key: cord-0730941-t3wjpagu
authors: Ghoneim, Sara; Butt, Muhammad Umer; Hamid, Osama; Shah, Aun; Asaad, Imad
title: The incidence of COVID-19 in patients with metabolic syndrome and non-alcoholic steatohepatitis: A population-based study()
date: 2020-09-09
journal: Metabol Open
DOI: 10.1016/j.metop.2020.100057
sha: 80e4eec9c1ed1b5fdc329114536b55488d0734c8
doc_id: 730941
cord_uid: t3wjpagu

BACKGROUND: The novel coronavirus disease (COVID-19) emerged from China in 2019 and rapidly spread worldwide. Patients with metabolic comorbid conditions are more susceptible to infection by COVID-19. Metabolic syndrome is a constellation of interlinked metabolic risk factors that predispose patients to increased risk of complications. Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and non-alcoholic steatohepatitis (NASH) is the aggressive form of NAFLD. OBJECTIVE: The aim of this study is to determine the relationship between metabolic syndrome components and the risk of COVID-19. METHODS: We reviewed data from a large commercial database (Explorys IBM) that aggregates electronic health records from 26 large nationwide healthcare systems. Using systemized nomenclature of clinical medical terms (SNOMED-CT), we identified adults with the diagnosis of metabolic syndrome and its individual components from 1999-2019. We included patients with the diagnosis of COVID-19 from December 2019 to May 2020. Comorbidities known to be associated with COVID-19 and metabolic syndrome such as obesity, diabetes mellitus, dyslipidemia, smoking, male gender, African American, and hypertension were collected. Univariable and multivariable analyses were performed to investigate whether metabolic syndrome or its individual components are independently associated with the risk of COVID-19. RESULTS: Out of 61.4 million active adult patients in the database, 8,885 (0.01%) had documented COVID-19. The cumulative incidence of COVID-19 was higher if metabolic syndrome was the primary diagnosis (0.10% vs 0.01% %, OR 7.00 [6.11–8.01]). The adjusted odds (aOR) of having COVID-19 was higher in patients if they were African Americans (OR 7.45 [7.14- 7.77]), hypertensive (aOR 2.53 [2.40 - 2.68]), obese (aOR 2.20 [2.10 2.32]), diabetic (aOR 1.41 [1.33- 1.48]) hyperlipidemic (OR 1.70 [1.56-1.74]) or diagnosed with NASH (OR 4.93 [4.05- 6.00]). There was a slight decrease in adjusted odds of having COVID-19 in males as compared to females (aOR 0.88 [0.84- 0.92]). CONCLUSION: The incidence of COVID-19 in patients with metabolic syndrome is high. Among all comorbid metabolic conditions, NASH had the strongest association with COVID-19.

The novel coronavirus disease (COVID- 19) 

The aim of this study is to determine the relationship between metabolic syndrome components and the risk of COVID-19.

We reviewed data from a large commercial database (Explorys IBM) that aggregates electronic health records from 26 large nationwide healthcare systems. Using systemized nomenclature of clinical medical terms (SNOMED-CT), we identified adults with the diagnosis of metabolic syndrome and its individual components from 1999-

In late December 2019, the People's Republic of China (Wuhan City of Hubei Province) observed an increased number of pneumonia cases of unknown etiology later confirmed by Chinese authorities to be caused by Coronavirus Disease 2019 (COVID- 19) . Subsequently, the virus was officially named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1, 2] This novel virus took China by storm and transcended international borders in no time reaching the world tally of 4,731,458 confirmed cases and 316,169 deaths by mid-May [2] . To date this virus has been transmitted to 216 countries. Currently, the United States has the highest number of confirmed cases 5,119,711 and reported deaths 163,651 [2] . The SARS-CoV-2 belongs to a group of B-coronavirus which is an enveloped positive-sense RNA virus of subgenus sarbecovirus [3] . It can easily move across species through the spike glycoprotein S1 that binds to angiotensin converting enzyme 2 (ACE2) receptor present on host cells. [4, 5] . This receptor is highly expressed in respiratory and gastrointestinal epithelial cells [5] . The clinical manifestations of COVID-19 are highly variable. Up to 74% of patients initially present with atypical pneumonia [6, 7] . Approximately 50% of patients develop hypoxia and 26% progress to acute respiratory distress syndrome (ARDS) requiring mechanical ventilation [7, 8] . According to previous research, the presence of comorbidities increases the mortality risk with cardiac disease and diabetes being the most important components to predict adverse outcomes [9] . The US Centers for Disease Control (CDC) reported in their Morbidity and Mortality Weekly Report on April 17 that among those with comorbid conditions, the most common were hypertension (49.7%), obesity (48.3%) diabetes mellitus (28.3%) and cardiovascular J o u r n a l P r e -p r o o f disease (27.8%) [10] . Reported data by race/ethnicity indicate that African American individuals bear a disproportionate burden of COVID-19 related outcomes [11] .

