An Analysis on the Relationship between Obesity and COVID-19

Mortality

Xinyue Liu

Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada, N6A 3K7

Keywords: COVID-19/SARS-Cov-2, Covid-19 Mortality, Obesity, ER Stress, Immune Response, Lung Compliance.

Abstract: Since 2020, obesity and coronavirus disease 2019 (COVID-19) have become two of the most globally

challenged health and medical conditions, and the proportion of obese population and numbers of deaths for

COVID-19 continue to grow. Obesity has been claimed as a possible risk factor of COVID-19 infection and

mortality by the World Health Organization (WHO) and the World Obesity Federation. However, the

mechanisms about why obesity worsens COVID-19 symptoms have not been extensively and thoroughly

studied. So, literature research was performed in this study to propose the reason for declaring obesity as a

risk factor of severe COVID-19 and COVID-19 mortality. In conclusion, obesity induces endoplasmic

reticulum (ER) stress and vitamin D deficiency, which causes localized inflammation and impedes the

immune responses to SARS-CoV-2 infections. As ER stress state prolongs, unfolded protein response (UPR)

and apoptosis may be induced, which give rise to injury of tissues and organs. Although the obese population

has increased lung surfactants to balance their increased chest wall restraints, SARS-Cov-2 infections strongly

impair lung surfactants and enhance mechanical compression. These elements decrease lung compliance in

obese COVID-19 patients; thus, the patients experience difficulties of breathing. Therefore, the susceptibility

to the COVID-19 mortality increases. Further research is still needed to test these theoretical ideas and to

explore more on relationships between obesity and COVID-19.

1 INTRODUCTION

SARS-CoV-2, a new strain of coronavirus caused

COVID-19, has killed over 4 million deaths since the

beginning of 2020. Researches on SARS-CoV-2 and

COVID-19 are being carried out urgently in many

laboratories. It has been discovered that obesity

seems to be one of the risk factors for COVID-19

mortality (Cuschieri, and Grech 2020). A meta-

analysis based on over three million cases has shown

a significant increase in the COVID-19 mortality rate

of the obese population (Wang, Xu, Wang, Hou,

Feng, and Yang 2021). However, there is very little

research studying why obese COVID-19 patients are

more susceptible to death. Therefore, this study will

discuss the relationship between obesity and COVID-

19 mortality. Furthermore, brief descriptions of each

potential cause will be outlined respectively. It is

acknowledged that these three factors are not the only

factors that push obesity as a risk factor of COVID-

19 mortality, but this study will pay attention to the

theoretical analysis of how these three factors become

the main factors resulting in death in obese people.

For further research, experiments are needed to

confirm the proposed mechanisms and some potential

physical activity interventions that could be taken to

decrease COVID-19 mortality in the obese

population.

Previous researches have shown that both obesity

and virus infections induce ER stress in cells

(Banerjee, Czinn, Reiter, and Blanchard 2020, Zhou,

and Liu 2010). ER usually serves as a protein

modifying and secretory site. However, under ER

stress, unfolded and misfolded proteins are

accumulated in ER, which exceed the normal protein

concentration of 100 mg/ml and impede the functions

of ER (Wu, and Kaufman 2006). The ER stress will

activate unfolded protein response (UPR) to rapidly

decrease protein translation rate and initiate ER-

associated degradation (ERAD). Therefore, unfolded

and misfolded proteins are eliminated and the

survival rates of the cells are increased (Sureda,

Alizadeh, Nabavi, Berindan-Neagoe, Cismaru,

Jeandet, Łos, Clementi, Nabavi, and Ghavami 2020).

However, if the condition of ER stress prolongs and

the effort of survival fails, apoptosis will be activated

Liu, X.

An Analysis on the Relationship between Obesity and COVID-19 Mortality.

DOI: 10.5220/0011244900003438

In Proceedings of the 1st International Conference on Health Big Data and Intelligent Healthcare (ICHIH 2022), pages 215-220

ISBN: 978-989-758-596-8

215

Table 1. General information of included studies (Wang, Xu, Wang, Hou, Feng, and Yang 2021)

to respond to irreversible ER stress (Sureda,

Alizadeh, Nabavi, Berindan-Neagoe, Cismaru,

Jeandet, Łos, Clementi, Nabavi, and Ghavami 2020).

