Introduction
Obesity increases the risk of severe COVID-19 by giving rise to a worse clinical
outcome and increased mortality, when compared to the general population [1]. Obesity alone is responsible for
20% of COVID-19 hospitalizations, whereas obesity in combination with type 2
diabetes and hypertension accounts for up to 60% of all COVID-19
hospitalizations [2]. In addition, infected
people with obesity (particularly those under 60 years of age) are more likely to
require acute care, admission to the intensive care unit, intubation, and mechanical
ventilation [3]. Even young patients are at
higher risk for a nonfavorable COVID-19 prognosis if they suffer from metabolic
dysfunctions [4]
[5]. Children usually develop an asymptomatic to
moderate infection causing few hospitalizations; but a recent meta-analysis
indicates that even childhood obesity is likely to increase the risk of severe
COVID-19 [6]. Albeit severe courses of
COVID-19 in children are rare, a novel pediatric hyperinflammatory condition termed
pediatric inflammatory multisystem syndrome, temporally associated with SARS-CoV-2
(PIMS-TS) or multisystem inflammatory syndrome (in children) (MIS(-C)), causes a
severe to fatal disease. Even though underlying factors are unclear, it turns out
that childhood obesity is a significant comorbidity [7]. This is a worldwide problem since, according to WHO reports, around
40% of the world population was estimated to be overweight or obese in 2016,
and the numbers are still increasing, thus obesity has reached pandemic levels [8] ([Table
1]).
Table 1 Key facts about obesity [7].
-
Worldwide obesity has nearly tripled from
1975–2016.
-
In 2016, 39% of adults aged 18 years and over
(39% of men and 40% of women) were
overweight.
-
Overall, about 13% of the world’s adult
population (11% of men and 15% of women)
were obese in 2016.
-
Over 340 million children and adolescents aged
5–19 were overweight or obese in 2016.
-
The prevalence of overweight and obesity among children
and adolescents aged 5–19 has risen dramatically
from just 4% in 1975 to just over 18% in
2016.
-
39 million children under the age of 5 were overweight or
obese in 2020.
-
Overweight and obesity are linked to more deaths
worldwide than underweight.
|
Emerging data suggest that several mechanisms are responsible for this increased
susceptibility of people with obesity for severe COVID-19 including, amongst others,
an impaired immune system and changes in SARS-CoV-2 entry receptors in obese
individuals [9]
[10]
[11]
[12]. In the current review, we
discuss these mechanisms in order to understand why patients with obesity have a
higher risk of developing severe COVID-19 symptoms not only in the acute phase of
the disease but also in relation to long-COVID, vaccine breakthrough infections and
re-infections. Furthermore, we discuss the effects of lockdown on obesity, and we
comment on possibilities for avoiding this interface between metabolic and
infectious diseases in potential future pandemics.
Adipose tissue
The adipose tissue is the largest endocrine organ in humans and, in addition to
adipocytes, it consists of pre-adipocytes, endothelial cells, fibroblasts,
leukocytes, and bone-marrow-derived macrophages [13]. Adipose tissue is classified into two main types, white adipose
tissue and brown adipose tissue. White adipose tissue is the more predominant form
in the human body, where it plays a major role in energy storage. The main function
of brown adipose tissue is thermogenesis [14]
[15]
[16]. It is becoming increasingly clear that
adipose depots serve distinct functions in males and females and have specific
physiological roles. However, the mechanisms that regulate the size and function of
specific adipose tissues in men and women remain poorly understood [17].
In addition to energy storage via triacylglycerols stored in adipocytes, adipose
tissue secretes “adipocytokines” or “adipokines”,
including, for example, adiponectin, leptin, resistin, and visfatin [13]. Other important factors produced include
the cytokines tumor necrosis factor (TNF), interleukin-6 (IL-6), interleukin-1
(IL-1), CC-chemokine ligand 2 (CCL2), plasminogen activator inhibitor type I
(PAI-I), and a number of complement factors [18]
[19]. Most of these factors are
known as pro-inflammatory mediators that induce immune cell infiltration
(e. g., macrophages) and play a major role in infectious diseases.
The major adipokines in adipose tissue are leptin and adiponectin, where leptin is
pro-inflammatory, and adiponectin is anti-inflammatory. In obesity, leptin is
increased and adiponectin is decreased compared to normal weight individuals [20]. Oppositely, circulating adiponectin
concentrations increase during caloric restriction [21].
