Am J Physiol Endocrinol Metab. 2020 Jul 1; 319(1): E105–E109.

Published online 2020 May 27. doi: 10.1152/ajpendo.00198.2020

PMCID: PMC7322508
PMID: 32459524

Obesity and COVID-19: immune and metabolic

derangement as a possible link to adverse clinical
outcomes
Emmanouil Korakas,1 Ignatios Ikonomidis,2 Foteini Kousathana,1 Konstantinos
Balampanis,1 Aikaterini Kountouri,1 Athanasios Raptis,1 Lina Palaiodimou,3 Alexander
Kokkinos,4 and Vaia Lambadiari 1

Author information Article notes Copyright and License information Disclaimer

This article has been cited by other articles in PMC.

Abstract
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INTRODUCTION
Obesity has long been associated with worse prognosis of viral infections (30).
Higher mortality rates and a prolonged, more severe clinical course was observed in
obese people in the 1957–1960 “Asian” and the 1968 “Hong Kong” influenzas
(22, 39), whereas more recently obesity was recognized as a predisposing factor for
worse clinical outcomes and death in the 2009 H1N1 pandemic. In accordance with
these previous results, recent reports have demonstrated a strong association of
worse clinical outcomes in COVID-19 disease with obesity, even in the absence of
any other comorbidity. In a study in a single French center, obesity [body mass
index (BMI) > 30 kg/m2] and severe obesity (BMI > 35 kg/m 2) were present in
47.6% and 28.2% of severe cases, respectively, whereas the need for interventional
mechanical ventilation (IMV) increased with BMI categories independently of age,
diabetes, and hypertension (31). Petrilli et al. (25) showed that among other factors,
BMI > 40 kg/m2 was a strong hospitalization risk factor, with an odds ratio (OR) of
6.2 in an academic health system in New York City. In a retrospective study by
Lighter et al. (17), patients aged under 60 yr with a BMI of 30–34 kg/m 2 were two
and 1.8 times more likely to be admitted to acute and critical care, respectively,
compared with individuals with BMI <30 kg/m 2, with the risk escalating for BMI
>35 kg/m2 (2.2 and 3.6 times, respectively). The unfavorable effects of obesity in the
course of viral infections have been attributed to the metabolic derangement and
chronic inflammation of the adipose tissue depots leading to blunted macrophage
activation and impaired T and B lymphocyte responses. However, whether these
mechanisms apply to the novel coronavirus infection remains unclear. In this
review, we briefly present the pathophysiology of the severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2) infection. We then discuss the possible
mechanisms through which the metabolic and immune derangement in obesity can
lead to more severe clinical outcomes, with their understanding being necessary in
the search for novel treatment targets in the future.
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PROCESS OF VIRAL INFECTION

SARS-CoV-2 consists of four different types of structural proteins: spike (S),
nucleocapsid (N), membrane (M), and envelope (E) proteins. The entry into host
cells is mediated by the S protein, which comprises two separate subunits: S1
subunit, responsible for binding to the host cell receptor, and S2 subunit, responsible
for the fusion between viral and cellular membranes. The cellular receptor for the
virus is the angiotensin-converting enzyme 2 (ACE2), which is expressed in type I
and type II alveolar epithelial cells in the lungs as well as in many other tissues such
as the heart, the endothelium, the kidneys, and the pancreas (23). After binding,
serine proteases such as TMPRSS2 mediate the cleavage of the spike, and then
proteases such as furin release the spike fusion peptide and facilitate viral entry into
the cells through endosomes. The infection results in increased cell apoptosis, which
triggers the activation of proinflammatory cytokines and chemokines and the
recruitment of inflammatory cells. On the other hand, the virus itself causes
increased apoptosis of lymphocytes (CD3, CD4, and CD8 T cells), and the
subsequent lymphocytopenia and impaired function of lymphocytes ends up in a
fulminant hypercytokinemia known as “cytokine storm” (40). This condition
resembles secondary hemophagocytic lymphohistiocytosis (sHLH) or macrophage
activation syndrome (MAS), a common finding in severe viral infections and sepsis,
which is characterized by excessive circulating levels of IL-6, IL-2, IL-7, TNFα,
CXC-chemokine ligand 10 (CXCL10), monocyte chemoattractant protein-1 (MCP-
1), macrophage inflammatory protein-1α (MIP1α), and other proinflammatory
molecules, and is associated with progression to acute respiratory distress syndrome
(ARDS) and multiorgan failure (21).
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OBESITY AS A RISK FACTOR FOR COVID-19: POSSIBLE

MECHANISMS
As we mentioned above, the association of obesity with prolonged recovery and
worse clinical outcomes in viral infections has long been known. In recent years, as
the role of adipose tissue as a distinct endocrine organ is being elucidated, obesity
has been considered an independent risk factor for increased susceptibility to
infections, sepsis, and higher mortality (9). This increased risk has been attributed to
the state of chronic, low-grade inflammation that characterizes obesity, which results
in metabolic and immune derangement. As the pathophysiology of SARS-CoV-2
infection is being unraveled, the links between the severity of clinical presentation
and the dysmetabolic background are revealed (Fig. 1).