The immune response is essential for defending

against viral infections. Nevertheless, the previous

study has shown that obesity will chronically

attenuate immune response by impeding the synthesis

of vitamin D, which is required for the functions of

the immune system (Banerjee, Czinn, Reiter, and

Blanchard 2020). Additionally, obesity causes a

decrease in lung compliance by lipid accumulation,

increasing chest wall compression, and relative

surfactant deficiency (Inselman, Chander, and Spitzer

2004). The decreased lung compliance requires more

forces during lung inflation and deflation. All these

factors contribute to COVID-mortality.

2 OBESITY, COVID-19, AND ER

STRESS

ER stress and its following mechanisms contribute to

COVID-19 mortality in the obese population by

causing organ damage. Both obesity and SARS-CoV-

2 infections cause ER stress, activating the UPR, and

triggering adaptive programs. The accumulation of

misfolded and unfolded proteins is detected by an

ER-specific chaperone called binding immunoglobin

protein (BiP, 78kDa), which then activates the three

ER stress sensors: protein kinase-like ER kinase

(PERK), the inositol-requiring ER-to-nucleus signal

kinase 1 (IRE1), and activating transcription factor 6

(ATF6) (Zhou, and Liu 2010). These three routes will

contribute to solving the problem of ER stress by

increasing ER folding efficiency, degrading unfolded

and misfolded protein by ubiquitin-proteasome

pathway or autophagy-dependent pathway, and

producing apoptotic signals if necessary (Zhou, and

Liu 2010).

It has been observed that many tissues like

adipose tissues, the liver, and the pancreas undergo

ER stress because the homeostasis is not balanced in

obese patients (Zhou, and Liu 2010). The

inflammatory responses can be augmented by

reducing adiponectin gene expression; however,

adiponectin plays an important role in autophagy-

mediated degradation (Zhou, and Liu 2010). The

decrease in adiponectin is observed in both of obese

and COVID-19 patients. COVID-19 patients with a

higher body mass index (BMI, 32.8 ± 9.5) have a

lower survival rate (75%) than non-COVID-19

patients (BMI, 30.2 ± 5.4; survival rate, 82%). Also,

nearly 4 times lower adiponectin level was

discovered in COVID-19 patients with respiratory

failure compared to non-COVID-19 respiratory

failure (Kearns, Ahern, Patrie, Horton, Harris, and

Kadl 2021). The decreased adiponectin level results

in the ineffectiveness of degrading misfolded and

unfolded proteins and a prolonged the chronic

inflammatory condition, which is harmful to the

human body and causes many other systematic

problems.

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Figure 1. Schematic representation of how obesity increases COVID-19 mortality by activating ER stress and apoptosis.

SARS-CoV-2 causes inhibition of translational attenuation and adiponectin transcription, leading to prolonged ER stress and

tissue and organ damage.

In a recent study, researchers have discussed how

coronavirus causes ER stress and interrupts the UPR

(Banerjee, Czinn, Reiter, and Blanchard 2020). In the

cases of COVID-19, hypoxia, another factor causing

ER stress, has been observed (Sureda, Alizadeh,

Nabavi, Berindan-Neagoe, Cismaru, Jeandet, Łos,

Clementi, Nabavi, and Ghavami 2020). The levels of

reactive oxygen species and Ca

are disrupted in the

infected cells (Banerjee, Czinn, Reiter, and Blanchard

2020). These disturbances are activated by ER stress

and lead to signal transductions and activations of the

UPR. However, the researchers also suggested that

coronavirus can interrupt the host UPR by interacting

with the host’s UPR pathways (Banerjee, Czinn,

Reiter, and Blanchard 2020). The route of PERK,

which has antiviral activities, could be disrupted by

the virus via constant eukaryotic translation initiation

factor 2 alpha (eIF2α) phosphorylation. This

phosphorylation also blocks the translation of the X-

box binding protein 1 (XBP1) transcriptional factor,

which can attenuate the ERAD quality control

mechanism and lead to prolonged ER stress and

inflammation state. Apoptosis is activated by the

UPR and inflammatory signals are increased

dramatically if obese patients are invaded by SARS-

CoV-2. Obesity accelerates this process as the

apoptosis continues in inflammatory tissues and

damages organs (Sureda, Alizadeh, Nabavi,

Berindan-Neagoe, Cismaru, Jeandet, Łos, Clementi,

Nabavi, and Ghavami 2020). As a one of the leading

causes of death, organ damages have been observed

in many deaths of obese COVID-19 patients.

