key: cord-0769017-jsf7c12i
authors: Cho, Dong-Hyuk; Choi, Jimi; Gwon, Jun Gyo
title: Metabolic Syndrome and the Risk of COVID-19 Infection: A Nationwide Population-Based Case-Control Study
date: 2021-05-27
journal: Nutr Metab Cardiovasc Dis
DOI: 10.1016/j.numecd.2021.05.016
sha: 47c78a8e38a7c814ecfde9ba5771272b4bbb2fc4
doc_id: 769017
cord_uid: jsf7c12i

Background and Aims Metabolic syndrome (MetS) is a chronic, low-grade inflammatory disease. This study aimed to investigate the impact of MetS on the risk and severity of COVID-19. Methods and Results We investigated a nationwide cohort with COVID-19 including all patients who underwent the test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Korea. The COVID-19 group included 4,070 patients with positive SARS-CoV-2 test results, and the age- and sex-matched control group included 27,618 subjects with negative SARS-CoV-2 test results. The endpoints were SARS-CoV-2 positivity and the severity of COVID-19. The prevalence of MetS was 24.7% and 24.5% in the COVID-19 and control groups, respectively. The presence of MetS was not associated with the risk of developing COVID-19. Among the components of MetS, central obesity was associated with a higher risk of COVID-19 infection (adjusted odds ratio [aOR], 1.17; 95% confidence interval [CI], 1.06–1.28, P = 0.001). The presence of MetS was significantly associated with severe COVID-19 (aOR, 1.25; 95% CI, 0.78–2.00, P = 0.352). Among the individual components of MetS, prediabetes/diabetes mellitus was associated with a higher risk of severe COVID-19 (aOR, 1.61; 95% CI, 1.21–2.13, P = 0.001). The risk of severe COVID-19 linearly increased according to the number of metabolic components (P for trend = 0.005). Conclusion In this nationwide cohort study, the individuals with MetS had significant increases in the risk of severe COVID-19 infection. These patients, particularly those with central obesity and insulin resistance, deserve special attention amid the COVID-19 pandemic.

Coronavirus disease (COVID- 19) , first reported in Hubei, China in December 2019, is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1] . This disease has spread rapidly and has caused global health and economic crises. The World Health Organization declared a global pandemic of COVID-19 in March 2020 [2] .

COVID-19 infection frequently causes severe pneumonia requiring hospitalization to the intensive care unit and invasive mechanical ventilation and often results in acute respiratory distress syndrome [3, 4] . In critically ill patients with COVID-19, the levels of inflammatory molecules and pro-inflammatory cytokines are highly increased, and the presence of the cytokine storm increases the severity and induces multi-organ dysfunctions and sepsis [5] .

Cardiometabolic disorders are commonly observed in patients with COVID-19 infection, and dysmetabolic conditions are associated with severity and mortality [6, 7] . Metabolic syndrome (MetS) is a constellation of multiple cardiometabolic risk factors, including insulin resistance, hypertension, and central obesity, which leads to endothelial and myocardial damage and cardiovascular events [8] . Visceral adipose tissue is metabolically bioactive and a source of pro-inflammatory cytokines [9] . The importance of MetS in increasing the risk and severity of COVID-19 infection has been investigated. In an urban population study conducted in the USA, MetS was associated with severe and fatal COVID-19 outcomes [10] .

Patients with diabetes mellitus and MetS who were hospitalized for COVID-19 had an increased risk of adverse outcomes [11] .

However, amid the ongoing pandemic, one key unanswered question is which individual components of MetS are associated with COVID-19 infection and severity. If individual components were strongly associated with COVID-19 infection, a preventive strategy would be established for patients with specific metabolic risk factors. Considering these, the aim of J o u r n a l P r e -p r o o f this study was to investigate the influence of MetS and its individual components on the positivity for SARS-CoV-2 and the severity of COVID-19 in a cohort covering the entire Korean population.