Fig. 1.
Possible mechanisms through which obesity leads to worse COVID-19 outcomes. ARDS,
acute respiratory distress syndrome; LV, left ventricle; MAS, macrophage activation
syndrome; NO, nitric oxide; RAAS, renin-angiotensin-aldosterone system; VTE, venous
thromboembolism.

Chronic Inflammation and Immune Dysregulation

The dysfunctional hypertrophic adipocytes in obesity produce an excessive amount
of cytokines such as IL-6, IL-8, monocyte chemoattractant protein-1 (MCP-
1/CCL2), leptin, and plasminogen activator inhibitor-1 (PAI-1), among others,
which leads to the increased recruitment of macrophages, especially polarized M1
macrophages (12, 19). These cells, in turn, produce high amounts of
proinflammatory molecules like IL-1β, IL-6, IL-8, TNFα, and MCP-1 (18), an effect
that is enhanced also by the action of the increased circulating levels of free fatty
acids (FFAs) through the NF-κB pathway (35). The cumulative effect of these
actions is a state of chronic inflammation and hypercytokinemia, which leads to
defective innate immunity and creates a conducive ground for the
hyperinflammatory response mediated through MAS in severe COVID-19 cases
(10). The adaptive immunity is also adversely affected in obesity, with several
studies showing a decline in naïve CD4+ T cells, as well as an imbalance of CD4+ T
helper cells toward Th17 and Th22 proinflammatory subsets (9, 20). Similarly, in
patients with COVID-19, peripheral counts of CD4+ and CD8+ T cells are low, but
with a higher ratio of proinflammatory Th17 cells (10). Even more interestingly, the
presence of increased levels of IL-1β in patients with COVID-19 infection suggests
that cell pyroptosis, mediated through the activation of the NOD-like receptor family
pyrin domain-containing 3 (NLRP3) inflammasome, might be strongly involved in
the pathogenesis of the infection (13). The role of inflammasome activation has
already been pointed out in studies on other coronavirus infections, where it was
demonstrated that Viroporin 3a activated the NLRP3 inflammasome during the
SARS-CoV infection (8), whereas another study on MERS-CoV infection revealed
increased amounts of pyroptotic markers (caspase-1 and IL-1β) in the patient group
(15). Even more importantly, in a study by Grailer et al. (11) in mice, the presence
of acute lung injury (ALI) after airway instillation of lipopolysaccharide (LPS) was
dependent on availability of NLRP3 and caspase-1, which are known features of the
NLRP3 inflammasome. As numerous studies both in humans and animal models
have shown, NLRP3 expression is increased in obesity, rendering it a pivotal factor
in recruitment of macrophages and immune activation (16, 27). Therefore, agents
that inhibit its action, such as colchicine, seem promising in the treatment of specific
COVID-19 patients. In addition, agents such as anakinra, an IL-1 blocker, and
tocilizumab, an IL-6 blocker, which have proven beneficial in the treatment of
rheumatoid arthritis, which is accompanied as well by an excessive cytokine release,
have been tested in randomized controlled trials (RCTs) in severe cases of COVID-
19, with favorable results and unremarkable adverse events so far (29, 37).

