key: cord-1000436-vc1n68iu
authors: Cheng, Yangyang; Yue, Ling; Wang, Zhiyang; Zhang, Junxia; Xiang, Guangda
title: Hyperglycemia associated with lymphopenia and disease severity of COVID-19 in type 2 diabetes mellitus
date: 2020-11-26
journal: J Diabetes Complications
DOI: 10.1016/j.jdiacomp.2020.107809
sha: f4260e1838d45f08c3ac9e266ebba103636cb5e2
doc_id: 1000436
cord_uid: vc1n68iu

Background Coronavirus disease 2019 (COVID-19) has been declared a global pandemic. COVID-19 is more severe in people with diabetes. The identification of risk factors for predicting disease severity in COVID-19 patients with type 2 diabetes mellitus (T2DM) is urgently needed. Methods Two hundred and thirty-six patients with COVID-19 were enrolled in our study. The patients were divided into 2 groups: COVID-19 patients with or without T2DM. The patients were further divided into four subgroups according to the severity of COVID-19 as follows: Subgroup A included moderate COVID-19 patients without diabetes, subgroup B included severe COVID-19 patients without diabetes, subgroup C included moderate COVID-19 patients with diabetes, and subgroup D included severe COVID-19 patients with diabetes. The clinical features and radiological assessments were collected and analyzed. We tracked the dynamic changes in laboratory parameters and clinical outcomes during the hospitalization period. Multivariate analysis was performed using logistic regression to analyze the risk factors that predict the severity of COVID-19 with T2DM. Results Firstly, compared with the nondiabetic group, the COVID-19 with T2DM group had a higher erythrocyte sedimentation rate (ESR) and levels of C-reactive protein (CRP), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), and procalcitonin (PCT) but lower lymphocyte counts and T lymphocyte subsets, including CD3+ T cells, CD8+ T cells, CD4+ T cells, CD16+CD56 cells, and CD19+ cells. Secondly, compared with group A, group C had higher levels of Fasting blood glucose (FBG), IL-6, TNF-α, and neutrophils but lower lymphocyte, CD3+ T cell, CD8+ T cell, and CD4+ T cell counts. Similarly, group D had higher FBG, IL-6 and TNF-α levels and lower lymphocyte, CD3+ T cell, CD8+ T cell, and CD4+ T cell counts than group B. Thirdly, binary logistic regression analysis showed that HbA1c, IL-6, and lymphocyte count were risk factors for the severity of COVID-19 with T2DM. Importantly, COVID-19 patients with T2DM were more likely to worsen from moderate to severe COVID-19 than nondiabetic patients. Of note, lymphopenia and inflammatory responses remained more severe throughout hospitalization for COVID-19 patients with T2DM. Conclusion Our data suggested that COVID-19 patients with T2DM are more likely to develop severe COVID-19 than those without T2DM and that hyperglycemia associated with the lymphopenia and inflammatory responses in COVID-19 patients with T2DM.

In December 2019, an outbreak of coronavirus disease 2019 The occurrence of type 2 diabetes mellitus (T2DM) has rapidly increased, especially in aging people, and has now become a serious global health problem. A national study from UK showed that type 1 and type 2 diabetes were both independently associated with a significant increased odd of in-hospital death with COVID-19 8 . Furthermore, increased COVID-19-related mortality was associated with complications of type 1 and type 2 diabetes 9 .

Additionally, recent evidence has shown that improved glycemic control is associated with better outcomes in patients with COVID-19 and pre-existing T2DM 10 . To better manage COVID-19 with T2DM globally, it is essential to understand the risk factors that predict the severe type of COVID-19 in patients with T2DM. Therefore, in this retrospective, single-center study, we compared clinical and laboratory characteristics of the diabetic and J o u r n a l P r e -p r o o f Journal Pre-proof non-diabetic in-hospital patients infected with COVID-19. we aimed to determine the predictors of disease severity in COVID-19 patients with T2DM.

In this retrospective study, a total of 236 COVID- 19 

Clinical features and biochemical assessments, based on the first measurement obtained from the patient on their day of admission, were obtained from each patient's electronic medical records for retrospective review. The height and weight were measured using standardized protocols. Body mass index (BMI) was calculated as weight (kg) divided by the 

Statistical analysis was performed using SPSS 25 statistical software. Data distributions were determined using the one-sample Kolmogorov-Smirnov test, and normally distributed data are represented by the mean ± standard deviation (SD). Nonnormally distributed data are The P-values were adjusted with a Bonferroni correction for multiple comparisons. 

Journal Pre-proof significant differences in gender, height, weight, BMI, ALT, AST, Scr, eGFR, UA, TC, TG, LDL-C, HDL-C, or CD4+/CD8+ between the two groups.