Metabolic syndrome (MetS) also known as syndrome X is a global problem. This syndrome feeds into the spread of diseases such as diabetes mellitus, hypertension and coronary disease. Non-alcoholic fatty liver disease is part of and victim of the global metabolic derangement seen with this condition [12] . Although a relationship between metabolic syndrome and COVID-19 severity might exist, It's currently unclear whether NASH is associated with a higher risk of SARS-CoV-2 infection. Our primary objective with this study was to identify whether metabolic syndrome or its individual components are independently associated with the diagnosis of COVID-19. Our secondary objective was to investigate whether a relationship exists between NASH and COVID-19.

This is a retrospective analysis of a large electronic health record (EHR)-based Board deemed studies using Explorys, as the dataset of record, to be exempt from approval because all patient information is de-identified. Explorys protects patient confidentiality by approximating each population count to 10. All counts between 0 and 10 are treated equally. For the purpose of this study, counts between 0 and 10 were approximated to be five [14] .

Adult subjects (age above 18 years) with active electronic health records since 1999 were identified using the search tool in Explorys. Using the SNOMED-CT diagnosis "Non-alcoholic steatohepatitis", we identified patients who were diagnosed with NASH between 1999-2020. Patients with the diagnosis of "fatty liver disease", "alcoholic hepatitis" and "alcoholic fatty liver disease" were excluded. We searched for metabolic syndrome using the SNOMED-CT diagnosis "Metabolic Syndrome". Patients with COVID-19 were identified by the SNOMED-CT diagnosis for coronavirus infection for the period of December 2019 to May 2020. All sub-diagnoses of COVID-19 including "pneumonia and "severe acute respiratory syndrome" were included. Controls were classified as those patients without the diagnosis of COVID-19. For our analysis, we identified cohorts of patients with and without COVID-19. It was not possible to perform propensity-score matching because this database only provides population-level data and not individual cases.

We collected cross-sectional information on patient demographics such as gender, race, and comorbidities known to be associated with metabolic syndrome such hypertension, diabetes, obesity and dyslipidemia by searching the database for their respective SNOMED-CT terms. Primary outcome of interest was COVID-19 cumulative incidence associated with different risk factors.

To assess the association between COVID-19 and patient demographic and metabolic characteristics we divided the whole cohort of patients into COVID-19 infected and non-COVID infected patients.

The cumulative incidence of COVID-19 since the start of the pandemic (December 2020 to May 2020) was calculated by dividing the number of patients diagnosed with COVID-19 by total number of patients each risk group. Categorical variables are presented as numbers and percentages and were compared using the Pearson χ2 test. Odds ratios are presented with 95% confidence intervals (CI). Univariate binary logistic model was constructed using COVID-19 as dependent variable and other variables as independent variables. To adjust for possible confounding, a multivariable model adjusting for all covariates mentioned in univariate variables were added. Independence among covariate risk factors was assessed using the variance inflating factor (VIF) with cut-off of significant collinearity set at VIF > 1.5. "Goodness-of-fit" was assessed for all regression models using the Hosmer-Lemeshow test, with P > 0.05 indicating good fit.

All statistical analysis was done using SAS version 9.4 (SAS Inst., Cary, NC).

Significance was defined as the 2-tailed value of P<0.05.

This study was exempt from approval by the Case Western Reserve University at Metrohealth Medical Center Institutional Review Board as the dataset obtained from Explorys platform is de-identified. 

We report a strong positive association between metabolic syndrome and the risk of COVID-19. To date, this is the first US-based large database study that looked at the relationship between metabolic syndrome, its individual components and SARS-CoV-2 infection. Individuals with diabetes mellitus, hypertension, and obesity have been shown to have higher morbidity and mortality from infections with COVID-19.

The cumulative prevalence of hypertension among our study population was 21%. Similar to our findings, the prevalence of hypertension among US adults was recently estimated to be 29% [15] . Furthermore, in our COVID-19 cohort, approximately 60% had a diagnosis of essential hypertension. Prior studies have also confirmed a higher incidence rate of hypertension among patients with COVID-19 [16] . Of all the metabolic syndrome components adjusted for in our model, the incidence of COVID-19 was highest among the hypertensive group. The frequency with which COVID-19 patients are hypertensive may not be entirely surprising since older patients appear to be at a particularly higher risk of infection and are also the ones most likely to be hypertensive. It is also unclear whether uncontrolled blood pressure is a risk factor for acquiring COVID-19 or whether controlled blood pressure among patients with hypertension is or is not a risk factor. Unfortunately, we are unable to distinguish J o u r n a l P r e -p r o o f between controlled and uncontrolled hypertension. But our observation raises the question about the susceptibility of hypertensive patients to SARS-CoV-2.

