Keywords COVID-19 - diabetes mellitus - hypertension - obesity
Introduction
Coronavirus disease 2019 (COVID-19) is an unprecedented global pandemic caused by
the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) that has affected
over 5 million persons globally at the time of this review.[1 ] Strikingly, it disproportionately affects persons with underlying endocrine conditions
such as obesity, diabetes mellitus, and hypertension. In the United States, the most
common co-existing condition affecting patients with COVID-19 is hypertension (49.7%)
followed by obesity (48.3%) and diabetes mellitus (28.3%).[2 ] These conditions are also associated with an increased risk of poor outcomes including
mortality.[3 ]
[4 ]
[5 ] In light of these risks, it is prudent to explore the pathophysiological mechanisms
that account for the observed trends. In this brief review, we discuss the molecular
basis of COVID-19 risks in obesity, diabetes mellitus, and hypertension with a focus
on immune dysregulation.
Common Immune Dysregulation Pathways
The human body has multiple protective mechanisms against viral infections. Broadly,
viruses gain cellular entry by attaching to viral cell surface receptors. Following
this, viral antigens are presented via the major histocompatibility complex to trigger
counteractive cellular and humoral immune responses. If immunological mediators are
expressed abnormally due to comorbid conditions, the resulting immunological response
can be catastrophic. The abnormal expression of immunological mediators appears to
be the predominant mechanism in dysregulated immune responses to COVID-19 in metabolic
disease that may result in a cytokine storm ([Fig. 1 ]).
Fig. 1 Immune dysregulation in metabolic disease leading to a pathological immunological
coronavirus disease 2019 response. Upstream secretion of interleukin-6 (IL-6) leads
to downstream activation of the trans- signaling and trans -pathway modes of IL-6 action resulting in severe end-organ injury. ACE2, angiotensin-converting
enzyme 2; DPP-4, dipeptidyl peptidase-4; MERS-CoV, Middle East respiratory syndrome-coronavirus;
mIL-6R, membrane bound interleukin-6 receptor; SARS-CoV-2, severe acute respiratory
syndrome coronavirus-2; sIL-6R, soluble interleukin-6 receptor; TNF-α, tumor necrosis
factor-alpha (image created using BioRenderTM).
SARS-CoV-2, a betacoronavirus and the causative agent of COVID-19, gains cellular
entry by binding to the cell membrane bound angiotensin-converting enzyme 2 (ACE2).[6 ] SARS-CoV-2 related coronaviruses such as Middle East respiratory syndrome-coronavirus
(MERS-CoV) and SARS-CoV also directly affect immune cells including monocytes, dendritic
cells, and T-cells.[7 ] The cellular entry of these betacoronaviruses is mediated by a glucose homeostasis
intermediary—dipeptidyl peptidase-4 (DPP-4)—an enzymatic cleaver of glucagonlike peptide-1
(GLP-1).[8 ] Following SARS-CoV-2 infection, immune cell releases interleukin-6 (IL-6), a proinflammatory
cytokine.[9 ] IL-6 has two main pleiotropic signaling pathways—cis- and trans- signaling. In cis -signaling, IL-6 initially binds to its membrane bound receptor (mIL-6R), found predominantly
on the surface of immune cells, followed by recruitment and activation of T-cells,
B-cells, and natural killer cells.[7 ] IL-6 secretion by recruited cells is enhanced and its exaggerated release is hypothesized
to trigger the onset of the cytokine release syndrome. When IL-6 binds to its soluble
receptor (sIL-6R) present on the vascular endothelium, it leads to the activation
of the trans- signaling pathway that in turn causes the release of vascular endothelial growth factor
(VEGF) and monocyte chemoattractant protein-1 (MCP-1). Vascular endothelial E-cadherin
levels decline as a consequence of trans- signaling, which in combination with elevated VEGF and MCP-1, can lead to increased
vascular permeability and leakage ([Fig. 1 ]). Ultimately, these effects result in syndromes such as acute respiratory distress
syndrome and hypotensive shock. A third, less dominant, pathway of IL-6 signaling
known as trans- pathway (different from trans- signaling) pathologically activates T-helper cells, a prelude to lung injury and shock.[7 ]
The pathological mediators of virus-triggered immune responses are elevated in metabolic
diseases such as obesity, diabetes mellitus, and hypertension. As an example, IL-6
levels are chronically elevated in obesity and progressively increase with increments
in body mass index.[10 ]
[11 ] This is thought to be consequent to the secretion of IL-6 by adipocytes in response
to chronic adipose tissue hypoxia.[12 ] C-reactive protein (CRP), a downstream product of IL-6 and a prognosticator of poor
COVID-19 outcomes, is also elevated in obesity.[11 ]