Leptin is almost exclusively expressed in differentiated adipocytes of the white
adipose tissue with subcutaneous fat showing a higher expression than visceral
adipose tissue [22]
[23]. Leptin released from adipocytes acts on
neurons to reduce appetite and to increase energy expenditure [20]. Leptin is closely linked to the immune
system where it stimulates the proliferation and activation of immune cells and
cytokine production [20].
Disease-specific subpopulations of adipose-resident immune cells can be found in
adipose tissue. These immune cells can be further separated into populations
specific for either visceral or subcutaneous adipose tissue [24]. An example of these immune cells are the
macrophages, which are heterogenous and can generally be defined in two separate
polarization states, M1 and M2 [25]
[26]. M1 macrophages are induced by
pro-inflammatory mediators, such as lipopolysaccharide (LPS) and
interferon-γ (IFN-γ), produce pro-inflammatory cytokines
(TNF-α, IL-6, IL-12) and generate reactive oxygen species, such as nitric
oxide (NO) via activation of iNOS (Nos2) [27]. M2 macrophages are induced, by among others, IL-4 and IL-13, and
they produce high levels of the anti-inflammatory cytokines IL-10 and
IL-1rα. Additionally, iNOS activity is blocked [27]. Overall, M2 macrophages are believed to
participate in the inhibition of inflammatory responses and in the promotion of
tissue repair and angiogenesis [25]. Both in
mice and humans, it has been shown that distinct macrophage populations with unique
characteristics direct inflammatory versus physiological changes in adipose tissue
[28].
Infection with SARS-CoV-2
Entry of SARS-CoV-2 into cells depends on binding of the viral spike
glycoproteins to extracellular domains of cellular angiotensin-converting enzyme
2 (ACE2). ACE2 exists in two forms, a membrane-spanning cellular and an unbound
soluble form [29]. Membrane-bound ACE2
(mACE2) constitutes the majority of ACE2; it contains a transmembrane domain
anchoring the cleavable N-terminal domain. A membrane-bound protease (secretase)
generates soluble ACE2 (sACE2) by enzymatic cleavage of mACE2. sACE2 appears in
the circulation in very low concentrations. Both mACE2 and sACE2 are capable of
binding the spike protein on the surface of SARS-CoV-2. After binding to mACE2,
the spike proteins are proteolytically activated by host cell proteases [29]
[30]
[31], resulting in fusion of
the viral envelope with the plasma membrane or the endosome membrane of the host
and viral entry into the cell.
ACE2 is part of the renin-angiotensin-aldosterone system (RAAS), where it mainly
controls the generation of the vasodilating angiotensin 1–7 from
angiotensin II. ACE2 also cleaves angiotensin I to angiotensin 1–9,
which can be further converted to angiotensin 1–7 by ACE [29]. ACE2, Ang-(1–7), and its
mitochondrial assembly (Mas) receptor constitute the vasoprotective arm of the
RAAS leading to anti-inflammatory and anti-fibrotic responses [29]
[32]
[33]
[34].
Diet and obesity have been shown to affect the expression of ACE2 in adipose
tissue [35]. Recently, it was demonstrated
that a decrease in sACE2 during weight loss was associated with improvements in
metabolic health [36]. Another factor,
neuropilin 1 (NRP-1), known to facilitate SARS-CoV-2 cell entry is highly
abundant in subcutaneous adipose tissue, and both NRP-1 and ACE2 levels are
decreased after weight loss [37]. However,
it is still not clear whether a high or a low expression is beneficial in
relation to health (reviewed in [32]).
Similarly, it is debated whether high levels of ACE2 in adipose tissue in
relation to SARS-CoV-2 is an advantage or not. Thus, it seems that not only the
abundance but also the functionality of the enzyme may be of importance.
Viruses including coronaviruses are primarily dependent on the host metabolism in
several stages of their life cycle. For example, an association of dyslipidemia
with the pathological development of COVID-19 was reported [38]. This raises the possibility that
exploitation of the host lipid metabolism, by using potential inhibitors, can
exhibit therapeutic benefits against COVID-19 [39]. Additionally, specific lipid supplementation can represent
another strategy to error-prone the formation of viral particles. Furthermore,
switching the lipid metabolism through the implementation of ketogenic diet
might be an approach to limit the effects of viral infection [40]. An experimental study associated with
computational analysis identified the potential inhibitory effect of flavonoids
against SARS-CoV-2 as they bind to essential viral targets required in virus
entry and/or replication [41].
Flavonoids also showed excellent immunomodulatory and anti-inflammatory
activities including the inhibition of various inflammatory cytokines. Further,
flavonoids showed a significant ability to reduce the exacerbation of COVID-19
in the case of obesity via promoting lipid metabolism [41].