3 OBESITY, COVID-19, AND

IMMUNE RESPONSE

Obesity gives rise to the hindrance and attenuation of

immune response to SARS-CoV-2, which increases

the risk of COVID-19 mortality. If obese patients stay

in chronic inflammation for a long time, the

inflammation will spread from local to systematic

inflammation and from adipose cells to mass cells

such as pulmonary epithelial and endothelial cells

(Cuschieri, and Grech 2020). The inflammation in the

airway increases the susceptibility to be infected by

SARS-CoV-2 and have airway diseases. Besides,

systematic inflammation can disrupt blood flow, thus

inducing hypoxia and impairing immune cell

functions and responses (Cuschieri, and Grech 2020).

The chronic and systematic inflammation condition

also delays immune responses, which gives SARS-

An Analysis on the Relationship between Obesity and COVID-19 Mortality

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CoV-2 viruses more time to replicate and spread.

Besides, the severe medical issue called cytokine

storm occurs and causes fatal problems in the human

body (Hammock, Wang, Gilligan, and Panigrahy

2020). The quick multiplication of the virus and

cytokine storm augments the therapeutic difficulties.

Figure 2. Schematic representation of how obesity increases COVID-19 mortality by the combination of vitamin D deficiency

and delayed immune responses. This combination gives more possibility of cytokine storm occurrence and increases in

COVID-19 mortality.

It has been reported that vitamin D deficiency was

shown in most of the obese patients. This deficiency

may be caused by co-morbidities of obesity like liver

steatosis and hyperparathyroidism (Cuschieri, and

Grech 2020). Vitamin D takes an important role in the

“modulation of both the innate and the adaptive

immune responses” (Cuschieri, and Grech 2020).

Therefore, if the vitamin D is deficient, the immune

responses cannot be efficient, the susceptibility of the

spread of SARS-CoV-2 in the body is increased, and

cytokine storm are induced. Obese patients themself

have delayed immune responses additionally with

vitamin D deficiency further worsens the symptoms

of COVID-19.

It is commonly known that obese patients have

various co-morbidities such as type 2 diabetes

mellitus, hypertension, respiratory muscle function

impairment, and cardiovascular diseases. These co-

morbidities are linked with cell dysfunctions,

impaired immune system, and increased risk of

COVID-19 mortality. SARS-CoV-2 can easily enter

pancreatic and myocardial cells through angiotensin-

converting enzyme 2 (ACE2) receptors, which are

commonly found in many cell types and “responsible

for anti-inflammatory responses” (Cuschieri, and

Grech 2020). The disruption of ACE2 signaling

pathways results in acute metabolic dysfunctions like

hyperglycemia and acute cell injury. For this reason,

COVID-19 patients with obesity and its co-

morbidities have a 2 to 3 times higher rate of being in

intensive care unit (Cuschieri, and Grech 2020) and

thus an augmented risk of mortality.

4 OBESITY, COVID-19, AND

LUNG COMPLIANCE

Decreased lung compliance in obese patients by

increased chest wall compression and surfactant

deficiency conduce to augmented COVID-19

mortality. It has often been seen that obese patients

have faster and shallower breaths. This symptom is

due to the stiff chest wall caused by mechanical

compression, accumulated lipid around the

diaphragm and in the abdomen, and increased work

of respiratory muscles (Cuschieri, and Grech 2020,

Inselman, Chander, and Spitzer 2004) A 33%

increase of respiratory rates (RR) and 29% and 44%

decreases of dynamic and specific lung compliance

were observed in obese rat models with a 31%

increase in weights (Inselman, Chander, and Spitzer

2004). The respiratory muscles try to adapt and

compromise the decreased lung compliance and “the

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increased mechanical and metabolic requirements for

chest wall expansion” (Inselman, Chander, and

Spitzer 2004, Mahadev, Salome, Berend, and King,

2013). However, the respiratory muscles adaptions

are not enough to compromise the increased

mechanical compression. Adding to the problem, the

stiffness of respiratory muscles is increased and

consequently further narrows the airway by 42.6 ±

8.6% (Inselman, Chander, and Spitzer 2004)