In this nationwide cohort study, the Korean cohort with COVID-19 included all and consecutive Koreans who underwent the test for SARS-CoV-2. South Korea experienced the Middle East respiratory syndrome outbreak in 2015, and the Korean government established a preparedness and response system for the next infectious disease [12] [13] [14] . In collaboration with the Korean Ministry of Health and Welfare, national and local governments, medical experts, and epidemic intelligence service officers applied the "trace, test, and treat" strategy for suspected patients with COVID-19 [12] . Amid the COVID-19 pandemic, the Korean Service of Korea database. Among consecutive subjects who underwent the SARS-CoV-2 test between January 1 and July 4, 2020, subjects who underwent a recent national health check-up within 3 years were enrolled in this analysis. For the protection of personal information, personal identification was blinded and age was expressed as a categorical variable by 10 years. The detailed study protocol has been previously described [7, 15, 16] .

Attending physicians and medical experts performed the SARS-CoV-2 test, based on careful history taking for exposure to COVID-19, which was conducted by epidemic intelligence service officers. The institutional review board of the Korea University Medical Center approved the protocol of this study (2020AN0292). The flowchart of the study population is shown in Figure 1 .

COVID-19 infection was confirmed by a positive result of the SARS-CoV-2 test with realtime reverse transcriptase PCR analysis of nasopharyngeal swab cultures [17] . Case patients were defined as those with positive SARS-CoV-2 test results, and for each case patient, up to 10 exact age-and sex-matched random controls were randomly selected and assigned from the subjects who had been exposed to COVID-19, but with a negative result of the SARS-CoV-2 test.

The Korean NHIS provides public health check-ups for manual workers annually and all Koreans aged over 40 years biennially. The public health check-up investigated anthropometric parameters, medical history of cardiovascular risk factors, medications, metabolic laboratory tests, and lifestyle factors [18] . Attending physicians assessed basic physical examination parameters. Height, weight, waist circumference (WC), and systolic and diastolic blood pressures (SBP and DBP) were measured on the day of the health checkup. All subjects fasted for 8 h before blood sampling. The total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglyceride (TG), and fasting blood glucose (FBG) levels were measured. Underlying medical history was J o u r n a l P r e -p r o o f identified using health insurance claims data. The International Classification of Diseases, Tenth Revision was used for the operational definition of each disease, followed by a recently published article using the Korean National Health Information Database [19] .

MetS was defined in accordance with the guidelines of the International Diabetes Federation and the American Heart Association [20] . Subjects with at least three of the following metabolic risk factors were defined as having MetS: 1) central obesity (modified cutoff for Koreans) [21] : WC of ≥ 80 cm for women or ≥ 90 cm for men; 2) hypertension: SBP of ≥ 130 mmHg or DBP of ≥ 85 mmHg or use of anti-hypertensives; 3) low HDL cholesterol level: HDL cholesterol level of < 50 mg/dL for women or < 40 mg/dL for men; 4) elevated TG level: TG level of ≥ 150 mg/dL or use of lipid-lowering medications; and 5) prediabetes/diabetes mellitus: FBG level of ≥ 100 mg/dL or use of diabetes medications.

The primary outcome was positivity for SARS-CoV-2. The secondary outcome was severe COVID-19, which was defined as a composite of admission to intensive care units, use of mechanical ventilation, or COVID-19-related mortality. Admission to intensive care units was defined as claim for the charge of intensive care units on medical bills; use of mechanical ventilation as medical insurance claim codes for mechanical ventilation (M5850 to M5860); and COVID-19-related mortality as termination of isolation owing to death.

The exact matching for age, sex, and region was performed between the COVID-19 and control groups. For each case patient, up to 10 controls were randomly selected. Continuous variables were presented as means (standard deviations) and categorical variables as J o u r n a l P r e -p r o o f frequencies and percentages. Using a conditional logistic regression model for matched data, we compared the differences in the demographic, anthropometric, clinical, and laboratory variables between the case and control groups. The difference of characteristics between the mild to moderate and severe COVID-19 groups were evaluated by logistic regression model.

We performed a multiple logistic regression analysis to investigate the association between MetS and its components and COVID-19 related outcomes after adjusting for age, sex, region, socioeconomic status, smoking history, alcohol consumption, physical activity, cardiovascular diseases (ischemic heart disease, peripheral artery disease, stroke, and heart failure), atrial fibrillation, chronic kidney disease, cancer, and non-alcoholic fatty liver disease. The results for association were represented odds ratio and 95% confidence interval.