Endothelial Dysfunction and Arterial Stiffness

A recent report by Varga et al. (34) pointed out for the first time the role of the
endothelium in the pathogenesis of COVID-19. More specifically, postmortem
histology of three patients with severe infection revealed viral inclusion structures in
endothelial cells, accumulation of inflammatory cells associated with the
endothelium, congestion of the small lung vessels, and endothelitis of the
submucosal vessels of the small intestine, implying that the virus uses the ACE2
receptors expressed on endothelial cells in a pattern similar to that of alveolar
infection, and therefore, the clinical presentation might be worse in vulnerable
patients with preexisting endothelial dysfunction. Obesity is such a typical example,
and the mechanisms that lead to vascular abnormalities are various. The
hyperinsulinemia and insulin resistance that is a common feature of obesity leads to
reduction in the insulin-stimulated phosphoinositide 3-kinase (PI3K) endothelial
nitric oxidase synthase (eNOS) signaling pathway, reducing the vasculoprotective
effects of nitric oxide (NO) and its anti-inflammatory actions (4). Increased
oxidative stress due to RAAS-induced activation of NADPH oxidase, xanthine
oxidase, and mitochondrial oxidative stress results in increased destruction of NO,
and its decreased bioavailability further induces macrophage activation (3). The
chronic exposure of endothelial cells to the increased circulating levels of leptin
observed in obesity leads to a decreased NO production and increased MCP-1
expression, which further enhances leukocyte infiltration into vascular cells (5, 32).
Perivascular adipose tissue (PVAT), exerting anticontractile effects on the
endothelium in lean individuals, contributes to vasoconstriction and endothelial
malfunction in obesity via increased secretion of TNFα, IL-6, reactive oxygen
species (ROS), and chemerin while downregulating NO production (26). Consistent
with the favorable results in hypercytokinemia and acute hyperinflammatory state,
the administration of tocilizumab to rheumatoid arthritis patients has been shown to
improve pulse wave velocity and brachial blood pressure, which were used as
indices of vascular function, and a similar benefit in COVID-19 patients could thus
be presumed (14).

Cardiovascular Events and Thrombosis

Another serious consideration in SARS-CoV-2 infection is its cardiovascular
manifestations. Acute cardiac injury is highly prevalent in patients with COVID-19
and is associated with worse clinical outcomes (13, 41). Although the relatively high
rate of heart failure (23%) that was observed in patients with COVID-19 could not
be explicitly attributed to exacerbation of a preexisting condition or a new
cardiomyopathy (7, 41), the presence of acute myocarditis was the definite cause of
death in 7% of patients in a case series of 150 patients with COVID-19, whereas in
other studies, postmortem histology revealed fulminant myocarditis with the
presence of inflammatory mononuclear infiltrates in myocardial tissue (28, 38). The
risk of venous thromboembolism also seems important, as in a significant
percentage of patients with severe infection, elevated levels of D-dimers have been
observed, whereas ∼71% of patients met clinical criteria for disseminated
intravascular coagulation (DIC) (33, 41). Obesity is a well-established risk factor for
cardiovascular disease (CVD) both per se and through its common comorbidities,
such as insulin resistance (IR), diabetes mellitus (DM), and hypertension. The most
common alteration in cardiac morphology in obesity is left ventricular (LV)
hypertrophy, with hypertension and IR being important determinants of the LV mass
(1, 2). In addition, obesity is associated with activation of the renin-angiotensin-
aldosterone system (RAAS), which leads to increased levels of angiotensin II, with
direct effects on the myocardium (36). Apart from structural changes, obesity is
associated with LV diastolic dysfunction and heart failure (1, 2, 24). Chronic
inflammation by the proinflammatory cytokines mentioned above leads to
upregulation of procoagulant factors (like the tissue factor) and adhesion molecules
(like P-selectin), downregulation of anticoagulant regulatory proteins (such as tissue
factor pathway inhibitor, antithrombin, and the protein C anticoagulation system),
increased thrombin generation, and enhanced platelet activation, thus increasing the
risk for thrombosis (6). Again, in patients with rheumatoid arthritis, the
administration of anakinra (mainly) and tocilizumab resulted in a simultaneous
improvement in oxidative stress and myocardial deformation, rendering these agents
a potential treatment option for patients with COVID-19 and cardiovascular
manifestations (14).
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CONCLUSIONS
Obesity has emerged as a major risk factor for worse COVID-19 outcomes. Chronic
inflammation and oxidative stress, hypercytokinemia, immune dysregulation,
endothelial dysfunction, and cardiovascular abnormalities are all possible
mechanisms through which the excess in adipose tissue could lead to the acute
hyperinflammatory state that characterizes severe SARS-CoV-2 infections and is
responsible for its complications. The lessons learned from other diseases with a
similar inflammatory profile, such as rheumatoid arthritis, provide useful insights
into the better understanding of these mechanisms and, above all, propose that
patients with obesity could be appropriate candidates for the use of agents such as
colchicine and anti-IL-1 and anti-IL-6 compounds early in the course of the disease,
benefiting from the amelioration of their preexisting, proinflammatory state. Of
course, large RCTs are necessary to further clarify the pathways through which
metabolic derangement leads to worse COVID-19 outcomes and establish the ideal
treatment regimen for each individual patient.
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DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the authors.
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AUTHOR CONTRIBUTIONS
E.K. drafted manuscript; E.K., I.I., F.K., K.B., A. Kountouri, A.R., L.P., A.
Kokkinos, and V.L. edited and revised manuscript; E.K., I.I., F.K., K.B., A.
Kountouri, A.R., L.P., A. Kokkinos, and V.L. approved final version of manuscript.
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