INTRODUCTION

Evidence from different studies have supported the notion that obesity increases the severity and mortality rate of COVID-19 patients. The co-morbidities associated with COVID-19 hospital admission are fairly similar to those associated with many other serious infectious illnesses that require hospital admission or ICU level care (^{Petrilli et al., 2020}). Nevertheless, it is appreciable that obesity is a risk factor for many COVID-19 complications, such as ICU admission, tracheal intubation, hospitalization and death.

The World Health Organization identifies non- communicable disorders such as obesity as a leading risk fac- tor resulting in critical illness with COVID-19. Obesity is a significant potential risk factor that was not illustrated in initial Chinese reports on COVID-19 patients circumstances which could probably explain why COVID-19 mortality rate is much higher in countries with higher obesity prevalence, such as Italy, relative to China and Japan (^{Rebelos et al., 2020}). There are numerous biochemical pathways by which COVID-19 can affect people with obesity, which is well reported to be pro-inflammatory condition (^{Caër et al., 2017}). Some of these mechanisms are chronic inflammation and activation of ACE2-RAS system which are caused by excess adipose tissue in obese people.

With regard to the pathophysiological mechanism connecting obesity and COVID-19, evidence in subjects with H1N1 infection in a research, showed that individuals with obesity have a more intense release of IL-8, compared to individuals with normal body weight, which is an important chemokine for a mechanism involved in the response to infection (^{Hagau et al., 2010}).

Fatty liver disease, which was formerly renamed Metabolic Associated Fatty Liver Disease (MAFLD), impacts 25 % of the world’s population. Recent studies showed that MAFLD patients with SARS-CoV-2 infection increases the severity of COVID-19 respiratory illness by up to 4-6 fold (^{Ji et al., 2020}a) while the severity of the respiratory illness in obese patients without MAFLD increases by up to 3 fold (^{Zheng et al., 2020}). There is also an increased risk of MAFLD progression to Non-Alcoholic SteatoHepatitis (NASH) in the long-term (^{Prins & Olinga, 2020}). This study aims to examine the potential association between obesity, hepatic steatosis and the severity of COVID-19 illness.

MATERIAL AND METHOD

Data was collected for consecutive laboratory- confirmed COVID-19 patients admitted at the hospital devoted completely by Jordanian Government to isolate and treat COVID-19 patients (Prince Hamza Hospital - PHH) between March and May 2020. Ethical Permission for the study was granted by Faculty of Medicine at Hashemite University. Patients younger than 15years were excluded. COVID-19 was diagnosed as a positive result by polymerase chain reaction (PCR) assay of oropharyngeal swab specimens.

Demographic information and past medical history were obtained, and blood samples were tested on the first day of hospital admission. A case was considered as a ‘Severe COVID-19’ case if the patient was admitted to the Intensive Care Unit (ICU). Hospital policy for admitting COVID-19 patients to the ICU included the following indications: Respiratory or cardiac arrests, respiratory rate ≥40 or ≤8 breaths/min, oxygen saturation < 90 % on 50 % oxygen, respiratory acidosis, pulse rate < 40 or >140 beats/min, Systolic blood pressure <90 mm Hg, sudden fall in level of consciousness and two or more organ failures.

Obesity was assessed by Body mass index (BMI). Patients with BMI ³30 were considered obese. The presence of hepatic steatosis was confirmed by a liver CT scan. The Fibrosis-4 score was calculated to estimate the degree of fibrosis in the liver by a formula that incorporated values for age, Liver enzymes (AST, ALT) and platelet count (^{Sterling et al., 2006}).

The liver CT scan used in this study was non-enhanced, which has been found to be better at measuring the hepatic Hounsfield unit and presence of steatosis (^{Wells et al., 2016}). Measurement of attenuation of liver only on unenhanced CT scans is best for prediction of pathologic fat content (^{Kodama et al., 2007}).

