key: cord-0777095-bq7460ca
authors: Wu, Jing; Zhang, Jingqi; Sun, Xiaohua; Wang, Lijuan; Xu, Yunfang; Zhang, Yuanyuan; Liu, Xingxiang; Dong, Chen
title: Influence of diabetes mellitus on the severity and fatality of SARS‐CoV‐2 infection
date: 2020-06-04
journal: Diabetes Obes Metab
DOI: 10.1111/dom.14105
sha: 862f31aee78fcce800a91e996ed5048968726656
doc_id: 777095
cord_uid: bq7460ca

AIMS: Diabetes mellitus is one of the most common comorbidities in Coronavirus disease 2019 (COVID‐19) patients. The objective of this study was to evaluate the influences of diabetes mellitus on the severity and fatality of SARS‐CoV‐2 infection. MATERIALS AND METHODS: Medical records of 66 hospitalized COVID‐19 patients were collected and classified into non‐severe (mild/moderate cases) and severe (severe/critical cases) groups, respectively. Logistic regression analysis was used to estimate the risk of severe COVID‐19 (severe/critical infection). In addition, a meta‐analysis including published studies reported the impacts of diabetes mellitus on severity and fatality of COVID‐19, and our current study was conducted using fixed‐effects models. RESULTS: There were 22 diabetic and 44 non‐diabetic cases among the 66 hospitalized COVID‐19 patients. As the results shown, seven cases (31.82%) were diagnosed as severe COVID‐19 in diabetic patients, which was significantly higher than that in non‐diabetic group (4/44, 9.09%, P = 0.033). After adjustment for age and gender, the results showed that diabetes mellitus was significantly associated with COVID‐19 severity (OR: 5.29, 95% CI: 1.07–26.02). A meta‐analysis further confirmed the positive association between diabetes mellitus and COVID‐19 severity (pooled OR = 2.58, 95% CI: 1.93–3.45). Moreover, the diabetic patients infected with SARS‐CoV‐2 showed to have 2.95‐fold higher risk of fatality compared to those patients without diabetes mellitus (95% CI: 1.93–4.53). CONCLUSIONS: Our findings provide new evidences that diabetes mellitus is associated with a higher risk of severity and fatality of COVID‐19. Therefore, intensive monitoring and antidiabetic therapy should be considered in diabetic patients with SARS‐CoV‐2 infection. This article is protected by copyright. All rights reserved.

Coronavirus disease 2019 , caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is an ongoing public health emergency of international significance [1] . Although the fatality of SARS-CoV-2 infection appears to be less than that observed in SARS-CoV and MERS-CoV infections, the new virus possesses strong transmissibility [2, 3] . As of April 3 rd , 2020, approximately 1,100,000 laboratory confirmed patients were presented in more than 200 countries/regions around the world. Moreover, the virus has led to the deaths of over 50,000 people, mostly the elderly or those with underlying chronic diseases [4] . Therefore, identification of risk factors for the severity and fatality of SARS-CoV-2 infection is urgently needed, to better understand and prevent this public health epidemic worldwide.

Accumulative clinical studies have suggested that diabetic patients with acute viral respiratory infections often lead to severe complications such as pneumonia, acute respiratory distress syndrome, organ failure, and even death [5] [6] [7] . For example, Yang et al. have reported that a known history of diabetes mellitus was an independent predictor for the fatality of SARS-CoV infection. More importantly, normalization of blood glucose levels and possible suppression of ketosis using intravenous This article is protected by copyright. All rights reserved.

insulin-glucose infusion or intensive insulin therapy have been shown to reduce mortality and morbidity in diabetic patients admitted to the intensive care unit [8] . In addition, Garbati et al. reported that 88% of MERS-CoV-infected diabetic patients had poor outcomes compared with 39% of individuals who had any type of non-diabetic comorbidity with MERS-CoV infection, suggesting that diabetes mellitus in particular is a major contributor to MERS severity [9] .