Multivariable restricted cubic splines with 5 knots were used to detect the possible nonlinear relationship between continuous variables and COVID-19 infection. All analyses were performed using the SAS Enterprise Guide software version 7.1 (SAS Institute, Cary, NC, USA) and R software version 4.0.2 (R Foundation for Statistical Computing, Vienna, Austria). Table 1 shows the demographic and clinical characteristics of 4,070 patients with COVID-19 infection and 27,618 age-and sex-matched controls. Age and the proportion of sex did not differ between the groups. The parameters of obesity, body mass index, and WC were higher in the COVID-19 group than in the control group. The COVID-19 group had a higher prevalence of diabetes mellitus and dyslipidemia and a lower prevalence of hypertension than the control group. In the comparison of the metabolic laboratory parameters between the COVID-19 and control groups, the mean LDL cholesterol level was higher, and the TG level J o u r n a l P r e -p r o o f was lower in the COVID-19 group. The mean levels of HDL cholesterol and FBG were not significantly different between the groups.

[ Table 1 ]

The impact of MetS and its components on the risk of COVID-19 infection was investigated. Table 2 [ Table 2 ]

Among each continuous variable of MetS, the WC and FBG level were significantly associated with a higher risk of COVID-19 infection (WC: aOR, 1.16; 95% CI, 1.11-1.21, P < 0.001; FBG level: aOR, 1.02; 95% CI, 1.01-1.03, P = 0.007). Figure 2 with a cubic spine curve reveals the linear association of the continuous WC and FBG level with a higher risk of COVID-19 infection. As shown in Figure 3 , the odds for the risk of COVID-19 infection did not increase according to the number of metabolic components (P for trend = 0.267).

Among the total of 4,070 patients with COVID-19, 293 patients with severe COVID-19 J o u r n a l P r e -p r o o f and 142 mortalities were identified. Table 3 and supplementary table show [ Table 3 ]

The linear association between the metabolic components and severe COVID-19 infection and mortality was also investigated. The FBG level was associated with a higher risk of severe COVID-19 infection (aOR, 1.05; 95% CI, 1.01-1.09, P = 0.015), and the WC was associated with a higher risk of mortality (aOR, 1.33; 95% CI, 1.03-1.72, P = 0.031). The association between the number of metabolic abnormalities and the risk of severe COVID-19 and mortality is shown in Figure 3 Amid the COVID-19 pandemic, it is a medical emergency to evaluate and stratify subjects with suspected COVID-19 infection. In the emergency medical situation, epidemiologic investigation is mainly emphasized for the quarantine and isolation of patients, and detailed medical history taking and physical examination for underlying cardiometabolic disorders are sometimes neglected. Therefore, the previously evaluated metabolic status in subjects with stable conditions is the novelty of our study.

Several studies have aimed to identify clinical and laboratory characteristics associated with severity [6, 22, 23] . However, studies focusing on metabolic profiles in patients with COVID-19 infection are rare. In a study of 287 patients with COVID-19, the prevalence of MetS was 66%, and MetS was associated with mortality and severity of COVID-19 [10] . In another multicenter retrospective study with 354 subjects, cardiometabolic disorders were J o u r n a l P r e -p r o o f associated with the severity of COVID-19 [11] . The findings of our study are consistent with those of previous studies. However, it is remarkable that these previous studies have included While the exact pathogenic mechanism by which MetS is associated with a higher risk of COVID-19 infection remains unclear, several potential mechanisms have been suggested.

