The SARS-CoV-2 pandemic has led to worldwide research aiming to identify the risk factors for developing critical illness and mortality caused by COVID-19. It quickly became apparent that besides older age, obesity is one of the most important risk factors for a more severe course of COVID-19, although the mechanisms remain largely unknown.3
Adipose (fat) tissue has traditionally been thought of as an energy depot with little other function.
Currently, it is well known that the key role of adipose tissue in metabolism is as an endocrine organ responsible for the secretion of bioactive molecules termed “adipokines.”1
Adipokines have hormone function, act as growth factors that modulate insulin resistance, act on the fat and glucose metabolism and participate in pro and anti-inflammatory responses.2
Deregulated adipokine expression is caused by excessive adiposity and adipocyte (i.e., fat cell) dysfunction. This is seen in obese individuals and has a link to the pathogenesis of several diseases through altered immune responses.1
Adipokines are classified as hormones, growth factors, angiogenic factors, and cytokines that are secreted by adipose tissue.
Among them, leptin, adiponectin, resistin, monocytes, and macrophage chemotactic protein 1, interleukin-6, IL-1β, tumor-necrosis factor, anti-inflammatory IL-10, and transforming growth factor-β are the most studied.
Adipokines affect appetite and satiety, glucose and lipid metabolism, blood pressure regulation, inflammation and immune functions. Precisely, they work as a network to regulate inflammation, insulin action, and glucose metabolism locally and systemically.
Obesity is commonly recognized to reflect a state of low-grade chronic inflammation.4
As mentioned above; adipose tissue produces a great number of adipokines that act as signaling molecules and have a wide array of effects on many organ-systems, including the lungs.
A probable underlying pathophysiological mechanism explaining the severity of obesity on COVID-19 infection may be due to abnormalities in the production of adipokines by adipose tissue, of which leptin and adiponectin have received the most attention.5
Leptin is primarily a pro-inflammatory adipokine that influences both innate and adaptive immune responses by stimulating production of proinflammatory cytokines and suppressing production of anti-inflammatory cytokines.
In contrast, adiponectin is a predominantly anti-inflammatory adipokine that inhibits pro-inflammatory cytokines and induces anti-inflammatory cytokines. It’s commonly appreciated that systemic leptin concentrations are upregulated, whereas adiponectin concentrations are paradoxically downregulated in obese individuals.6
Indeed, imbalanced production of adipokines could provide an attractive mechanistic explanation for the obesity-associated risk of severe COVID-19 infections (see figure below).
Fig: A schematic overview of the hypothesized difference between non-obese and obese individuals in the severity of SARS-CoV-2 infection7
Soon after the pandemic started and more and more people entered intensive care units, testing positive for COVID-19, they grew increasingly short of breath and many ended up on ventilators.
In addition to this course of disease, patients frequently shared one additional attribute; which was obesity.8
Since the pandemic began, dozens of studies have reported that many of the sickest COVID-19 patients have been obese people. Recently, this association has come into sharper focus as large new population studies have cemented the relationship and demonstrated that even people who are merely overweight are at higher risk.
For example, in the first meta-analysis of its kind, an international team of researchers pooled data from scores of peer-reviewed papers capturing 399,000 patients.
The study found that obese people who contracted SARS-CoV-2 were:
People with obesity are more likely than normal-weight people to have other diseases that are independent risk factors for severe COVID-19, including heart disease, lung disease, and diabetes. They are also prone to metabolic syndrome, in which blood sugar levels, fat levels, or both are unhealthy and blood pressure may be high.
A recent study of 287 hospitalized COVID-19 patients found that metabolic syndrome itself substantially increased the risks of ICU admission, ventilation, and death.10
Why are obese people more vulnerable to COVID-19?
The physical pathologies that render people with obesity vulnerable to severe COVID-19 begin with mechanics: Fat in the abdomen pushes up on the diaphragm, causing it to impinge the lungs and restrict airflow. This reduced lung volume leads to collapse of airways in the lower lobes of the lungs, where more blood arrives for oxygenation than in the upper lobes.
There are also other issues compound these mechanical problems.
The blood of people with obesity has an increased tendency to clot. When this becomes severe; it independently peppers the small vessels of the lungs with clots.11
It is thought that the mechanism behind this is that COVID changes the signaling and the virus injures endothelial cells, which respond by activating the coagulation system.
Immunity also weakens in people with obesity, partly because fat cells infiltrate the organs where immune cells are produced and stored, such as the spleen, bone marrow, and thymus. Essentially, obese people are losing immune tissue in exchange for adipose tissue, making the immune system less effective in either protecting the body from pathogens or responding to a vaccine.
Beyond an impaired response to infections, people with obesity also suffer from chronic, low-grade inflammation.
As mentioned above, fat cells secrete several inflammation-triggering chemical messengers called cytokines, and more come from immune cells called macrophages that sweep in to clean up dead and dying fat cells.
Experts believe that much of the added risk from obesity is immune-mediated and recommend that obese and overweight people should take extra care to avoid getting sick.
In summary, there is much that we have learned about COVID-19 and especially how it affects certain segments of the population with other comorbidities, and exercising, sound nutrition and losing even a little weight can improve the metabolic health of a person with obesity and reduce their chances of developing severe COVID-19 if they become infected.
References:
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3 Lighter, J. et al. Obesity in Patients Younger Than 60 Years Is a Risk Factor for COVID-19 Hospital Admission. Clin Infect Dis 71, 896-897, doi:10.1093/cid/ciaa415 (2020).
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8 Wadman, M. Why COVID-19 is more deadly in people with obesity—even if they're young, 2020).
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10 Xie, J. et al. Metabolic Syndrome and COVID-19 Mortality Among Adult Black Patients in New Orleans. Diabetes Care, doi:10.2337/dc20-1714 (2020).
11 Matacic, C. Blood vessel injury may spur disease's fatal second phase. Science 368, 1039-1040, doi:10.1126/science.368.6495.1039 (2020).