As one of the most important public health problemsin the 21 st century, diabetes mellitus affects more than 400 million adults around the world [10] . However, the effects of diabetes mellitus on the severity and fatality of SARS-CoV-2 infection has been investigated in very limited. Therefore, the first objective of this study was to explore the association between diabetes mellitus and COVID-19 severity in hospitalized patients. Then, we combined our results with those of previously published studies in a meta-analysis. This assessment should be helpful for the management of diabetic patients with SARS-CoV-2 infection.

From Jan 23 to Mar 9, 2020, a total of 66 COVID-19 patients were admitted to Huai'an Fourth people's hospital, which is the sole hospital caring for COVID-19 patients in Huai'an city. Huai'an city is located in the hinterland of Northern Jiangsu, 

Demographic and clinical features were extracted from electronic medical records using a standardized data collection form. All data were checked by a team of trained physicians. In the present study, all of the laboratory tests were examined within 24 hours of hospital admission. The SARS-CoV-2 RNA was isolated from each pharyngeal swab specimen and amplified using qRT-PCR kits (BGI Genomics, Beijing, China), which was recommended by the Chinese Center for Disease Control and Prevention (CDC). Other routine laboratory tests, including lymphocyte counts, neutrophil counts, and serum levels of AST (aspartate aminotransferase), ALT (alanine aminotransferase), FPG (fasting plasma glucose), CK (Creatine kinase), CRP (C-reactive protein), TC (total cholesterol) and TG (triglyceride) were measured using commercial reagents according to the manufacture's introductions.

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In line with the American Diabetes Association guidelines, patients were identified as having diabetes mellitus if they were currently treated with insulin or oral hypoglycemic agents, or had FPG concentration ≥7.0 mmol/L at least two separate occasions [12] .

In the present study, the mild/moderate and severe/critical COVID-19 cases were classified into non-severe and severe groups, respectively. Continuous variables were expressed as mean ± SD or median (interquartile range). Categorical variables were expressed as numbers (%). The unpaired t-test, χ² test, or Fisher's exact test was used to compare the characteristics of COVID-19 patients with or without diabetes mellitus, as appropriate. Logistic regression analysis was used to estimate the risk of COVID-19 severity (severe/critical infection) by calculating the odds ratios (OR) and 95 % confidence intervals (CIs). Statistical analyses were performed using SAS 9.4 software (SAS Institute, Cary, NC, USA), a two-sided P value <0.05 was defined as statistically significant.

Based on the guidelines of the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) [13] , this meta-analysis was conducted combining the results of the present study and the previous studies reported the effects of diabetes mellitus on the severity and fatality of hospitalized COVID-19 cases. The exclusion criteria were as following: (1) repeated articles, letters, comments, editorials, and expert opinions; (2) case reports; (3) review and meta-analysis articles; (4) studies without available data. First, we searched the relevant studies in PubMed, Embase, medRxiv, Cochrane library, and CNKI databases for articles published up to 03/20/2020, using the following terms: "COVID-19 or SARS-CoV-2 or 2019-nCoV or NCIP" and "diabetes" or "diabetes mellitus". To be included in the meta-analysis This article is protected by copyright. All rights reserved.

for the associations between diabetes mellitus and COVID-19 severity, the study had to: (1) grouping patients with COVID-19 based on disease severity; (2) show available data for the number of diabetic patients with SARS-CoV-2 infection; (3) be published in English or Chinese; and (4) including at least 20 cases. We searched the reference lists of relevant publications manually to identify more studies. Finally, twelve studies met the criteria [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] . Second, we searched the relevant studies for the meta-analysis of the relationship between diabetes mellitus and COVID-19 fatality as described above. Included articles had to: (1) show available data on the number of diabetic patients; (2) show available data on the number of deaths of SARS-CoV-2 infected diabetic patients; (3) be published in English or Chinese; and (4) including at least 20 cases. In total, six studies satisfied the criteria [26] [27] [28] [29] [30] [31] . The quality of all included studies was evaluated using the Newcastle-Ottawa Scale (NOS) ( Table S1 ). Figure S1 depicted the flow of the study selection process. Two authors (JW and JZ) independently extracted the data and, if they had disagreements, discussed with a third author (CD). We extracted information about the authors, date of publication, sample size, range of age, the number of diabetes mellitus cases, the number of severe or fatality cases, and the effect size. Potential heterogeneity between studies was examined using I 2 judgment model. If I 2 < 50%, it means that there is no heterogeneity among the included studies and fixed-effects model can be selected; otherwise, it means that the results of the independent studies are not the same due to sampling errors, random-effects model must be selected [32] . The funnel plot and Egger's test were used to examine potential publication bias [33] . This meta-analysis was performed using the package of "Meta" in R software (R version 3.6.1). All reported P values were two-tailed, and those < 0.05 were considered statistically significant unless otherwise specified.