There was a strong association between dyslipidemia and COVID-19.

Dyslipidemia was the second most common diagnosis in the COVID-19 cohort after hypertension with a reported incidence rate of 46.8%. Little data exists on whether dyslipidemia predisposes individuals to a higher risk of SARS-CoV-2. One proposed mechanism may involve the pro-inflammatory response induced by accumulated cholesterol in atherosclerotic plaques. ACE2 receptor is also highly expressed by activated macrophages [17] . The findings of our study therefore support the adverse association between dyslipidemia and infection by SARS-CoV-2.

Subjects with diabetes had an overall higher risk of COVID-19 than those without, possibly attributed to a dysfunctional innate immune system. Potential mechanisms suggested to increase the susceptibility of diabetic patients to SARS-CoV-Obesity has been shown to be an independent risk factor for infection by this novel virus. In our cohort, obesity was strongly associated with COVID-19 and the third most prevalent metabolic risk factor after dyslipidemia and hypertension. A disproportionate number of obese patients with COVID-19 should be anticipated since it has been previously documented for different viral pathogens including influenza [24] [25] [26] [27] . Although the exact mechanism by which obese patients might be more susceptible to COVID-19 infection is not yet defined, several parameters play a role. First patients with obesity have altered respiratory physiology including reduced functional residual capacity and expiratory reserve volume as well as hypoxemia and ventilation/perfusion abnormalities [25] . Second, obesity is associated with impaired immune response [28] .

Third, ACE2 enzyme expression in adipose tissue shows high affinity for SARS-CoV-2 and may contribute to the significant association between this metabolic risk factor and COVID-19 [29] .

There is limited data linking pre-existing liver disease with SARS-CoV-2 infection.

NAFLD is unambiguously related to increased liver-related and all-cause mortality [30] .

The progression of NAFLD to NASH is mirrored by increased activation of hepatic and systemic inflammatory cascades. Only recently has NASH been accepted as an inflammatory disorder [31] . Circulating inflammatory markers are more pronounced in patients with NASH compared to those with simple steatosis. Macrophages in hepatic parenchyma and adipose tissue release proinflammatory cytokines supporting liver injury and progression of NAFLD. Of all the metabolic risk factors investigated in this study, having NASH had the strongest association with the incidence of COVID-19.

Whether the heightened inflammatory response seen in NASH increases the susceptibility to SARS-CoV-2 remains to be explored.

The cumulative incidence of COVID-19 was higher in women than in men (60% vs 40%). In Switzerland, early incidence reports documented higher cases of COVID-19 in women [32] . However, across all countries, prevalence studies have shown men with COVID-19 are at more risk of worse outcomes and death [32] . In our univariate analysis, males and females had comparable susceptibility to COVID-19. This is in line with what is currently reported by CDC [10] . The mechanisms accounting for the sex imbalance with regards to reported cases and case fatality are currently unknown and it's unclear whether gender is a risk factor for COVID-19. More clinical and basic research investigating the role of gender in the susceptibility to COVID-19 is needed in the future.

Preliminary prevalence reports have unmasked the racial disparities that exist in COVID-19 incidence and mortality [33] . Among all variables analyzed in our study, being African American had the strongest association with COVID-19. In Chicago alone, 70% of all COVID-19 deaths were seen in African Americans who only represent 29% of the city's population [33] . It is unclear if African Americans are infected more often, but social determinants of health appear to be powerful predictors of SARS-CoV-2 infectivity and mortality. African Americans are more likely to carry out high risk essential jobs, including low wage jobs that cannot be done remotely [33] . They are more likely to have co-morbid conditions such as hypertension, obesity, or diabetes.

They are also more likely to be uninsured, more segregated and in concentrated poverty ultimately leading to higher COVID-19 susceptibility. Even after adjusting for J o u r n a l P r e -p r o o f serious co-morbid conditions, we observed the highest association among this race and COVID-19. In view of our findings, and as more data emerges, surveillance data on racial disparities in COVID-19 incidence and mortality will be critical to guide policy, health care and intervention efforts and mitigate the adverse consequences of this disease on the vulnerable populations.

