L), PCT (0.15ng/ml vs 0.06ng/ml), WBC (7.95×1012 vs 6.18×1012), IL-2R 9 (1273U/ml vs 442U/ml), IL-6 (97.0pg/ml vs 3.2pg/ml), IL-8 (30.5pg/ml vs 11.0pg/ml) and TNF-α (11.6pg/ml vs 8.5pg/ml). However, lymphocytes were lower in non-survivors. IL-10 levels of 78.9% of non-survivors were less than 5.0 pg/ml (Table 1) .

We found non-survivors had higher fasting plasma glucose (5.86mmol/L vs 5.03mmol/L).

Thus, we divided all patients into three groups according to the tertile range of fasting plasma glucose (FPG), including group one (4.09-4.91 mmol/L), group two (4.91-5.38 mmol/L) and group three (5.38-6.09 mmol/L). The results indicated that patients with higher FPG had higher IL-6 (2.8pg/ml vs 4.9pg/ml vs 6.9pg/ml), IL-8(11pg/ml vs 10.9pg/ml vs 18.1pg/ml), CRP (2.9mg/L vs 15.05mg/L vs 35.6mg/L), and mortality (1.92% vs 6.12% vs 22%).

Lymphocyte counts were lower in patients with better FPG (1.44×10 12 vs 1.14×10 12 vs 1.1×10 12 ). After adjusting for age and gender, the risk of death increased 3.54 folds for each tertile increment (CI 1.25-10.06, P=0.018) ( Table 2 ).

In our study, all the patients with COVID-19 were elderly patients, and the median ages of every group were more than 60 years old. Aged people are more susceptible to COVID-19, and some researchers think it may be associated with a higher frequency of comorbidities [10] . We found that there were 48 patients combined with hypertension, 17 patients with cardiovascular disease and cerebrovascular diseases. We found the rates of hypertension, 10 cardiovascular disease and cerebrovascular diseases were higher in non-survivors. These disorders share underlying pathophysiology related to the renin-angiotensin system (RAS).

Especially, activity of the angiotensin-converting enzyme 2 (ACE2) is dysregulated in cardiovascular disease, and this enzyme is used by SARS-CoV-2 to initiate the infection [11] .

According to our study, the patients with chronic pulmonary diseases have higher mortality.

Patients with poor pulmonary function are more likely to appear respiratory failure under the attack of COVID-19.

The mortality of patients with BUN, Cr, eGFR, CKMB, CTnl and infection indexes (CRP, WBC, lymphocyte, etc) increased, and the level of SpO2 decreased. Theses results indicated that non-survivors were more likely to develop complications including acute respiratory distress syndrome (ARDS), acute cardiac injury, acute kidney injury, shock and secondary infections. Besides, we found that AST was strongly associated with the mortality risk.

Previous studies also revealed that AST increase was more frequent than ALT in severe patients upon admission [12, 13] . Recently, Lei F's study confirms that elevated liver injury indicators, particularly AST, are strongly associated with the mortality risk according to 5771 adult patients with COVID-19 pneumonia. It indicates that liver injury indicators should be monitored during hospitalization.

Non-survivor reported higher FPG level (5.86 vs 5.03 mmol/L) compared with survivors.

Previous studies analyzed clinical characteristics of the patients with diabetes which revealed 11 that the poor FPG controlled could worsen the outcome of the new coronavirus disease [14] .

In a retrospective study of 2041 patients with COVID-19, the results revealed that elevation of blood glucose level predicted worse outcomes in hospitalized patients with COVID-19 [15] . Another study found that blood glucose levels were elevated in patients and tight glycemic control may be an important consideration for improving clinical outcomes [16] .

ACE2 receptors also express on β cells, therefore, the virus might also directly attack the pancreas. It may render infected COVID-19 patients more prone to hyperglycemia [17] .

Our study firstly analyzed the influence of fasting blood glucose on the prognosis of patients without diabetes. We found that the levels of IL-6, IL-8 and CRP were higher in the patients with higher FPG. The count of lymphocytes was lower in the highest FPG group. These indicate that FPG levels are associated with infection and immunity in COVID-19 patients.

The mechanism remains unclear. It might be associated with impaired innate immunity, adaptive immunity and altered metabolisms according to the previous studies [18, 19] . Recent study reveal that elevated glucose levels directly induce viral replication and proinflammatory cytokine expression. It may also make T cell infected by virus more easily.

The viral infections could increase the expression of programmed cell death protein 1 (PD-1) by T cells. This might explain why elevated glucose levels during CoV-2 infection may lead to T cell dysfunction and lymphopenia [20] . Our study indicates that patients with higher FPG also have higher mortality. Even in patients without diabetes, FPG is still a risk factor of death. 12 There are several limitations in our study. This study was retrospective, and some data of cases were incomplete due to relatively insufficient medical resources, which may lead to bias. Moreover all medical resources were collected from two centers, so the sample size was relatively limited. Although obesity is linked to an increased risk of COVID-19 [21] , detailed data on body mass index of the patients with COVID-19 are lacking in this study, for the reason that we didn't acquire the weight and height of all patients involved in our study.

Finally, we examined the association between COVID-19 and FPG, but we cannot demonstrate causality.

In conclusion, non-survivors combined with more existing diseases, severe infection, impairedimmunity and worsen function of various organs. Because the increase of fasting plasma glucose is strongly associated with the risk of mortality in patients without diabetes, the novel parameter may need to be monitored during hospitalization. 

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The work was supported by the Science and Technology Project of