CT scan diagnostic criteria for steatosis are liver attenuation of at least 10 Hounsfield Units (HU) less than that of the spleen or absolute liver attenuation of less than 40 HU. Unenhanced CT scans have a sensitivity for steatosis ranging from 43 to 95 % and a specificity of 90-100 % (Wells et al.).

Continuous variables were expressed as mean (range). Differences between categorical variables were examined with the chi-squared test or the Fisher's exact test as appropriate.

The association between exposure factors such as obesity, liver steatosis and liver steatosis among obese patient vs. the outcome of COVID-19 severity was assessed by using the Spearman bivariate correlation coefficient with significance at 0.05 % level (2 tailed).

The Odds Ratio (OR) between exposure factors such as obesity, liver steatosis and liver steatosis among obese patient vs. the outcome of our interest (COVID-19 severity) was assessed by using the binary logistic regression. The Odds Ratio adjusted for covariates such as age, sex, smoking, diabetes and hypertension was assessed by multinomial logistic regression analysis.

Statistical analyses were two-sided and significance was set at p< 0.05. All statistical tests were performed using SPSS version 23.0 (SPSS Inc., Chicago, USA).

Granted ethical Permission was obtained from Hashemite University-Jordan.

RESULTS

Data was collected for 302 patients. 72 patients younger than 15 years were excluded. 230 patients aged between 15 and 84 years were enrolled in this study. Tables I and II show their characteristic.

The presence of obesity was associated with an around 290 fold increased risk of severe COVID-19 illness. This association remained significant even after adjusting for age, sex, smoking, diabetes and hypertension. The presence of hepatic steatosis was associated with an around 17 fold increased risk of severe COVID-19 illness. This association remained significant even after adjusting for age, sex but not for smoking, diabetes and hypertension. The presence of both obesity and liver steatosis together was associated with an over 300 fold increased risk of severe COVID-19 illness. This association remained significant even after adjusting for age, sex, smoking, diabetes and hypertension. Table III. The association between hepatic steatosis or obesity, or both and COVID-19 illness severity.

Table I Demographic data, co morbidities, ICU admissions and mortality. 

Table II Biochemical and radiological findings and ICU admissions. 

Table III Multivariable-adjusted association between hepatic steatosis or obesity, or both (as exposure) and COVID-19 severity (as the outcome). 

DISCUSSION

Jordanian health authority policy regarding management of COVID-19 pandemic was to admit and isolate every patient with positive PCR COVID-19 regardless of symptoms or clinical condition in early 2020. Many individuals were tested for COVID-19 only because they were in close contact with COVID-19 patients. Therefore most patients were asymptomatic. This also explains why the laboratory tests on admission for most patients were within normal range. Most patients did not require more than paracetamol as treatment.

Wuhan's results demonstrate that hypertension (30%), diabetes (22 %), and coronary artery disease (22 %), all of which are more prevalent in people with obesity, were the most common co morbidities in patients needing hospitalization (^{Chiappetta et al., 2020}). The percentage of these co-morbidities was lower by about 50 % in our cohort of patients: with hypertension (17 %), diabetes (11 %), cardiac disease (6 %). However, the ICU patient prevalence of the above mentioned co-morbidities was higher: hypertension (100 %), diabetic (58 %) and cardiac disease (42 %).

Furthermore, BMI positively and strongly correlates with ICU admission increasing the risk of severe COVID- 19 illness to around 300 folds. This is consistent with other published results (^{Portincasa et al., 2020}). Additionally, the presence of hepatic steatosis increased the risk of severe COVID-19 illness to around 17 folds. The presence of hepatic steatosis among obese patient increased the risk to over 300 folds.