An important strength of our study is that we used a large national database and reported data on over 65 million active adult subjects. We also provided comprehensive epidemiological information on the risk of COVID-19 in patients with serious metabolic risk factors. Our results are therefore consistent with established data suggesting that metabolic syndrome and its individual components might be significantly associated with SARS-CoV-2 infection. We also report a new association between NASH and the COVID-19 that is yet to be explored in literature.

There are several limitations to this study that should be addressed.

Observational studies preclude us from addressing causality. Due to the design of Explorys, we could not establish temporal relationships between the duration of metabolic risk factors, their severity and impact of interventions on the associated risk of COVID-19. Second, being a retrospective database, patient-related information and data may be missing or incomplete. Moreover, the prevalence and natural disease progression of NAFLD is difficult to estimate as accurate diagnosis requires tissue analysis. The prevalence of NASH is estimated to be between 1.5%-6.45% based on a few biopsy series [34] . The reported prevalence of NASH in our study was 0.09%. We excluded those with the diagnosis of fatty liver disease to increase the accuracy in our reporting; as the latter may be caused by drugs, viruses or alcohol. But even though the J o u r n a l P r e -p r o o f NASH population was underrepresented in the current study, we still saw a significant relationship with COVID-19 independent of other metabolic risk factors. Finally, as this is a retrospective study reliant on diagnosed SNOMED-CT codes, it is impossible to verify the accuracy of diagnoses and it is prone to coding errors. These limitations however are counterbalanced by a larger sample size and absence of reporting bias which usually results from selective publications from specialized centers.

In our large US-based cohort study, we found the cumulative incidence of COVID-19 to be the highest among patients with metabolic syndrome and its individual components. The findings of our study support the adverse association between this syndrome and SARS-CoV-2. NASH had the strongest relationship with COVID-19.

Although the full pathogenic scenario is far to be elucidated, this association envisage the possibility of a complex bidirectional interface between SARS-CoV-2 and the distal inflammatory pathways perpetuated by NASH. A better understanding of the mechanisms underscoring COVID-19 affinity for patients with metabolic syndrome is needed and demonstrates the importance of care with this risk group in prophylaxis, monitoring and treatment. 

Pattern of early human-to-human transmission of Wuhan

WHO, 2020b. Coronavirus disease 2019

A novel coronavirus from patients with pneumonia in China

The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak -an update on the status

Covid-19 and the digestive system

Clinical and laboratory features of severe acute respiratory syndrome vis-à-vis onset of fever

Characteristic features and outcomes of severe acute respiratory syndrome intensive care unit patients

Clinical course and outcomes of critically ill patients with SARS-COV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study

Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention

Hospitalization rates and characteristics of patients hospitalized with laboratory-confirmed coronavirus disease 2019-COVID-NET, 14 states

COVID-19 and African Americans

Nonalcoholic fatty liver disease and fibrosis associated with increased risk of cardiovascular events in a prospective study

Hypertension prevalence and control among adults: United States, 2011-2014pdf icon

Characterization of ACE and ACE2 Expression within Different Organs of the NOD Mouse

COVID-19, hypertension and cardiovascular diseases: Should we change the therapy?

SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is enriched in specific cell subsets across tissues

ACE and ACE2 activity in diabetic mice

COVID-19 pandemic, coronaviruses, and diabetes mellitus

Activation of the GLP-1 receptor by liraglutide increases ACE2 expression, reversing right ventricle hypertrophy, and improving the production of SP-A and SP-B in the lungs of Type 1 diabetes rats

Tissue specific up regulation of ACE2 in rabbit model of atherosclerosis by atorvastatin: role of epigenetic histone modifications

Acute respiratory distress syndrome leads to reduced ratio of ACE/ACE2 activities and is prevented by angiotensin-(1-7) or an angiotensin II receptor antagonist

Pioglitazone upregulates angiotensin converting enzyme 2 expression in insulin-sensitive tissues in rats with high-fat diet-induced nonalcoholic steatohepatitis

Obesity and respiratory hospitalizations during influenza seasons in Ontario, Canada: a cohort study

Underweight, overweight, and obesity as independent risk factors for hospitalization in adults and children from influenza and other respiratory viruses. Influenza Other Respir Viruses

Obesity and risk of respiratory tract infections: results of an infection-diary based cohort study

Altered respiratory physiology in obesity

Obesity and the risk and outcome of infection

Obesity reviews: an official journal of the international association for the study of obesity

NASH is an Inflammatory Disorder: Pathogenic, Prognostic and Therapeutic Implications

Increased overall mortality and liver-related mortality in non-alcoholic fatty liver disease

Impact of sex and gender on COVID-19 outcomes in Europe

African Americans may be dying from COVID-19 at a higher rate

The epidemiology of nonalcoholic steatohepatitis