Mechanisms responsible for an increased risk of severe COVID-19 in
obesity
Obesity, in particular visceral obesity, is a risk factor for the development of
metabolic syndrome, cardiovascular disease [42]
[43], blood
hypercoagulability [44], and vitamin D
deficiency [45], which are furthermore all
risk factors for COVID-19 severity [46].
A number of mechanisms are responsible for the increased risk of severe COVID-19
and mortality in people with adiposity [47]
[48]
[49]. One explanation may be the physical
stress on ventilation by obstructing diaphragm excursion. Furthermore, obesity
is associated with an increased risk of pulmonary fibrosis, chronic obstructive
pulmonary disorder, and reduced respiratory function [50].
Another reason is an impairment of the immune system in people with adiposity.
Obesity is characterized by hyperplasia and hypertrophy of adipocytes and
accumulation of macrophages in the adipose tissue, resulting in the development
of crown-like structures of necrotic adipocytes encircled by macrophages [42] ([Fig.
1]). In obesity, a switch from an anti-inflammatory M2 type to the
pro-inflammatory M1 form of macrophages is observed [14]. Adiponectin can also affect
macrophages by stimulating the production of anti-inflammatory cytokines [51]. Similarly, adiponectin-deficient mice
display an increased expression of pro-inflammatory M1 type markers and
decreased anti-inflammatory M2 type markers [52]. Thereby, obesity may lead to a baseline state of chronic
inflammation. In adipose tissue of people with obesity the expression of
pro-inflammatory cytokines, such as TNF-α, IL-6 and IL-1β, is
upregulated.
Fig. 1 Chronic inflammation in adipose tissue of obese
individuals: There are several reasons why obesity can lead to a severe
course of COVID-19. One possible cause is the chronic inflammatory
reaction in the adipose tissue. In adipose tissue with hypertrophic
adipocytes, there is a mass production of pro-inflammatory cytokines,
such as IL-6, IL-1β, and TNF-α. In addition, more and
more immune cells invade the adipose tissue. These cells produce
inflammatory substances themselves. Being overweight thereby leads to a
low-grade chronic inflammation. If an infection with SARS-CoV-2 then
occurs, there is a high risk of an overreaction of the immune system
leading to hyperinflammation and cytokine storm. This represents a
potentially life-threatening derailment of the immune system, which can
further lead to paracrine injuries.
In patients who died from COVID-19, a higher prevalence of CD68-positive
macrophages in visceral adipose tissue was observed compared to control patients
without COVID-19. As expected, these were accompanied by crown-like structures,
signs of adipocyte stress and death [46].
Previously, obesity was shown to increase the duration of type A influenza virus
shedding in adults, whereas this was not the case for type B influenza [53]. Adipocytes and other adipose
tissue-resident cells, such as adipo-stromal cells, and macrophages have also
been shown to be targets for adenovirus subtype 36, but not subtype 2 [54]. Therefore, it has been suggested that
adipose tissue may act as a reservoir for the SARS-CoV-2 virus, whereby it would
facilitate the spread of the virus and stimulate the immune response [54]. Indeed, a recent study showed that
SARS-CoV-2 RNA could be found in adipose tissue of both men and women that had
died due to COVID-19. In male individuals who were obese with a body mass index
(BMI) >30, SARS-CoV-2 could also be detected in the liver. In women,
there was no correlation between BMI and viral load in the adipose tissue [55]. In another study, the presence of
SARS-CoV-2 in adipose tissue was confirmed in more than 60% of COVID-19
autopsy cases. In 25 out of the 29 COVID-19 cases in this study, comorbidities
were present with 34% patients being overweight or with obesity [56].
It was demonstrated that SARS-CoV-2 is able to infect mature differentiated and
lipid-laden adipocytes but not preadipocytes or immature precursors [55]. Whether this is due to different ACE2
concentrations, or another mechanism is not known yet. An alteration in carbon
metabolism with increased circulating levels of glucose and free fatty acids
were observed in COVID-19 patients [57].
High levels of such free fatty acids may increase the levels of adipokines,
myokines and cytokines, which further promote inflammatory processes.
Furthermore, cytokines are able to damage the vascular endothelium and activate
the RAAS, which may lead to increased blood pressure, atherosclerosis, and
thrombosis [58].
This chronic inflammation and imbalance between pro-inflammatory and
anti-inflammatory factors in obesity is a risk factor for additional pathogenic
infections, such as SARS-CoV-2, which may lead to an abnormal immune response
reaching pathogenic levels [1].