[13 ] Similarly, IL-6 levels are elevated in diabetes mellitus and insulin resistance
states.[14 ] Further, IL-6 receptors are also upregulated in type 1 diabetes mellitus, predisposing
T-cells to be more sensitive to circulating IL-6.[15 ] This leads to a consequent elevation in CRP that is also common in diabetes mellitus.[16 ] Equally, IL-6 levels are elevated in hypertension that was well illustrated by Luther
et al, who demonstrated the role of angiotensin II as a direct stimulator of IL-6
production.[17 ]
[18 ] Luther et al also reported that the stimulatory effect of IL-6 on angiotensin II
was blocked by the use of angiotensin receptor blockers (ARBs) and mineralocorticoid
receptor antagonists such as spironolactone.[17 ] Another study of diabetic mice infected with the betacoronavirus, MERS-CoV, reported
a prolonged course of severe infection.[19 ] This was accompanied by a reduction in CD4+ T-cells and a pathological elevation
of IL-17α, a proinflammatory cytokine, confirming the presence of immune dysregulation
in diabetes mellitus.[19 ]
DPP-4, a proinflammatory molecule and a coronavirus receptor, is also elevated in
obesity, diabetes mellitus, and hypertension.[20 ] DPP-4 is directly proportional to measures of visceral adiposity such as intra-abdominal
fat and waist-hip ratio.[21 ] In persons with diabetes mellitus, DPP-4 levels correlate linearly with glycemic
control.[22 ] DPP-4 has also been identified as a therapeutic target in diabetes, suggesting a
critical role for DPP-4 in the pathophysiology of diabetes.[23 ] Finally, the trans -pathway of IL-6 may be overactive in obesity, diabetes mellitus, and hypertension
and may represent the final common pathway in the causative pathophysiology of acute
end-organ injury. Taken together, the enhanced secretion and activity of these immune
mediators in metabolic diseases are key to understanding the risk of severe COVID-19
(see [Fig. 1 ]).
Specific Immune Dysregulation Pathways
Obesity
Obesity is also linked to increased levels of interleukins such as IL-1 and tumor
necrosis factor-alpha (TNF-α) that may exacerbate the IL-6-mediated immune dysregulation.
This is worsened by hyperinsulinemia-induced T-cell dysfunction, a consequence of
increased body adiposity. Additionally, obesity is associated with an increased propensity
for risks including diabetes mellitus, hypertension, obstructive sleep apnea, and
obesity hypoventilation syndrome that further enhance the risks of severe disease
by both immune and nonimmune-mediated mechanisms. While DPP-4 inhibition as a therapeutic
target to reduce COVID-19 severity remains speculative, GLP-1 receptor analogues have
been proven to be immunoregulatory and lung protective in animal models.[24 ]
Diabetes Mellitus
Immune dysregulation is multifactorial in diabetes mellitus. In addition to the aforementioned-effects,
ACE2 levels are augmented in diabetes mellitus that presumably facilitates viral entry
into respiratory and other tissues.[25 ] A disintegrin and metallopeptidase domain 17 (ADAM17), the enzymatic cleaver of
ACE2, is lower in mouse models of diabetes mellitus, which may increase the risk of
COVID-19 infection.[24 ]
[25 ] Co-existing complement deficits, impaired antigen presenting cell function, elevated
TNF-α and IL-8, and compromised T-cell function all independently contribute to the
dysregulated immune milieu of diabetes mellitus.[27 ]
[28 ]
[29 ] In addition, the co-existence of other risk factors including obesity and hypertension
further amplifies the pre-existing immunological dysfunction in diabetes.
Hypertension
Hypertension has additional features of immune dysregulation, manifesting as elevated
IL-17 and diminished T-cell and natural killer cell function.[30 ]
[31 ] Hypertension is also associated with an overactive sympathetic drive and elevated
angiotensin II, both of which contribute to a compromised immune response.[32 ] While sympathetic overdrive has indirect pleiotropic effects on immunity, angiotensin
II directly stimulates the secretion of IL-6, which orchestrates the pathological
host immune response as detailed above.[17 ]
[33 ] ACE inhibitors (which are inhibitors of ACE1) and ARBs have been speculated to raise
COVID-19 risks through a potential increase in ACE2, but emerging clinical evidence
refutes this theory.[34 ]
[35 ]
[36 ]
[37 ]
Conclusion
Patients with COVID-19 infection in the setting of metabolic diseases such as obesity,
diabetes mellitus, and hypertension independently have a significantly worse outcome
than those without these diseases. As each of these diseases is associated with dysregulation
of the immune system leading to cytokine storm and consequent severe COVID-19. Further
research is needed to elucidate the specific immune-deregulatory mechanisms that lead
to severe COVID-19 in patients with metabolic disorders.