A large New York City cohort report revealed that obesity (BMI 30-40) is strongly correlated with a progression to serious illness with a relatively increased odds ratio than any cardiovascular or pulmonary condition (Petrilli et al.). Another study in the early days of the Italian epidemic demonstrated that the Case-fatality rate of patients hospitalized with COVID-19 was about 20 %. Older age, obesity and disease severity upon admission were factors related with increased risk of death (^{Giacomelli et al., 2020}). Even after adjustment for other possibly confounding factors such as age, gender, race and troponin levels, obesity was reported to be associated with significantly higher levels of ICU admission and mortality in hospitals (^{Palaiodimos et al., 2020}). Higher demand for assisted ventilation beyond pure oxygen support (Invasive Mechanical Ventilation or Non-Invasive Ventilation) and increased admission to intensive or semi-intensive care units has been identified in patients in overweight and obesity (^{Busetto et al., 2020}).

A large study in UK assessed liver fat and liver fibro- inflammatory disease by MRI. The study concluded that hepatic steatosis, rather than underlying obesity, increases the risk of infection and hospitalization for COVID-19 (^{Zhu et al., 2021}). Another study showed higher frequency of hepatic steatosis at CTscan among COVID-19-positive patients (^{Medeiros et al., 2020}). Furthermore, a computed tomography study demonstrated that hepatic steatosis is an independent risk factor for severe disease in patients with COVID-19 (^{Palomar-Lever et al., 2020}). On the contrary, a study concluded that the prevalence of steatosis and significant liver fibrosis was high in COVID-19 patients but was not associated with clinical outcomes (^{Sacks et al., 2018}).

A study titled “Liver Fibrosis Index FIB-4 Is Associated with Mortality in COVID-19” illustrated that FIB-4 is associated with mortality in COVID-19, independent of underlying conditions including liver diseases. The study recommended FIB-4 as a simple and inexpensive approach to risk-stratify individuals with COVID-19 (Li et al., 2020).

Our study showed rather a weak correlation between FIB-4 and ICU admission. Additional studies are needed to confirm these findings and to better understand the underlying mechanisms for why the association is greater in those with obesity.

Several reports indicate that obesity may be a very significant consideration in younger people (^{Lighter et al., 2020}; ^{Klang et al., 2020}). A report of 3,615 New York patients revealed that obesity was strongly correlated with hospital and ICU admittance for patients under 60 years of age (Lighter et al.). Another study showed that hospitalized patients younger than 50 with morbid obesity are more likely to die from COVID-19. This is particularly relevant in the western world where obesity rates are high. In the same context, the findings of another study found a greater prevalence of obesity in younger hospitalized patients (Klang et al.).

This is similar to what is suggested by literature. Data suggests a viral shedding time 5 days longer and abnormal liver function x7 folds in patients with MAFLD. (^{Ji et al., 2020}a) There is an increased risk of symptomatic infection in MALFD patients (Ji et al., 2020b).

Most patients in this cohort did not have symptoms and did not require treatment or antiviral medication. Therefore this could be the reason for the generally unaltered liver function enzymes.

Some limitations of this study should be recognized. While the liver was assessed by CT scan for severe steatosis, patients included in our study did not undergo liver biopsy, thus COVID-19 severity in relation to liver histology could not be assessed.

Another common characteristic of obesity is vitamin D deficiency, which raises the risk of bacterial infections and impairs the immunity response (^{Bouillon et al., 2019}) Vitamin D has several mechanisms by which it eliminates the chance of microbial infection and death according to an analysis of the role of vitamin D in lowering the risk of common cold, which divides these mechanisms into three groups: physical barrier, cellular natural immunity and adaptive immunity (^{Rondanelli et al., 2018}). Level of Vitamin D was not tested in patients in this study.

CONCLUSIONS

BMI remained the most noticeable factor that strongly correlated with COVID-19 severity. Obesity even in the absence of hepatic steatosis greatly increased the risk for severe COVID-19. This association remained significant after adjusting for likely confounders. The presence of liver steatosis even in non-obese patients increased the risk for severe COVID-19 but to a much lesser degree compared to obesity. The risk of steatosis to COVID-19 severity was greater in those with, than those without obesity. This association also remained significant after adjusting for likely confounders.