The upregulation of TNF-α, IL-6 and IL-1β in people with obesity
inhibits insulin signaling [59], and
consecutively this cytokine upregulation leads to an increase in leptin and
plasminogen activator inhibitor-1 and a reduced release of adiponectin [60]. An inverse correlation to glucose
intolerance and type 2 diabetes has been observed [61]. Adiponectin modulates a number of
metabolic processes, including glucose regulation and fatty acid oxidation [62]. Low adiponectin blood levels thereby
cause an inappropriate increase in the immune response in COVID-19.
Overall, these impairments of the immune system may contribute to a chronic state
of low-grade inflammation in the ectopic visceral adipose tissue in people with
obesity ([Fig. 1]). In combination with
an infection like SARS-CoV-2, this may lead to an overreaction of the immune
system, a so-called hyperinflammation resulting in a cytokine storm that can
lead to paracrine injuries in other organs with progression to acute respiratory
syndrome [63].
Post-COVID and long-term consequences in relation to obesity
During the COVID-19 pandemic, social isolation and (semi)-lockdown were imposed
upon populations in the interest of infection control. All over the world,
obesity increased during the pandemic due to dramatic changes in the daily
routines, such as a reduction in physical activity and negative changes in the
eating habits [64]. In the US, the
COVID-19 pandemic promoted weight gains in adults with those already being obese
being more susceptible [65]. However, in
particular children with obesity have been shown to be at a higher risk of
negative lifestyle changes and weight gain during lockdown [66]. As such, several studies have shown
that not just adults gain weight, but that also obesity in adolescents and
children has increased due to COVID-19 lockdowns [67]. For example, in China, a study
performed on 12 889 Chinese college students aged 17–27 years showed
that their weight significantly increased during a 4-month lockdown in early
2020. This weight gain was associated with increased sedentary time and an
increase in COVID-19-related stress and depression [68]. Another study from South Korea showed
that in 226 children between 4 and 14 years old, school closure was
significantly associated with an increased BMI [69].
Different studies have shown that an unhealthy, high-fat diet might increase the
susceptibility to various infectious diseases [70]. For example, experimental animals on a high-fat diet had
exhibited a two-fold increase in mortality, an enhancement in respiratory
lesions and an increased production of cytokines when infected with H1N1
influenza [71]. The individual nutrition
pattern is also known to be able to change the gut microbiota, which might cause
metabolic changes that might affect the susceptibility for getting infected with
SARS-COV-2 in a positive or negative direction [70].
Numerous factors contribute to childhood and adolescent obesity, including
amongst others gender, biology, geographical and socio-economical aspects [72]
[73]
[74]. Non-communicable
diseases, such as overweight and obesity are largely preventable. At the
individual level, people can choose to limit energy intake by eating healthier
food consisting of, for example, fruit, vegetables and whole grains.
Furthermore, regular physical activity spread throughout the week is important.
However, for individuals to follow these recommendations, supportive
environments and communities are fundamental in shaping people’s mind,
by making the choice of healthier foods and regular physical activity the
easiest choice. This means that the healthiest alternative should be accessible,
available and affordable [8].
Evidence from the SARS-CoV-1 outbreak in 2002–2003 suggests that there is
a likelihood of long-term metabolic sequelae from COVID-19. In survivors of
SARS-CoV-1, long-term metabolic abnormalities including dyslipidemia and
cardiovascular disease as well as signs of abnormal glucose metabolism with
insulin resistance and hyperglycemia, and diabetes have been observed for up to
12 years [75]
[76]. More and more studies are emerging
showing similar tendencies after infections with SARS-CoV-2, where up to
40% of people that were infected with SARS-CoV-2 suffer from symptoms of
long-COVID [77]
[78]
[79], such as difficulties in concentration, cognitive dysfunction,
amnesia, depression, fatigue, and anxiety [80]
[81]
[82]. Therefore, people post discharge
following COVID-19 will need close monitoring for risk factor control [83].
To avoid severe COVID-19, vaccination was proven to be highly effective [84]. However, currently a high number of
SARS-CoV-2 vaccine breakthrough infections and reinfections occur when people
are exposed to the Omicron SARS-CoV-2 variants. The relationship between obesity
and vaccine efficacy remains unclear, but as T-cell responses in obese
individuals are impaired, it might imply that COVID-19 vaccines are less
effective in obese individuals [85]. This
was supported in latest findings indicating that obesity and other metabolic
dysfunctions might promote vaccine breakthrough SARS-CoV-2 infections [84]
[86]
[87]. Furthermore, for
reinfections, it was recently shown that at least one of the comorbidities
obesity, diabetes, asthma, heart disease, lung disease, and high blood pressure
was present in 50% of all cases [88].