The baseline characteristics of the different subgroups are shown in Table 2 and Figure   1 . Compared with groups A and C, group D had more males. Patients in groups D and C were older than those in group A. Compared with group A, group C had higher FBG, IL-6, TNF-α, and neutrophil counts but lower lymphocyte, CD3+ T cell, CD8+ T cell, and CD4+ T cell counts. Likewise, group D had higher FBG, IL-6 and TNF-α, but lower lymphocyte, CD3+ T cell, CD8+ T cell, and CD4+ T cell counts than group B. In terms of the use of medications, compared with group A, group B used a higher proportion of glucocorticoids and intravenous immunoglobulin. Accordingly, compared with group C, group D used a higher proportion of glucocorticoids and intravenous immunoglobulin ( Table 2 ).

To explore the relationship between the glucose levels and other variables, correlation analyses were performed. (Table 3) . 

COVID-19 pneumonia is caused by a new type of coronavirus, which has caused a global pandemic. Six coronaviruses are known to cause human disease 12 .The purpose of this retrospective study was to determine the predictors of disease severity in COVID-19 patients with T2DM. We mainly illustrated that (1) COVID-19 patients with T2DM suffer from more severe inflammatory responses and less lymphocyte than those without T2DM; (2) COVID-19 patients with T2DM are more likely to worsen from moderate to severe disease;

(3) inflammation and lymphocyte resolve more slowly in T2DM patients with COVID-19;

and (4) receptor expressed in the human respiratory system, cardiovascular system, digestive system and urinary system, may contribute to the increased urea nitrogen 20 .

Immune system imbalances may induce the secretion of inflammatory cytokines 21 .Chronic inflammation is also closely related to T2DM 22 .From SARS and MERS studies, an increase in pro-inflammatory cytokines was linked to lung inflammation and extensive lung injury 23,24 , and cytokine storms are often associated with disease severity 25 .

Here, the levels of inflammatory factors are elevated in the diabetic population compared to non-diabetic, Moreover, correlation analysis showed that hyperglycemia including FBG, 2 H BG and Hba1c was associated with inflammatory factors. These data indicated that hyperglycemia may affect the inflammatory responses in COVID-19 conditions.

We should note the limitations of the study. First, because a cross-sectional design was used, causal relationships could not be established. Second, the sample size was relatively small. Third, there was a discrepancy in the ages of diabetic patients with severe disease compared to non-diabetic patients in the study. Thus, it is difficult to rule out the effect of age on the poor prognosis, and some further studies of large samples are needed to explore the issue. Finally, our study was restricted to Han Chinese patients, and it is unclear whether our results can be generalized to other ethnic groups.

In summary, our findings demonstrated that COVID-19 patients with T2DM are more likely than those without T2DM to develop severe COVID-19, and lymphopenia and increased inflammation induced by hyperglycemia may be responsible for the severity of COVID-19. The data suggested that better glycemic control is essential to improve clinical outcomes in COVID-19 patients with diabetes. 3.6-6.11 5.9(5.2,8.6) 5.4(5,5.8) 9.2 (7.2,11.3) <0.001 140-400 242(198,300.8) 242(199.5,315.5) 244(185.5,292.5) (13, 47) 21 (11, 43) 32 (17, 63) 0.002 CRP, mg/L 0- 8 11.7(4.3,31.3) 7.4(3.5,19.4) 15.5(7.5,64) <0.001 J o u r n a l P r e -p r o o f

IL

We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us.

We confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, with respect to intellectual property. In so doing we confirm that we have followed the regulations of our institutions concerning intellectual property. We further confirm that any aspect of the work covered in this manuscript that has involved human patients has been conducted with the ethical approval of all relevant bodies and that such approvals are acknowledged within the manuscript. We understand that the Corresponding Author is the sole contact for the Editorial process (including Editorial Manager and direct communications with the office). he is responsible for communicating with the other authors about progress, submissions of revisions and final approval of proofs. We confirm that we have provided a current, correct email address which is accessible by the Corresponding Author and which has been configured to accept email from (Guangda64@hotmail.com).

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Abbreviations: ALT, alanine aminotransferase

BUN, serum urea nitrogen; SCr, serum creatinine; eGFR, estimated glomerular filtration rate; UA, uric acid

TC, total cholesterol; TG, triglyceride; HDL, high-density lipoprotein cholesterol

LDL, low-density lipoprotein cholesterol; LDH, lactate dehydrogenase

ESR, erythrocyte sedimentation rate

Data are n (%), n/N (%) and median (IQR)

UA

Abbreviations: ALT, alanine aminotransferase

AST, aspartate aminotransferase; BUN, serum urea nitrogen

Src, serum creatinine; eGFR, estimated glomerular filtration rate

UA, uric acid; FBG, fasting blood glucose; postprandial 2-hour blood glucose (2 h BG)

HDL, high-density lipoprotein cholesterol

LDL, low-density lipoprotein cholesterol; LDH lactate dehydrogenase

ESR, erythrocyte sedimentation rate

Data are n (%), n/N (%) and median (IQR)

*: P<0.05 compared with group A, †: P<0.05 compared with group B

We the undersigned declare that this manuscript is original, has not been published before and is not currently being considered for publication elsewhere. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us. We understand that the Corresponding Author is the sole contact for the Editorial process. He/she is responsible for communicating with the other authors about progress, submissions of revisions and final approval of proofs J o u r n a l P r e -p r o o f