Cardiometabolic disorders are characterized by enhanced low-grade systemic inflammation [24] . In middle-aged men with MetS, epicardial adipose tissue was associated with inflammation represented by the high-sensitivity C-reactive protein level and subclinical myocardial dysfunction, suggesting that the inflammatory activity of epicardial adipose tissue induced myocardial dysfunction [9] . In a predominantly non-Hispanic black population with MetS, inflammatory biomarkers predicted COVID-19 mortality [10] . Metabolic inflammation may facilitate COVID-19 infection and intensify the inflammatory cytokine storm [25] . ACE2 physiologically counteracts the renin-angiotensin-aldosterone system and serves as the cellular entry for SARS-CoV-2 [26] . The high expression of angiotensinconverting enzyme 2 (ACE2) in the lungs and kidneys explains the most common manifestations of severe COVID-19: acute respiratory distress syndrome and acute kidney injury [27] . In a diabetic animal model, ACE levels were upregulated mainly in the serum, lung, liver, and heart, and ACE2 levels were elevated mainly in the serum, pancreas, and liver J o u r n a l P r e -p r o o f [28] . In another animal model, a high fat diet increased adipose mRNA expression of angiotensinogen and ACE2. This induced a rise in BP, suggesting that adipocytes express ACE2, which is dysregulated in individuals with metabolic disorders [29] . The elevated expression of ACE2 could be a possible link between the dysmetabolic status and the severity of COVID-19. The data mining from recent publications on COVID-19 and diabetes mellitus also revealed that dysregulation of ACE2 indicates a higher risk of COVID-19 infection [30] .

organs. This suggests that COVID-19 not only impairs the respiratory system, but also the vascular endothelial system [31] . Endothelial dysfunction is one of the key pathological mechanisms of MetS; thus, chronic endothelial dysfunction may predispose an individual to poor COVID-19 related outcomes [32] . However, further studies are needed to clarify the pathophysiology between MetS and individual metabolic disorders, and the risk of a severe COVID-19 infection.

MetS is a constellation of cardiometabolic disorders. We investigated the impact of its individual components on COVID-19. The strong association of two metabolic components, central obesity and impaired fasting glucose, with COVID-19 is a novel finding of this study. Impaired glucose homeostasis and insulin resistance induce alveolar microvascular angiopathy and interstitial fibrosis. Thus, diabetic patients frequently experience symptoms of respiratory involvement and are at a higher risk of developing respiratory infections, such as pneumonia [33] . Furthermore, the plasma level of IL-6, which is an inflammatory and metabolic biomarker, was significantly higher in diabetic patients than in non-diabetic patients [34] . Visceral adipose tissue is a bioactive organ that secretes several proinflammatory cytokines [9] . Therefore, central obesity may impair the immune response to SARS-CoV-2. Furthermore, inflammatory cells, such as dendritic cells, macrophages, and J o u r n a l P r e -p r o o f cytotoxic T cells, accumulate in the adipose tissue and create an imbalance in the systemic immune cell population [35] . In obese individuals, their physique increases the chances of developing obstructive sleep apnea, and often induces the development of pulmonary hypertension and myocardial dysfunction [35] .

Previous epidemiological studies report hypertension as a common cardiovascular disorder in patients with COVID-19 [22] . Additionally, poor BP control is associated with a higher risk of developing severe COVID-19 [36] . In hypertensive patients, the activation of the renin-angiotensin-aldosterone system results in a pro-coagulant and inflammatory response, which predisposes patients to COVID-19 induced multi-organ failure [37] . However, there are limited studies reporting the linear association between BP levels and the development of COVID-19 related morbidity. In the current study, higher blood pressure was associated with a lower risk of COVID-19 infection. The increased risk of COVID-19 in subjects with lower BP may reflect unrecognized confounding factors such as cachexia or sarcopenia; however, the exact pathophysiology is unclear in the current study. Further studies investigating the linear association between BP levels and COVID-19 related morbidity are needed.

This study acknowledges some limitations that warrant discussion. This study has a crosssectional observational design, indicating that our findings only imply associations between MetS and COVID-19 infection, but not causality. We performed multiple logistic regression analyses; however, the effects of residual confounding factors may explain this association. 

The authors declare that they have no competing interests.

The institutional review board of the Korea University Medical Center approved the protocol of this study (2020AN0292). Informed consent was waived because the current study is based on retrospective analysis. The adjusted odds ratio with 95% confidence interval was demonstrated. The WC and FBG level were associated with a higher risk of COVID-19 infection.

COVID-19, coronavirus disease; WC, waist circumference; FBG, fasting blood glucose 

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The authors thank the participants in this study.J o u r n a l P r e -p r o o f