(Inselman, Chander, and Spitzer 2004, Mahadev,

Salome, Berend, and King 2013). The narrower

airway is fatal for COVID-19 patients as they have

acute respiratory distress syndrome (ARDS), which

can further decrease blood oxygen levels and

deteriorate the symptoms of hypoxia. The reduced

chest wall compliance can increase dead space during

breathing and increase ventilation heterogeneity,

which may result in more severe pulmonary

dysfunctions. Besides, the continued airway

inflammation and airway narrowing are associated

with surfactant dysfunction (Mahadev, Salome,

Berend, and King 2013).

Figure 3. Dynamic and specific compliance in control and obese rats at age 8 weeks. Values are means ± SE. *p < 0.05; ** p

< 0.001. Both dynamic and specific lung compliance are reduced in obese rats (n = 16) when compared with control rats (n

= 14) (Inselman, Chander, and Spitzer 2004).

To compromise increased chest wall

compressions, a slight increase in lung surfactant

levels of large aggregates (14%) and small aggregates

(35%) has been observed in obese rat models

(Inselman, Chander, and Spitzer 2004). However,

these changes can result in a deficiency of lung

surfactants and impairment of lung functions. As

COVID-19 may result in lung injury, the surfactant

can progressively aggregate and lead to “a loss of

overall surface activity in the lung” (Inselman,

Chander, and Spitzer 2004) and lung instability

(Schousboe, Wiese, Heiring, Verder, Poorisrisak,

Verder, and Nielsen 2020)]. The lung surfactant

deficiency can be fatal because it increases the

difficulty of breathing in obese COVID-19 patients

and further augments COVID-19 severity. It has been

monitored that if COVID-19 patients’ lung

compliances further decrease to 42 ± 3 mL/cmH2O

and the breaths become shallower, it is likely to cause

hyperinflation that gives rise to more severe diseases

and deaths (Roesthuis, van den Berg, and van der

Hoeven 2020).

5 CONCLUSIONS

This study has discussed the relationship between

obesity and COVID-19 mortality and proposed three

possible mechanisms of how obesity deteriorate the

symptoms of COVID-19 symptoms. Obese

individuals are more susceptible to death from

COVID-19 because of ER stress-mediated apoptoses,

defective immune responses, and decreased lung

compliances. These three factors accelerate the

process and severity of COVID-19. Obesity causes

prolonged inflammation and ER stress. These two

conditions expedite the action of driving degradation

machinery UPR to activate apoptotic mechanisms.

Along with SARS-CoV-2 infections, acute organ

damage will be induced in the obese population. Also,

obese people have dysfunctional immune systems

due to vitamin D deficiency, cytokine storms, and

disrupted ACE2 signal pathways. These hindered

immune responses increase therapeutic difficulties.

Lastly, obesity results in a decreased lung compliance

and lung volume by increasing chest wall

compression and lung surfactant dysfunction.

COVID-19 patients may have lung injury which

accelerates the aggregation of lung surfactants,

leading to lung instability and dysfunctions, and then

An Analysis on the Relationship between Obesity and COVID-19 Mortality

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contributing to COVID-19 mortality. These factors

should be noticed when treating obese COVID-19

patients. Obesity, a chronic and metabolic disease,

should be put more attention on because it not only

causes a wide range of co-morbidities but may be

fatal especially when people are invaded by viruses.

This study may have important implications

regarding to the development of valuable approaches

to reduce COVID-19 mortality in the obese

population. Future studies and experiments are

needed to test whether these three reasons primarily

cause increased COVID-19 mortality in the obese

population. Also, efficient treatments and

interventions can be considered based on these three

factors.

ACKNOWLEDGMENTS

The author is grateful to Dr. Shibin Cheng (Brown

University) and Xinyue Qiu (Yale University) for

their instructions and support. The author

acknowledges for creating figures using Sketchbook

application and Microsoft PowerPoint software.

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