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There were 22 diabetic and 44 non-diabetic cases among 66 hospitalized COVID-19 patients included in this study. As the results shown, seven cases (31.82%) were diagnosed as severe SARS-CoV-2 infections in diabetic patients, which was significantly higher than that in non-diabetic group (4/44, 9.09%, P=0.033).

Compared with the non-diabetic COVID-19 cases, diabetic patients with SARS-CoV-2 infection were more likely to be with higher levels of CRP (P=0.001) and neutrophil counts (P=0.033) on admission. As expected, the mean BMI was 26.75 ± 2.68 kg/m 2 in diabetic patients, which was significantly higher than that in non-diabetic cases (24.97 ± 3.07 kg/m 2 , P=0.027). However, no significant differences were observed in other characteristics between the two groups ( Table 1) .

As the results shown in Table 2 0.04). The estimated effect sizes were similar in the sensitivity analysis, regardless of exclusion of any single study one-at-a-time (Figure1-B) . Furthermore, subgroup analysis results revealed the pooled OR was 3.04 (95% CI: 2.03-4.56) for the patients aged <50 years and 2.58 (95% CI: 1.93-3.26) for the patients aged ≥50 years, respectively (Fig 2) . In addition, the funnel plots and the Egger's test (t=0.60, P = 0.559) did not show the existence of potential publication bias in the present meta-analysis ( Figure S2-A) . 4) . Sensitivity analysis showed that the exclusion of any single study one-at-a-time did not alter the direction or statistical difference (Figure 3-B) . Similarly, the funnel plots and the Egger's test (t=0.22, P = 0.834) did not show the existence of potential publication bias in the present study ( Figure S2 -B).

To our knowledge, this is the first study to address the effect of diabetes mellitus on COVID-19 severity and the first meta-analysis to investigate the associations of diabetes mellitus with the severity and fatality of SARS-CoV-2 infection. As the results shown, among our hospitalized cases, the severity rate of SARS-CoV-2

This article is protected by copyright. All rights reserved. infection in diabetic patients was 31.82%, which was much higher than in non-diabetic COVID-19 patients (9.09%). In the present meta-analysis, diabetic patients with COVID-19 showed to have 2.58-and 2.95-fold higher risks of severity and fatality compared to the non-diabetic COVID-19 patients, respectively. Indeed, the chronic conditions influencing the severity of SARS-CoV-2, such as diabetes, hypertension, and obesity, have also been addressed in other respiratory illnesses such as SARS and MERS. For example, Yang et al. have reported that the prevalence of known diabetes among dead SARS patients was much higher (21.5%) than in survivors (3.9%) [8] . In addition, the OR for severe MERS-CoV infection has been reported to range from 7.2 to 15.7 in diabetic subjects [34] [35] .

Although the exact interaction between diabetes mellitus and virus infection has not been well understood, the results from previous studies could partially explain our findings. First, host defense to virus infection is largely mediated by innate immunity and the synthesis of related cytokines, such as interleukins, interferon, and etc. [36] .

However, diabetes and its related conditions can downregulate the immune system by impairing the function of innate immunity, such as chemotaxis, phagocytosis, and the activity of neutrophils and macrophages, and then lead to severe illnesses [37] .

Second, the most recent studies reported that many patients with a severe and particularly fatal course of COVID-19 seemed to die from small pulmonary emboli/thrombosis [38, 39] . Considering that diabetic mellituswas significantly associated with the development of myocardial infarction and cerebrovascular thromboses, it is rational to hypothesize that diabetes mellitus might increase poor outcomes of SRAS-CoV-2 infection by inducing a hypercoagulable state in COVID-19 patient. Third, similar to SARS-CoV, SARS-CoV-2 infection is mediated by the binding of its spike protein to the cellular receptor angiotensin-converting enzyme 2 (ACE2), which also plays a pivotal role in the development of diabetes This article is protected by copyright. All rights reserved. mellitus [40, 41] . Furthermore, in addition to the heart and lung, ACE2 can be expressed in brain, liver, placenta and kidneys, providing a potential mechanism for the severity symptoms and multi-organ dysfunction that can be observed in severe COVID-19 patients [42] . Last, the results from previous studies reported that influenza virus and SARS-CoV infection could induce transient elevation of FPG levels [41, 43] . Although the similar effects of SARS-CoV-2 infection were not observed in our patients, it cannot conclude that SARS-CoV-2 infection did not affect the FPG level because of the limited sample size in the present study.

Recently, increasing clinical studies noticed that circulating CRP levels, lymphocyte, and neutrophil counts were significantly associated with COVID-19 severity. For example, Zhang et al's study in Wuhan reported that the median CRP level was 47.6 mg/L (IQR: 20.6-87.1mg/L) in severe COVID-19 patients, which was much higher than in non-severe patients [20] . CRP is well known asa sensitive acute-phase reactant and plays an instructive role in the acquired immune response [44] . Additionally, both neutrophil and lymphocyte counts were significant predictors of CRP in SARS-CoV infections [44] . Similarly, our results showed that CRP levels and neutrophilcounts were clearly increased in diabetic patients with SARS-CoV-2 infection. However, no significant difference in lymphocyte counts was observed between COVID-19 patients with and without diabetes mellitus. In addition, our present results showed that adjustment for lymphocyte count and CRP could significantly affect the associations between diabetes mellitus and COVID-19 severity (Table S2) , indicating that more studies should be conducted to explore the characteristics of inflammation induced by SARS-CoV-2 infection in diabetic patient.

After pooling all studies together with a larger sample size, we observed a significant association of diabetes mellitus with the severity and fatality of SARS-COV-2 infection. Sensitivity analysis with exclusion of studies one by one did not change the This article is protected by copyright. All rights reserved.

results materially, suggesting that each included study might not have a particularly strong influence on the results. However, some limitations of our study should be discussed. First, publication bias is inevitable in any meta-analysis, and relevant articles may be missed as we only included English-and Chinese-written studies.

Second, some studies lacked the information necessary to be properly evaluated. For example, most researchers did not explain the exact date of biomarkers measurement such as viral load, lymphocyte counts, CRP, ALT, AST, and etc. Additionally, the potential impact of antidiabetic drugs on the outcomes of included diabetic patients has not been addressed in most studies. It might weak the interpretation of our findings. Third, due to the limited number of patients and outcomes in our study, the adjustment might cause over-fitting issue of the multivariable model. Therefore, more studies with large samples should be conducted to validate our findings, although the adjustment for potential confounding one-at-a-time did not alter the direction or statistical difference except the lymphocyte count and CRP (Table S2) . Last, given the included studies were retrospective study design, there may be a bias regarding collecting medical information in a retrospective manner. Therefore, caution should be considered to interpret findings. However, it would be difficult to conduct randomized controlled trials because of ethical issues.

In summary, our present findings provided new evidence that diabetes mellitus could significantly increase the risks of severity and fatality of SARS-CoV-2 infection. This article is protected by copyright. All rights reserved. 

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Non-diabetic cases, n (%) Diabetic cases, n (%)

This article is protected by copyright. All rights reserved.The authors thank Yonghong Zhang and Zhirong Guo (Soochow University) for their suggestions on the work.